This document discusses different types of diabetes mellitus, including the four main types (type 1, type 2, gestational, and specific types) and focuses on monogenic diabetes mellitus. It defines monogenic diabetes as rare forms resulting from mutations in a single gene, describes their inheritance and clinical characteristics. It then discusses challenges in detection and introduces a biomarker screening pathway used in a study involving genetic testing to identify cases of monogenic diabetes in patients diagnosed under age 30.
Slide Presentation
Diabetes Melliuts Type 2 management basics are life style modifications followed by use of Metformin
What is the best and safest next pharmacologic choice
Slide Presentation
Diabetes Melliuts Type 2 management basics are life style modifications followed by use of Metformin
What is the best and safest next pharmacologic choice
SGLT2 Inhibitors v Sitagliptin (SITA) as Add-on Therapy to Metformin Chris Sevald, PhD
SGLT2 inhibitors are the latest class of FDA-approved oral therapies to lower blood glucose in type-2 diabetes.Systematic review and meta-analysis to compare glucose-lowering and weight-loss effects of SGLT2s vs. the most-prescribed DPP-4 inhibitor, SITA. Poster presented at the 21st annual meeting of ISPOR, May, 2016, in Washington DC.
Dpp4i vs sglt2 inhibitors against the motionSujoy Majumdar
A debate showing why SGLT2 inhibitors have not have a major advantage over DPP4 inhibitors as the next add on drug after Metformin in the management of Type 2 Diabetes
Clinical Impact of New NAFLD/NASH Data From San Francisco 2018hivlifeinfo
Expert faculty summarize key NAFLD/NASH studies from this important annual conference. Use these slides to review data on noninvasive screening, clinical outcomes, emerging treatments.
Ira M. Jacobson, MD
Philip N. Newsome, PhD, FRCPE
Format: Microsoft PowerPoint (.ppt)
File Size: 421 KB
Released: December 3, 2018
SGLT2I The paradigm change in diabetes managementPraveen Nagula
Just like ARNI, SGLT2I have changed the face of diabetes management and they have a good profile in multimodality management because of pleiotropic effects
EMPA-REG: un punto de inflexión en el tratamiento de la diabetes
18/11/15 20:00h Casa del Corazón (Madrid)
http://empareg.secardiologia.es
#EMPAREG
Resultados del estudio EMPA-REG
Dr. Domingo Marzal Martín, Complejo Hospitalario de Mérida (Badajoz)
@domingomarzal
SGLT2 Inhibitors v Sitagliptin (SITA) as Add-on Therapy to Metformin Chris Sevald, PhD
SGLT2 inhibitors are the latest class of FDA-approved oral therapies to lower blood glucose in type-2 diabetes.Systematic review and meta-analysis to compare glucose-lowering and weight-loss effects of SGLT2s vs. the most-prescribed DPP-4 inhibitor, SITA. Poster presented at the 21st annual meeting of ISPOR, May, 2016, in Washington DC.
Dpp4i vs sglt2 inhibitors against the motionSujoy Majumdar
A debate showing why SGLT2 inhibitors have not have a major advantage over DPP4 inhibitors as the next add on drug after Metformin in the management of Type 2 Diabetes
Clinical Impact of New NAFLD/NASH Data From San Francisco 2018hivlifeinfo
Expert faculty summarize key NAFLD/NASH studies from this important annual conference. Use these slides to review data on noninvasive screening, clinical outcomes, emerging treatments.
