This document discusses metabolic syndrome, which is a cluster of conditions that increase the risk of heart disease, diabetes, and other issues. It defines metabolic syndrome and explores its underlying pathophysiology. Specifically, it examines the roles of abdominal obesity, insulin resistance, abnormal lipid levels, inflammation, and how these factors can progress to type 2 diabetes or cardiovascular disease if not properly managed. The document also reviews biomarkers like proinsulin, adiponectin, and CRP that can help diagnose metabolic syndrome and its complications earlier and guide treatment decisions.
The document provides guidelines for diabetes care in Massachusetts that were updated in 2007. It includes sections on diagnosing and classifying diabetes, preventing type 2 diabetes, diabetes medications and treatment approaches, cardiovascular risk reduction, hypertension, nephropathy, retinopathy, neuropathy, self-management education, nutrition, physical activity, tobacco use, and inpatient glucose control. The guidelines are intended to improve diabetes care by highlighting essential components of management and offering accompanying tools for primary care providers.
El documento describe los principios fundamentales del Islam, incluyendo la creencia en un solo Dios, la práctica de los cinco pilares como la oración y el ayuno, y la vida y enseñanzas del profeta Mahoma. Explica que el Islam ofrece una guía unificada para la humanidad sobre la creación, propósito y destino, y que promueve la justicia, igualdad y erradicación de la injusticia.
El documento discute los desafíos del sistema de seguridad social en el Perú. Uno de cada cuatro peruanos mayores de 65 años no recibe pensión debido a que muchos trabajadores no participan en los sistemas de jubilación públicos o privados. Los sistemas de pensiones existentes excluyen a las mayorías y deben articularse para garantizar el derecho universal a la seguridad social reconocido en la constitución. La cobertura de la seguridad social es baja, afectando principalmente a trabajadores independientes e informales.
The document provides information about Jakarta, Indonesia, including:
- Jakarta is the capital city of Indonesia with over 10 million residents from diverse ethnic and cultural backgrounds.
- The city has a long history dating back to the 14th century and reflects influences from Portuguese, Dutch, and Japanese colonial periods.
- Modern Jakarta is a bustling metropolis and economic center, but also retains elements of its traditional, rural roots. It faces challenges of pollution, congestion, and high costs of living.
Catálogo de la exposición "45 KM" en la Galería Utopia Parkway. Desde el 29 de abril al 3 de junio de 2016. C/ Reina, 11 28004 Madrid Tel +34 91 532 88 44 info@galeriautopiaparkway.com
El documento resume la historia de los sistemas operativos desde la década de 1940 hasta la actualidad. Los primeros sistemas operativos surgieron en la década de 1950 para controlar la ejecución de programas en computadoras. En los años 1960 aparecieron conceptos importantes y sistemas como UNIX. En los años 1970 y 1980 se desarrollaron los primeros sistemas operativos para computadoras personales como MS-DOS, MacOS y Windows. En la década de 1990 surgió Linux. El documento también brinda detalles sobre los sistemas operat
Calendario rfeta 2016 rev 10 calendario 2016 1Francisco Ramon
El documento presenta el calendario de competiciones de tiro con arco en España para 2016, dividiéndolo mes a mes. Incluye campeonatos nacionales e internacionales, ligas, grandes premios y torneos postales entre enero y diciembre. Las competiciones se realizarán en formatos como ronda a 18m, campo, 3D y por equipos en diferentes provincias y países de Europa.
The document provides guidelines for diabetes care in Massachusetts that were updated in 2007. It includes sections on diagnosing and classifying diabetes, preventing type 2 diabetes, diabetes medications and treatment approaches, cardiovascular risk reduction, hypertension, nephropathy, retinopathy, neuropathy, self-management education, nutrition, physical activity, tobacco use, and inpatient glucose control. The guidelines are intended to improve diabetes care by highlighting essential components of management and offering accompanying tools for primary care providers.
El documento describe los principios fundamentales del Islam, incluyendo la creencia en un solo Dios, la práctica de los cinco pilares como la oración y el ayuno, y la vida y enseñanzas del profeta Mahoma. Explica que el Islam ofrece una guía unificada para la humanidad sobre la creación, propósito y destino, y que promueve la justicia, igualdad y erradicación de la injusticia.
El documento discute los desafíos del sistema de seguridad social en el Perú. Uno de cada cuatro peruanos mayores de 65 años no recibe pensión debido a que muchos trabajadores no participan en los sistemas de jubilación públicos o privados. Los sistemas de pensiones existentes excluyen a las mayorías y deben articularse para garantizar el derecho universal a la seguridad social reconocido en la constitución. La cobertura de la seguridad social es baja, afectando principalmente a trabajadores independientes e informales.
The document provides information about Jakarta, Indonesia, including:
- Jakarta is the capital city of Indonesia with over 10 million residents from diverse ethnic and cultural backgrounds.
- The city has a long history dating back to the 14th century and reflects influences from Portuguese, Dutch, and Japanese colonial periods.
- Modern Jakarta is a bustling metropolis and economic center, but also retains elements of its traditional, rural roots. It faces challenges of pollution, congestion, and high costs of living.
Catálogo de la exposición "45 KM" en la Galería Utopia Parkway. Desde el 29 de abril al 3 de junio de 2016. C/ Reina, 11 28004 Madrid Tel +34 91 532 88 44 info@galeriautopiaparkway.com
El documento resume la historia de los sistemas operativos desde la década de 1940 hasta la actualidad. Los primeros sistemas operativos surgieron en la década de 1950 para controlar la ejecución de programas en computadoras. En los años 1960 aparecieron conceptos importantes y sistemas como UNIX. En los años 1970 y 1980 se desarrollaron los primeros sistemas operativos para computadoras personales como MS-DOS, MacOS y Windows. En la década de 1990 surgió Linux. El documento también brinda detalles sobre los sistemas operat
Calendario rfeta 2016 rev 10 calendario 2016 1Francisco Ramon
El documento presenta el calendario de competiciones de tiro con arco en España para 2016, dividiéndolo mes a mes. Incluye campeonatos nacionales e internacionales, ligas, grandes premios y torneos postales entre enero y diciembre. Las competiciones se realizarán en formatos como ronda a 18m, campo, 3D y por equipos en diferentes provincias y países de Europa.
Valderrobres es la capital de la comarca del Matarraña y ofrece varias oportunidades para el turismo alternativo como senderismo, observación de aves, y eventos culturales como ferias de artesanía y festivales en el castillo. Algunas de las atracciones principales son la ruta de los árboles milenarios, el Centro de Estudios y Observación de las Aves, y las celebraciones de Semana Santa.
Francisca Andrea Vásquez González presenta su currículum vitae, destacando su experiencia laboral en hoteles como The Ritz-Carlton y American Airlines, donde ha ocupado roles como agente de recepción, concierge y servicio al cliente. Posee educación en gestión hotelera y gastronomía, con dominio de idiomas como inglés, francés y español. Sus fortalezas incluyen orientación al servicio, trabajo en equipo y habilidades computacionales.
Este documento presenta una lección sobre cómo combinar correspondencia en Word. Explica que se partirá de una carta base y una lista de destinatarios para crear varias cartas personalizadas. Detalla los pasos para seleccionar la lista de destinatarios, incorporar sus datos como el bloque de direcciones y saludo, y visualizar una vista previa de los resultados. Finalmente, muestra cómo se pueden imprimir o combinar todas las cartas personalizadas en un solo documento.
El documento lista varios cursos de formación que se ofrecerán en octubre y noviembre de 2011. En octubre se ofrecerán cursos de recursos para animadores y de animaciones y pasacalles. En noviembre se ofrecerá un curso de monitor/a de tiempo libre que otorgará una titulación oficial tras 160 horas de clase y 90 de prácticas.
El documento habla sobre cómo las marcas deben crear contenido digital pensando en el público en lugar de en la marca misma. Sugiera que las marcas conozcan su historia y estrategia pero que se comuniquen de manera cercana y relevante para diferentes audiencias. También recomienda probar diferentes tácticas de contenido para enganchar al público.
TUTORIAL Intel® Learning Series Software Suite Classroom Management Tutorialnorali100
Este documento describe un programa de gestión de clases que ofrece una interfaz fácil de usar para que profesores enseñen y estudiantes aprendan de forma colaborativa. El programa permite a los profesores ver a los estudiantes conectados, enviar y recibir mensajes, distribuir archivos, recolectar trabajos de estudiantes identificados y activar opciones desde una barra de herramientas.
El documento proporciona información sobre Geolodía 12, una iniciativa para celebrar el Día Mundial de la Tierra que ofrece excursiones guiadas de geología en todas las provincias españolas. La Sociedad Geológica de España coordina el evento, que tiene como objetivos promover la observación geológica del entorno, dar a conocer el patrimonio geológico de España y fomentar las vocaciones científicas. El 6 de mayo de 2012 se llevarán a cabo excursiones gratuitas de
Este documento ofrece consejos sobre cómo encontrar un empleo, incluyendo cómo preparar un currículum vitae, carta de presentación, y tener éxito en una entrevista de trabajo. Explica la importancia de prepararse revisando ejemplos de CV, practicando para entrevistas, y aprendiendo sobre el proceso de búsqueda de empleo.
This document summarizes Anthony Billoni's master's thesis which examined using an art gallery excursion to generate ideas and heighten aesthetic experiences. The study had participants identify a challenge and view art to record ideas. It found that the excursion easily generated useful ideas for challenges. It also positively changed most participants' orientation toward art. The results suggest further developing excursion tools and strengthening the relationship between creativity and art gallery education.
Este documento resume varios proyectos de obras públicas realizadas o en proceso en el municipio de El Dorado, Meta. Incluye la mejora y mantenimiento de vías, la construcción de obras de protección en márgenes de ríos, la reconstrucción de vías y canalización de caños después de una calamidad pública, la construcción de un cerramiento perimetral para un matadero, y estudios para la construcción de vivienda social. También describe proyectos gestionados para un puente, mejoras a parques, y el mejoramiento de
This document summarizes a field trip taken by a primary school class to a local bakery called Horno Axaty. The summary is:
The class used their town as a resource to learn, gaining meaningful experience by visiting the local bakery and industrial park. They observed the raw materials and process for making bread, from mixing the dough to baking the finished loaves. The students thanked the bakery staff and local authorities for facilitating their educational visit.
This document is a Ph.D. thesis that examines the correlation between metabolic syndrome, impaired glucose regulation, and testosterone values. The thesis contains an introduction and literature review on metabolic syndrome, testosterone, and glucose metabolism. It then outlines the hypothesis, materials and methods, results, discussion, and conclusions of the author's personal contribution to the research. The thesis finds that metabolic syndrome prevalence increases with age and is linked to factors like sex, activity level, weight status, medical history, lipid and glycemic profiles, and testosterone values. Low testosterone and hypogonadism are also associated with these risk factors. Metabolic syndrome and low testosterone are both more prevalent in patients with type 2 diabetes compared to non
This review article summarizes research on the impact of coffee consumption on health. It finds that coffee contains several bioactive compounds like caffeine, chlorogenic acids, and diterpenes. While caffeine can increase blood pressure short-term, coffee drinking appears to reduce the risk of cardiovascular diseases like heart disease and stroke. Coffee is also associated with a reduced risk of type 2 diabetes and liver disease. The effects of coffee on cancer risk depend on the specific cancer type, but coffee drinking may lower overall cancer risk and mortality. However, the clinical evidence comes mostly from observational studies rather than randomized trials.
This document provides guidelines for diagnosing and managing sexually transmitted infections (STIs) through a syndromic approach. It outlines algorithms for diagnosing and treating common STI syndromes like vaginal discharge syndrome, lower abdominal pain, male urethritis syndrome, and others. Treatment typically involves a combination of antibiotics like ceftriaxone, azithromycin, and metronidazole. It emphasizes the importance of counseling, partner treatment, and preventing transmission.
