Diabetic Complications
The How And Why

GR Sridhar, Endocrine and Diabetes Centre, Visakhapatnam - 530002.

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Diabetes mellitus is defined, based on the risk of getting complications beyond a certain level of blood glucose. Sir Robert Hutchison appealed, '.from making the cure of the disease more grievous than the endurance of the same, Good Lord, deliver us.' Beyond the cut-off mark of normal blood glucose, enduring the condition would, eventually be 'more grievous' than attempts to control it.

The prevalence of diabetes mellitus is increasing over time, especially in developing countries such as India. It is being diagnosed nearly a decade earlier than in the west. In a large computerized database of individuals with endocrine diseases at Visakhapatnam, we reported the following demographic and risk factors (1).

Prevalence of risk factors in diabetes mellitus (n: 8959)

Male-female 5638(M)-3321(F)
Known hypertension 2073 (23.14%)
Known coronary artery disease 397(4.43%)
Current smokers (men) 1264 (22.4%)
Sedentary: Men 2572 (45.6%)
Sedentary: Women 2986 (89.9%)

In addition we looked at the prevalence of known complications of diabetes mellitus at the time of entry into the database. The details are given below:

Prevalence of known complications in diabetes mellitus (n: 8959)

In this chapter we shall examine the pathogenesis of diabetic vascular complications, which account for most morbidity and mortality. This would allow us to understand why complications set in and as a corollary, allow us to prevent them from developing.

Complications in diabetes can be grouped into

  1. Microvascular complications
  2. Macrovascular complications

Both micro and macrovascular complications result from dysfunction and damage of vascular endothelial cells. Microvascular disease is diabetic-specific and is similar across different ethnic groups (2). Macrovascular complications result from other factors as well including cultural, ethnic or genetic, in addition to hypertension, dyslipidemia and central obesity (3). That is they are caused by a combination of specific abnormalities along with an acceleration of vasculopathies found in non-diabetic population also (4). Both metabolic and hormonal imbalances contribute to the complications.

Mechanisms in the pathogenesis of complications

The three possible mechanisms leading to diabetic complications are

Overglycation of proteins When proteins are exposed over long times to hyperglycemia, there is condensation of glucose with primary amines to form Schiff bases. The glucose-protein adducts spontaneously rearrange to form Amadori products and advanced glycation end products (AGE). Reactive oxygen species generated from the glycation process increase cross-linking of extracellular matrix, quench nitric oxide and may damage DNA (5). When hyperglycemia is chronic, glycation products result in irreducible destruction of tissues, the 'hyperglycemic memory' (6). AGE formation can cause pathological changes by (a) rapid formation of AGE by glucose in the cell can directly alter protein function in target tissues, (b) AGEs alter signal transduction pathways involving ligands on extracellular matrix, (c) AGEs alter the level of signals such as cytokines, hormones and free radicals, through interactions with AGE -specific cellular receptors (7), A recent study has shown that interaction between the advanced glycation endproducts and their receptor is involved in the development of accelerated atherosclerosis. The receptor can be a new target for therapeutic agents in the treatment of diabetic macrovascular disease (8). Clinical studies are under way to see whether inhibitors of AGE have a significant role in the prevention or treatment of diabetic retinopathy, neuropathy and accelerated atherosclerosis.

Increase in polyol pathway activity Activation of polyol pathway is an acute response to hyperglycemia. Raised intracellular glucose levels as a result of hyperglycemia occur in insulin-independent tissues such as nerve, glomerulus, lens and retina. Aldose reductase, the rate-limiting enzyme of the polyol pathway catalyses the reduction of glucose to sorbitol, which is subsequently converted to fructose. Sorbitol, which does not easily cross cell membranes, accumulates within the cell. It may damage through osmotic effects (eg in the lens), by altering the redox state of pyridine nucleotides (ie increasing the NADH/NAD ratio) and by depleting intracellular myoinositol levels. Myoinositol depletion in animals may impair peripheral nerve function, probably by inhibiting Na-K-ATPase activity. This would impede sodium ion extrusion, increasing intracellular Na concentration, which can inhibit depolarization and slow nerve conduction velocity. Although inhibitors of aldose reductase decrease certain neurological and renal abnormalities in diabetic rats, the few clinical studies have shown no effect of these drugs on diabetic vascular complications (9). A more complete understanding of the full web of consequences of sorbitol pathway activation allows tissue-specific interventions tailored to the predominant impact of the sorbitol pathway (10).