Ira M. Jacobson, MD
Philip N. Newsome, PhD, FRCPE
Format: Microsoft PowerPoint (.ppt)
File Size: 421 KB
Released: December 3, 2018
SGLT2I The paradigm change in diabetes managementPraveen Nagula
Just like ARNI, SGLT2I have changed the face of diabetes management and they have a good profile in multimodality management because of pleiotropic effects
EMPA-REG: un punto de inflexión en el tratamiento de la diabetes
18/11/15 20:00h Casa del Corazón (Madrid)
http://empareg.secardiologia.es
#EMPAREG
Resultados del estudio EMPA-REG
Dr. Domingo Marzal Martín, Complejo Hospitalario de Mérida (Badajoz)
@domingomarzal
Acase with Maturity onset diabetes of young falsy diagnosed as type 1 diabetes mellitus ,
Mody is a rare type of diabetes due to autosomal dominant gene mutation, occurs in young age beloww 25 years old, usually mild hypoglycemia and no ketosis
Memorias Conferencia Científica Anual sobre Síndrome Metabólico 2017 - Programa Científico
Futuro en el tratamiento de la DM2
Dr. Guillermo E. Umpierrez
Professor of Medicine in the Division of Endocrinology at Emory University School of Medicine, Section Head, Diabetes and Endocrinology. USA. Editor en Jefe del BJM Open Diabetes Research and Care
Diabetes Mellitus: DR L H Hiranandani Hospital, MumbaiKrishna Singh
A group of metabolic disorders characterized by hyperglycemia resulting from defects in insulin secretion, insulin action, or both.
Visit: https://www.hiranandanihospital.org/
Objectives for the call:
Provide an overview of why glucose control is important in surgical patient outcomes
.Demonstrate an understanding of how anesthetics and surgery can impact the body's ability to remain within glycemic boundaries
.Outline the optimal surgical patient glycemic goal range
.To identify the effectiveness of tight glycemic control on mortality and morbidity of adult patients during the intra and post-operative period
.To discuss possible change ideas to implement glucose control
WATCH: http://goo.gl/3vGq2B
These lecture slides, by Dr Sidra Arshad, offer a quick overview of physiological basis of a normal electrocardiogram.
Learning objectives:
1. Define an electrocardiogram (ECG) and electrocardiography
2. Describe how dipoles generated by the heart produce the waveforms of the ECG
3. Describe the components of a normal electrocardiogram of a typical bipolar leads (limb II)
4. Differentiate between intervals and segments
5. Enlist some common indications for obtaining an ECG
Study Resources:
1. Chapter 11, Guyton and Hall Textbook of Medical Physiology, 14th edition
2. Chapter 9, Human Physiology - From Cells to Systems, Lauralee Sherwood, 9th edition
3. Chapter 29, Ganong’s Review of Medical Physiology, 26th edition
4. Electrocardiogram, StatPearls - https://www.ncbi.nlm.nih.gov/books/NBK549803/
5. ECG in Medical Practice by ABM Abdullah, 4th edition
6. ECG Basics, http://www.nataliescasebook.com/tag/e-c-g-basics
New Directions in Targeted Therapeutic Approaches for Older Adults With Mantl...i3 Health
i3 Health is pleased to make the speaker slides from this activity available for use as a non-accredited self-study or teaching resource.
This slide deck presented by Dr. Kami Maddocks, Professor-Clinical in the Division of Hematology and
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The Ohio State University Comprehensive Cancer Center, will provide insight into new directions in targeted therapeutic approaches for older adults with mantle cell lymphoma.
STATEMENT OF NEED
Mantle cell lymphoma (MCL) is a rare, aggressive B-cell non-Hodgkin lymphoma (NHL) accounting for 5% to 7% of all lymphomas. Its prognosis ranges from indolent disease that does not require treatment for years to very aggressive disease, which is associated with poor survival (Silkenstedt et al, 2021). Typically, MCL is diagnosed at advanced stage and in older patients who cannot tolerate intensive therapy (NCCN, 2022). Although recent advances have slightly increased remission rates, recurrence and relapse remain very common, leading to a median overall survival between 3 and 6 years (LLS, 2021). Though there are several effective options, progress is still needed towards establishing an accepted frontline approach for MCL (Castellino et al, 2022). Treatment selection and management of MCL are complicated by the heterogeneity of prognosis, advanced age and comorbidities of patients, and lack of an established standard approach for treatment, making it vital that clinicians be familiar with the latest research and advances in this area. In this activity chaired by Michael Wang, MD, Professor in the Department of Lymphoma & Myeloma at MD Anderson Cancer Center, expert faculty will discuss prognostic factors informing treatment, the promising results of recent trials in new therapeutic approaches, and the implications of treatment resistance in therapeutic selection for MCL.
