1362576395 metabolic and pathologic consequences of diabetes

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

MellitusMellitus

Sanjeev Kelkar Sanjeev Kelkar Conjoint Lecturer, Faculty of Health,Conjoint Lecturer, Faculty of Health,

The University of Newcastle AustraliaThe University of Newcastle Australia

Metabolic and Pathologic Consequences Metabolic and Pathologic Consequences of Diabetes Mellitusof Diabetes Mellitus

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

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

Even in controlled Diabetes – there is a Even in controlled Diabetes – there is a diabetic statediabetic 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 itPractitioners with no special training in itSome of the remaining by consultant Some of the remaining by consultant

internistsinternistsSome by internists practicing diabetes Some by internists practicing diabetes

exclusivelyexclusivelyFew by endocrionologistsFew by endocrionologists


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

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

average 7.5 years of diabetes and average 7.5 years of diabetes and 53% only underwent a BP check up ever 53% only underwent a BP check up ever

in that period - BUDSin that period - BUDS


20 % having tissue damage at the time of 20 % having tissue damage at the time of diagnosis 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 cytoplasm to Medicine has graduated from cytoplasm to nucleus – Molecular biology has come to nucleus – Molecular biology has come to fore and knowledge of biochemistry is fore 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?


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

and action, i.e. resistance putative to the and action, i.e. resistance putative to the T2T2

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

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

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

Components of Diabetic StateComponents of Diabetic State

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

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

fatty acid issuesfatty acid issues Vasoactivity Growth Factors and other Vasoactivity Growth Factors and other

defectsdefects


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 normal An important factor in stress and in normal

or diabetic physiologyor diabetic physiology A brief overview of these will be taken A brief overview of these will be 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 of Insulin has salutary effects on all aspects of protein metabolismprotein metabolism

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

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

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

Alteration in protein metabolismAlteration in protein metabolism

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

Regulation of protein degradation appears Regulation of protein degradation appears to be a more important or useful action of to be a more important or useful action of insulin, more than protein synthesisinsulin, more than protein 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 sites in Insulin binds to insulin responsive sites in the nucleus, influencesthe 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 the Structural proteins – affects all cells in the

body in insulin sufficiency and normal body in insulin sufficiency and normal amino acid levelsamino acid levels

Altered metabolism of organsAltered metabolism of organs

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

Diverts the preferred glucose metabolism of Diverts the preferred glucose metabolism of skeletal and cardiac muscle partly or 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 oxidation metabolism may not proceed to full oxidation causing acid productscausing acid products

Hypercoagulation stateHypercoagulation state

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

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

VII and XVII and X Increase in PF4, PDGF, PAI, inflammatory Increase in PF4, PDGF, PAI, inflammatory

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

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

Immune functionImmune function

Bacterial endotoxemia causes delayed Bacterial endotoxemia causes delayed and slower numerical response of PMN and slower numerical response of PMN cells, with decreased diapedesis and cells, with 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 above 250 distinctly poor in blood glucose above 250 mg / dL. Lymphocytic responses are poormg / dL. Lymphocytic responses are poor

Immune functionImmune function

Natural killer cells have reduced killing Natural 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 are the superoxide bursts of PMN cells are decreaseddecreased

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 maximallyAffects the tissue environment maximally 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 N Covalent binding of glucose with the N terminal of proteins – directly proportional terminal of proteins – directly proportional to the length and degree of hyperglycemiato the length and degree of hyperglycemia

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


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

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

Basement membranes change electrical Basement membranes change electrical charge and reduces impedance to the charge and reduces impedance to the outflow of proteins 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 than These effects are more significant than thought a few years earlierthought 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 in Free radicals are normally generated in the metabolic process. Hyperglycemia, the metabolic process. Hyperglycemia, smoking, ionizing radiation cause more of smoking, ionizing radiation cause more of itit

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

Free Radicals and Tissue DamageFree Radicals and Tissue Damage

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

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

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

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

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

Sorbitol Pathway AbnormalitySorbitol Pathway Abnormality

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

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

Depletes myoinositol activates PKC and Depletes myoinositol activates PKC and depresses PKA causing dysfunctiondepresses PKA causing dysfunction


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

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


Exacerbates formation of AGEs, oxidative Exacerbates formation of AGEs, oxidative stress and depletes intracellular osmolytes stress and depletes intracellular osmolytes like myoinositollike 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 endothelial liberation of NO as the potent endothelial derived relaxation factor causing derived relaxation factor causing vasodilatationvasodilatation

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

Fed, Fasting and Post absorptive statesFed, Fasting and Post absorptive states

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

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

In fasting it is maintained by HGO and In fasting it is maintained by HGO and neoglucogenesisneoglucogenesis

Counter-regulatory HormonesCounter-regulatory Hormones

Glucagon is the orchestrator of the Glucagon is the orchestrator of the synergism and enhancement of the CRH synergism and enhancement of the CRH response.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 various Increasse insulin resistance by various cellular mechanisms cellular mechanisms

At reducing affinity for binding of I with IR,At reducing affinity for binding of I with IR, Causing GLUTs to locate inside the Causing GLUTs to locate inside the

cytosol, cytosol, Increasing the flow of substances of the Increasing the flow of substances of the

neoglucogenic potential neoglucogenic potential

ConclusionConclusionOnly broad details of the complexity of the Only broad details of the complexity of the

dysregulated metabolism are presented dysregulated metabolism are presented herehere

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

the mechanisms of why things happen the the mechanisms of why things happen the way they happenway they happen

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

1362576395 metabolic and pathologic consequences of diabetes

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