2017 eacts guidelines on perioperative medication in adult cardiac surgeryJimmy Wea
This document provides guidelines on perioperative medication management for adult cardiac surgery patients. It addresses recommendations for antiplatelet therapy, anticoagulation, beta-blockers, statins, antibiotics and other medications before, during and after surgery. Specific guidance is given for conditions like atrial fibrillation and different types of surgical procedures. The goal is to provide evidence-based guidance to reduce risks and optimize outcomes for cardiac surgery patients.
The document discusses malignant hyperthermia, a rare genetic condition triggered by certain anesthetic agents. It can cause a severe hypermetabolic state and muscle rigidity. If not rapidly treated, it can result in death from complications like cardiac arrest or brain damage. The document outlines strategies for preventing and treating malignant hyperthermia in the operating room, including having emergency supplies and medication available, monitoring patients closely, and educating staff on treatment protocols.
The document reviews the association between COVID-19 and diabetes. It summarizes the general characteristics of COVID-19, including its incubation period, modes of transmission, clinical presentation, and diagnosis. It then discusses the relationship between diabetes and viral infections in general, and explores some potential pathophysiological mechanisms linking COVID-19 and diabetes. The review suggests chronic inflammation, immune dysfunction, and direct pancreatic damage as possible underlying factors. It notes that more research is needed to fully understand this relationship and its clinical implications.
This document provides a summary of health indicators in OECD countries. It begins with an introduction that describes the document as the 2013 edition of Health at a Glance, which presents recent comparable data on key health indicators across 34 OECD countries. The data is drawn from contributions of national health agencies and aims to monitor health status, determinants, health workforce, health care activities, and quality of care.
2018 esc guidelines for the management of cardiovascular disease during pregn...Vinh Pham Nguyen
This document provides guidelines for the management of cardiovascular diseases during pregnancy published by the European Society of Cardiology (ESC) in 2018. It was developed by an international task force and provides recommendations on risk assessment, diagnosis, treatment and management for a variety of heart conditions that may occur during pregnancy. The guidelines reflect recent advances and aim to improve outcomes for both mothers and infants.
Nutrition for the ageing brain: Towards evidence for an optimal dietNutricia
This article reviews the latest research on nutrition and cognitive aging. It discusses normal and pathological cognitive decline in aging. Several key mechanisms of brain aging are explored, including oxidative stress, neuroinflammation, and autophagy. The review examines the potential for specific nutrients and dietary patterns to prevent cognitive decline through these mechanisms. While some studies link nutrients like polyphenols, flavonoids, vitamins and omega-3 fatty acids to cognitive benefits, the research is inconsistent and more work is needed to determine optimal doses and relationships between diet and brain health in older adults.
Valderrobres es la capital de la comarca del Matarraña y ofrece varias oportunidades para el turismo alternativo como senderismo, observación de aves, y eventos culturales como ferias de artesanía y festivales en el castillo. Algunas de las atracciones principales son la ruta de los árboles milenarios, el Centro de Estudios y Observación de las Aves, y las celebraciones de Semana Santa.
Francisca Andrea Vásquez González presenta su currículum vitae, destacando su experiencia laboral en hoteles como The Ritz-Carlton y American Airlines, donde ha ocupado roles como agente de recepción, concierge y servicio al cliente. Posee educación en gestión hotelera y gastronomía, con dominio de idiomas como inglés, francés y español. Sus fortalezas incluyen orientación al servicio, trabajo en equipo y habilidades computacionales.
Este documento presenta una lección sobre cómo combinar correspondencia en Word. Explica que se partirá de una carta base y una lista de destinatarios para crear varias cartas personalizadas. Detalla los pasos para seleccionar la lista de destinatarios, incorporar sus datos como el bloque de direcciones y saludo, y visualizar una vista previa de los resultados. Finalmente, muestra cómo se pueden imprimir o combinar todas las cartas personalizadas en un solo documento.
El documento lista varios cursos de formación que se ofrecerán en octubre y noviembre de 2011. En octubre se ofrecerán cursos de recursos para animadores y de animaciones y pasacalles. En noviembre se ofrecerá un curso de monitor/a de tiempo libre que otorgará una titulación oficial tras 160 horas de clase y 90 de prácticas.
El documento habla sobre cómo las marcas deben crear contenido digital pensando en el público en lugar de en la marca misma. Sugiera que las marcas conozcan su historia y estrategia pero que se comuniquen de manera cercana y relevante para diferentes audiencias. También recomienda probar diferentes tácticas de contenido para enganchar al público.
TUTORIAL Intel® Learning Series Software Suite Classroom Management Tutorialnorali100
Este documento describe un programa de gestión de clases que ofrece una interfaz fácil de usar para que profesores enseñen y estudiantes aprendan de forma colaborativa. El programa permite a los profesores ver a los estudiantes conectados, enviar y recibir mensajes, distribuir archivos, recolectar trabajos de estudiantes identificados y activar opciones desde una barra de herramientas.
El documento proporciona información sobre Geolodía 12, una iniciativa para celebrar el Día Mundial de la Tierra que ofrece excursiones guiadas de geología en todas las provincias españolas. La Sociedad Geológica de España coordina el evento, que tiene como objetivos promover la observación geológica del entorno, dar a conocer el patrimonio geológico de España y fomentar las vocaciones científicas. El 6 de mayo de 2012 se llevarán a cabo excursiones gratuitas de
Este documento ofrece consejos sobre cómo encontrar un empleo, incluyendo cómo preparar un currículum vitae, carta de presentación, y tener éxito en una entrevista de trabajo. Explica la importancia de prepararse revisando ejemplos de CV, practicando para entrevistas, y aprendiendo sobre el proceso de búsqueda de empleo.
This document summarizes Anthony Billoni's master's thesis which examined using an art gallery excursion to generate ideas and heighten aesthetic experiences. The study had participants identify a challenge and view art to record ideas. It found that the excursion easily generated useful ideas for challenges. It also positively changed most participants' orientation toward art. The results suggest further developing excursion tools and strengthening the relationship between creativity and art gallery education.
Este documento resume varios proyectos de obras públicas realizadas o en proceso en el municipio de El Dorado, Meta. Incluye la mejora y mantenimiento de vías, la construcción de obras de protección en márgenes de ríos, la reconstrucción de vías y canalización de caños después de una calamidad pública, la construcción de un cerramiento perimetral para un matadero, y estudios para la construcción de vivienda social. También describe proyectos gestionados para un puente, mejoras a parques, y el mejoramiento de
This document summarizes a field trip taken by a primary school class to a local bakery called Horno Axaty. The summary is:
The class used their town as a resource to learn, gaining meaningful experience by visiting the local bakery and industrial park. They observed the raw materials and process for making bread, from mixing the dough to baking the finished loaves. The students thanked the bakery staff and local authorities for facilitating their educational visit.
This document is a Ph.D. thesis that examines the correlation between metabolic syndrome, impaired glucose regulation, and testosterone values. The thesis contains an introduction and literature review on metabolic syndrome, testosterone, and glucose metabolism. It then outlines the hypothesis, materials and methods, results, discussion, and conclusions of the author's personal contribution to the research. The thesis finds that metabolic syndrome prevalence increases with age and is linked to factors like sex, activity level, weight status, medical history, lipid and glycemic profiles, and testosterone values. Low testosterone and hypogonadism are also associated with these risk factors. Metabolic syndrome and low testosterone are both more prevalent in patients with type 2 diabetes compared to non
This review article summarizes research on the impact of coffee consumption on health. It finds that coffee contains several bioactive compounds like caffeine, chlorogenic acids, and diterpenes. While caffeine can increase blood pressure short-term, coffee drinking appears to reduce the risk of cardiovascular diseases like heart disease and stroke. Coffee is also associated with a reduced risk of type 2 diabetes and liver disease. The effects of coffee on cancer risk depend on the specific cancer type, but coffee drinking may lower overall cancer risk and mortality. However, the clinical evidence comes mostly from observational studies rather than randomized trials.
This document provides guidelines for diagnosing and managing sexually transmitted infections (STIs) through a syndromic approach. It outlines algorithms for diagnosing and treating common STI syndromes like vaginal discharge syndrome, lower abdominal pain, male urethritis syndrome, and others. Treatment typically involves a combination of antibiotics like ceftriaxone, azithromycin, and metronidazole. It emphasizes the importance of counseling, partner treatment, and preventing transmission.
2017 eacts guidelines on perioperative medication in adult cardiac surgeryJimmy Wea
This document provides guidelines on perioperative medication management for adult cardiac surgery patients. It addresses recommendations for antiplatelet therapy, anticoagulation, beta-blockers, statins, antibiotics and other medications before, during and after surgery. Specific guidance is given for conditions like atrial fibrillation and different types of surgical procedures. The goal is to provide evidence-based guidance to reduce risks and optimize outcomes for cardiac surgery patients.
The document discusses malignant hyperthermia, a rare genetic condition triggered by certain anesthetic agents. It can cause a severe hypermetabolic state and muscle rigidity. If not rapidly treated, it can result in death from complications like cardiac arrest or brain damage. The document outlines strategies for preventing and treating malignant hyperthermia in the operating room, including having emergency supplies and medication available, monitoring patients closely, and educating staff on treatment protocols.
The document reviews the association between COVID-19 and diabetes. It summarizes the general characteristics of COVID-19, including its incubation period, modes of transmission, clinical presentation, and diagnosis. It then discusses the relationship between diabetes and viral infections in general, and explores some potential pathophysiological mechanisms linking COVID-19 and diabetes. The review suggests chronic inflammation, immune dysfunction, and direct pancreatic damage as possible underlying factors. It notes that more research is needed to fully understand this relationship and its clinical implications.
This document provides a summary of health indicators in OECD countries. It begins with an introduction that describes the document as the 2013 edition of Health at a Glance, which presents recent comparable data on key health indicators across 34 OECD countries. The data is drawn from contributions of national health agencies and aims to monitor health status, determinants, health workforce, health care activities, and quality of care.
2018 esc guidelines for the management of cardiovascular disease during pregn...Vinh Pham Nguyen
This document provides guidelines for the management of cardiovascular diseases during pregnancy published by the European Society of Cardiology (ESC) in 2018. It was developed by an international task force and provides recommendations on risk assessment, diagnosis, treatment and management for a variety of heart conditions that may occur during pregnancy. The guidelines reflect recent advances and aim to improve outcomes for both mothers and infants.
Nutrition for the ageing brain: Towards evidence for an optimal dietNutricia
This article reviews the latest research on nutrition and cognitive aging. It discusses normal and pathological cognitive decline in aging. Several key mechanisms of brain aging are explored, including oxidative stress, neuroinflammation, and autophagy. The review examines the potential for specific nutrients and dietary patterns to prevent cognitive decline through these mechanisms. While some studies link nutrients like polyphenols, flavonoids, vitamins and omega-3 fatty acids to cognitive benefits, the research is inconsistent and more work is needed to determine optimal doses and relationships between diet and brain health in older adults.
This review discusses the role of TRIB3, a stress-induced protein, in linking metabolic dysfunction and cancer. TRIB3 regulates multiple stress response pathways including PI3K/AKT/mTOR and autophagy pathways. It does so through its pseudokinase and ubiquitination functions. TRIB3 expression is associated with insulin resistance, diabetes, and atherosclerosis by suppressing insulin signaling. Cancer cells can alter TRIB3 expression or localization to promote cell survival and growth. TRIB3 may act as a switch between homeostasis and disease in metabolic stress responses, making it a potential biomarker and therapeutic target for metabolic diseases and cancer.