Target Audience
Hematology/oncology fellows, attending faculty, and other health care professionals involved in the treatment of patients with mantle cell lymphoma (MCL).
Learning Objectives
1.) Identify clinical and biological prognostic factors that can guide treatment decision making for older adults with MCL
2.) Evaluate emerging data on targeted therapeutic approaches for treatment-naive and relapsed/refractory MCL and their applicability to older adults
3.) Assess mechanisms of resistance to targeted therapies for MCL and their implications for treatment selection
Report Back from SGO 2024: What’s the Latest in Cervical Cancer?bkling
Are you curious about what’s new in cervical cancer research or unsure what the findings mean? Join Dr. Emily Ko, a gynecologic oncologist at Penn Medicine, to learn about the latest updates from the Society of Gynecologic Oncology (SGO) 2024 Annual Meeting on Women’s Cancer. Dr. Ko will discuss what the research presented at the conference means for you and answer your questions about the new developments.
Flu Vaccine Alert in Bangalore Karnatakaaddon Scans
As flu season approaches, health officials in Bangalore, Karnataka, are urging residents to get their flu vaccinations. The seasonal flu, while common, can lead to severe health complications, particularly for vulnerable populations such as young children, the elderly, and those with underlying health conditions.
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This year, the flu season is expected to coincide with a potential increase in other respiratory illnesses. The Karnataka Health Department has launched an awareness campaign highlighting the significance of flu vaccinations. They have set up multiple vaccination centers across Bangalore, making it convenient for residents to receive their shots.
To encourage widespread vaccination, the government is also collaborating with local schools, workplaces, and community centers to facilitate vaccination drives. Special attention is being given to ensuring that the vaccine is accessible to all, including marginalized communities who may have limited access to healthcare.
Residents are reminded that the flu vaccine is safe and effective. Common side effects are mild and may include soreness at the injection site, mild fever, or muscle aches. These side effects are generally short-lived and far less severe than the flu itself.
Healthcare providers are also stressing the importance of continuing COVID-19 precautions. Wearing masks, practicing good hand hygiene, and maintaining social distancing are still crucial, especially in crowded places.
Protect yourself and your loved ones by getting vaccinated. Together, we can help keep Bangalore healthy and safe this flu season. For more information on vaccination centers and schedules, residents can visit the Karnataka Health Department’s official website or follow their social media pages.
Stay informed, stay safe, and get your flu shot today!
- Video recording of this lecture in English language: https://youtu.be/lK81BzxMqdo
- Video recording of this lecture in Arabic language: https://youtu.be/Ve4P0COk9OI
- Link to download the book free: https://nephrotube.blogspot.com/p/nephrotube-nephrology-books.html
- Link to NephroTube website: www.NephroTube.com
- Link to NephroTube social media accounts: https://nephrotube.blogspot.com/p/join-nephrotube-on-social-media.html
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The "New Drug Discovery and Development" process involves the identification, design, testing, and manufacturing of novel pharmaceutical compounds with the aim of introducing new and improved treatments for various medical conditions. This comprehensive endeavor encompasses various stages, including target identification, preclinical studies, clinical trials, regulatory approval, and post-market surveillance. It involves multidisciplinary collaboration among scientists, researchers, clinicians, regulatory experts, and pharmaceutical companies to bring innovative therapies to market and address unmet medical needs.
Explore natural remedies for syphilis treatment in Singapore. Discover alternative therapies, herbal remedies, and lifestyle changes that may complement conventional treatments. Learn about holistic approaches to managing syphilis symptoms and supporting overall health.
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Microteaching is a unique model of practice teaching. It is a viable instrument for the. desired change in the teaching behavior or the behavior potential which, in specified types of real. classroom situations, tends to facilitate the achievement of specified types of objectives.
