Acute and chronic complications of DM

1. Moderator: Dr. DINESH PURI
Presenter: Dr. KAPIL DEV

2. OBJECTIVES
1. To understand the pathophysiology of acute complications of DM due
to:
 Diabetic Ketoacidosis
 Hyperosmolar state
2. To understand the pathophysiology of chronic complications of DM
due to hyperglycemia (micro vascular and macro
vascular complications)
3. To gain an understanding of the mechanisms that lead
to glucose induced vascular damage.

3. INTRODUCTION
 Diabetes mellitus -Group of metabolic disorders that share a
common feature of HYPERGLYCEMIA
 Prevalence of diabetes in India- 50.8 million(2010)
 Expected to rise to 87 million in 2030

4. Diabetes
 Type 1 DM: absolute deficiency of insulin cause by beta cell
destruction
 Type 2 DM: combination of peripheral resistance to insulin
action and inadequate secretory response
 Results from defects in Insulin secretion, action or most
commonly both

5. Pathogenesis of Type 1 DM
 Lack of insulin is caused by an immunologically mediated destruction
of the beta cells
 Genetic susceptibility: multiple loci are associated, most commonly
MHC class II
 The autoimmune insult is chronic by the time the patients first
presents, 80-90% b cell destruction has already occurred

6. Pathogenesis of Type 2 DM
 Environmental factors play a large role (lifestyle, dietary habits etc.)
 2 Metabolic defects
 Decreased ability of peripheral tissues to respond to insulin
 b-cell dysfunction that is manifested as impaired insulin secretion

7. COMPLICATIONS OF DIABETES
Acute complications
• Diabetic ketoacidosis
• HHS
Chronic complications
• Microcvascular/ Macrovascular
• Microvascular Nephro/Retino/Neuropathy
• Macrovascular CAD, PVD, CVD
Others

8. Hyperglycemia
 Overall net reduction in effective circulation insulin with a net increase
in counter regulatory hormones (epinephrine, cortisol, glucagon)
 Hyperglycemia is due to:
 Impaired peripheral utilization in tissue (post prandial)
 Increased gluconeogenesis (fasting state)
 Insulin deficiency is more prominent in DKA over HHS
• HHS ketoacidosis is not seen
• Glucose levels are much higher in HHS than in DKA

10. Diabetic nephropathy
Diabetic nephropathy is characterized clinically as a triad of hypertension,
proteinuria, and, ultimately, renal impairment

11. Retinopathy
• Retinopathy has the highest correlation with severity and duration of
diabetes
• Hyperglycemia is the primary cause of diabetic retinopathy but the
specific pathophysiologic mechanisms are not well understood.
 Death of microvascular contractile cells (pericytes) and the loss of intracellular
contacts which leads to microaneurysms and leakage.

 Growth factors have been implicated in the development of the next phase -
proliferative retinopathy.
 Vascular Endothelium Growth Factor (VGEF)

12. Classification of Diabetic Retinopathy
• Pre proliferative
• increased vascular permeability
• venous dilation
• Microaneurysms
• intraretinal hemorrhage
• Fluid leakage
• Retinal ischemia.
• Proliferative
• Neovascularization
• Vitreous hemorrhage
• Fibrous proliferation (scarring).

13. Diabetic Neuropathy
 Sensorimotor neuropathy (acute/chronic)
 Ulceration (painless), Charcot arthropathy, Callosities.
 Autonomic neuropathy
 Mononeuropathy cranial nerve palsies (mc- IV,VI,VII)
Spontaneous
Entrapment
External pressure palsies
Proximal motor neuropathy

14. MECHANISMS
 Hyperglycemia and susceptibility
 Endothelial cells and mesangial cells
MECHANISMS
 *Increased flux through Polyol pathway
 *Intracellular synthesis of AGEprecursors
 *Activation of PKC pathway
 *Increased hexosamine pathway activity

15. POLYOL PATHWAY
Nature 414:813–820,
2001.

16. Aldose reductase pathway
• Certain cells are unable to regulate glucose uptake in
hyperglycemic states (ex. Endothelial cells)
• In a hyperglycemic state glucose is metabolized intracellularly
by an enzyme aldose reductase into sorbitol and eventually into
fructose
• Intracellular NADPH is used as a cofactor in the pathway but is
also used to regenerate glutathione
• Glutathione is an antioxidant which prevent which decreases cellular
susceptibility to oxidative stress

17. INCREASED AGE PRECURSORS
 Non enzymatic reaction btwn sugars & amine residues
 From reactive carbonyl grp like 3 deoxyglucosone, glyoxal,
methylglyoxal
MECHANISM:
 Modification of intracellular proteins (regulation of gene transcription)
 Modify extracellular matrix protein (changes signaling between the
matrix and cell and causes cellular dysfunction)
 Modify circulating proteins (albumin. Bind to AGE receptors and
activate , causing production of inflammatory cytokines & growth
factors, in turn causes vascular pathology)

