This document discusses the metabolic and pathologic consequences of uncontrolled diabetes mellitus on the cellular and tissue level. It outlines how even in a controlled diabetic state, hyperglycemia can alter tissue physiology and biochemical processes. Specifically, it describes how uncontrolled diabetes can lead to alterations in plasma composition, protein and organ metabolism, coagulation, and immune function through mechanisms such as glycosylation, oxidative stress, and hormonal imbalances.
Diabetes mellitus is a metabolic condition that is usually diagnosed accidentally when patient present to the hospital for another ailment.
Currently, about 425 million people in the world are living with DM (IDF data). A total of about 16 million people are living with diabetes in the African Region and by 2045, an estimated 41 million people will be affected.
PCOS IS THE THIEF OF WOMENHOOD........an enigmatic condition must be understood and managed according to the age it presents.......contact dr jaideep at jaideep malhotraagra@gmail.com for CME AND WORKSHOPS IN YOUR CITY
The worldwide explosion of obesity has resulted in an ever-increasing prevalence of type 2 diabetes. The importance of insulin resistance and β-cell dysfunction to the pathogenesis of type 2 diabetes was debated for a long time; many thought that insulin resistance was the main abnormality in type 2 diabetes, and that inability to secrete insulin was a late manifestation. This notion is now challenged. This presentation deals with the important contributing factors in the development of type 2 diabetes mellitus.
Shashikiran Umakanth made this presentation at the "First Endocrine Update Program” – ENDO EGYPT 2015, from 17-20 December 2015 in the Historic City of Luxor, Egypt. This endocrine update was organised by the Egyptian Association of Endocrinology , Diabetes and Atherosclerosis (EAEDA) in collaboration with the Endocrine Society, USA.
Relationship of Metabolic syndrome and cognitive impairment has been discussed. Metabolic causes of Dementia and their reversibility has been discussed.
Sleep apnoea in pcos by dr alka mukherjee nagpur m.s. indiaalka mukherjee
Polycystic ovary syndrome (PCOS), the most common endocrine disorder of pre-menopausal women, is characterized by chronic hyperandrogenism, oligoanovulation, obesity and insulin resistance. Importantly, PCOS women are at increased risk for glucose intolerance, type 2 diabetes and cardiovascular disorders. Recent reports indicate an unexpectedly high prevalence of obstructive sleep apnea (OSA) in PCOS. Alterations in sex steroids (i.e. high androgen and low estrogen levels) and increased visceral adiposity in PCOS could potentially contribute to the increased prevalence of OSA in this disorder. There is some evidence to suggest that there may be strong associations between the presence and severity of OSA and the metabolic disturbances that characterize PCOS. Causal mechanisms in the link between PCOS and OSA remain to be elucidated. Clinicians who manage PCOS patients should be aware of the high prevalence of OSA in these patients and systematically evaluate these women for sleep disturbances.
This is a brief discussion on diabetes mellitus as medical emergency that can be encountered in any dental office.
What to do in such conditions is what I've briefly tried to explain over here.
Regards,
Dr. Abhishek Sharma
(M.D.S - 2016 Batch ; Oral & Maxillofacial Surgery)
Diabetes mellitus is a metabolic condition that is usually diagnosed accidentally when patient present to the hospital for another ailment.
Currently, about 425 million people in the world are living with DM (IDF data). A total of about 16 million people are living with diabetes in the African Region and by 2045, an estimated 41 million people will be affected.
PCOS IS THE THIEF OF WOMENHOOD........an enigmatic condition must be understood and managed according to the age it presents.......contact dr jaideep at jaideep malhotraagra@gmail.com for CME AND WORKSHOPS IN YOUR CITY
The worldwide explosion of obesity has resulted in an ever-increasing prevalence of type 2 diabetes. The importance of insulin resistance and β-cell dysfunction to the pathogenesis of type 2 diabetes was debated for a long time; many thought that insulin resistance was the main abnormality in type 2 diabetes, and that inability to secrete insulin was a late manifestation. This notion is now challenged. This presentation deals with the important contributing factors in the development of type 2 diabetes mellitus.
Shashikiran Umakanth made this presentation at the "First Endocrine Update Program” – ENDO EGYPT 2015, from 17-20 December 2015 in the Historic City of Luxor, Egypt. This endocrine update was organised by the Egyptian Association of Endocrinology , Diabetes and Atherosclerosis (EAEDA) in collaboration with the Endocrine Society, USA.