Title: Sense of Taste
Presenter: Dr. Faiza, Assistant Professor of Physiology
Qualifications:
MBBS (Best Graduate, AIMC Lahore)
FCPS Physiology
ICMT, CHPE, DHPE (STMU)
MPH (GC University, Faisalabad)
MBA (Virtual University of Pakistan)
Learning Objectives:
Describe the structure and function of taste buds.
Describe the relationship between the taste threshold and taste index of common substances.
Explain the chemical basis and signal transduction of taste perception for each type of primary taste sensation.
Recognize different abnormalities of taste perception and their causes.
Key Topics:
Significance of Taste Sensation:
Differentiation between pleasant and harmful food
Influence on behavior
Selection of food based on metabolic needs
Receptors of Taste:
Taste buds on the tongue
Influence of sense of smell, texture of food, and pain stimulation (e.g., by pepper)
Primary and Secondary Taste Sensations:
Primary taste sensations: Sweet, Sour, Salty, Bitter, Umami
Chemical basis and signal transduction mechanisms for each taste
Taste Threshold and Index:
Taste threshold values for Sweet (sucrose), Salty (NaCl), Sour (HCl), and Bitter (Quinine)
Taste index relationship: Inversely proportional to taste threshold
Taste Blindness:
Inability to taste certain substances, particularly thiourea compounds
Example: Phenylthiocarbamide
Structure and Function of Taste Buds:
Composition: Epithelial cells, Sustentacular/Supporting cells, Taste cells, Basal cells
Features: Taste pores, Taste hairs/microvilli, and Taste nerve fibers
Location of Taste Buds:
Found in papillae of the tongue (Fungiform, Circumvallate, Foliate)
Also present on the palate, tonsillar pillars, epiglottis, and proximal esophagus
Mechanism of Taste Stimulation:
Interaction of taste substances with receptors on microvilli
Signal transduction pathways for Umami, Sweet, Bitter, Sour, and Salty tastes
Taste Sensitivity and Adaptation:
Decrease in sensitivity with age
Rapid adaptation of taste sensation
Role of Saliva in Taste:
Dissolution of tastants to reach receptors
Washing away the stimulus
Taste Preferences and Aversions:
Mechanisms behind taste preference and aversion
Influence of receptors and neural pathways
Impact of Sensory Nerve Damage:
Degeneration of taste buds if the sensory nerve fiber is cut
Abnormalities of Taste Detection:
Conditions: Ageusia, Hypogeusia, Dysgeusia (parageusia)
Causes: Nerve damage, neurological disorders, infections, poor oral hygiene, adverse drug effects, deficiencies, aging, tobacco use, altered neurotransmitter levels
Neurotransmitters and Taste Threshold:
Effects of serotonin (5-HT) and norepinephrine (NE) on taste sensitivity
Supertasters:
25% of the population with heightened sensitivity to taste, especially bitterness
Increased number of fungiform papillae
2. Diabetes mellitus classification
1 Type 1 diabetes
2 Type 2 diabetes
3 Gestational diabetes mellitus (GDM)
4 Specific types of diabetes due to other causes, e.g., monogenic
diabetes syndromes
(such as neonatal diabetes and maturity-onset diabetes of the young
[MODY]), diseases of the exocrine pancreas (such as cystic fibrosis),
and drug-induced diabetes American Diabetes Association. Classification and diagnosis of diabetes. Sec. 2. In Standards of Medical Carein Diabetes—2015.
Diabetes Care 2015;38(Suppl.1):S8–S16
3. Monogenic diabetes mellitus
• rare forms of diabetes result from mutations in a single gene
• reduce the body's ability to produce insulin
• account for about 1 to 5 percent of all cases of diabetes in young people.
