Metabolic and Pathologic Consequences of Diabetes Mellitus Sanjeev Kelkar Conjoint Lecturer, Faculty...

Metabolic and Pathologic Metabolic and Pathologic Consequences of Diabetes Consequences of Diabetes

MellitusMellitus

Sanjeev Kelkar Sanjeev Kelkar

Conjoint Lecturer, Faculty of Conjoint Lecturer, Faculty of Health,Health,

The University of Newcastle The University of Newcastle AustraliaAustralia

Metabolic and Pathologic Metabolic and Pathologic Consequences of Diabetes MellitusConsequences of Diabetes Mellitus

This is a picture of the cellular and This is a picture of the cellular and tissue world of Diabetes.tissue world of Diabetes.

A backdrop for our thinking about A backdrop for our thinking about DiabetesDiabetes

Even in controlled Diabetes – there is Even in controlled Diabetes – there is a diabetic statea diabetic state

In uncontrolled state the tissue world In uncontrolled state the tissue world alters significantlyalters significantly


What is the state of control?What is the state of control?

70% of Diabetics are treated by General 70% of Diabetics are treated by General Practitioners with no special training in Practitioners with no special training in itit

Some of the remaining by consultant Some of the remaining by consultant internistsinternists

Some by internists practicing diabetes Some by internists practicing diabetes exclusivelyexclusively

Few by endocrionologistsFew by endocrionologists


HbA1c = 8.9% average of 2660 HbA1c = 8.9% average of 2660 patients in 26 tertiary care centers of patients in 26 tertiary care centers of his country his country

DiabCare AsiaDiabCare Asia7.5 % ever underwent foot 7.5 % ever underwent foot

examination in average 7.5 years of examination in average 7.5 years of diabetes and diabetes and

53% only underwent a BP check up 53% only underwent a BP check up ever in that period - BUDSever in that period - BUDS


20 % having tissue damage at the 20 % having tissue damage at the time of diagnosis time of diagnosis

< 30 % under good control< 30 % under good controlGDM not in focusGDM not in focusSeverity and seriousness being noted Severity and seriousness being noted

now- a- days now- a- days


Medicine has graduated from Medicine has graduated from cytoplasm to nucleus – Molecular cytoplasm to nucleus – Molecular biology has come to fore and biology has come to fore and knowledge of biochemistry is crucial knowledge of biochemistry is crucial to understanding of the disorderto understanding of the disorder

Are we confident of in this Are we confident of in this department?department?

How about physiology?How about physiology?


There is a diabetic state out there!!There is a diabetic state out there!!Maintained by inadequate insulin Maintained by inadequate insulin

secretion and action, i.e. resistance secretion and action, i.e. resistance putative to the T2putative to the T2

Then there is Gluconeogenesis fuelled Then there is Gluconeogenesis fuelled and controlled by counter-regulatory and controlled by counter-regulatory hormoneshormones

Body states of fed fasting and post-Body states of fed fasting and post-absorptive periods and physical exertion absorptive periods and physical exertion


The 3 states have a seesaw of insulin The 3 states have a seesaw of insulin and counter-regulatory hormonesand counter-regulatory hormones

Continuous attempt in normal Continuous attempt in normal physiology to equilibrate the physiology to equilibrate the unstable disequilibrium caused by unstable disequilibrium caused by food, absorption, fasting and exertionfood, absorption, fasting and exertion

These states have distinct impacts These states have distinct impacts on insulin actionson insulin actions

Components of Diabetic StateComponents of Diabetic State

Discussion excludes presence of organ Discussion excludes presence of organ damage (structural) but emphasizes damage (structural) but emphasizes functional derangements of uncontrolled functional derangements of uncontrolled diabetesdiabetes

Premise – Hyperglycemia alters tissue Premise – Hyperglycemia alters tissue physiology and blood composition and physiology and blood composition and could have transgressive effects on normal could have transgressive effects on normal checks and balances leading to altered checks and balances leading to altered metabolism and pathologic consequences metabolism and pathologic consequences


Biochemical alterationsBiochemical alterationsAlterations of plasma compositionAlterations of plasma compositionAltered substrate metabolismAltered substrate metabolismAltered organ metabolismAltered organ metabolismAltered coagulationAltered coagulationAltered immune functionAltered immune function