Hemodynamic abnormalities Blood flow through the microcirculation is normally tightly regulated by autonomic innervation, local reflexes, circulating mediators and locally produced vasoactive substances such as nitric oxide (vasodilator) and endothelin (vasoconstrictor). Early hemodynamic abnormalities include increased blood flow in skin, retina and kidney. These appear early in insulin-dependent diabetes mellitus before evidence of structural microvascular damage. These abnormalities are related to the duration and severity of hyperglycemia, and are irreversible following chronic hyperglycemia (11). Microvascular changes may develop in a specific subgroup of susceptible diabetic subjects (4). Diabetes is also associated with hypercoagulation. Plasma levels of plasminogen activator inhibitor I are increased and may account for decreased fibrinolysis. In addition endothelial dysfunction may reduce the anticoagulant properties of the endothelium.

Diabetes and accelerated atherosclerosis

Diabetes is a well-known risk factor for atherosclerosis, and cardiovascular disease is the most common complication of type 2 diabetes mellitus in Europeans (12).
Factors responsible for accelerated atherosclerosis in diabetes include

Genetic mechanisms Genetic polymorphisms in renin-angiotensin system have been implicated in the pathogenesis of diabetic vascular disease (13,14). Plasma levels of lipoprotein (a) were reported to be high in type 2 diabetes patients from Australia (14).

Lipid abnormalities Disorders of lipid are common in diabetes mellitus, and include hypertriglyceridemia, low HDL cholesterol and elevated LDL cholesterol (14). Type 1 diabetic patients with insulin deficiency may have increased levels of chylomicrons and VLDL, which are corrected by insulin therapy. Type 2 diabetic patients often have hypertriglyceridemia in part because of obesity. When liver is overloaded with dietary carbohydrate and free fatty acids from adipocytes, VLDL triglyceride production is stimulated. Increased FFA levels are due to resistance by adipocytes to antilipolytic action of insulin, and triglyceride clearance may be impaired by reduction in lipoprotein lipase levels.
Elevated LDL cholesterol results from may causes including

Elevated LDL levels become atherogenic when they are oxidized to minimally modified LDL, which induces formation of chemotactic factors.

Low HDL cholesterol is seen in poorly controlled diabetes, especially type 2 variety and could contribute to coronary artery disease in women. Low HDL levels may be due to

Platelets, prostaglandins Increased aggregation of platelets may contribute to atherogenesis and microangiopathy. Enhanced adhesiveness of platelets at sites of vessel injury is seen in both forms of diabetes, even before clinical atherosclerosis due to (15)

Hyperinsulinemia in diabetic complications

Insulin sensitivity is controlled by genetic factors, and is reduced in type 2 diabetes independent of obesity. The presence of one condition ie type 2 diabetes or hypertension predicts the subsequent appearance of the other. However insulin resistance may anticipate or precipitate diabetes, hypertension or dyslipidemia, but is insufficient by itself to directly full-blown conditions of either. Insulin resistance stands for a conglomerate of changes; whether a marker of mechanism, it is likely to result in cardiovascular morbidity.

In conclusion
Microvascular complications are more of a specific diabetic etiology. Macrovascular complications result from others, both nature and nurture, including life style factors such as sedentary habits and smoking (1). An understanding of the pathogenesis makes it clear that unbridled hyperglycemia could ultimately lead to complications; it is also possible there could be a time window, beyond which achieving euglycemia may not reverse biochemical processes that occurred during the period of prolonged hyperglycemia.


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