• In most cases, the gene mutation is inherited
4. • Heterogeneous clinical characteristics
• Important implications for management
• Allows appropriate counseling of other family members
Monogenic diabetes mellitus
5. Problems in detection
• Clinical features, probability calculator still has limitation
• Molecular genetic testing is not feasible
6. • GAD, Islet autoantibodies, C-peptide has been shown to be a
highly sensitive and specific biomarker for discriminating
between type 1 and type 2 diabetes and MODY
• Combined diagnostic performance of the two biomarkers as a
screening pathway has not been assessed
Problems in detection
8. Subject
• Diagnosed at age 30 years or younger
• Currently aged younger than 50 years
• In the catchment areas of the Royal Devon and Exeter NHS
Foundation Trust (Exeter, U.K.) and Ninewells Hospital (Dundee,
U.K.)
9. Dia
Non-insulin
treated
T2DM or
atypical T1DM
DiaDiagnosed < 30 yr oldDiagnosed < 30 yr old
Dia
Diagnosed < 30 yr
old
Insulin treated
DiaDiagnosed < 30 yr oldC-peptide (UCPCR)
DiaDiagnosed < 30 yr oldGAD & IA2 Antibodies
DiaDiagnosed < 30 yr old
Genetic testing:
All monogenic subtypes
-
-
+
+ Monogenic
diabetes
T1DM
T1DM
+
-
Non-insulin treated
11. Urinary C-peptide/creatinine ratio
(UCPCR)
• Spot urine
• 2 h after the largest carbohydrate-containing meal of the day
• Post to the laboratory within 72 h
• Electrochemiluminescence immunoassay (lower limit of the C-peptide assay was 0.03 nmol/L)
12. Glutamic Acid Decarboxylase, Islet Autoantibody Measurement
• Checked for previous GAD and IA2 results
• Commercial ELISA assays (RSR Ltd., Cardiff, U.K.)
• Considered positive for antibodies if their results were >99th percentile
• were considered positive for an- tibodies if their results were .99th centile (64 World Health
Organization units/mL for GAD and 15 World Health Organiza- tion units/mL for IA2)
13. Molecular Genetic Testing
• DNA sequencing of HNF1A, HNF4A, and GCK was performed by
PCR amplification of purified genomic DNA, followed by Sanger
DNA sequencing of each gene’s exons and flanking intronic regions.
• Targeted Next-Generation Sequencing for 35 Genes in Which
Mutations Are Known to Cause Monogenic Diabetes.
15. Flow chart of patients recruited as part of UNITED. Biomarker screening pathway in 1,376 patients with no
known genetic cause for their diabetes in Exeter and Tayside.
Beverley M. Shields et al. Dia Care 2017;40:1017-1025
16. Baseline characteristics of the 1365 patients who completed the biomarker screening pathway with no existing known cause for their diabetes: Data
shown as median (IQR)
Characteristics Median(IQR1,IQR3)
Male (n (%)) 706 (52%)
Age at diagnosis (y) 13 (8,21)
Age at recruitment (y) 29 (19,40)
Duration of diabetes (y) 13.6 (5.6, 22.7)
BMI* (kg/m2
) 25.7 (23.2, 29.0)
HbA1c 8.7 (7.8, 9.9)
Current treatment (n (%)): Diet OHA Insulin
+/- OHA
15 (1%) 69 (5%) 1281 (94%)
White Caucasian (n(%)) 1389 (98%)
Pediatric (<20years) (n(%)) 351 (26%)
17. Distribution of genetic causes of 54 confirmed cases of monogenic diabetes in Exeter and Dundee. Data presented as
number of cases caused by mutations in each gene - grey bars indicate cases where the diagnosis was made prior to this
study, black bars are those diagnosed as a result of the biomarker pathway.
19. Conclusion
• biomarker screening pathway is a systematic, cheap and easily
implemented approach to screening
• picked up new cases of monogenic diabetes, even in areas of
existing high detection
• high NPV of 99.9% indicates it is an extremely effective approach
for ruling out monogenic diabetes.