This document provides guidelines from the European Society of Cardiology (ESC) on the diagnosis and management of hypertrophic cardiomyopathy (HCM). It was written by an international task force of experts in HCM. The guidelines cover definitions of HCM, epidemiology, etiology, diagnostic criteria and techniques, genetic testing and family screening, and recommendations for managing symptoms, arrhythmias, left ventricular outflow tract obstruction, and other complications of HCM. The task force performed an extensive review of the literature to update clinicians on the latest understanding and approaches to diagnosis and treatment of this genetic cardiac condition.
American Dietetic Association._ Elliott, Laura_ McCallum, Paula Davis_ Molsee...MarthyRavello1
This document provides an overview of the second edition of "The Clinical Guide to Oncology Nutrition" published by the American Dietetic Association. It discusses topics covered in the guide including cancer statistics, screening methods, changes in metabolism from cancer and cancer treatment, diet and cancer prevention, medical nutrition therapy, nutrition support, management of side effects, complementary therapies, nutrition for survivors and in palliative care, and clinical management in oncology settings. The guide serves as a comprehensive reference for dietitians and other health professionals working in oncology.
The review evaluated the effectiveness of ACE inhibitors (ACEi) and angiotensin receptor blockers (ARB) for adults with early stage chronic kidney disease without diabetes. Four randomized controlled trials with 2,177 participants were included. Low to moderate quality evidence from two studies found that ACEi had no impact on mortality or cardiovascular events compared to placebo in people with stage 3 kidney disease. One study found no difference in risk of end-stage kidney disease between ACEi and placebo in people with eGFR >45 mL/min/1.74 m2. No published studies directly compared ARB to placebo. In summary, there is currently insufficient evidence to determine the effectiveness of ACEi or ARB for patients
This document is a PhD thesis that investigates using data-driven techniques and modeling to help with glucose metabolism modeling and short-term blood glucose predictions in Type 1 Diabetes Mellitus (T1DM). The thesis describes clinical trials conducted to collect glucose and insulin data from T1DM patients. It then discusses developing discrete-time and continuous-time models of the glucose-insulin system and using these models to build linear multi-step predictors for short-term blood glucose prediction. The goal is to create an advisory tool to help T1DM patients maintain normal blood glucose levels.
This document provides a case study on pancreatic cancer. It describes a 71-year old male patient diagnosed with stage 4 pancreatic cancer that had metastasized to the liver and lungs. He was admitted to the hospital with generalized weakness, chills, fever and hypotension as side effects of his chemotherapy treatment for pancreatic cancer. The document details the patient's medical history, diagnosis, treatments received in the hospital including medications, nutritional interventions and evaluations over his hospital stay. It also includes appendices with further details on medications, labs, nutritional needs calculations and multiple nutrition assessments conducted on the patient during his admission.
This document provides clinical practice guidelines for the diagnosis and treatment of hyperprolactinemia from The Endocrine Society. It was developed by an international task force using the GRADE framework to formulate evidence-based recommendations. The guidelines cover evaluating the cause of hyperprolactinemia, managing drug-induced cases, treating prolactinomas in nonpregnant and pregnant patients, and addressing resistant or malignant prolactinomas. The task force created strong and weak recommendations based on the available evidence to provide guidance to healthcare professionals in diagnosing and managing hyperprolactinemia.
This thesis investigates the role of ghrelin in mediating stress-induced metabolic changes. The author found that ghrelin elicits an increase in caloric intake in response to stress while promoting the utilization of carbohydrates as a fuel source. Mice lacking a functional ghrelin signaling system did not show metabolic changes from chronic stress. Pharmacological blockade of ghrelin reduced stress-induced ghrelin secretion and subsequent caloric intake, improving metabolic outcomes from stress.
The document provides updated guidelines for the treatment of sexually transmitted diseases (STDs) from the Centers for Disease Control and Prevention (CDC). Key updates include:
1) Expanded evaluation for cervicitis and trichomoniasis.
2) New treatment recommendations for bacterial vaginosis and genital warts.
3) Information on the clinical efficacy of azithromycin for chlamydial infections in pregnancy and the roles of Mycoplasma genitalium and trichomoniasis in urethritis/cervicitis.
This document provides information on various diseases, health conditions, and advisories on health promotion from the Philippines Department of Health. It includes overviews of specific diseases like cancer, hepatitis, influenza, and more, with details on causes, symptoms, treatment and prevention. The document also contains advisories on seasonal health issues, blood donation, and general health tips.
Herstel-Yoga bij kanker en de rol in de NL gezondheidszorg.Peter Haima, Ph.D.
In deze presentatie gehouden tijdens het 2023 congres van de Vereniging van Yoga Docenten Nederland beschrijft Dr. Peter Haima de veranderingen in de NL gezondheidszorg, de toenemende belangstelling voor Integrative Medicine en de positieve rol van Yoga bij kanker. Hij legt helder uit wat de wetenschappelijke evidentie is voor yoga bij kanker en wat een speciale zachte vorm van yoga, herstel-yoga, kan betekenen voor mensen met kanker.
Workshop herstel yoga en helende ademhaling voor mensen met/na kanker of chronische ziekte. In samenwerking met stichting Zindividu. Hengelo 13 okt. 2019.
In deze workshop eerst een yoga sessie met zachte yoga en ademhalingsoefeningen die het immuunsysteem activeren en leiden tot een diepe lichamelijke en geestelijke ontspanning. Na de pauze uitwisselingen van de ervaringen en een lezing over deze vorm van herstel yoga. Hoerin een wetenscaheppelijke onderbouwing waarom herstel yoga zo helend werkt voor mensen met een ziekte.
Voeding & Kanker, gezonde voedingskeuzes voor preventie en bestrijding van ka...Peter Haima, Ph.D.
Kankerinloophuis 11 april 2019.
- De meeste volwassenen hebben slapende microtumoren die niet kwaadaardige worden omdat ons lichaam ze onder controle houdt
- een ongezonde levensstijl en voeding bevordert het ontstaan van tumoren, een gezonde levensstijl en voeding remt het ontstaan van kanker.
- kanker komt in het Westen veel meer voor dan in Aziatische landen zoals India
- fruit, groente en specerijen maken het verschil: Hoe meer fruit en groente, des te lager de kans op het krijgen van kanker.
- Bepaalde groentes en fruit zijn erg effectief (knoflook, kool, kurkuma, groene thee, blauwe bessen……..).
Belangrijkste aanpassingen aan dieet:
- Veel en vers fruit en groente, kruiden (kleur, smaak en geur); liefst biologisch. (minimaal 7+ : 2 x 150 g fruit + 5 x 75 g groente)
- Groente en fruit kiezen die effectief zijn in bestrijden kankercellen en met juiste bereidingswijze, bv. koolsoorten.
- Keuze vetten, boter, vlees, vis, melk, kaas, eieren is erg belangrijk (omega 3/6 balans) gras gevoerde dieren, biologisch.
- geen zonnebloem- mais of arachide olie; neem olijfolie
- Elke dag lijnzaad en/of walnoten, ongebrande noten
- Weinig kant en klaar producten, geen pakjes en zakjes, geen frituur
- Voorkom overgewicht en teveel (snelle) suikers, geraffineerd meel
- Veel vezels
- Matig met vlees, m.n. rood vlees (alle vlees behalve kip en gevogelte)
Mensen die kanker overleven heben veel dingen gemeen:
- Passen hun voeding aan
- Passen hun leven aan:
- Meer ontspanning, minder Stress
- Meer bewegen
- Sociale contacten
- Geloof in genezing en hun eigen kracht om dit te beïnvloeden
- Psychische wonden uit het verleden worden geheeld
- Zingeving
Door Yoga/mindfulness…..; praatgroep; familie opstellingen; coaching/therapie , zingeving..........
GEZONDE VOEDING VOOR LICHAAM & GEEST- Dr. Peter Haima – Food Passionistas, 25...Peter Haima, Ph.D.
GEZONDE VOEDING VOOR LICHAAM & GEEST- hoe je zelf de regie kunnen nemen over je geestelijke en lichamelijke gezondheid!
- Dr. Peter Haima – Lezing-deel 1, Food Passionistas, 25-6-'16.
In zijn lezing stelt Dr. Peter Haima dat je gezondheid voor een belangrijk deel zelf in de hand hebt en dat je door gezonde voeding, levenshouding en levensstijl, langer gezond en jong blijft (en de kans op ziekte vermindert). Peter Haima is moleculair bioloog en werd in 2010 zelf geconfronteerd met kanker. Hij vertelt op inspirerende wijze hoe het veranderen van voedingsgewoontes en lifestyle doorslaggevend is geweest in de totale genezing van lichaam en geest. Peter's missie is mensen te inspireren om in hun eigen kracht te gaan staan en zo een positieve bijdrage te leveren aan hun eigen gezondheid en genezing.
Peter Haima's lezingen zijn altijd goed onderbouwd en met beide benen op de grond. Hij deelt met mensen zijn grote kennis en eigen ervaringen en vertelt wat de meeste artsen ze niet zullen en kunnen vertellen. Naast reguliere behandelingen, kun je volgens hem ook zelf actief bijdragen aan je herstel door simpele en slimme aanpassing van je voedingsgewoontes. Bewustwording over de slechte kwaliteit van de hedendaagse voeding in onze westerse samenleving is hierbij essentieel.
Tijdens de lezing krijg je heldere en praktische tips waarmee je zelf aan de slag kan.
Ook gaat hij in op de relatie tussen lichaam en geest en hoe het verminderen van de dagelijkse chronische stress essentieel is om de gezond te bevorderen. Stress is desastreus voor het immuunsysteem en gezondheid. Yoga en een goede ademhaling zijn makkelijke methodes om de dagelijkse stress om te buigen naar rust en zo het immuunsysteem te stimuleren.
This document discusses complement system activation and its role in hemocompatibility testing. It provides background on the complement system and how activation can lead to infusion hypersensitivity reactions. The document recommends that all intravenously administered drugs be tested for direct complement activation as a risk factor for infusion hypersensitivity reactions. It outlines methods for measuring complement system activation in vitro using human sera and in animal models to test hemocompatibility of medical devices, nanomedicines, and biological therapies.
This document provides an overview of bone structure, function, composition, and disease. It discusses bone proteins including collagen, biomarkers of bone formation like BAP and osteocalcin, and resorption like CTX. Bone metabolism involves calcium, phosphate, PTH, and vitamin D. Osteoporosis results from imbalanced bone turnover. Therapies aim to reduce resorption with bisphosphonates or HRT, or stimulate formation with PTH or growth factors. Biomarkers like BAP and CTX can monitor therapy response by detecting changes within months.
1. Metabolic Syndrome
and associated pathologies
TECOmedical Clinical and Technical Review
March 2013
Authors:
Andreas Pfützner, M.D., Ph.D.,1, 2
and Peter Haima, Ph.D.,3
1. IKFE – Institute for Clinical Research and Development, Mainz/Germany
Concept: BEVAIR (Beta-cell dysfunction, Visceral Adipogenesis Insulin Resistance) Patent pending
2. University of Applied Sciences, Rheinbach/Germany
3. Life-Force biomedical communication, Netherlands
3. 3
1 Introduction
Metabolic syndrome is a combination of risk factors — abdominal obesity, hypertension, high blood sugar levels, insulin
resistance (IR), abnormal cholesterol levels, hyperlipidemia and inflammatory states — that increase the risk of heart
disease, stroke, diabetes type 2, fatty liver disease and PCOS (in young women). Having any of these conditions increase
the risk of serious disease. If more than one of these conditions occur in combination, the risk is even greater.
