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