20. Discussion
• Health economic evaluation of the pathway for detecting the
common forms of MODY (GCK, HNF1A, and HNF4A) has
shown cost-saving
• Help with management, prognosis, and advice on risk to other
family members
21. Discussion• Only 8 out of 51 (16%) of patients with a genetic diagnosis of
monogenic diabetes in our cohort were in the pediatric age range
(younger than 20 years) at the time of recruitment
• We showed that by using clinical features alone, over half of the
cases of monogenic diabetes would be missed.
22. limitation
• Small numbers of patients to evaluate the sensitivity of the pathway
• Coincidental Type 1 diabetes with MODY
• Screening using C-peptide and antibody testing, the PPV is still fairly low at 20%
• Further studies are integrating the pathway with clinical features, such as the MODY
calculator
• this study comprised a 98% white population and assesses patients at a median of 14 years
after diagnosis.
25. • Common MODY gene, mechanism
• Benefit for pt
https://www.ncbi.nlm.nih.gov/pubmed/22218698?access_num=22218698&li
nk_type=MED&dopt=Abstract
Calculator.
weaker for detect-
ing MODY in insulin-treated patients
compared with non–insulin-treated
patients
26.
27. Type OMIM Gene/protein Description
MODY 1 125850
hepatocyte nuclear
factor 4α
Due to a loss-of-function mutation in the HNF4α gene. 5%–10% cases.
MODY 2 125851 glucokinase
Due to any of several mutations in the GCK gene. 30%–70% cases. Mild fasting hyperglycemia throughout life.
Small rise on glucose loading. Patients do not tend to get diabetes complications and do not require treatment.[17]
MODY 3 600496
hepatocyte nuclear
factor 1α
Mutations of the HNF1α gene (a homeobox gene). 30%–70% cases. Tend to be responsive to sulfonylureas. Low
renal threshold for glucose.
MODY 4 606392
insulin promoter
factor-1
Mutations of the IPF1 homeobox (Pdx1) gene. < 1% cases. Associated with pancreatic agensis in homozygotes a
occasionally in heterozygotes.
MODY 5 137920
hepatocyte nuclear
factor 1β
One of the less common forms of MODY, with some distinctive clinical features, including atrophy of the pancreas
and several forms of renal disease. Defect in HNF-1 beta gene. 5%–10% cases.
MODY 6 606394
neurogenic
differentiation 1
Mutations of the gene for the transcription factor referred to as neurogenic differentiation 1. Very rare: 5 families
reported to date.
MODY 7 610508 Kruppel-like factor 11 KLF11 has been associated with a form of diabetes[18] that has been characterized as "MODY7" by OMIM.[19]
MODY 8 609812
Bile salt dependent
lipase
CEL has been associated with a form of diabetes[20] that has been characterized as "MODY8" by OMIM.[21] It is ver
rare with five families reported to date. It is associated with exocrine pancreatic dysfunction.
MODY 9 612225 PAX4 Pax4 is a transcription factor. MODY 9 is a very rare medical condition.
MODY 10 613370 INS Mutations in the insulin gene. Usually associated with neonatal diabetes. Rare < 1% cases.
MODY 11 613375 BLK Mutated B-lymphocyte tyrosin kinase, which is also present in pancreatic islet cells. Very rare.
Permanent
neonatal
diabetes
mellitus
606176 KCNJ11 and ABCC8
A newly identified and potentially treatable form of monogenic diabetes is the neonatal diabetes caused by activat
mutations of the ABCC8 or KCNJ11 genes which encode subunits of the KATP channel. < 1% cases. Tend to respo
to sulfonylureas.