Metabolic syndrome is now present in up to 40 % of the United States adult population (prevalence on average 25 % of
the population and 40+ % from age 60 and higher) [2] and is associated with a nearly a two fold increase in cardiovascular
events, independent of the presence of diabetes mellitus. Obesity is the dominant key feature of metabolic syndrome
[1, 2], although patients of normal weight may also suffer from IR and metabolic syndrome, and obesity and metabolic
syndrome do not always occur in concordance as there is some evidence for conditions of benign obesity [3–7]. The
epidemic of obesity in in adults and children in both industrialized and third world countries is regarded as one of the most
serious public health problems of the 21st
century.
Many (especially overweight) people with IR are able to compensate for the increasing insulin requirement, so that the
blood sugar does not rise at first. Late stage β-cell dysfunction then develops into clinically manifest type 2 diabe-
tes in approximately one third of these patients [31]. Development of macrovascular damages may, therefore, already
have developed before type 2 diabetes is clinically manifest (normal or impaired glucose tolerance test result). These
macrovascular damages are, in part, irreversible, need to be treated lifelong and still are the actual cause of death in
75 % of diabetes type 2 patients.
Up to now, the underlying pathomechanisms of metabolic syndrome are not detected at all or only very late and
inadequately. In this review we discuss the latest clinical insights into Metabolic syndrome and related disease like
diabetes type 2, fatty liver disease, coronary disease and PCOS. Conventional diagnosis is discussed alongside the use
of new biomarkers. Three new biomarkers appear to be particularly suitable for early diagnosis and therapy selection due
to their stability and studies that are presently available: intact Proinsulin, Adiponectin and hsCRP [29]. In addition, the
effect of the therapy used on pathophysiological basic components can be checked by means of these new markers.
4. 4
(1) TG ≥ 1.695 mmol/L and HDL ≤ 0.9 mmol/L (male), ≤1.0 mmol/L (female).
(2) Waist/hip ratio 0.90 (male) 0.85 (female), or body mass index 30 kg/m2.
(3) Urinary albumin excretion ratio ≥ 20 μg/min or albumin/creatinine ratio ≥ 30 mg/g.
(4) Waist circumference ≥ 94 cm (male), ≥80 cm (female).
(5) TG ≥ 2.0 mmol/L and/or HDL 1.0 mmol/L or treated for dyslipidemia.
(6) Men, greater than 40 inches (102 cm) and women, greater than 35 inches (88 cm).
(7) Equal to or greater than 150 mg/dL (1.7 mmol/L).
(8) Men, Less than 40 mg/dL (1.03 mmol/L) and women, Less than 50 mg/dL (1.29 mmol/L).
(9) Equal to or greater than 130/85 mm Hg or use of medication for hypertension.
(10) Equal to or greater than 100 mg/dL (5.6 mmol/L) or use of medication for hyperglycemia.
(11) Defined as waist circumference with ethnicity specific values (If BMI is 30 kg/m², central obesity can be assumed and waist
circumference does not need to be measured).
(12) TG 150 mg/dL (1.7 mmol/L), or specific treatment for this lipid abnormality.
(13) HDL 40 mg/dL (1.03 mmol/L) in males, 50 mg/dL (1.29 mmol/L) in females, or specific treatment for this lipid abnormality.
(14) Systolic BP 130 or diastolic BP 85 mm Hg, or treatment of previously diagnosed hypertension.
(15) FPG 100 mg/dL (5.6 mmol/L), or previously diagnosed type 2 diabetes.
2 Metabolic syndrome
a. Definition and pathophysiology of metabolic syndrome
Metabolic syndrome is a cluster of risk factors — abdominal obesity, hypertension, high blood sugar levels, IR, abnormal
cholesterol levels, hyperlipidemia and inflammatory states — that increase the risk of heart disease, stroke, diabetes
type 2, fatty liver disease and PCOS (in young women). It has also been variously termed X syndrome, insulin resistance
syndrome, metabolic syndrome X, cardiometabolic syndrome, syndrome X, Reaven's syndrome, and CHAOS (in Australia).
The diagnostic criteria for metabolic syndrome have been set out by different organizations with slight variations in these
criteria as shown in Table 1 [8].
WHO
World Health Organization
EGIR
European Group for the Study
of Insulin Resistance
NCEP
US National Cholesterol
Education Program
IDF
International Diabetes
Federation
Presence of one of
following:
Insulin resistance AND two
or more of following:
Presence of three of
following (2004):
Central obesity (11)
AND
any two of following:
DM / IGT / IFG / Insulin
resistance
Central obesity (4)
Elevated waist
circumference (6)
Raised TG (12)
AND two of the following: Dyslipidemia (5) Elevated TG (7) ▼ HDL (13)
BP ≥ 140/90 BP ≥ 140/90
Reduced HDL (8) ▲ BP (16)
Dyslipidemia (1) FBG ≥ 6.1 mmol/L (110
mg/dL)
Elevated BP (9) ▲ FBG (17)
Central obesity (2) Elevated fasting glucose (10)
Microalbuminuria (3)
BP: blood pressure, DM: diabetes mellitus, FBG: fasting blood glucose, HDL: high density lipoproteins, IFG: impaired fasting glucose, IGT: impaired glucose
tolerance, TG: triglycerides.
Table 1: Comparison of definitions of the metabolic syndrome.
5. 5
Figure 1: the link between obesity, inflammation, β-cell dysfunction, insulin
resistance and cardiovascular risk [28, 29]
Oxidative stress, which is defined as imbalance between
the production and inactivation of reactive oxygen
species, has a major pathophysiological role in all the
components of metabolic syndrome [20–24]. Oxidative
stress and consequent inflammation induce insulin
resistance (IR) which likely initiates metabolic syndrome
and massive damage of pancreatic β-cell dysfunction.
The association between the metabolic syndrome and
inflammation is well documented [9]. Welsh et al. [10]
demonstrated that adiposity leads to higher levels of
the “acute phase” inflammatory protein CRP (C-reactive
protein) and accumulating evidence demonstrates a close
link among metabolic syndrome, chronic inflammation and
oxidativestress[11].Infact,theoxidativestress-inflammation
pathway has important roles in all the individual components of Metabolic syndrome including vascular alterations
[11-15]. Figure 1 shows the link between obesity, inflammation, insulin resistance, β-cell dysfunction, and cardiovascular
risk. [28, 29]. Adipo(cyto)kines (e.g. Adiponectin) and other factors produced by fat tissue and antiinsulinemic hormones
play a key role in the process.
b. The role of adipokines
Multiple adipokines can be held responsible for the negative consequences of abdominal adipogenesis on insulin
resistance. The growth of lipid tissue is induced by the differentiation of mesenchymal stem cells to become
preadopocytes and finally mature lipid cells. In this stage peripheral monocytes/macrophages migrate into the lipid tissue
and are kept at a constantly increased level of activation by the secretion of a whole pattern of proinflammatory cytokines
from the pre-adipocyte. In consequence many adipokines have been identified which have been previously described
to be associated with inflammatory conditions in other parts of the body, and which have a known negative influence on
insulin sensitivity, e. g. IL-6 and TNFα. A list of some recently described prominent adipokines is provided in Table 2 [31].
Adiponectin and leptin have been studied most extensively
andplayamajorroleinlipidmetabolismandthedevelopment
of obesity. Further adipokines are resistin and visfatin that
also seem to be linked to insulin resistance and metabolic
syndrome. They are currently under evaluation regarding
their clinical value.
I. Adiponectin
Adiponectin owns an exceptional place in this listing. It is secreted by the mature adipocytes (and the connective tissue)
and not by the pre-adipocytes and has a synergistic action to insulin. High plasma adiponectin concentrations result
in an improvement of insulin sensitivity. An increase in body weight with differentiation of stem cells to pre-adipocytes
is associated with a suppression of adiponectin concentrations in the circulation [38]. Other disease conditions that
have been described to be correlated with a suppression of adiponectin levels include, but are not limited to metabolic
syndrome, atherosclerosis and any kind of obesity. Adiponectin may, therefore, be regarded as an indicator of the
activity of pre-adipocytes. Female patients have higher reference values than male patients. Several plasma sub-fractions
have been described that are differentiated by the agglomeration of different numbers of single adiponectin molecules.
However, they have as of yet not shown any difference in their changing behaviour following therapeutic interventions.
For practical use it does, therefore, not really matter, whether “High Molecular Weight” or “Low Molecular Weight”
adiponectin is determined for diagnostic purposes, as long as the same sub-fraction is used to draw any diagnostic or
clinical conclusions [40]. Adiponectin levels respond quickly to changes in insulin resistance and the metabolic situation
in the lipid tissue. It is, therefore, suitable to track slight changes in insulin resistance, e.g. the metabolic deterioration
induced by the hormonal changes in women with polycystic ovary syndrome (PCOS) [41, 42].
Leptin Free Fatty acids
Interleukine-6 PAI-I and tPA
Retinol Binding protein 4 Angiotensin II
Adipsin (Complementation factor D) TNF-alpha
Adiponectin Visfatin
Resistin Vaspin
Table 2: Recently described adipokines
Anti-insulinemic hormones
Insulin Resistance
β-Cell
Dysfunction
β-Cell
Dysfunction
IL-6, TNFα etc.
Free
Fatty Acids
Angiotensin
Insulin-
requirement
Insulin
Proinsulin
Insulin
Proinsulin
Adiponectin
Adipogenesis
Lipid Cell
Pre-Adipocyte
Stem Cell
Stem Cell
Stem Cell
Leptin
Anti-insulinemic hormones
Insulin Resistance
β-Cell
Dysfunction
IL-6, TNFα etc.
Free
Fatty Acids
Angiotensin
Insulin-
requirement
Insulin
Proinsulin
Adiponectin
Adipogenesis
OBESITY
Lipid Cell
Pre-Adipocyte
Leptin AdiponectinC
B
Arteriosclerosis HypertensionDyslipidemia
Arteriosclerosis HypertensionDyslipidemia
Hyperglycemia
Intact
Proinsulin
hsCRP
6. 6
II. Leptin
Leptin is a 16kDa non-glycosylated protein that is predo-
minantly secreted by mature lipid cells, but can also de-
rive in minor amounts from the stomach, intestine tract,
muscle and breast tissue. The plasma leptin levels reflect
the actual amount of lipid tissue, the size of the adipocytes
and their triglyceride content. In consequence, plasma leptin
concentrations are elevated in case of obesity and decre-
ase with a loss in body weight [43]. These changes are in-
fluenced by the actual insulin and glucose concentrations
and by inflammatory cytokines. In addition, leptin plays a
role in the control of energy consumption, in angiogenesis,
fertility, bone formation and many other endocrine body
functions [44]. Leptin levels are higher in female patients,
most probably because of the larger amount of subcuta-
neous lipid tissue and a higher stimulation by estrogens in
women. Leptin concentrations decrease in a cold environment and during adrenergic stimulation. The brain uses leptin as
an important control variable for appetite regulation. It carries the information, whether “sufficient” amounts of lipid tissue
are prevalent and, therefore, leptin, like insulin, belongs to the lipostatic molecules. The lipostatic factors orchestrate to-
gether with the short-acting incretines (e. g. GLP-1, ghrelin, GIP, cholecystokinin (CCK), obestatin, PYY etc.) the nutritional
behaviour of the human organism (see Figure 2, [45]).
c. Development into diabetes
Oxidative stress and consequent inflammation induce IR, which likely initiates metabolic syndrome. Afterwards, there are
2 principal pathways of metabolic syndrome development [16]:
A. With preserved pancreatic beta cells function and
insulin hypersecretion which can compensate for
insulin resistance. This pathway leads mainly to the
macrovascular complications of metabolic syndrome.
B. With massive damage of pancreatic beta cells leading
to progressively decrease of insulin secretion and to
hyperglycemia (e.g. overt type 2 diabetes).
This pathway leads to both microvascular and
macrovascular complications.
