Diabetes-specific microvascular disease is a leading cause of blindness, renal failure and nerve damage, and diabetes-accelerated atherosclerosis leads to increased risk of myocardial infarction, stroke and limb amputation. Four main molecular mechanisms have been implicated in glucose-mediated vascular damage. All seem to reflect a single hyperglycaemia-induced process of overproduction of superoxide by the mitochondrial electron-transport chain. This integrating paradigm provides a new conceptual framework for future research and drug discovery.

http://www.chem.uwec.edu/Chem454/BiochemDiabetes.pdf

Biochemistry and molecular cell biology of diabetic complications

It is increasingly apparent that not only is a cure for the current worldwide diabetes epidemic required, but also for its major complications, affecting both small and large blood vessels. These complications occur in the majority of individuals with both type 1 and type 2 diabetes. Among the most prevalent microvascular complications are kidney disease, blindness, and amputations, with current therapies only slowing disease progression. Impaired kidney function, exhibited as a reduced glomerular filtration rate, is also a major risk factor for macrovascular complications, such as heart attacks and strokes. There have been a large number of new therapies tested in clinical trials for diabetic complications, with, in general, rather disappointing results. Indeed, it remains to be fully defined as to which pathways in diabetic complications are essentially protective rather than pathological, in terms of their effects on the underlying disease process. Furthermore, seemingly independent pathways are also showing significant interactions with each other to exacerbate pathology. Interestingly, some of these pathways may not only play key roles in complications but also in the development of diabetes per se. This review aims to comprehensively discuss the well validated, as well as putative mechanisms involved in the development of diabetic complications. In addition, new fields of research, which warrant further investigation as potential therapeutic targets of the future, will be highlighted.

Mechanisms of Diabetic Complications

Products of advanced protein glycosylation (advanced glycation end products, or AGEs) accumulate in tissues as a function of time and sugar concentration. AGEs induce permanent abnormalities in extracellular matrix component function, stimulate cytokine and reactive oxygen species production through AGE-specific receptors, and modify intracellular proteins. Pharmacologic inhibition of AGE formation in long-term diabetic animals prevents diabetic retinopathy, nephropathy, neuropathy, and arterial abnormalities in animal models. Clinical trials in humans are currently in progress.

/pdf/advanced-protein-glycosylation-in-diabetes-and-aging-3u0tpm4hku.pdf

Advanced protein glycosylation in diabetes and aging

https://estudogeral.sib.uc.pt/bitstream/10316/5348/1/file612dd379704c461297578bde77f1762e.pdf

Diabetes and mitochondrial function: role of hyperglycemia and oxidative stress.

Context: Diabetic complications appear to be multifactorial in origin, but in particular, the biochemical process of advanced glycation, which is accelerated in diabetes as a result of chronic hyperglycemia and increased oxidative stress, has been postulated to play a central role in these disorders. Advanced glycation involves the generation of a heterogenous group of chemical moieties known as advanced glycated end products (AGEs), this reaction occurring as a result of a nonenzymatic reaction with glucose interacting with proteins, lipids, and nucleic acids, and involves key intermediates such as methylglyoxal. Evidence Synthesis: In this review we report on how these AGEs may exert deleterious effects in diabetes, as well as address current strategies to interrupt the formation or action of AGEs. First, AGEs act directly to induce cross-linking of long-lived proteins such as collagen to promote vascular stiffness, and, thus, alter vascular structure and function. Second, AGEs can interact with certain...

/pdf/the-role-of-advanced-glycation-end-products-in-progression-ez2bybickx.pdf

The role of advanced glycation end products in progression and complications of diabetes

This study evaluated the relationship between the development of fluorescence related to advanced glycosylation end products (AGEs) in the kidney and experimental diabetic nephropathy over a 32-wk period. Control, untreated diabetic, and aminoguanidine-treated diabetic rats were followed for 32 wk with eight weekly measurements of urinary albumin excretion. After 32 wk, collagen-related fluorescence in aorta and kidney (whole kidney, isolated glomeruli, and renal tubules) and glomerular ultrastructure were evaluated. Diabetes was associated with a significant increase in collagen-related fluorescence in the aorta and kidney. Aminoguanidine prevented the increases in collagen-related fluorescence in aorta, isolated glomeruli, and renal tubules but not in whole kidney. Diabetes was associated with increased albuminuria, fractional mesangial volume, and glomerular basement membrane (GBM) thickness. Aminoguanidine attenuated the rise in albuminuria and prevented mesangial expansion without influencing GBM thickness in diabetic rats. The concomitant changes in collagen-related fluorescence, albuminuria, and mesangial expansion with aminoguanidine therapy are consistent with the hypothesis that AGEs may play a role in the development of diabetic nephropathy.