Relationship of Metabolic syndrome and cognitive impairment has been discussed. Metabolic causes of Dementia and their reversibility has been discussed.
Sleep apnoea in pcos by dr alka mukherjee nagpur m.s. indiaalka mukherjee
Polycystic ovary syndrome (PCOS), the most common endocrine disorder of pre-menopausal women, is characterized by chronic hyperandrogenism, oligoanovulation, obesity and insulin resistance. Importantly, PCOS women are at increased risk for glucose intolerance, type 2 diabetes and cardiovascular disorders. Recent reports indicate an unexpectedly high prevalence of obstructive sleep apnea (OSA) in PCOS. Alterations in sex steroids (i.e. high androgen and low estrogen levels) and increased visceral adiposity in PCOS could potentially contribute to the increased prevalence of OSA in this disorder. There is some evidence to suggest that there may be strong associations between the presence and severity of OSA and the metabolic disturbances that characterize PCOS. Causal mechanisms in the link between PCOS and OSA remain to be elucidated. Clinicians who manage PCOS patients should be aware of the high prevalence of OSA in these patients and systematically evaluate these women for sleep disturbances.
This is a brief discussion on diabetes mellitus as medical emergency that can be encountered in any dental office.
What to do in such conditions is what I've briefly tried to explain over here.
Regards,
Dr. Abhishek Sharma
(M.D.S - 2016 Batch ; Oral & Maxillofacial Surgery)
Diabetes mellitus (DM):- It is a metabolicdisorder characterized by hyperglycaemia, (fasting plasma glucose ≥ 126 mg/dl and/or ≥ 200 mg/dl 2 hours after 75 g oral glucose),glycosuria, hyperlipidaemia, negative nitrogen balance and sometimes ketonaemia.
Diabetes mellitus, one of the major public health problems worldwide, is a metabolic disorder of multiple etiologies distinguished by a failure of glucose homeostasis with disturbances of carbohydrate, fat and protein metabolism as a result of defects in insulin secretion and/or insulin action.
According to International Diabetes Federation (IDF) report, elevated blood glucose is the third uppermost risk factor for premature mortality, following high blood pressure and tobacco use globally
Cardiovascular diseases, neuropathy, nephropathy, and retinopathy are among the major risks that are associated with diabetes.These chronic complications may lead to hardening and narrowing of arteries (atherosclerosis) that could advance to stroke, coronary heart disease, and other blood vessel diseases, nerve damage, kidney failure, and blindness with time
Two major types of diabetes mellitus are
1. Insulin-dependent diabetes mellitus (IDDM) / juvenile onset diabetes mellitus
2. Noninsulin-dependent diabetes mellitus (NIDDM) / maturity onset diabetes mellitus
Insulin-dependent diabetes mellitus (IDDM) / juvenile onset diabetes mellitus
There is β cell destruction in pancreatic islets; majority of cases are autoimmune (type 1A) antibodies that destroy β cells are detectable in blood, but some are idiopathic (type 1B)-no βcell antibody is found.
2.Noninsulin-dependent diabetes mellitus (NIDDM) / maturity onset diabetes mellitus
Type 2 diabetes mellitus (T2DM) is the most prevalent metabolic disease worldwide.
There is no loss or moderate reduction in β cell mass: insulin in circulation is low. normal or even high. no anti-β -cell antibody is demonstrable: has a high degree of genetic predisposition: generally has a late onset (past middle age). Over 90% cases of diabetes are type 2 DM
Abnormality in gluco-receptor of β cells so that they respond at higher glucose concentration or relative β cell deficiency. In either way. insulin secretion is impaired: may progress to β cells failure.
Reduced sensitivity of peripheral tissues to insulin: reduction in number of insulin receptors, “down regulation” of insulin receptors.
Insulin history:
Insulin was discovered in 1921 by Banting and Best who demonstrated the hypoglycaemic action of an extract of pancreas prepared after degeneration of the exocrine part due to ligation of pancreatic duct.
It was first obtained in pure crystalline form in 1926 and the chemical structure was fully worked out in 1956 by Sanger.
Insulin is a two chain polypeptide having 51 amino acids and MW about 6000.
The A-chain has 21 while B-chain has 30 amino acids.
Insulin is synthesized in the β cells of pancreatic islets as a single chain peptide Preproinsulin (110 AA) from which
Similar to 1362397185 metabolic and pathologic consequences of diabetes (20)
ARTIFICIAL INTELLIGENCE IN HEALTHCARE.pdfAnujkumaranit
Artificial intelligence (AI) refers to the simulation of human intelligence processes by machines, especially computer systems. It encompasses tasks such as learning, reasoning, problem-solving, perception, and language understanding. AI technologies are revolutionizing various fields, from healthcare to finance, by enabling machines to perform tasks that typically require human intelligence.