An insulin-resistant state – as the key phase of metabolic syndrome – constitutes the major risk factor for the development
of diabetes mellitus. Hyperinsulinemia appears to be a compensatory mechanism that responds to increased levels of
circulating glucose. Fasting glucose is presumed to remain normal as long as insulin hypersecretion can compensate for
insulin resistance. The fall in insulin secretion leading to hyperglicemia occurs as a late phenomenon.
3 Insulin resistance and diabetes mellitus type 2
In type 2 diabetes, fat, liver, and muscle cells do not respond correctly to insulin anymore. Due to this insulin resistance
(IR), blood sugar does not enter these cells and consequently high levels of sugar build up in the blood. This is called
hyperglycemia. Type 2 diabetes usually occurs slowly over time. Most people with the disease are overweight when they
are diagnosed. Type 2 diabetes can also develop in people who are thin. This is more common in the elderly. Family
history and genes play a large role in type 2 diabetes. Low activity level, poor diet, and excess body weight around the
waist increase the risk.
Figure 3: The relationship between metabolic syndrome, insulin resistance,
hyper-insulinemia and hyperglycemia (overt type 2 diabetes), adapted from [16]
M e t a b o l i c S y n d r o m e
insulin resistance
Life time
Diabetes type 2
Pancreatic beta cells
stress damage
Hyperinsulinemia
Macrovascular
+ Microvascular
complications
Macrovascular
complications
Food intake
excess
Genetic
background
Physical
inactivity
Adipogenesis
Overweight
A
Obesity
Hyperinsulinemia HyperglycemiaB
Figure 2: Factor controlling appetite and food uptake
7. 7
Diabetes type 2 is one possible outcome of Metabolic syndrome. Diabetes type 2 and obesity are two diseases with
continuously growing prevalence over the past decades that have both reached pandemic dimensions in their distribution.
Approximately 4–5 % of the world population are currently affected and the annual incidence in Western Europe is
approximately 10 %. Type 2 diabetes is conventionally diagnosed via elevated blood glucose and glycosylated
hemoglobin (HbA1c) levels.
a. Pathophysiology
The major underlying mechanisms of diabetes type 2 are
the development of systemic insulin resistance and a col-
lapsed insulin secretion by pancreatic β-cells. IR is cha-
racterized by a general decrease of the insulin sensitivity
of the peripheral cells, which on a receptor level is asso-
ciated with a genetically determined change in the insulin
receptor molecule and a reduction of the overall number of
insulin receptors on the cells (post-receptor defects have
also been described in literature). Figure 4, shows the rela-
tion between IR, decreased insulin secretion and adiposity.
b. Development stages of β-cell dysfunction
If a patient shows hereditary or acquired insulin resistance, this will initially be compensated for by an appropriate additional
secretion of insulin. Insulin, however, is the only (known) physiological hormone that stimulates adipogenesis. As a
consequence, this leads to a strong tendency to develop adipose tissue, especially with increased intake of calories. In
advanced stage, the processing of the insulin precursor molecule proinsulin becomes insufficient and increasing amounts
of intact proinsulin are being secreted. Proinsulin has only a fraction of the blood sugar reducing effect of insulin, but has
the same adipogenic potency [3–5].
In consequence, elevated plasma intact Proinsulin levels
are a highly specific direct indicator for advanced β-cell
dysfunction and a highly specific indirect indicator for cli-
nically relevant insulin resistance [21]. Using the fasting
intact proinsulin concentrations and under consideration
of the level of insulin resistance (e. g. by means of the
HOMA score [22]), it is possible to introduce a clinically
useful staging of β-cell dysfunction that allows for a dif-
ferential diagnosis and selection of a pathophysiologically
oriented differential therapy of type 2 diabetes mellitus [23].
This staging is presented in Figure 5 and further detailed
in Table 3.
Figure 5: Staging of β-cell dysfunction by means of insulin resistance and
composition of the β-cell secretion product [23]
Stage Description Insulin Proinsulin Glucose
I Insulin sensitive Normal Normal Normal
II
Insulin resistance without
qualitative secretion disorder
Elevated Normal
Normal or
elevated
III a
Insulin resistance with major
β-cell secretion disorder
Normal/Elevated Elevated
Normal or
elevated
III b Collapsed β-cell secretion Low Elevated to normal (in end stage) Elevated
Table 3: Staging of β-cell dysfunction by means of insulin resistance and composition of the β-cell secretion product [23]
1. Cause of Disease:
Reduced Insulin Effectiveness
(Insulin resistance)
Increased
Insulin
requirements
Visceral Adipogenesis
Weight gain
Hormones and cytokines
from the lipid tissue reduce
insulin sensitivity and induce
dyslipidemia, hypertension
and atherosclerosis
With sufficient food supply new adipose
tissue is built up supported by insulin
but even more by proinsulin
2. Cause of Disease:
Deteriorated Insulin Secretion
(β-Cell dysfunction)
Increased Insulin- and Proinsulin-
Secretion
D
Y
S
L
I
P
I
D
E
M
I
A
A
T
H
E
R
O
S
C
L
E
R
O
S
I
S
H
Y
P
E
R
T
E
N
S
I
O
N
Figure 4: Relation between insulin resistance, β-cell dysfunction, obesity
and the resulting complications [19, 20]
8. 8
II. HOMA score to assess early stages of β-cell dysfunction
The HOMA (Homeostasis model assessment) score is an easy method to estimate the degree of insulin resistance
non-diabetic or early stage diabetic patients [24,25]. It can be applied only if intact proinsulin levels are in the normal range,
as the total secretion activity of the β-cell is under this condition represented by the fasting insulin levels. The HOMA score
is based on the assumption that under normal conditions, a normal blood glucose value is associated with a matching
normal insulin level, which may vary individually from patient to patient. Insulin resistance is indicated, if at this normal
insulin level, an elevated blood glucose is observed, or if more insulin is required to maintain blood glucose at its normal
level.
After determining the fasting serum insulin and fasting plasma glucose levels the HOMA-IR score is calculated as follows:
HOMA = Insulin [μU/ml] x Glucose [mmol/l] /22.5.
Insulin resistance is assumed if the score value exceeds 2 [25]. Of particular interest are changes in the HOMA score
during therapeutic interventions, as a score reduction represents an improvement in insulin sensitivity. Again, the HOMA
score should only be used in patients with stage I and II of β-cell dysfunction (see Figure 3), because intact Proinsulin is
an additional marker for β-cell activity that is not considered in the HOMA-IR score equation.
III. Intact proinsulin testing to assess late stage β-cell dysfunction
Intact proinsulin is produced in the pancreatic β-cells and is normally further processed to insulin and C-peptide. It is
only seen in low concentrations in the plasma of healthy subjects, as it is rapidly degraded (T 1/2
is 15 minutes). Proinsulin
cleavage products (like des32,33) are stable for several hours. As these fragments are inactive and can make up to 50 %
of total Proinsulin, only assays specifically measuring intact proinsulin are suitable to indicate advanced β-cell dysfunction
and IR.
An increase in the insulin demand, as provided by insulin resistance in later stages of type 2 diabetes mellitus, can result
in increased expression of proinsulin into the blood (see Figure 3). When intact proinsulin is secreted together with or
instead of insulin in the fasting state (stage III of β-cells dysfunction, Figure 3) the HOMA score cannot be used to assess
the level of β-cells dysfunction [26, 27]. Intact proinsulin is also able to lower glucose values but is not considered in the
HOMA equations. Measurement of fasting intact proinsulin has been shown to be a very specific indicator and clinically
significant IR.
In clinical practice, fasting morning intact proinsulin can be used as highly specific indicator of of late stage β-cell
dysfunction and clinically relevant IR. It can also to serve as the basis for the selection of an insulin resistance therapy,
and to monitor the therapeutic effect on β-cell dysfunction.
c. Diagnosis of insulin resistance and diabetes type 2
I. Glucose testing
Today, diagnosis and therapy of the type 2 diabetes mellitus is still based on blood sugar values and the associated
values for glycosylated hemoglobin (HbA1c). WHO 2011 guidelines describe that fasting glucose should be 127 mg/dl
and HbA1c 48 mmol/mol. In addition an oral glucose tolerance test (OGTT) is often performed. During an OGGT glucose
is given and blood samples taken afterward to determine how quickly it is cleared from the blood. WHO recommends for
a 75g oral dose in all adults: the dose is adjusted for weight only in children.
Glucose levels 11.1 mmol/L ( 200 mg/dL) at 2 hours confirms the diagnosis of diabetes (see Table 4).
Glucose
levels
Normal
Impaired fasting
glycaemia
Impaired glucose
tolerance
Diabetes
mellitus
Venous Plasma Fasting 2hrs Fasting 2hrs Fasting 2hrs Fasting 2hrs
(mmol/L) 6.1 7.8 6.1 7.0 7.8 7.0 7.8 7.0 11.1
(mg/dL) 110 140 110 126 140 126 140 126 200
Table 4: 1999 WHO Diabetes criteria - Interpretation of Oral Glucose Tolerance Test
9. 9
IV. Intact proinsulin combined with oral glucose tolerance testing to identify prediabetes
patients.
Because of the blood sugar reducing effect of Proinsulin, some patients may already be suffering from β-cell dysfunction
years before clinical manifestation of elevated blood sugar levels. It has been shown that elevation of fasting intact
proinsulin is an indicator of insulin resistance and severe β-cell dysfunction. Earlier detection of prediabetic patients is
important to prevent irreversible cardiovascular damages.
In a recent pilot study [57] it was investigated whether elevation of intact proinsulin after 1 and 2 hours in the course of
an oral glucose tolerance test (OGTT) may be an indicator of the development of type 2 diabetes. Patients were enrolled
based on previous results of OGTT: 11 healthy subjects (7 female, 4 male, age: 59 ± 20 yrs.), 10 patients with Impaired
Glucose Tolerance (IGT; 6 female, 6 male, age: 62 ± 10 yrs.), and 10 patients with overt type 2 diabetes (6 female, 4 male,
age: 53 ± 11 yrs.). Another OGTT was performed with measurement of glucose and intact proinsulin levels after 0h, 1 h and
2 hours. Five years later. The diabetes status of the patients was confirmed and correlated with the earlier OGTT results.
Patients with diabetes (Fig. 6) had elevated fasting glucose levels after 1 and 2 h (diabetes: 0/1/2 h:
121 ± 20/230 ± 51/213 ± 24 mg/dL; prediabetes: 102 ± 9/168 ± 57/149 ± 34 mg/dL; normals: 94 ± 8/140 ± 29/90 ± 24 mg/dL).
Proinsulin values after 2 hours were elevated in diabetes and prediabetes vs. control 27 ± 10 pmol/L and 28 ± 6 pmol/L,
respectively, vs. 10 ± 5 pmol/L (p0.05 vs. both other groups).
Five years later, all patients with IGT and three normal subjects had developed overt type 2 diabetes. All manifesting
patients had elevated intact proinsulin levels ( 11 pmol/L) after 1 and 2 h. A value 20 pmol/L after 2 h was always
indicative for β-cell dysfunction and progressive disease development. However, because of the multiple existing pheno-
types of type 2 diabetes, a value 20 pmol/L, however, does not automatically exclude diabetes in an individual patient.
Two out of 10 patients with initial IGT were in fact normal according to the WHO diabetes criteria during the second
OGTT. However, proinsulin values were 33 and 36 pmol/L after 2 hours, confirming β-cell dysfunction and progressive
disease development.
In conclusion: Five year after an initial oral glucose
tolerance test, all patients with elevated intact proinsulin
levels after 1 h and 2 h had developed overt Type 2 diabetes,
irrespective of the observed blood glucose values in the
OGTT. Increasing intact proinsulin levels after 1 h and 2 h in
the OGTT indicate stress-related β-cell dysfunction and may
be an effective predictor for type 2 diabetes development
in a mid-term future.