Transient
neonatal
diabetes
601410
610374 ABCC8 Some forms of neonatal-onset diabetes are not permanent. < 1% cases. Tend to respond to sulfonylureas.
Editor's Notes
1 Type 1 diabetes (due to β-cell destruction, usually leading to absolute insulin deficiency)
2 Type 2 diabetes (due to a progressive insulin secretory defect on the background of insulin resistance)
3 Gestational diabetes mellitus (GDM) (diabetes diagnosed in the second or third trimester of pregnancy that is not clearly overt diabetes)
4 Specific types of diabetes due to other causes, e.g., monogenic diabetes syndromes (such as neonatal diabetes and maturity-onset diabetes of the young [MODY]), diseases of the exocrine pancreas (such as cystic fibrosis), and drug- or chemical-induced diabetes (such as in the treatment of HIV/AIDS or after organ transplantation)
heterogeneous clinical characteristics may not be reliable in predicting the underlying pathogenesis
Many patients are misclassified as having either type 1 or 2 diabetes
It is estimated that at least 80% of patients with Maturity Onset Diabetes of the Young (MODY) are misdiagnosed
Important implications for management of an individual’s diabetes, a prognosis, and recognition of associated clinical features;
The most common form of diabetes in children and young adults is type 1 diabetes, accounting for 90% of cases.
Patients with MODY misclassified as type 1 diabetes will be treated with insulin.
mutations in the HNF1A or HNF4A genes respond well to low-dose sulphonylureas and those with MODY because of mutations in the GCK gene require no pharmacological treatment
weaker for detect-
ing MODY in insulin-treated patients
compared with non–insulin-treated
patients.
GAD and IA2 islet autoanti- bodies with cross-sectional studies showing they are present in 80% of patients with type 1 diabetes and in ,1% of patients with MODY
Furthermore, the combined diag- nostic performance of the two bio- markers as a screening pathway has not been formally assessed.
screening pathway using both C-peptide and islet autoanti- bodies to exclude type 1 diabetes in two populations with previously high pickup rates of MODY (3)
The UNITED biomarker screening pathway to investigate etiology of diabetes in patients diagnosed at age 30 years or younger.
Genetic testing is carried out on all patients who have endogenous insulin (UCPCR ≥0.2 nmol/mmol) and do not have either GAD or IA2 islet autoantibodies. Patients without endogenous insulin or with GAD and/or IA2 islet autoantibodies are classed as having type 1 diabetes.
(
Recruitment bias
To determine whether there was any potential bias in recruitment of MODY patients that may affect our prevalence estimate, we also obtained summary data on the number of patients with pre- viously confirmed monogenic diabetes in each study area who had not been re- cruited into this study)
+
UCPCR >=0.2 nmol/mmol were considered to have significant en- dogenous insulin secretion (10).
(UCPCR
-The total quantity of C-peptide excreted in the urine per day represents 5%–10% of pancreatic secretion, compared with only 0.1% of secreted insulin
-24h UCPCR to glucagon test : Two-hour postprandial urinary C-peptide/creatinine quotient turned out to be slightly less sensitive (89%) than the glucagon test (94%) and of equal specificity (96%). Glucagon-stimulated plasma C-peptide and postprandial urinary C-peptide excretion correlated significantly among insulin-requiring diabetics (r = 0.73), but not among non-insulin-requiring diabetics (r = 0.23))
(Dynex DSX automated ELISA system (Launch Diag- nostics, Longfield, U.K.)
Patients were considered positive for antibodies if their results were >99th centile (64 World Health Organization units/mL for GAD and 15 World Health Organization units/mL for IA2)
(Both meth- ods are highly specific and sensitive (GAD antibodies, 98 and 84%, and IA-2 anti- bodies, 99 and 74%, respectively).
The prevalence of GAD and IA-2 antibodies in maturity-onset diabetes of the young is the same as in control subjects (< 1%). )
Significant Endogenous Insulin and Negative Antibody Results
(Dosage analysis of HNF1A, HNF4A, and GCK for partial- and whole- gene deletions was also performed by multiplex ligation-dependent probe am- plification using the MRC-Holland MODY multiplex ligation-dependent probe am- plification kit (P241-B1). )
If no patho- genic mutation was identified in HNF1A, HNF4A, or GCK, further targeted next- generation sequencing 35 monogenic diabetes genes
(all genes in which mutations are known to cause MODY, neonatal dia- betes, and other genetic diabetic syn- dromes) using a custom SureSelect exon-capture assay (Agilent Technolo- gies, Santa Clara, CA) (17) (see Supple- mentary Data and Supplementary Table 1 for methodology, sensitivity, and details of genes tested).