Ethanol (CH3CH2OH), or beverage alcohol, is a two-carbon alcohol
that is rapidly distributed in the body and brain. Ethanol alters many
neurochemical systems and has rewarding and addictive properties. It
is the oldest recreational drug and likely contributes to more morbidity,
mortality, and public health costs than all illicit drugs combined. The
5th edition of the Diagnostic and Statistical Manual of Mental Disorders
(DSM-5) integrates alcohol abuse and alcohol dependence into a single
disorder called alcohol use disorder (AUD), with mild, moderate,
and severe subclassifications (American Psychiatric Association, 2013).
In the DSM-5, all types of substance abuse and dependence have been
combined into a single substance use disorder (SUD) on a continuum
from mild to severe. A diagnosis of AUD requires that at least two of
the 11 DSM-5 behaviors be present within a 12-month period (mild
AUD: 2–3 criteria; moderate AUD: 4–5 criteria; severe AUD: 6–11 criteria).
The four main behavioral effects of AUD are impaired control over
drinking, negative social consequences, risky use, and altered physiological
effects (tolerance, withdrawal). This chapter presents an overview
of the prevalence and harmful consequences of AUD in the U.S.,
the systemic nature of the disease, neurocircuitry and stages of AUD,
comorbidities, fetal alcohol spectrum disorders, genetic risk factors, and
pharmacotherapies for AUD.
Title: Sense of Smell
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 primary categories of smells and the concept of odor blindness.
Explain the structure and location of the olfactory membrane and mucosa, including the types and roles of cells involved in olfaction.
Describe the pathway and mechanisms of olfactory signal transmission from the olfactory receptors to the brain.
Illustrate the biochemical cascade triggered by odorant binding to olfactory receptors, including the role of G-proteins and second messengers in generating an action potential.
Identify different types of olfactory disorders such as anosmia, hyposmia, hyperosmia, and dysosmia, including their potential causes.
Key Topics:
Olfactory Genes:
3% of the human genome accounts for olfactory genes.
400 genes for odorant receptors.
Olfactory Membrane:
Located in the superior part of the nasal cavity.
Medially: Folds downward along the superior septum.
Laterally: Folds over the superior turbinate and upper surface of the middle turbinate.
Total surface area: 5-10 square centimeters.
Olfactory Mucosa:
Olfactory Cells: Bipolar nerve cells derived from the CNS (100 million), with 4-25 olfactory cilia per cell.
Sustentacular Cells: Produce mucus and maintain ionic and molecular environment.
Basal Cells: Replace worn-out olfactory cells with an average lifespan of 1-2 months.
Bowman’s Gland: Secretes mucus.
Stimulation of Olfactory Cells:
Odorant dissolves in mucus and attaches to receptors on olfactory cilia.
Involves a cascade effect through G-proteins and second messengers, leading to depolarization and action potential generation in the olfactory nerve.
Quality of a Good Odorant:
Small (3-20 Carbon atoms), volatile, water-soluble, and lipid-soluble.
Facilitated by odorant-binding proteins in mucus.
Membrane Potential and Action Potential:
Resting membrane potential: -55mV.
Action potential frequency in the olfactory nerve increases with odorant strength.
Adaptation Towards the Sense of Smell:
Rapid adaptation within the first second, with further slow adaptation.
Psychological adaptation greater than receptor adaptation, involving feedback inhibition from the central nervous system.
Primary Sensations of Smell:
Camphoraceous, Musky, Floral, Pepperminty, Ethereal, Pungent, Putrid.
Odor Detection Threshold:
Examples: Hydrogen sulfide (0.0005 ppm), Methyl-mercaptan (0.002 ppm).
Some toxic substances are odorless at lethal concentrations.
Characteristics of Smell:
Odor blindness for single substances due to lack of appropriate receptor protein.
Behavioral and emotional influences of smell.
Transmission of Olfactory Signals:
From olfactory cells to glomeruli in the olfactory bulb, involving lateral inhibition.
Primitive, less old, and new olfactory systems with different path
These simplified slides by Dr. Sidra Arshad present an overview of the non-respiratory functions of the respiratory tract.