This first study is very promising, as early detection of pre-
diabetes using intact proinsulin as biomarker, may allow
life style and other interventions to prevent irreversible
cardiovascular damages in diabetes patients that are often
the actual cause of death.
60
time [min]
glucose[mg/dl]
glucose
0
0
50
200
150
100
250
120
Normal
Prediabetes
Diabetes
Normal
Prediabetes
Diabetes
60
time [min]
intactproinsulin[pmd/L]
intact proinsulin
0
0
5
20
15
10
25
30
35
120
Figure 6: Glucose and intact Proinsulin levels during oral glucose tolerance
testing of healthy, Prediabetes and clinically manifest diabetes type 2
subjects [30]
10. 10
4 Diabetes related cardiovascular disease
Today, diagnosis and therapy of the type 2 diabetes mellitus is still based on blood sugar values and the associated
values for glycosylated hemoglobin (HbA1c). But even with good blood sugar adjustment, patients still have an increased
cardiovascular risk. Still, 75 % of patients with type 2 diabetes die of cardiovascular events, whereas this is only true for
35 % of patients with type 1 diabetes, although these patients also have an increased blood sugar level. Today, differences
in mortality can be explained by the underlying pathologic developments in type 2 diabetes on a metabolic and vascular
level.
a. Pathophysiology
Pathophysiologically, type 2 diabetes is characterized by insulin resistance and defective secretion of the pancreas. In
particular, IR is closely associated with macrovascular complications, since insulin receptors exist on the endothelial cells
of large vessels, whose function is not to absorb glucose, but to activate NO synthesis in the cells. NO is the mediator
of numerous vasoprotective mechanisms and finally protects the organism against the development and progression of
atherosclerosis [29]. In case of IR not only metabolic but also vascular receptors will be affected and, consequently,
not only the insulin requirement or the blood sugar will rise, but usually there is a parallel decrease of the protection of
the vessel cells against the deposition of foam cells, a key step in the development of atherosclerosis. Many (especially
overweight) people with insulin resistance are able to compensate for the increasing insulin requirement, so that the
blood sugar does not rise at first. An additional malfunction of the insulin-producing β-cells of the pancreas then leads
to clinically manifest type 2 diabetes in approximately one third of these patients [31]. Development of macrovascular
damages may, therefore, already commence in a stage of the disease in which type 2 diabetes is not yet clinically manifest,
but where, for example, “only” a disturbed glucose tolerance is present. For this reason, many type 2 diabetes patients
already show cardiovascular damages during the first clinical diagnosis of their disease and these damages are, in part,
not reversible any more. They need to be treated lifelong and cardiovascular damages are often the actual cause of death.
IR-induced hyperinsulinemia leads to a strong tendency to develop adipose tissue (insulin is the only physiological
hormone that stimulates adipogenesis), especially with increased intake of calories. If there is a simultaneous β-cell
dysfunction, proinsulin is increasingly present in the secretion product, which has only a fraction of the blood sugar
reducing effect of insulin, but has the same adipogenic potency [32-34] (Fig. 7A).
Both hormones also increase adipogenesis and lead to intensified differentiation of mesenchymal stem cells into pre-
adipocytes and finally into adipocytes [35]. At this stage, adipose tissue, a highly active endocrine organ, secretes
hormones directed against insulin, e. g. estrogenes, which in turn enhances insulin resistance [36]. At the same time, the
amount of circulating adiponectin is suppressed, a hormone of the white adipose tissue and the connective tissue, which
has strong vessel-protective and anti-atherosclerotic properties [37,38]. A vicious circle is created within which insulin
resistance, β-cell dysfunction and adipogenesis mutually affect each other negatively. The differentiated pre-adipocytes
in turn secrete further molecules, which in their totality can maintain or even enhance the metabolic syndrome, e. g.
angiotensin, IL-6, TNFα, free fatty acids, RBP4 or PAI-1 Fig. 7B). The consequence is the development or enhancement
of hypertension, dyslipidemia and increased macrophage activation which ultimately contributes to atherosclerosis [39].
These pathophysiological associations result in a higher atherosclerosis risk, especially if the insulin requirement rises
further due to hyperglycemia and toxic concentrations of glucose occurring in the plasma, and, at the same time, the
present insulin resistance seriously interferes with the vessel-protective NO-production in the endothelium (Fig. 7C).
11. 11
Anti-insulinemic hormones
Insulin Resistance
Insulin Resistance
β-Cell
Dysfunction
β-Cell
Dysfunction
IL-6, TNFα etc.
Free
Fatty Acids
Angiotensin
Insulin-
requirement
Insulin
Proinsulin
Insulin
Proinsulin
Insulin-
requirement
Adiponectin
Anti-insulinemic hormones
Adiponectin
Adipogenesis
Lipid Cell
Pre-Adipocyte
Adipogenesis
Lipid Cell
Stem Cell
Stem Cell
Stem Cell
Pre-Adipocyte
Leptin
Anti-insulinemic hormones
Insulin Resistance
β-Cell
Dysfunction
IL-6, TNFα etc.
Free
Fatty Acids
Angiotensin
Insulin-
requirement
Insulin
Proinsulin
Adiponectin
Adipogenesis
OBESITY
Lipid Cell
Pre-Adipocyte
Leptin AdiponectinC
B
A
Arteriosclerosis HypertensionDyslipidemia
Arteriosclerosis HypertensionDyslipidemia
Hyperglycemia
Intact
Proinsulin
hsCRP
Figure 7: The relation between insulin resistance, obesity and the development of cardiovascular risk
12. 12
b. Biochemical markers for diagnosis and therapy selection
Routine diagnostics of high blood pressure involves measurement of lipids, HbA1c and glucose. However, the underlying
pathomechanisms described above are not detected at all or only very late and inadequately. Therefore, numerous new
laboratory markers for classification of metabolic and vascular risk have been investigated and described in recent years.
Three of these markers appear to be particularly suitable for diagnosis and therapy selection due to their stability and
studies that are presently available: intact Proinsulin, Adiponectin and hsCRP [29].
I. Proinsulin – a blood glucose independent marker to assess insulin resistance and β-cell
dysfunction
The significance of intact proinsulin as β-cell function marker has already been described in chapter 3. Intact proinsulin
occurs in plasma in increased fasting levels only if a clinically significant IR exists already [27]. Thus, intact Proinsulin is
an indirect, but highly specific marker for late stage β-cell dysfunction.
Many (especially overweight) people with insulin resistance are able to compensate for the increasing insulin requirement,
so that the blood sugar does not rise at first. Late stage β-cell dysfunction then develops into clinically manifest type 2
diabetes in approximately one third of these patients [31]. Development of macrovascular damages may, therefore, already
have developed before type 2 diabetes is clinically manifest (normal or impaired glucose tolerance test result). These
macrovascular damages are, in part, irreversible and need to be treated lifelong (and often are the actual cause of death).
Measurement of Proinsulin allows for early detection and treatment of these prediabetic patients to prevent irreversible
cardiovascular damages.
In view of this it appears to be reasonable to adapt the therapy to the β-cell dysfunction. Prospective studies have
demonstrated already that intervention by mobility, Metformin, glitazones or insulin will protect the β-cell and lead to a
decrease of the proinsulin level, an effect that could not be observed with sulfonylurea [46-48].
Only assays specifically measuring intact Proinsulin are suitable. Fasting values 11 pmol/L are considered as normal.
Fasting values 11 pmol/L are indicative of β-cell dysfunction, insulin resistance and cardiovascular risk.
Increasing intact proinsulin levels after 1 and 2 hours in an oral glucose tolerance test are highly indicative for stressrelated
β-cell dysfunction and may be a strong predictor for type 2 diabetes development and cardiovascular damages in a
mid-term future (see chapter 3 [57]). A proinsulin value 20 pmol/L at any time point (1 or 2 hours) is indicative for β-cell
dysfunction and progressive disease development.
II. Adiponectin – a visceral adipose tissue activity marker to predict cardiovascular risk
The fat and connective tissue hormone adiponectin is a reverse indicator of visceral adipose tissue activity. As such it is
regarded as a good marker of insulin resistance and metabolic syndrome. High plasma adiponectin concentrations result
in an improvement of insulin sensitivity. Even though adiponectin appears to be less suitable for the initial diagnosis of
insulin resistance than intact proinsulin [49], it is an excellent indicator of the metabolic overall situation, which responds
very sensitively to successful interventional therapeutic approaches. An increase of adiponectin under therapy shows an
improvement of the risk profile.
Clinical studies showed that values below 7 mg/l were associated with an increased risk of cardiovascular events [37, 38].
Values between 7 and 10 mg/L are regarded as grey zone, values 10 mg/L are considered as normal.
13. 13
III. hsCRP – a chronic inflammation marker to predict cardiovascular risk
The increasing amount of abdominal lipid tissue exposes the patient to an increased macrovascular risk. The
proinflammatory adipokines deriving from the pre-adipocyte activate the immune system not only locally but also
systematically, i.e. mononuclear cells in the circulation are also alerted. Especially in the postprandial state, these
monocytes/macrophages may be loaded with LDL particles. At the same time, these cells play a key role in the
pathophysiology of atherosclerosis, as they penetrate into the vessel wall by means of further inflammatory proteins and
enzymes, which finally leads to cholesterol deposit and plaque formation. A known, “acute phase” inflammatory protein
involved in this process is C-reactive protein (CRP), which is produced in the liver.
Whereas the application of intact proinsulin and adiponectin for therapy selection and therapy control is just beginning
to assert itself now in type 2 diabetes, the use of highly sensitive C-reactive protein (hsCRP) as inflammatory marker of
cardiovascular risk especially in cardiology has already reached a high level of general acceptance. While CRP has been
considered to be an unspecific indicator of inflammation of any origin in the past, it could be shown tha t h sCRP-values,
stratified into three risk groups, have their own predictive value for cardiovascular risk in the low measurement range
( 10 mg/l) [50]. Values in this range, when determined with a highly sensitive test method (therefore: “high sensitivity CRP”
or “hsCRP”), describe a stepwise increased cardiovascular risk in patients with and without diabetes mellitus (Table 5
[50, 52]). This staging has been confirmed in numerous studies and meta analyses and has been included in the official
diagnosis criteria of the American Heart Association [51].
A reduction of the hsCRP in the course of the observation shows an improvement of the cardiovascular risk profile [53].
5 Other metabolic syndrome-associated diseases
a. Fatty liver disease
With the increasing prevalence of obesity and Metabolic syndrome an increase of nonalcoholic fatty liver disease (NAFLD)
is obvious. Patients with insulin resistance and other symptoms of metabolic syndrome should therefore be screened for
NAFLD and its progressive and chronic form NASH (non-alcoholic steatohepatitis) [56]. While most patients with steatosis
tend to have a benign clinical course, a significant proportion of those with NASH have a progressive disease with a risk of
developing liver cirrhosis and hepatocellular carcinoma [12]. In the USA, 7 % of all liver transplants are based on diagnosis
of NASH [23]. The diagnostic challenge is to predict NAFLD patients that are likely to progress into liver disease, initiate
therapy and life style changes and to monitor the efficacy of the measures.
Conventional markers of liver damage, liver transaminases (AST/ALT), frequently provide incorrect information about
liver damage. For example, it could be shown that up to 25–30 % of the patient with fibrosis liver damage have normal
transaminase levels [59, 60]. Hepatocyte cell death, specifically hepatocyte apoptosis, is considered to play a crucial role
in the formation of liver fibrosis or liver cirrhosis. Numerous studies have demonstrated that hepatocyte apoptosis can
be specifically assessed by means of caspases cleaved fragments of Keratin 18 (ccK18), a major intermediate filament
protein, expressed by hepatocytes. The biomarker CcK18 as determined by the M30 Apoptosense®
ELISA allows prediction
of the level of fibrosis (staging), steatosis and NASH and can improve decisions on therapeutic regiments for patients.