Flow chart of patients recruited as part of UNITED. Biomarker screening pathway in 1,376 patients with no known genetic cause for their diabetes in Exeter and Tayside.11 dropped out. Seventeen new cases of monogenic diabetes detected (*one case identified through exome sequencing).
A total of 2,288 patients were eligible in area, and 1,418 subjects (62%) in total consented to the study and were recruited: 716 from the Exeter area and 702 from Dundee. A total of 11 pa- tients dropped out (9 did not provide blood samples for antibody testing, and 2 did not provide samples for DNA testing).
Of the 1,407 remaining patients, 1,365 had no known genetic cause for their diabetes.
subse- quent results on the screening pathway are based on these patients. A total of 42 patients had a known genetic cause for their diabetes prior to participating in this pathway: 34 patients had con- firmed monogenic diabetes (Table 1), and 8 patients had cystic fibrosis–related diabetes.
Identifies 17 New Cases of Monogenic Diabetes
2 pa- tients were anuric because of renal failure and therefore went straight on to antibody testing.
those diagnosed with monogenic diabetes as part of the study were less likely to have a parent known to be affected than those with a previous known monogenic diagnosis (8 out of 17 [47%] vs. 29 out of 34 [85%];
the proportion of known monogenic diabetes prior to the study in the recruited population (34 out of 1,407 [2.4%]) was similar to the proportion in the nonrecruited pop- ulation (26 out of 870 [3.0%]) (P = 0.4), suggesting no overall bias in recruitment.
There was no difference in terms of age at diagnosis (mean 18 vs. 19 years; P = 0.5), age at time of recruitment (using 2011 for nonrecruited patients) (32 vs. 32 years; P = 0.98), or sex (35 female vs. 45% male; P = 0.4).
standard clinical criteria for MODY (age at diagnosis younger than 25 years, non– insulin-requiring, and a parent known to be affected with diabetes)
higher pickup rate and PPV (57.6%) than the biomarker pathway, but the majority of monogenic cases would have been missed (63% compared with 0% for the biomarker pathway)
MODY probability calculator also had a higher PPV (40.4%), but missed more cases (55%)
Prevalence performance
(U.K. UCPCR cost of £10.80 and antibodies cost of £20),
The cost-effectiveness of additional testing for other forms of monogenic diabetes has not been assessed. change from insulin to sulphonylur- eas is still possible in cases diagnosed with ABCC8 and KCNJ11
(Cost saving ADA 2013: The testing policy yielded an average gain of 0.012 QALYs and resulted in an ICER of 205,000 USD. Sensitivity analysis showed that if the MODY prevalence was 6%, the ICER would be ∼50,000 USD. If MODY prevalence was >30%, the testing policy was cost saving. Reducing genetic testing costs to 700 USD also resulted in an ICER of ∼50,000 USD.) type 2 diabetic patients 25–40 years old with a MODY prevalence of 2%.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3867988/
few studies that have systematically screened whole populations for monogenic diabetes.
The majority of studies have been in pediatric populations only, with only two studies that have screened adults
การศึกษานี้พบว่าการใช้biomarker based pathway สามารถinclude คนไข้เพิ่มขึ้นได้
, or whether this would result in more missed patients because of reduced testing.
clinically defined, rather than ge- netically confirmed, MODY (31) or use low cutoffs for antibody positivity,
To determine whether there was any potential bias in recruitment
26 patients with a diagnosis of monogenic diabetes in the Exeter and Tayside regions who met study inclusion criteria but were not recruited to the UNITED study. Therefore, the proportion of known monogenic diabetes prior to the study in the recruited population (34 out of 1,407 [2.4%]) was similar to the proportion in the nonrecruited pop- ulation (26 out of 870 [3.0%]) (P = 0.4)
(e.g., renal cysts associated with HNF1B) >>. Bad prognosis?