Learning objectives:
1. Enlist the non-respiratory functions of the respiratory tract
2. Briefly explain how these functions are carried out
3. Discuss the significance of dead space
4. Differentiate between minute ventilation and alveolar ventilation
5. Describe the cough and sneeze reflexes
Study Resources:
1. Chapter 39, Guyton and Hall Textbook of Medical Physiology, 14th edition
2. Chapter 34, Ganong’s Review of Medical Physiology, 26th edition
3. Chapter 17, Human Physiology by Lauralee Sherwood, 9th edition
4. Non-respiratory functions of the lungs https://academic.oup.com/bjaed/article/13/3/98/278874
Prix Galien International 2024 Forum ProgramLevi Shapiro
June 20, 2024, Prix Galien International and Jerusalem Ethics Forum in ROME. Detailed agenda including panels:
- ADVANCES IN CARDIOLOGY: A NEW PARADIGM IS COMING
- WOMEN’S HEALTH: FERTILITY PRESERVATION
- WHAT’S NEW IN THE TREATMENT OF INFECTIOUS,
ONCOLOGICAL AND INFLAMMATORY SKIN DISEASES?
- ARTIFICIAL INTELLIGENCE AND ETHICS
- GENE THERAPY
- BEYOND BORDERS: GLOBAL INITIATIVES FOR DEMOCRATIZING LIFE SCIENCE TECHNOLOGIES AND PROMOTING ACCESS TO HEALTHCARE
- ETHICAL CHALLENGES IN LIFE SCIENCES
- Prix Galien International Awards Ceremony
Knee anatomy and clinical tests 2024.pdfvimalpl1234
This includes all relevant anatomy and clinical tests compiled from standard textbooks, Campbell,netter etc..It is comprehensive and best suited for orthopaedicians and orthopaedic residents.
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.
Acute scrotum is a general term referring to an emergency condition affecting the contents or the wall of the scrotum.
There are a number of conditions that present acutely, predominantly with pain and/or swelling
A careful and detailed history and examination, and in some cases, investigations allow differentiation between these diagnoses. A prompt diagnosis is essential as the patient may require urgent surgical intervention
Testicular torsion refers to twisting of the spermatic cord, causing ischaemia of the testicle.
Testicular torsion results from inadequate fixation of the testis to the tunica vaginalis producing ischemia from reduced arterial inflow and venous outflow obstruction.
The prevalence of testicular torsion in adult patients hospitalized with acute scrotal pain is approximately 25 to 50 percent
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
Associate Division Director for Ambulatory Operations
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
NVBDCP.pptx Nation vector borne disease control programSapna Thakur
NVBDCP was launched in 2003-2004 . Vector-Borne Disease: Disease that results from an infection transmitted to humans and other animals by blood-feeding arthropods, such as mosquitoes, ticks, and fleas. Examples of vector-borne diseases include Dengue fever, West Nile Virus, Lyme disease, and malaria.
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1362397185 metabolic and pathologic consequences of diabetes
1. Metabolic and PathologicMetabolic and Pathologic
Consequences of DiabetesConsequences of Diabetes
MellitusMellitus
Sanjeev KelkarSanjeev Kelkar
Conjoint Lecturer, Faculty of Health,Conjoint Lecturer, Faculty of Health,
The University of Newcastle AustraliaThe University of Newcastle Australia
2. Metabolic and Pathologic ConsequencesMetabolic and Pathologic Consequences
of Diabetes Mellitusof Diabetes Mellitus
This is a picture of the cellular and tissueThis is a picture of the cellular and tissue
world of Diabetes.world of Diabetes.
A backdrop for our thinking aboutA backdrop for our thinking about
DiabetesDiabetes
Even in controlled Diabetes – there is aEven in controlled Diabetes – there is a
diabetic statediabetic state
In uncontrolled state the tissue worldIn uncontrolled state the tissue world
alters significantlyalters significantly
3. Metabolic and Pathologic ConsequencesMetabolic and Pathologic Consequences
of Diabetes Mellitusof Diabetes Mellitus
What is the state of control?What is the state of control?