Direct effects of hyperglycemia – Direct effects of hyperglycemia –

Glycosylation / Oxidant stressGlycosylation / Oxidant stress

Sorbitol pathway abnormalitiesSorbitol pathway abnormalities

Specific lipid abnormalities and Specific lipid abnormalities and omega fatty acid issuesomega fatty acid issues

Vasoactivity Growth Factors and Vasoactivity Growth Factors and other defectsother defects


Cellular functional alterations of Cellular functional alterations of counter-regulatory hormones counter-regulatory hormones leading toleading to

metabolic consequences - metabolic consequences -

An important factor in stress and in An important factor in stress and in normal or diabetic physiologynormal or diabetic physiology

A brief overview of these will be A brief overview of these will be taken taken

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 of Results in inadequate suppression of

glucagon leading to enhancement of glucagon leading to enhancement of above and ketone bodies later above and ketone bodies later

Alteration in protein metabolismAlteration in protein metabolism

Insulin has salutary effects on all aspects Insulin has salutary effects on all aspects of protein metabolismof protein metabolism

Anti-proteolytic, anti-catabolic. Even in Anti-proteolytic, anti-catabolic. Even in short term deficiencies these effects are short term deficiencies these effects are lostlost

Alanine and glutamine the neoglucogenic Alanine and glutamine the neoglucogenic amino acids are released form tissuesamino acids are released form tissues

Insulinopenia causes degradation of Insulinopenia causes degradation of neutral alkaline and basic proteins at neutral alkaline and basic proteins at equivalent rates equivalent rates

Alteration in protein metabolismAlteration in protein metabolism

Excessive unregulated protein Excessive unregulated protein degradation can be halted by basal degradation can be halted by basal levels of insulinlevels of insulin

Regulation of protein degradation Regulation of protein degradation appears to be a more important or appears to be a more important or useful action of insulin, more than useful action of insulin, more than protein synthesisprotein synthesis

In insulinopenic states large vacuoles In insulinopenic states large vacuoles containing mitochondria, RER,SER, containing mitochondria, RER,SER, increases fragility of the lysosomes increases fragility of the lysosomes

Insulin and Protein synthesisInsulin and Protein synthesis

Insulin binds to insulin responsive Insulin binds to insulin responsive sites in the nucleus, influencessites in the nucleus, influences

Gene transcription process all throughGene transcription process all through Affects nonstructural cellular proteins Affects nonstructural cellular proteins enzymes and polysomesenzymes and polysomes Structural proteins – affects all cells in Structural proteins – affects all cells in

the body in insulin sufficiency and the body in insulin sufficiency and normal amino acid levelsnormal amino acid levels

Altered metabolism of organsAltered metabolism of organs

Insulinopenia leads to increase in Insulinopenia leads to increase in lipoprotein lipases to release the FFAs and lipoprotein lipases to release the FFAs and glycerol from adipocytesglycerol from adipocytes

Diverts the preferred glucose metabolism Diverts the preferred glucose metabolism of skeletal and cardiac muscle partly or of skeletal and cardiac muscle partly or substantially to FFA metabolism substantially to FFA metabolism

Tissue lipases are depleted and FFA Tissue lipases are depleted and FFA metabolism may not proceed to full metabolism may not proceed to full oxidation causing acid productsoxidation causing acid products

Hypercoagulation stateHypercoagulation state

It is now accepted to be a It is now accepted to be a hypercoagulation state due to –hypercoagulation state due to –

Primary platelet hyperaggregabiltyPrimary platelet hyperaggregabilty Increased activity of procoagulant protein Increased activity of procoagulant protein

factor VII and Xfactor VII and X Increase in PF4, PDGF, PAI, inflammatory Increase in PF4, PDGF, PAI, inflammatory

cytokines, glycation and improper action cytokines, glycation and improper action of antithrombin III, of antithrombin III,

Hyperlipdemia and dehydration changing Hyperlipdemia and dehydration changing the rheology of he bloodthe rheology of he blood

Immune functionImmune function

Bacterial endotoxemia causes Bacterial endotoxemia causes delayed and slower numerical delayed and slower numerical response of PMN cells, with response of PMN cells, with decreased diapedesis and decreased diapedesis and chemotaxis and lower adherence chemotaxis and lower adherence