Retardation by Aminoguanidine of Development of Albuminuria, Mesangial Expansion, and Tissue Fluorescence in Streptozocin-Induced Diabetic Rat

Streptozotocin (STZ) diabetes was induced in spontaneously hypertensive (SHR) and normotensive Wistar-Kyoto (WKY) rats. Body weight, blood pressure, renal function, glycaemic control and proteinuria were assessed monthly for 32 weeks. At 32 weeks, the animals were killed and glomerular basement membrane (GBM) thickness and fractional mesangial volume were measured. There was no significant difference in renal function between diabetic SHR and diabetic WKY. Diabetic SHR showed an earlier and larger rise in total proteinuria and urinary albumin excretion than diabetic WKY. Urinary albumin excretion was increased more than tenfold in diabetic SHR compared to diabetic WKY after 32 weeks of diabetes. GBM thickness was significantly increased in diabetic SHR compared with diabetic WKY. Both diabetic WKY and diabetic SHR showed mesangial expansion when compared to their nondiabetic counterparts. On the other hand, both hypertensive models showed increased glomerular volume, which was not influenced by the presence of diabetes. The diabetic SHR model has features of accelerated nephropathy, as evidenced by increased albuminuria and GBM thickness. This suggests that pre-existing hypertension may play an important role in the progression of diabetic renal disease.

Effects of genetic hypertension on diabetic nephropathy in the rat--functional and structural characteristics.

The clinical, radiologic, and pathological features of eight cases of fibrohistiocytic bone lesions histologically identical to the nonossifying fibroma of childhood arc presented. They differed from the childhood lesion in their clinical and radiological features. They occurred in adults, a

Benign fibrous histiocytoma of bone.

We compared the effects of the angiotensin-converting enzyme inhibitor enalapril and a conventional antihypertensive regimen (hydralazine and metoprolol) on kidney function, albuminuria, and glomerular ultrastructure in hypertensive diabetic and nondiabetic rats. Diabetes was induced with streptozocin at 8 wk of age in spontaneously hypertensive (SHR) rats. Antihypertensive drugs were administered in drinking water from the time of induction of diabetes in all groups. Blood pressure reduction was equal in the diabetic and nondiabetic SHR rats receiving either enalapril or hydralazine plus metoprolol. In diabetic SHR rats, there was a rise in serum creatinine after 32 wk, which did not occur in diabetic rats treated with either antihypertensive regimen or in nondiabetic rats. Both drug regimens reduced albuminuria in diabetic and nondiabetic SHR rats to a similar degree. Enalapril and the combination of hydralazine and metoprolol were associated with decreased glomerular basement membrane thickness and glomerular volume in diabetic and nondiabetic SHR rats without significant effect on fractional mesangial volume. Thus, antihypertensive therapy retards the development of albuminuria, glomerular basement membrane thickening, and glomerular hypertrophy in the rat in the presence or absence of diabetes. No specific benefit of angiotensin-converting enzyme inhibition was observed in these hypertensive models of nephropathy. Human studies comparing the effects of different classes of antihypertensive drugs on kidney function, proteinuria, and glomerular morphology are warranted.

Nephropathy in model combining genetic hypertension with experimental diabetes. Enalapril versus hydralazine and metoprolol therapy.

This study has evaluated the effects of the angiotensin converting enzyme inhibitor Enalapril on glomerular ultrastructure and albuminuria in normotensive and hypertensive diabetic rats. Streptozotocin-diabetes was induced in Wistar Kyoto and spontaneously hypertensive rats. Enalapril was administered in drinking water in diabetic normotensive, control hypertensive and diabetic hypertensive rats. Enalapril therapy prevented an increase in glomerular basement membrane thickness in diabetic normotensive, control hypertensive and diabetic hypertensive rats without any significant effect on fractional mesangial volume. Enalapril decreased albuminuria in diabetic normotensive, control hypertensive and diabetic hypertensive rats. Thus, enalapril retards the development of glomerular basement membrane thickening and albuminuria in the rat, in the presence or absence of hypertension.

/pdf/enalapril-retards-glomerular-basement-membrane-thickening-3w5i1ko5la.pdf

Belinda E. Clarke

Papers

Retardation by Aminoguanidine of Development of Albuminuria, Mesangial Expansion, and Tissue Fluorescence in Streptozocin-Induced Diabetic Rat

Effects of genetic hypertension on diabetic nephropathy in the rat--functional and structural characteristics.

Benign fibrous histiocytoma of bone.

Nephropathy in model combining genetic hypertension with experimental diabetes. Enalapril versus hydralazine and metoprolol therapy.

Enalapril retards glomerular basement membrane thickening and albuminuria in the diabetic rat.