70% of Diabetics are treated by General70% of Diabetics are treated by General
Practitioners with no special training in itPractitioners with no special training in it
Some of the remaining by consultantSome of the remaining by consultant
internistsinternists
Some by internists practicing diabetesSome by internists practicing diabetes
exclusivelyexclusively
Few by endocrionologistsFew by endocrionologists
4. Metabolic and Pathologic ConsequencesMetabolic and Pathologic Consequences
of Diabetes Mellitusof Diabetes Mellitus
HbA1c = 8.9% average of 2660 patients inHbA1c = 8.9% average of 2660 patients in
26 tertiary care centers of his country26 tertiary care centers of his country
DiabCare AsiaDiabCare Asia
7.5 % ever underwent foot examination in7.5 % ever underwent foot examination in
average 7.5 years of diabetes andaverage 7.5 years of diabetes and
53% only underwent a BP check up ever53% only underwent a BP check up ever
in that period - BUDSin that period - BUDS
5. Metabolic and Pathologic ConsequencesMetabolic and Pathologic Consequences
of Diabetes Mellitusof Diabetes Mellitus
20 % having tissue damage at the time of20 % having tissue damage at the time of
diagnosisdiagnosis
< 30 % under good control< 30 % under good control
GDM not in focusGDM not in focus
Severity and seriousness being notedSeverity and seriousness being noted
now- a- daysnow- a- days
6. Metabolic and Pathologic ConsequencesMetabolic and Pathologic Consequences
of Diabetes Mellitusof Diabetes Mellitus
Medicine has graduated from cytoplasm toMedicine has graduated from cytoplasm to
nucleus – Molecular biology has come tonucleus – Molecular biology has come to
fore and knowledge of biochemistry isfore and knowledge of biochemistry is
crucial to understanding of the disordercrucial to understanding of the disorder
Are we confident of in this department?Are we confident of in this department?
How about physiology?How about physiology?
7. Metabolic and Pathologic ConsequencesMetabolic and Pathologic Consequences
of Diabetes Mellitusof Diabetes Mellitus
There is a diabetic state out there!!There is a diabetic state out there!!
Maintained by inadequate insulin secretionMaintained by inadequate insulin secretion
and action, i.e. resistance putative to theand action, i.e. resistance putative to the
T2T2
Then there is Gluconeogenesis fuelledThen there is Gluconeogenesis fuelled
and controlled by counter-regulatoryand controlled by counter-regulatory
hormoneshormones
Body states of fed fasting and post-Body states of fed fasting and post-
absorptive periods and physical exertionabsorptive periods and physical exertion
8. Metabolic and Pathologic ConsequencesMetabolic and Pathologic Consequences
of Diabetes Mellitusof Diabetes Mellitus
The 3 states have a seesaw of insulin andThe 3 states have a seesaw of insulin and
counter-regulatory hormonescounter-regulatory hormones
Continuous attempt in normal physiologyContinuous attempt in normal physiology
to equilibrate the unstable disequilibriumto equilibrate the unstable disequilibrium
caused by food, absorption, fasting andcaused by food, absorption, fasting and
exertionexertion
These states have distinct impacts onThese states have distinct impacts on
insulin actionsinsulin actions
9. Components of Diabetic StateComponents of Diabetic State
Discussion excludes presence of organ damageDiscussion excludes presence of organ damage
(structural) but emphasizes functional(structural) but emphasizes functional
derangements of uncontrolled diabetesderangements of uncontrolled diabetes
Premise – Hyperglycemia alters tissuePremise – Hyperglycemia alters tissue
physiology and blood composition and couldphysiology and blood composition and could
have transgressive effects on normal checkshave transgressive effects on normal checks
and balances leading to altered metabolism andand balances leading to altered metabolism and
pathologic consequencespathologic consequences
10. Components of Diabetic StateComponents of Diabetic State
Biochemical alterationsBiochemical alterations
Alterations of plasma compositionAlterations of plasma composition
Altered substrate metabolismAltered substrate metabolism
Altered organ metabolismAltered organ metabolism
Altered coagulationAltered coagulation
Altered immune functionAltered immune function
11. Components of Diabetic StateComponents of Diabetic State
Direct effects of hyperglycemia –Direct effects of hyperglycemia –
Glycosylation / Oxidant stressGlycosylation / Oxidant stress
Sorbitol pathway abnormalitiesSorbitol pathway abnormalities
Specific lipid abnormalities and omegaSpecific lipid abnormalities and omega
fatty acid issuesfatty acid issues
Vasoactivity Growth Factors and otherVasoactivity Growth Factors and other
defectsdefects
12. Components of Diabetic StateComponents of Diabetic State