18. AGE PRECURSORS

19. AGE GENERATION - CONTD
 RECEPTORS:
 RAGE
 AGE receptor:AGE-R1, AGE-R2, and AGE-R3/galactin-3
 ezrin, radixin, and moesin (ERM) family
RAGE: Ig superfamily of receptors.
 Activation of secondary messenger PK- C.
 Target for rage signalling is NF-B transcription of intercellular adhesion
molecule-1, E- selectin, endothelin 1, tissue factor, VEGF, cytokines

21. Advanced glycation products in
vascular pathology.

22. Advanced glycation products in
nephropathy

23. Advanced glycation products are
metabolized to small peptides

24. ACTIVATION OF PK-C

25. ACTIVATION OF PK-C
 Hyperglycemia ↑ synthesis of a DAG
 A cofactor for protein kinase-C α, β, δ
 Effects gene expression –
↓eNOS
↑endothelin
↑TGF β
↑PAI- 1
George King, showing that inhibition of PKC prevented early changes in
the diabetic retina and kidney

26. INCREASED FLUX THROUGH HEXOSAMINE
PATHWAY

27. INCREASED FLUX THROUGH HEXOSAMINE
PATHWAY
 GFAT (glutamine:fructose-6 phosphate amidotransferase)
 Fructose-6 phosphate to glucosamine-6 phosphate and finally to
UDP N-acetyl glucosamine.
 N-acetyl glucosamine gets attached to serine and threonine residues
of transcription factors  changes in gene expression
 phosphorylation, and overmodification by this glucosamine often
results in pathologic changes in gene expression
 increased modification of Sp1  ↑TGFβ 1, PAI 1

28. SUPEROXIDE PRODUCTION BY ETC

29. SUPEROXIDE PRODUCTION BY ETC
 In diabetic cells – more glucose oxidized in the TCA cycle  more
NADH and FADH2  voltage gradient across mitochondrial
membrane increases
 Electron transfer inside complex III is blocked  coenzyme Q
donates electrons to molecular oxygen, generating superoxide
 Mn SOD degrades O2⁰- to H2O2 subsequently H2O and O2

31. SUPEROXIDE PRODUCTION BY ETC
 Hyperglycemia ↑ production of ROS
 If mitochondria ETC is removed, the effect of hyperglycemia on ROS
production is lost
 UCP effect mitochondrial electron transport chain is the source of
the hyperglycemia-induced superoxide

32. SUPEROXIDE ACTIVATES 4 MECHANISMS
Nature 414:813–820, 2001

33. UNIFIED PATHWAY
 Hyperglycemia in cells, decrease activity of enzyme GAPDH
 Intermediates upstream to GAPDH -↑
 ↑ glyceraldehyde-3-phosphate *activates AGE pathway
*activates the PKC pathway

34. UNIFIED PATHWAY
 ↑ F6P increases flux through hexosamine pathwayUDP-GlcNAc
 Inhibition of GAPDH increases intracellular levels glucose  ↑ flux
through the polyol pathway
 Hyperglycemia induced superoxide inhibits GAPDH activity by
modifying the enzyme with poly ADP-ribose

35. PARP ACTIVATION

36. PARP ACTIVATION
 PARP : nucleus, inactive
 increased ROS in the mitochondria, induce DNA strand breaks 
activating PARP
 PARP splits the NAD into : nicotinic acid and ADP-ribose
 PARP makes polymers of ADP-ribose accumulate on GAPDH and
other nuclear proteins leads to reduced activity

37. MACROVASCULAR
COMPLICATIONS

38. MACROVASCULAR COMPLICATIONS
 Hyperglycemia is not the major determinant of macrovascular
disease(UKPDS)
 Insulin resistance ↑ FFA flux from adipocytes into arterial
endothelial cells ↑ FFA oxidation  generate NADH and
FADH2overproduction of ROS
 Activates AGEs, PKC, the hexosamine pathway and NFB pathway

39. REFERENCES
 Williams Textbook of Endocrinology 12th Edition
 Brownlee M: Banting Lecture 2004,The Pathobiology of Diabetic
complications.Diabetes 54:1615-27
 Gohs, Copper M E, The Role of Advanced Glycation End Products in Progression
and Complications of Diabetes. J Clin Endocrinol Metab, 93(4):1143–1152
 Yamagashi S, Matsui T, Advanced glycation end products, oxidative stress and
diabetic nephropathy. Oxidative Medicine and Cellular Longevity 3:2, 101-108

41. Diagnostic criteria for diabetic ketoacidosis (DKA)
and hyperosmolar hyperglycemic state (HHS)