Phagocytosis and killing after that is Phagocytosis and killing after that is distinctly poor in blood glucose distinctly poor in blood glucose above 250 mg / dL. Lymphocytic above 250 mg / dL. Lymphocytic responses are poorresponses are poor

Immune functionImmune function

Natural killer cells have reduced killing Natural killer cells have reduced killing capacity and CD4+ lymphocytes capacity and CD4+ lymphocytes decreasedecrease

Antibody dependent cellular Antibody dependent cellular cytotoxicity, the superoxide bursts of cytotoxicity, the superoxide bursts of PMN cells are decreasedPMN cells are decreased

Opsonization defects have been Opsonization defects have been suggestedsuggested

Normoglycemia restores all immune Normoglycemia restores all immune functionsfunctions

Direct Effects of HyperglycemiaDirect Effects of Hyperglycemia

GlycosylationGlycosylationOxidant Stress Oxidant Stress Sorbitol pathway abnormalities Sorbitol pathway abnormalities Specific lipid abnormalitySpecific lipid abnormality

Affects the tissue environment Affects the tissue environment maximallymaximally

Affects the tissues with no insulin Affects the tissues with no insulin resistance ie free entry of glucose resistance ie free entry of glucose

Glycosylation of ProteinsGlycosylation of Proteins

Covalent binding of glucose with the Covalent binding of glucose with the N terminal of proteins – directly N terminal of proteins – directly proportional to the length and degree proportional to the length and degree of hyperglycemiaof hyperglycemia

Form unstable Schiff’s base, Form unstable Schiff’s base, undergoes many rearrangements to undergoes many rearrangements to form Amadori products and then AGE form Amadori products and then AGE products with brown and non brown products with brown and non brown fluorescence fluorescence


Collagen, basement membrane Collagen, basement membrane proteins, DNAs, vascular and neural proteins, DNAs, vascular and neural tissues are particularly disposed to tissues are particularly disposed to form AGEform AGE

Single strand breaks in DNA and Single strand breaks in DNA and impaired repair is knownimpaired repair is known

Basement membranes change Basement membranes change electrical charge and reduces electrical charge and reduces impedance to the outflow of proteins impedance to the outflow of proteins


All proteins glycate – Structural and All proteins glycate – Structural and long lasting proteins are more long 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 a quench nitric oxide to produce a proaggregatory, vasoconstrictive, proaggregatory, vasoconstrictive, prothrombotic tissue atmosphereprothrombotic tissue atmosphere


These effects are more significant These effects are more significant than thought a few years earlierthan thought a few years earlier

Cause functional abnormalities of the Cause functional abnormalities of the proteins that glycateproteins that glycate

May cause damage / mutation to the May cause damage / mutation to the DNAsDNAs

Free Radicals and Tissue DamageFree Radicals and Tissue Damage

Free radicals are normally generated Free radicals are normally generated in the metabolic process. in the metabolic process. Hyperglycemia, smoking, ionizing Hyperglycemia, smoking, ionizing radiation cause more of itradiation cause more of it

Enzymatic mechanisms quench them Enzymatic mechanisms quench them within limits. Endothelial tissue is within limits. Endothelial tissue is deficient in these defenses. Excess deficient in these defenses. Excess can overwhelm the capacity of it.can overwhelm the capacity of it.

Free Radicals and Tissue DamageFree Radicals and Tissue Damage

If not quenched the superoxide If not quenched the superoxide radicals continue to produce radicals continue to produce peroxides from COOH radical or from peroxides from COOH radical or from lipids and continue tissue damagelipids and continue tissue damage

SOD, GSSG, and vit C are strong and SOD, GSSG, and vit C are strong and E is a week quencher. Endothelium E is a week quencher. Endothelium has low concentration of SODhas low concentration of SOD

Omega 3 and 6 Fatty AcidsOmega 3 and 6 Fatty Acids

Fatty acids with 3 and 6 unsaturated Fatty acids with 3 and 6 unsaturated bonds, hence known as such, EPA and bonds, hence known as such, EPA and DHA are W3. DHA are W3.

W6 leads through AA pathway to a W6 leads through AA pathway to a proaggregatory, prothrombotic, proaggregatory, prothrombotic, vasoconstrictive state due to TXA2.vasoconstrictive state due to TXA2.