Cellular functional alterations of counter-Cellular functional alterations of counter-
regulatory hormones leading toregulatory hormones leading to
metabolic consequences -metabolic consequences -
An important factor in stress and in normalAn important factor in stress and in normal
or diabetic physiologyor diabetic physiology
A brief overview of these will be takenA brief overview of these will be taken
13. Alteration in plasma compositionAlteration in plasma composition
Insulin deficiency leads to –Insulin deficiency leads to –
Hyperglycemia, diuresis, dehydration,Hyperglycemia, diuresis, dehydration,
electrolyte loss and thirstelectrolyte loss and thirst
Triglycerides release from adipocytesTriglycerides release from adipocytes
Protein breakdownProtein breakdown
Results in inadequate suppression ofResults in inadequate suppression of
glucagon leading to enhancement ofglucagon leading to enhancement of
above and ketone bodies laterabove and ketone bodies later
14. Alteration in protein metabolismAlteration in protein metabolism
Insulin has salutary effects on all aspects ofInsulin has salutary effects on all aspects of
protein metabolismprotein metabolism
Anti-proteolytic, anti-catabolic. Even in shortAnti-proteolytic, anti-catabolic. Even in short
term deficiencies these effects are lostterm deficiencies these effects are lost
Alanine and glutamine the neoglucogenic aminoAlanine and glutamine the neoglucogenic amino
acids are released form tissuesacids are released form tissues
Insulinopenia causes degradation of neutralInsulinopenia causes degradation of neutral
alkaline and basic proteins at equivalent ratesalkaline and basic proteins at equivalent rates
15. Alteration in protein metabolismAlteration in protein metabolism
Excessive unregulated proteinExcessive unregulated protein
degradation can be halted by basal levelsdegradation can be halted by basal levels
of insulinof insulin
Regulation of protein degradation appearsRegulation of protein degradation appears
to be a more important or useful action ofto be a more important or useful action of
insulin, more than protein synthesisinsulin, more than protein synthesis
In insulinopenic states large vacuolesIn insulinopenic states large vacuoles
containing mitochondria, RER,SER,containing mitochondria, RER,SER,
increases fragility of the lysosomesincreases fragility of the lysosomes
16. Insulin and Protein synthesisInsulin and Protein synthesis
Insulin binds to insulin responsive sites inInsulin binds to insulin responsive sites in
the nucleus, influencesthe nucleus, influences
Gene transcription process all throughGene transcription process all through
Affects nonstructural cellular proteinsAffects nonstructural cellular proteins
enzymes and polysomesenzymes and polysomes
Structural proteins – affects all cells in theStructural proteins – affects all cells in the
body in insulin sufficiency and normalbody in insulin sufficiency and normal
amino acid levelsamino acid levels
17. Altered metabolism of organsAltered metabolism of organs
Insulinopenia leads to increase in lipoproteinInsulinopenia leads to increase in lipoprotein
lipases to release the FFAs and glycerol fromlipases to release the FFAs and glycerol from
adipocytesadipocytes
Diverts the preferred glucose metabolism ofDiverts the preferred glucose metabolism of
skeletal and cardiac muscle partly orskeletal and cardiac muscle partly or
substantially to FFA metabolismsubstantially to FFA metabolism
Tissue lipases are depleted and FFATissue lipases are depleted and FFA
metabolism may not proceed to full oxidationmetabolism may not proceed to full oxidation
causing acid productscausing acid products
18. Hypercoagulation stateHypercoagulation state
It is now accepted to be a hypercoagulationIt is now accepted to be a hypercoagulation
state due to –state due to –
Primary platelet hyperaggregabiltyPrimary platelet hyperaggregabilty
Increased activity of procoagulant protein factorIncreased activity of procoagulant protein factor
VII and XVII and X
Increase in PF4, PDGF, PAI, inflammatoryIncrease in PF4, PDGF, PAI, inflammatory
cytokines, glycation and improper action ofcytokines, glycation and improper action of
antithrombin III,antithrombin III,
Hyperlipdemia and dehydration changing theHyperlipdemia and dehydration changing the
rheology of he bloodrheology of he blood
19. Immune functionImmune function
Bacterial endotoxemia causes delayedBacterial endotoxemia causes delayed
and slower numerical response of PMNand slower numerical response of PMN
cells, with decreased diapedesis andcells, with decreased diapedesis and
chemotaxis and lower adherencechemotaxis and lower adherence
Phagocytosis and killing after that isPhagocytosis and killing after that is
distinctly poor in blood glucose above 250distinctly poor in blood glucose above 250