Canbay et al. concluded that serological investigation, including the biomarker ccK18 can predict progression of NAFLD
into NASH in obese patients [55].
hsCRP fasting value Cardiovascular risk
10 mg/L No assessment possible
3-10 mg/L High
1-3 mg/L Average
0-1 mg/L Low Table 5: hsCRP cardiovascular risk groups
14. 14
Liver damage biomarker Cardiovascular risk
Caspases cleaved Keratin 18
(ccK18: M30 Elisa)
Hepatocyte apoptosis
Keratin 18 (cleaved and
uncleaved: M65 Elisa)
Hepatocyte apoptosis
and necrosis
Alpha Glutathione
STransferase (α GST, serum)
Hepatocyte damage
Pi Glutathione
S-Transferase (π GST, serum)
Bile duct damage
Collagen IV (serum) Increased collagen
deposition
Table 6: Various liver damage biomarkers
For each diabetic patient, liver biomarker levels were expressed as a percentage of the upper limit of the normal range for the specific marker (upper limit for
ccK18: 186 U/L; K18: 183 U/L; α GST: 12 µg/L).
Liver damage biomarkers in diabetic patients
%ofupperlimitnormalrange
Patients
600 %
500 %
300 %
200 %
100 %
0 %
400 %
CCK18 (M30)
K18 (M65)
alpha GST
Figure 8: Liver damage biomarkers in diabetic patients
In a recent study by Pfützner et al [58], liver transaminases (ALT/AST) and liver damage biomarkers ccK18, K18 and α GST
were measured in 32 diabetic patients and 36 healthy subjects. ALT/AST levels were elevated in only 22/13 % of diabetic
patients. In contrast, all biomarkers were highly elevated in up to 65 % of the cases (above reference range, ccK18: 50 %;
K18: 65 %; α GST: 58 %) and showed similar behavior in most patients (Figure 8), indicating ongoing liver damage. This
pilot study supports the use of liver damage biomarkers in diabetic patients to diagnose fatty liver disease and predict
possible progression to NASH.
b. PCOS: polycystic ovary syndrome
The polycystic ovary syndrome (PCOS) is induced by a deterioration of the hormonal regulation in female patients and is
characterized by chronic anovulation and hyperandrogenism. It is one of the most frequent endocrine disorders in young
female patients (prevalence 6 %). PCOS is often associated with obesity and IR. During the PCOS development increased
LH levels induce an increased synthesis of steroids in the ovaries, which in turn leads to an increased modification of
androgens into estrogens in the lipid tissue. The acyclic production of these estrogens results in increased secretion of
LH from the pituary gland. Another source of increased androgen concentrations in patients with PCOS is a suppression
of the production of sex-hormone-binding globulin (SHBG) in the liver, which leads to increased formation of biologically
active androgens. The increased formation of all these “anti-insulinemic” hormones may frequently result in development
of a metabolic insulin resistance and an increased insulin secretion to compensate for the higher needs.
Insulin resistance does not represent the only cause for PCOS development, but the accompanying hyperinsulinemia
supports the development by the acceleration of ovarian and adrenal androgen production. This understanding of the
pathophysiological disease background has led to the use of insulin sensitizing drugs in the affected patients. Therapy
with metformin resulted in a significant decrease in circulating androgen levels, an increase in SHBG concentrations,
a normalization of the menstrual cycle and an improvement in the fertility [54]. Similar effects have been reported for
intervention with glitazones (rosiglitazone, pioglitazone). The key parameters for diagnosing insulin resistance in PCOS
patients appear to be the HOMA score and adiponectin or intact proinsulin.
Canbay et al. demonstrated that patients with PCOS also have increased risk for developing non-alcoholic steatohepatitis
(NASH). Due to this association they advise to investigate female NASH patients for PCOS and PCOS patients for NASH
[55].
Liver damage can also be assessed using other biomarkers. A list of some recently described liver damage biomarkers
is shown in Table 6.
15. 15
6 Risk assessment and therapy of metabolic syndrome-associated pathologies
a. Diagnosis and risk assessment
Up to now, the underlying pathomechanisms described above are not detected at all or only very late and inadequately.
As discussed in chapter 3, intact Proinsulin, Adiponectin and hsCRP appear to be particularly suitable for diagnosis and
therapy selection due to their stability and studies that are presently available [29]. In addition, the effect of the therapy
used on pathophysiological basic components can be checked by means of these new risk markers.
The values for intact proinsulin, adiponectin and hsCRP can be used to assess
• β-cell function,
• insulin sensitivity
• patient's individual cardiovascular risk
Increased proinsulin and hsCRP levels and low adiponec-
tin values indicate insulin resistance with β-cell dysfunction
and impending macrovascular complications. Adiponectin
increase, on the other hand, is accompanied by significant
improvement of metabolic status and cardiovascular pro-
gnosis. In addition biomarkers for liver damage and pro-
gression to NASH can be included like ccK18, K18, α GST
and collagen IV (see chapter 4a).
b. Therapy and monitoring
Proinsulin, adiponectin and hsCRP are independent risk factors for type 2 diabetes as well as for macrovascular
complications. According to present knowledge, all three risk factors will be improved in particular through changes in
lifestyle (weight reduction and more physical activity) and through pathophysiologically oriented medicinal treatment.
Improvements have been observed especially with pioglitazone, GLP-1 analogs, SGLT-2 inhibitors and insulin (Table 7,
Pfützner et al [58] ). Such positive evidence is not available for other oral antidiabetic drugs, for example, sulfonylurea [11,
13, 14, 19].
Intact Proinsulin: 11 pmol/l = low risk
≥11 pmol/l = high risk
≥10 mg/l = low risk
≥1–3 mg/l = average risk
≥3–10 mg/l = high risk
≥10 mg/l = unspecific
0–1 mg/l = low risk
7–10 mg/l = grey zone
≤ 7 mg/l = high risk
Adiponectin:
hsCRP:
Figure 9: Assessment of biomarkers for risk assessment of metabolic
syndrome associated pathologies
Intervention intact Proinsulin Adiponectin hsCRP
Diet Exercise
Sulphonylurea/Glinides
Metformin
Pioglitazone
DPPIV-Inhibitors
GLP-1 Analogs
SGLT-2 Inhibitors
Insulin (early)
Insulin (late)
β-Cell Dysfunction Visceral tissue
activity
Chronic systemic
inflammation
( (
((
Table 7: effect of various therapies on biomarkers
16. 16
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Martin Schlattjan, Jochen Erhard, Guido Gerken,
and Ali Canbay.
Evaluation of Biomarkers of NAFLD in a Cohort
of Morbidly Obese Patients.
Journal of Nutrition and Metabolism Volume 2011,
doi:10.1155/2011/369168.
[56] Bernsmeier et al.
Nicht-alkoholische Fettleber und Steatohepatitis.
Hepatische Manifestationen des metabolischen
Syndroms.
Schweiz Med Forum 2011; 11: 43-57
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IKFE, Mainz, Germany, paper in preparation.
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IKFE, Mainz, Germany, paper in preparation.
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Hepatocellular proliferation in patients with
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abnormal aminotransferase levels.
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20. 20
Intact Proinsulin (TECO®
)
Cat. No.: TE1012
Tests: 96
Method: ELISA
Range: ~ 3 – 100 pmol/l
Sensitivity: 0.3 pmol/l
Incubation time: 2.5 hours
Sample volume: 50 µl
Sample type: Serum, EDTA / Heparin plasma, cell culture
Sample preparation: Fasting blood sample collection.
Due to higher stability, EDTA or heparin plasma samples are preferred to serum samples.
Plasma: the sample collection can take place in HbA1C-tubes.
These samples are stable at room temperature and should be centrifuged within 48 hours.
Plasma should be used in the assay or can be stored in aliquots, stable 2 years at -20 °C.
Serum: centrifuge whole blood within 4 hours. Proteases degrade intact proinsulin in serum,
do not store longer than 1 day at 2–8 °C.
Serum should be used in the assay or can be stored in aliquots at -20 °C.
Avoid repeated freeze/thaw cycles.
Reference values: After fasting: mean 3.99 pmol/l +/- 1.58 SD
≤ 11 pmol/l (normal secretion)
11 pmol/l (dysfunction of secretion)
Species: Human
Specificity: No cross-reactivity has been observed:
*not present in Serum and Plasma samples
Intended use:
Proinsulin is produced in the pancreatic β-cells and is normally further processed to insulin and C-peptide. It is only
seen in low concentrations in the plasma of healthy subjects. An increase in the insulin demand, as provided by insulin
resistance in later stages of type 2 diabetes mellitus, can result in increased expression of proinsulin into the blood. Intact
proinsulin is rapidly degraded, but is considered to be an independent cardiovascular risk factor. The intact molecule and
its degradation products are known to block fibrinolysis because of plasminogen-activator inhibitor (PAI-1) stimulation.
In clinical practice, fasting morning intact proinsulin can be used as highly specific indicator of clinically relevant insulin
resistance, to serve as the basis for the selection of an insulin resistance therapy, and to monitor the therapeutic effect
on β-cell dysfunction.
Patients with type 2 diabetes mellitus and with elevated fasting intact proinsulin levels should be regarded and treated
as insulin resistant, in order to reduce the risk for further cardiovascular damage. Elevated fasting intact proinsulin levels
may also be seen in patients with insulinoma, a benign insulin producing tumor of the pancreas.
• Diabetes II
• Staging of insulin resistance and ß-cell dysfunction
• Therapy selection
• Therapy monitoring
• Identification of high risk patients for CAD
• Polycystic ovary Syndrome (PCOS)
• Insulinoma
Human Insulin 10 000 pmol/l
Human C-Peptide 50 000 pmol/l
Des (31,32) - Proinsulin 200 pmol/l
Split (32,33) - Proinsulin 5000 pmol/l
Des (64,65) - Proinsulin* 200 pmol/l
1000 pmol/l Split (65,66) - Proinsulin
21. 21
Adiponectin high sensitive (TECO®
)
Total Human Adiponectin
Cat. No.: TE1013
Tests: 96
Method: ELISA
Range: 1 – 100 ng/ml native Adiponectin
Sensitivity: 0.6 ng/ml
Incubation time: 2 hours
Sample volume: 5 µl (dilute 1:300 serum and plasma).
For other biological fluids see protocol for dilutions
Sample type: Serum, heparin plasma, breast milk, urine, saliva, CSF, cell culture
Sample preparation: Blood collection - fasting is recommended.
Samples are stable for maximum 2 days at room temperature.
Long-term storage stable for maximum 2 years at -20 °C.
Max. 5 freeze and thaw cycles.
Reference values:
Comprehensive clinical reference data related to age and gender are available for this test.
Species: Human
Intended use:
Adiponectin is a 30kDa protein and its percentage in serum proteins is 0.01 %. In vivo, it appears with different oligomers
and it is mainly synthesized by adipocytes. Until now, IGF-1 is the only known natural inductor of synthesis.
Low Adiponectin levels are closely associated with insulin resistance and metabolic syndrome as well as an increased risk
of type 2 diabetes mellitus and cardiovascular disease.
Today, Adiponectin is thought to act as an endogenic insulin sensitizer by decreasing excessive glucose levels without
increasing insulin concentrations and by stimulating the burning of adipose tissue in muscle and liver.
Adiponectin is associated with glucose and lipid metabolism and is assumed to have direct antiatherogenic characteristics.
Furthermore, it is involved in inflammatory processes.