W3 produce prostanoid 3 and IL 5 series W3 produce prostanoid 3 and IL 5 series that leads to an opposite effectsthat leads to an opposite effects

Vasodilator effects of eicosanoids are Vasodilator effects of eicosanoids are added on by NO production added on by NO production

Sorbitol Pathway AbnormalitySorbitol Pathway Abnormality

Hyperglycemia leads to accumulation Hyperglycemia leads to accumulation of excess glucose in numerous cells of excess glucose in numerous cells and tissues, activates aldose and tissues, activates aldose reductase reductase

Result – excess sorbitol accumulation Result – excess sorbitol accumulation and fructose, both osmotically active and fructose, both osmotically active

Depletes myoinositol activates PKC Depletes myoinositol activates PKC and depresses PKA causing and depresses PKA causing dysfunctiondysfunction


A link between hyperglycemia, A link between hyperglycemia, cellular osmoregulation, oxidative cellular osmoregulation, oxidative stress, altered signal transduction stress, altered signal transduction and tissue damageand tissue damage

It is an early component of the It is an early component of the complicating cascade of complicating cascade of hyperglycemia related biochemical hyperglycemia related biochemical abnormalities under discussionabnormalities under discussion


Exacerbates formation of AGEs, Exacerbates formation of AGEs, oxidative stress and depletes oxidative stress and depletes intracellular osmolytes like myoinositolintracellular osmolytes like myoinositol

Excess fructose is a potent glycating Excess fructose is a potent glycating agentagent

Taurine is a new important intracellular Taurine is a new important intracellular substance for functional and vascular substance for functional and vascular integrity of he cells and tissuesintegrity of he cells and tissues

Vasoactive NOVasoactive NO

Sorbitol osmotic and sorbitol redox Sorbitol osmotic and sorbitol redox hypothesis may impact on the proper hypothesis may impact on the proper liberation of NO as the potent liberation of NO as the potent endothelial derived relaxation factor endothelial derived relaxation factor causing vasodilatationcausing vasodilatation

NO as a neurotransmitter also could NO as a neurotransmitter also could affect, if abnormal, the vascular affect, if abnormal, the vascular smooth muscle and neural blood flowsmooth muscle and neural blood flow

Fed, Fasting and Post absorptive Fed, Fasting and Post absorptive statesstates

Fed state results in continuous Fed state results in continuous absorption of nutrients and absorption of nutrients and stimulates insulin – lasts for five stimulates insulin – lasts for five hours after foodhours after food

Post absorptive state stimulates Post absorptive state stimulates glucagon to cause release of the glucagon to cause release of the hepatic glucose to supply tissues hepatic glucose to supply tissues with glucosewith glucose

In fasting it is maintained by HGO In fasting it is maintained by HGO and neoglucogenesisand neoglucogenesis

Counter-regulatory HormonesCounter-regulatory Hormones

Glucagon is the orchestrator of the Glucagon is the orchestrator of the synergism and enhancement of the synergism and enhancement of the CRH response.CRH response.

Without glucagon the responses are Without glucagon the responses are weaker, especially NE and E, cortisolweaker, especially NE and E, cortisol

Make glucose available to brain most Make glucose available to brain most importantly and other tissues importantly and other tissues

Counter-regulatory HormonesCounter-regulatory Hormones

Increasse insulin resistance by Increasse insulin resistance by various cellular mechanisms various cellular mechanisms

At reducing affinity for binding of I At reducing affinity for binding of I with IR,with IR,

Causing GLUTs to locate inside the Causing GLUTs to locate inside the cytosol, cytosol,

Increasing the flow of substances of Increasing the flow of substances of the neoglucogenic potential the neoglucogenic potential

ConclusionConclusion

Only broad details of the complexity Only broad details of the complexity of the dysregulated metabolism are of the dysregulated metabolism are presented herepresented here

It is a broad framework for thinking It is a broad framework for thinking Hopefully it helps you to concentrate Hopefully it helps you to concentrate

on the mechanisms of why things on the mechanisms of why things happen the way they happenhappen the way they happen

Details will be unfolding in the course Details will be unfolding in the course at different points of timeat different points of time

Metabolic and Pathologic Consequences of Diabetes Mellitus Sanjeev Kelkar Conjoint Lecturer, Faculty...

Documents

Transcript of Metabolic and Pathologic Consequences of Diabetes Mellitus Sanjeev Kelkar Conjoint Lecturer, Faculty...