mg / dL. Lymphocytic responses are poormg / dL. Lymphocytic responses are poor
20. Immune functionImmune function
Natural killer cells have reduced killingNatural killer cells have reduced killing
capacity and CD4+ lymphocytes decreasecapacity and CD4+ lymphocytes decrease
Antibody dependent cellular cytotoxicity,Antibody dependent cellular cytotoxicity,
the superoxide bursts of PMN cells arethe superoxide bursts of PMN cells are
decreaseddecreased
Opsonization defects have beenOpsonization defects have been
suggestedsuggested
Normoglycemia restores all immuneNormoglycemia restores all immune
functionsfunctions
21. Direct Effects of HyperglycemiaDirect Effects of Hyperglycemia
GlycosylationGlycosylation
Oxidant StressOxidant Stress
Sorbitol pathway abnormalitiesSorbitol pathway abnormalities
Specific lipid abnormalitySpecific lipid abnormality
Affects the tissue environment maximallyAffects the tissue environment maximally
Affects the tissues with no insulinAffects the tissues with no insulin
resistance ie free entry of glucoseresistance ie free entry of glucose
22. Glycosylation of ProteinsGlycosylation of Proteins
Covalent binding of glucose with the NCovalent binding of glucose with the N
terminal of proteins – directly proportionalterminal of proteins – directly proportional
to the length and degree of hyperglycemiato the length and degree of hyperglycemia
Form unstable Schiff’s base, undergoesForm unstable Schiff’s base, undergoes
many rearrangements to form Amadorimany rearrangements to form Amadori
products and then AGE products withproducts and then AGE products with
brown and non brown fluorescencebrown and non brown fluorescence
23. Glycosylation of ProteinsGlycosylation of Proteins
Collagen, basement membrane proteins,Collagen, basement membrane proteins,
DNAs, vascular and neural tissues areDNAs, vascular and neural tissues are
particularly disposed to form AGEparticularly disposed to form AGE
Single strand breaks in DNA and impairedSingle strand breaks in DNA and impaired
repair is knownrepair is known
Basement membranes change electricalBasement membranes change electrical
charge and reduces impedance to thecharge and reduces impedance to the
outflow of proteinsoutflow of proteins
24. Glycosylation of ProteinsGlycosylation of Proteins
All proteins glycate – Structural andAll proteins glycate – Structural and
long lasting proteins are morelong lasting proteins are more
susceptible - Albumin, Anti thrombin 3,susceptible - Albumin, Anti thrombin 3,
Hemoglobin are prime examplesHemoglobin are prime examples
AGEs cause inflammatory changes,AGEs cause inflammatory changes,
releases TNF alpha and cytokines,releases TNF alpha and cytokines,
quench nitric oxide to produce aquench nitric oxide to produce a
proaggregatory, vasoconstrictive,proaggregatory, vasoconstrictive,
prothrombotic tissue atmosphereprothrombotic tissue atmosphere
25. Glycosylation of ProteinsGlycosylation of Proteins
These effects are more significant thanThese effects are more significant than
thought a few years earlierthought a few years earlier
Cause functional abnormalities of theCause functional abnormalities of the
proteins that glycateproteins that glycate
May cause damage / mutation to theMay cause damage / mutation to the
DNAsDNAs
26. Free Radicals and Tissue DamageFree Radicals and Tissue Damage
Free radicals are normally generated inFree radicals are normally generated in
the metabolic process. Hyperglycemia,the metabolic process. Hyperglycemia,
smoking, ionizing radiation cause more ofsmoking, ionizing radiation cause more of
itit
Enzymatic mechanisms quench themEnzymatic mechanisms quench them
within limits. Endothelial tissue is deficientwithin limits. Endothelial tissue is deficient
in these defenses. Excess can overwhelmin these defenses. Excess can overwhelm
the capacity of it.the capacity of it.
27. Free Radicals and Tissue DamageFree Radicals and Tissue Damage
If not quenched the superoxide radicalsIf not quenched the superoxide radicals
continue to produce peroxides fromcontinue to produce peroxides from
COOH radical or from lipids and continueCOOH radical or from lipids and continue
tissue damagetissue damage
SOD, GSSG, and vit C are strong and E isSOD, GSSG, and vit C are strong and E is
a week quencher. Endothelium has lowa week quencher. Endothelium has low
concentration of SODconcentration of SOD
28. Omega 3 and 6 Fatty AcidsOmega 3 and 6 Fatty Acids
Fatty acids with 3 and 6 unsaturated bonds,Fatty acids with 3 and 6 unsaturated bonds,
hence known as such, EPA and DHA are W3.hence known as such, EPA and DHA are W3.
W6 leads through AA pathway to aW6 leads through AA pathway to a
proaggregatory, prothrombotic, vasoconstrictiveproaggregatory, prothrombotic, vasoconstrictive
state due to TXA2.state due to TXA2.