Clinical significance:
• Obesity
• Arteriosclerosis
• Energy metabolism
• Coronary diseases
• Metabolic syndrome
• Polycystic ovary syndrome (PCOS)
mg/l
Men Adult 8-10
Female Adult 10-12
Cut-off 10
22. 22
Adiponectin, Mouse
Total Adiponectin
Cat. No.: E091M
Tests: 96
Method: ELISA
Range: 0.025 - 1 ng/ml native Adiponectin
Sensitivity: ~ 0.01 ng/ml
Incubation time: 3 hours
Sample volume: 100 µl (after dilution 1:10’000)
Sample type: Serum and plasma
Sample preparation: Generally, samples should be refrigerated as soon as possible following collection. Samples
are stable maximum 2 days at room temperature. Long-term storage up to 2 years at -20 °C
or below. Maximun 5 freeze and thaw cycles.
Species: Mouse
Adiponectin, Rat
Total Adiponectin
Cat. No.: E091R
Tests: 96
Method: ELISA
Range: 0.25 – 10 ng/ml native Adiponectin
Sensitivity: ~ 0.01 ng/ml
Incubation time: 3 hours
Sample volume: 100 µl (after dilution 1:1’500)
Sample type: Serum and plasma
Sample preparation: Samples are stable for maximal 2 days at room temperature.
Long-term storage up to 2 years at -20 °C or below. Maximum 5 freeze/thaw cycles.
Species: Rat
23. 23
hsCRP
Cat. No.: 7033
Tests: 96
Method: Sandwich ELISA
Range: 0.005 – 0.1 mg/L (0.5 – 10 mg/L), standardisation NIBSC 85/506
Sensitivity: 0.1 mg/L
Incubation time: 65 minutes
Sample volume: 5 uL (1 :100 diluted)
Sample type: Serum
Sample preparation: Centrifuge collected blood within 60 minutes.
Specimen which cannot be assayed within 24 hours, should be frozen at minus 20°C or lower,
and will be stable for up to 6 months. Specimen should not be repeatedly frozen and thawed
before testing. Avoid grossly hemolytic, lipemic or turbid samples.
Species: Human, Monkey
Intended use:
CRP is synthesized in the liver and is a well established indicator for inflammatory processes. CRP assays provide useful
information for the diagnosis, therapy and monitoring of inflammatory processes and associated diseases. Measurement
of low level CRP by using hsCRP assays is useful in the risk assessment of coronary heart diseases, diabetes mellitus
type 2 and metabolic syndrome (American Heart association).
24. 24
Leptin, human (TECO®
)
Cat. No.: TE1015
Tests: 96
Method: ELISA
Range: 1 – 100 ng/ml, recombinant Leptin WHO NIBSC 97/594
Sensitivity: 0.2 ng/ml
Incubation time: 2 hours
Sample volume: 20 µl
Sample type: Serum, heparin and EDTA plasma, urine, saliva, cell culture.
Sample preparation: Normal food intake rhythm provided, samples should be collected till 2 p.m. Leptin shows a
moderate circadian variation with a peak at 2 a.m., the leptin values at that time are about 30
to 100 % higher.
This variation together with the influence of food intake needs to be taken into account when
blood samples are collected. Whole blood should be refrigerated as soon as possible
following collection.
Samples are stable for maximal 2 days at room temperature.
Long-term storage stable for maximal 2 years at -20 °C.
Max. 5 freeze and thaw cycles.
Reference values: Leptin levels depend on age and gender and must be referred to the percentage body fat
(such as BMI). Comprehensive clinical reference data are available for this test.
Species: Human
Intended use:
Leptin, the product of the ob gene, is a recently discovered proteohormone. It is almost exclusively produced by
differentiated adipocytes and is thought to play a key role in the regulation of body weight. Leptin has an influence on the
central nervous system, mainly on the hypothalamus, by suppressing food ingestion and increasing energy consumption.
Beside its influence on food intake, leptin has been shown to have a strong effect on reproduction and a number of
metabolic and endocrine axes.
As leptin is of great importance for reproductive functions, infertility may be due to inadequate leptin production. The
most important variable determining the circulating leptin concentration is the body fat mass as leptin level and fat mass
increase exponentially. Due to its pleiotropic effects, leptin is a valuable parameter with regard to:
• Metabolic syndrome
• Obesity
• Cachexia and other metabolic disorders
• Eating disorders
25. 25
Leptin, Mouse/Rat
Cat. No.: E06
Tests: 96
Method: ELISA
Range: 25 – 1600 pg/ml
Sensitivity: 10 pg/ml
Incubation time: 3.5 hours
Calibration: WHO NIBSC 97/626 (39, 40)
Sample volume: 100 µl (rat: after 1:5 – 1:10 dilution; mouse: after 1:20 dilution)
Sample type: Serum, plasma, cell culture
Sample preparation: Serum samples could be stored at -20 °C.
Avoid repeated freezing/thawing of specimens.
Species: Mouse, rat
Intended use:
This mouse/rat-Leptin EIA provides a tool for investigation of leptin effects on energy metabolism. Beside energy metabolism
leptin influences several further endocrine axes.
In male mice leptin reduces the effect of starvation on testosterone, ACTH and corticosterone. In female mice leptin delays
starvation induced ovulation.
Leptin, the product of the ob gene, is a recently discovered proteohormone. It is almost exclusively produced by
differentiated adipocytes and is thought to play a key role in the regulation of body weight. Leptin has an influence on the
central nervous system, mainly on the hypothalamus, by suppressing food ingestion and increasing energy consumption.
Beside its influence on food intake, leptin has been shown to have a strong effect on reproduction and a number of
metabolic and endocrine axes. As leptin is of great importance for reproductive functions, infertility may be due to
inadequate leptin production. The most important variable determining the circulating leptin concentration is the body fat
mass as leptin level and fat mass increase exponentially.
26. 26
GLP-1, Total
Total Glucagon-like peptide 1
Cat. No.: KT-876
Tests: 96
Method: ELISA
Range: 1.8 – 55 pmol/l
Sensitivity: 0.91 pmol/l
Incubation time: 20 – 24 hours
Sample volume: 100 µl
Sample type: EDTA plasma, serum, cell culture
Sample preparation: Fasting sample collection by using a Vacutainer EDTA plasma tube. Separation of plasma
within 1 hour after blood collection. The use of a protease inhibitor cocktail is required. DPP-4
inhibitor should be added right after blood collection. Recommended is the BDTM P700 Blood
Collection and Preservation System containing DPP-4 protease inhibitor.
Extraction of the samples is strongly recommended by using Oasis® HLB 3 cc Cartridge,
Extraction Kit KT-910, or ethanol protein precipitation. Store maximum 3 hours at 2 – 8 °C.
For longer storage at -70 °C.
Maximum 3 freeze and thaw cycles.
Reference values: Depending on blood collection fasting or none fasting the values are different.
Species: Human, rat, mouse, goat
Specificity: GLP-1 (7-36) 100 %
GLP-1 (9-36) 100 %
GLP-1 (9-37) 0.1 %
GLP-1 (7-37) 0.1 %
GLP-1 (1-36) 0.1 %
GLP-2 0.1 %
Glucagon 0.1 %
27. 27
GLP-1 (7-36), Active Human
Active Glucagon-like peptide 1 (7-36)
Cat. No.: KT-871
Tests: 96
Method: ELISA
Range: 2.11 – 158.3 pg/ml = 0.64 - 48 pmol/l
Sensitivity: 1 pg/ml = 3.298 pmol/l
Incubation time: 20 – 24 hours
Sample volume: 100 µl
Sample type: Plasma
Sample preparation: Fasting sample collection by using a Vacutainer EDTA plasma tube. Separation of plasma
within 1 hour after blood collection. The use of a protease inhibitor cocktail is required. DPP-4
inhibitor should be added right after blood collection. Recommended is the BDTM P700 Blood
Collection and Preservation System containing DPP-4 protease inhibitor.
Extraction of the samples is strongly recommended by using Oasis®
HLB 3 cc Cartridge,
Extraction Kit KT-910, or ethanol protein precipitation. Store maximum at 2 – 8 °C for 3 hours.
For longer storage at -70 °C. Avoid freeze and thaw cycles.
Reference values: Depending on blood collection fasting or none fasting the values are different.
Species: Human
Specificity: GLP-1 (7-36) 100 %
GLP-1 (9-36) 0.1 %
GLP-1 (9-37) 0.1 %
GLP-1 (7-37) 0.1 %
GLP-1 (1-36) 0.1 %
GLP-2 0.1 %
Glucagon 0.1 %
28. 28
Resistin
Cat. No.: E50
Tests: 96
Method: ELISA
Range: 20 – 1000 pg/ml
Sensitivity: 12 pg/ml
Incubation time: 4 hours
Sample volume: 15 µl (dilute 1:21; recommended)
Sample type: Serum, plasma, cell culture medium, salvia, breast milk and urine.
Sample preparation: Haemolytic samples appear to show falsely high Resistin levels. Whole blood should be chilled
as soon as possible following collection. Serum and plasma samples are stable for maximal
2 days at room temperature. Long-term storage at -20 °C, stable for maximal 2 years.
Maximum 3 freeze/thaw cycles.
Reference values: Women: 7.0 ng/ml +/- 2.5 SD (referred to BMI ~ 25 kg/m²)
Men: 6.0 ng/ml +/- 2.5 SD (referred to BMI ~ 25 kg/m²)
Species: Human
Intended use:
Resistin (FIZZ3) is a hormone influencing fat metabolism and inflammation processes. In humans, it is expressed in bone
marrow and transported by macrophages into adipose tissue. Resistin stimulates pre-adipocyte proliferation and lipolysis
of mature adipocytes probably by influencing MAPK signaling. With regard to the importance of Resistin in disorders of
energy metabolism, a significant reduction could be shown in patients with anorexia nervosa. It has been demonstrated
that Resistin enhances the expression of specific cell markers such as VACM-1 and ICAM-1 and thus may influence
endothelial inflammatory processes, and thereby arteriosclerosis. Moreover, due to its association with Endothelin-1,
Resistin also plays a role in cardiovascular diseases.
Resistin is relevant to medical conditions such as:
• Obesity
• Insulin resistance, diabetes
• Arteriosclerosis
• Inflammation
• Lipolysis
29. 29
Fetuin-A, Human
Cat. No.: KT-800
Tests: 96
Method: ELISA
Range: 12.5 – 370 ng/ml
Sensitivity: 5.0 ng/ml
Incubation time: 3 hours
Sample volume: 10 µl (dilute 1:10.000)
For other biological fluids see protocol for dilutions
Sample type: Serum
Sample preparation: Serum should be separated within 3 hours after blood collection,
measure or store at -20 °C. Max. 3 freeze and thaw cycles.
Reference values:
Species: Human
Intended use:
Fetuin-A synthesized in the liver is secreted into the blood stream and it is deposited, accumulated as a non-collagenous
protein in mineralized bones and teeth.
Fetuin-A acts as an important circulating inhibitor of ectopic calcification, a frequently seen complication in degenerative
diseases. Low Fetuin-A level may be associated with higher cardiovascular mortality in chronic renal failure, liver cancer
and liver cirrhosis patients on long-term dialysis.
Human Fetuin-A represents a natural inhibitor of tyrosine kinase activity of the insulin receptor. Fetuin-A may play a
significant role in regulating post-prandial glucose disposition, insulin sensitivity, weight gain, and fat accumulation and
may be a novel therapeutic target in the treatment of type 2 diabetes, obesity, and other insulin-resistant conditions.
• Fetuin-A level ( 0.35 g/l) indicates a higher risk of cardiovascular calcification and increase mortality in ESRD-patients.
• Fetuin-A level ( 1.00 g/l) in elderly population, an independent risk factor of type II diabetes.
• Fetuin-A is an important predictor of death in acute myocardial infarction.
• Involved with the regulation of calcium metabolism and osteogenesis.
mg/l Mean (g/l) SD (g/l)
0.35 – 0.95 0.57 0.13