Microvascular complications of diabetes pathophysiology

MICROVASCULAR COMPLICATIONS OF DIABETES MELLITUS PATHOPHYSIOLOGY

BY: - MWIZERWA Jean-Luc ( 5th year medical student at UNIVERSITY OF RWANDA)

INTRODUCTIONConsistent with clinical evidence defining the critical role of

hyperglycemia in microvascular disease.

Data indicate that high intracellular levels of glucose in cells that cannot down-regulate glucose entry:

endothelium, glomerulinerve cells

INTRODUCTION – con’t

result in microvascular damage via four distinct, diabetes-specific pathways that were sequentially discovered

(1) increased polyol pathway flux(2) increased formation of advanced glycation end-product (AGE),(3) activation of protein kinase C (PKC)(4) increased hexosamine pathway flux.

Mechanisms of microvascular damage initiated by intracellular hyperglycemia.

Overproduction of reactive oxygen species (ROS) in response to high glucose is thought to:

inhibit glyceraldehyde-3-phosphate dehydrogenase (GAPDH), thus

increasing the concentration of upstream glycolytic metabolites that are shunted into alternative pathways.

Among these are:(1) conversion of glucose to sorbitol depletes NADPH, thus preventing the regeneration of ROS scavengers;

(2) conversion of fructose-6-phosphate to uridine diphosphateN-acetylglucosamine (UDP-GLcNAc) leads to protein modifications that alter gene expression;

(3) glyceraldehyde-3 phosphate is metabolized toform diacylglycerol (DAG), which in turn activates protein kinase C (PKC), resulting in altered vascular hemodynamics

(4) carbonyls formed by multiple mechanisms, including oxidation of glyceraldehyde-3 phosphate to form methylglyoxal, react irreversibly with proteins to formdysfunctional products (advanced glycosylated end-products, AGE) that cause intracellular and extracellular vascular changes.

1. Polyol pathway It has been extensively studied in diabetic nerve cells and is also present

in endothelial cells.

Many cells contain aldose reductase, an enzyme that convertstoxic aldehydes to their respective alcohols (polyol pathway).

Aldose reductase has a low affinity for glucose, in case of intercellular hyperglycemia, this pathway can account for up to one-third of glucose flux, converting glucose to sorbitol.

excess sorbitol was originally thought to cause osmotic damage, more recent data instead suggest that the real culprit is the consumption of NADPH during glucose reduction.

NADPH is required to regenerate reduced glutathione (GSH), athiol that detoxifies reactive oxygen species, NADPH consumption prevents the clearance of damaging free radicals.

2. HEXOSAMINE PATHWAY

Increased shunting of glucose through the hexosaminepathway via diversion of the glycolytic intermediate, fructose- 6-phosphate, is also postulated to play a role in microvascular disease.

The hexosamine pathway contributes to insulin resistance, producing substrates that, when covalently

linked to transcription factors, stimulate the expression of proteins, such as transforming growth factor and plasminogen activator inhibitor, that enhance microvascular damage.

3. FORMATION OF DAGDicarbonyl formation from direct auto-oxidation of glucose also

contributes to AGE formation

Intracellular endothelial hyperglycemia stimulates glycolysis and, with this, an increase in the de novo synthesis of diacylglycerol (DAG) from the glycolytic intermediate, glyceraldehyde-3-phosphate

DAG, in turn, activates several isoforms of protein kinase C (PKC) that are present in these cells.

This inappropriate activation of PKC alters bloodflow and changes endothelial permeability, in part via effects on nitric oxide pathways, and also contributes to thickening of the extracellular matrix.

4.Formation of advanced glycosylation end-products (AGEs) The formation of irreversibly glycated proteins called (AGEs) also causes

microvascular damage in diabetes.

When present in high concentrations:

glucose can react reversibly and nonenzymatically with protein amino groups to form an unstable intermediate, a Schiff base,

which then undergoes an internal rearrangement to form a more stable glycated protein, also known as an early glycosylation product (Amadoriproduct) such as hemoglobin A1c

Such a reaction accounts for the formation of glycated HbA, also known as HbA1c.

In diabetics, elevated glucose leads to increased glycation of HbA within red blood cells. Because red blood cells circulate for120 days, measurement of HbA1c in diabetic patients servesas an index of glycemic control over the preceding months.

Early glycosylation products can undergo a further series ofchemical reactions and rearrangements, often involving theformation of reactive carbonyl intermediates, leading to theirreversible formation of AGE.

AGE damage the microvasculature Via 3 major pathways:

(1) intracellular AGE formation from proteins involved in transcription alters endothelial gene expression

(2) irreversible cross linking of AGE adducts formed from matrix proteins results in vascular thickening and stiffness

(3) binding of extracellular AGE adducts to AGE receptors (RAGE) on macrophages and endothelium stimulates NF-κB-regulated inflammatory cascades and resultant vascular dysfunction.

Explanation of figure The formation of advanced glycosylation end-products (AGEs) occurs via

multiple pathways:

1) The reversible formation of glycated proteins (Amadori products), such as hemoglobin A1c, through a complex series of chemical reactions, or 2) the direct oxidation of glucose and its metabolites (eg, glyceraldehyde-3 phosphate, G3P), result in the production of reactive dicarbonyls.

These moieties react irreversibly with proteins to form AGE.

More recent information suggests that increased flux through these four pathways is induced by a common factor

overproduction of mitochondrial-derived reactive oxygen species generated by increased flux of glucose through the TCA cycle

The end result of these changes in the microvasculature is:

1)an increase in protein accumulation in vessel walls,

2) endothelial cell dysfunction,

3) loss of endothelial cells, and,

4) occlusion.

Evidence suggests that all four of these pathways may actually be linked by a common mechanistic element:

Hyperglycemia induced oxidative stress.

In particular, the increase in electron donors that results from shunting glucose through the tricarboxylic acid cycle

increases mitochondrial membrane potential by pumping proteins across the mitochondrial inner membrane.

This increased potential prolongs the half-life of superoxide generating enzymes, thus increasing the conversion of O2 to O2–.

These increased reactive oxygen species lead:

to inhibition of the glycolytic enzyme, glyceraldehyde-3phosphate dehydrogenase (GADPH), and

a resultant increase in upstream metabolites that can now be preferentially diverted into the four mechanistic pathways

REFERENCES

Gary D. H., Stephen J. M.Pathophysiology of diseases- An introduction to clinical medicine, seventh edition. Chapter 18 Disorders of the Endocrine Pancreas, pg 534-538.