W3 produce prostanoid 3 and IL 5 series thatW3 produce prostanoid 3 and IL 5 series that
leads to an opposite effectsleads to an opposite effects
Vasodilator effects of eicosanoids are added onVasodilator effects of eicosanoids are added on
by NO productionby NO production
29. Sorbitol Pathway AbnormalitySorbitol Pathway Abnormality
Hyperglycemia leads to accumulation ofHyperglycemia leads to accumulation of
excess glucose in numerous cells andexcess glucose in numerous cells and
tissues, activates aldose reductasetissues, activates aldose reductase
Result – excess sorbitol accumulation andResult – excess sorbitol accumulation and
fructose, both osmotically activefructose, both osmotically active
Depletes myoinositol activates PKC andDepletes myoinositol activates PKC and
depresses PKA causing dysfunctiondepresses PKA causing dysfunction
30. Sorbitol Pathway AbnormalitySorbitol Pathway Abnormality
A link between hyperglycemia, cellularA link between hyperglycemia, cellular
osmoregulation, oxidative stress, alteredosmoregulation, oxidative stress, altered
signal transduction and tissue damagesignal transduction and tissue damage
It is an early component of theIt is an early component of the
complicating cascade of hyperglycemiacomplicating cascade of hyperglycemia
related biochemical abnormalities underrelated biochemical abnormalities under
discussiondiscussion
31. Sorbitol Pathway AbnormalitySorbitol Pathway Abnormality
Exacerbates formation of AGEs, oxidativeExacerbates formation of AGEs, oxidative
stress and depletes intracellular osmolytesstress and depletes intracellular osmolytes
like myoinositollike myoinositol
Excess fructose is a potent glycatingExcess fructose is a potent glycating
agentagent
Taurine is a new important intracellularTaurine is a new important intracellular
substance for functional and vascularsubstance for functional and vascular
integrity of he cells and tissuesintegrity of he cells and tissues
32. Vasoactive NOVasoactive NO
Sorbitol osmotic and sorbitol redoxSorbitol osmotic and sorbitol redox
hypothesis may impact on the properhypothesis may impact on the proper
liberation of NO as the potent endothelialliberation of NO as the potent endothelial
derived relaxation factor causingderived relaxation factor causing
vasodilatationvasodilatation
NO as a neurotransmitter also couldNO as a neurotransmitter also could
affect, if abnormal, the vascular smoothaffect, if abnormal, the vascular smooth
muscle and neural blood flowmuscle and neural blood flow
33. Fed, Fasting and Post absorptive statesFed, Fasting and Post absorptive states
Fed state results in continuous absorptionFed state results in continuous absorption
of nutrients and stimulates insulin – lastsof nutrients and stimulates insulin – lasts
for five hours after foodfor five hours after food
Post absorptive state stimulates glucagonPost absorptive state stimulates glucagon
to cause release of the hepatic glucose toto cause release of the hepatic glucose to
supply tissues with glucosesupply tissues with glucose
In fasting it is maintained by HGO andIn fasting it is maintained by HGO and
neoglucogenesisneoglucogenesis
34. Counter-regulatory HormonesCounter-regulatory Hormones
Glucagon is the orchestrator of theGlucagon is the orchestrator of the
synergism and enhancement of the CRHsynergism and enhancement of the CRH
response.response.
Without glucagon the responses areWithout glucagon the responses are
weaker, especially NE and E, cortisolweaker, especially NE and E, cortisol
Make glucose available to brain mostMake glucose available to brain most
importantly and other tissuesimportantly and other tissues
35. Counter-regulatory HormonesCounter-regulatory Hormones
Increasse insulin resistance by variousIncreasse insulin resistance by various
cellular mechanismscellular mechanisms
At reducing affinity for binding of I with IR,At reducing affinity for binding of I with IR,
Causing GLUTs to locate inside theCausing GLUTs to locate inside the
cytosol,cytosol,
Increasing the flow of substances of theIncreasing the flow of substances of the
neoglucogenic potentialneoglucogenic potential
36. ConclusionConclusion
Only broad details of the complexity of theOnly broad details of the complexity of the
dysregulated metabolism are presenteddysregulated metabolism are presented
herehere
It is a broad framework for thinkingIt is a broad framework for thinking
Hopefully it helps you to concentrate onHopefully it helps you to concentrate on
the mechanisms of why things happen thethe mechanisms of why things happen the
way they happenway they happen
Details will be unfolding in the course atDetails will be unfolding in the course at
different points of timedifferent points of time