Insulin resistance is a uniform finding in type 2 diabetes, as are abnormalities in the microvascular and macrovascular circulations. These complications are associated with dysfunction of platelets and the neurovascular unit. Platelets are essential for hemostasis, and knowledge of their function is basic to understanding the pathophysiology of vascular disease in diabetes. Intact healthy vascular endothelium is central to the normal functioning of smooth muscle contractility as well as its normal interaction with platelets. What is not clear is the role of hyperglycemia in the functional and organic microvascular deficiencies and platelet hyperactivity in individuals with diabetes. The entire coagulation cascade is dysfunctional in diabetes. Increased levels of fibrinogen and plasminogen activator inhibitor 1 favor both thrombosis and defective dissolution of clots once formed. Platelets in type 2 diabetic individuals adhere to vascular endothelium and aggregate more readily than those in healthy people. Loss of sensitivity to the normal restraints exercised by prostacyclin (PGI 2 ) and nitric oxide (NO) generated by the vascular endothelium presents as the major defect in platelet function. Insulin is a natural antagonist of platelet hyperactivity. It sensitizes the platelet to PGI 2 and enhances endothelial generation of PGI 2 and NO. Thus, the defects in insulin action in diabetes create a milieu of disordered platelet activity conducive to macrovascular and microvascular events. Diabetes Care 24:1476 -1485, 2001I nsulin resistance (IR) (i.e., resistance to insulin-stimulated glucose uptake) presents in a majority of individuals with type 2 diabetes; it appears to be a common precursor of both diabetes and macrovascular disease (1). IR is a multisystem disorder that is associated with multiple metabolic and cellular alterations. Factors that contribute to IR are genetics, obesity, physical inactivity, and advancing age (2). Metabolic disturbances that commonly occur in patients with IR are atherogenic dyslipidemia, hypertension, glucose intolerance, and a prothrombotic state (1,2).Atherogenic dyslipidemia is characterized by three lipoprotein abnormalities: elevated VLDL, small LDL particles, and decreased HDL cholesterol levels (the lipid triad), also named the atherogenic lipoprotein phenotype (2). This triad is the hallmark of people with diabetes and IR and appears to be an atherogenic phenotype independent of elevated levels of LDL cholesterol (2). As a corollary, most patients with IR have this phenotype even if they are not diabetic, and it may precede the development of diabetes by many years (2).Hypertension, a well-established risk factor for macrovascular events, is also associated with IR. In fact, a direct relationship between plasma insulin concentration and blood pressure has been noted (1). Although the list of multifactorial events that link hypertension and IR is growing (3), currently, the emphasis rests on the role of the endothelial cell.Hypertension is a component of the metabolic synd...

One of the most overlooked of all serious complications of diabetes is cardiovascular autonomic neuropathy. There is now clear evidence that suggests activation of inflammatory cytokines in diabetic patients and that these correlate with abnormalities in sympathovagal balance. Dysfunction of the autonomic system predicts cardiovascular risk and sudden death in patients with type 2 diabetes. It also occurs in prediabetes, providing opportunities for early intervention. Simple tests that can be carried out at the bedside with real-time output of information – within the scope of the practicing physician – facilitate diagnosis and allow the application of sound strategies for management. The window of opportunity for aggressive control of all the traditional risk factors for cardiovascular events or sudden death with intensification of therapy is with short duration diabetes, the absence of cardiovascular disease and a history of severe hypoglycemic events. To this list we can now add autonomic dysfunction and neuropathy, which have become the most powerful predictors of risk for mortality. It seems prudent that practitioners should be encouraged to become familiar with this information and apply risk stratification in clinical practice. Several agents have become available for the correction of functional defects in the autonomic nervous system, and restoration of autonomic balance is now possible.

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Diabetic autonomic neuropathy can cause heart disease, gastrointestinal symptoms, genitourinary disorders, and metabolic disease. Strict glycemic control can slow the onset of diabetic autonomic neuropathy and sometimes reverse it. Pharmacologic and nonpharmacologic therapies are available to treat symptoms.

The present study has been designed to determine melatonin levels in type 2 diabetic patients and test the relationship between the autonomic nervous system and melatonin dynamics. Thirty-six type 2 diabetic patients and 13 age-matched healthy subjects were recruited for the study. Circadian rhythm of melatonin secretion was assessed by measuring serum melatonin concentrations between 02:00-04:00 and 16:00-18:00 hr. Melatonin dynamics were re-evaluated with respect to autonomic nervous system in diabetic patients with autonomic neuropathy who were diagnosed by the cardiovascular reflex tests, heart rate variability (HRV), and 24-hr blood pressure monitoring. Nocturnal melatonin levels and the nocturnal melatonin surge were low in the diabetic group (P = 0.027 and 0.008 respectively). Patients with autonomic neuropathy revealed decreased melatonin levels both at night and during day when compared with healthy controls (P < 0.001 and 0.004 respectively) while the melatonin dynamics were similar to controls in patients without autonomic neuropathy. Nocturnal melatonin level was positively correlated with nocturnal high and low frequency components of HRV (P = 0.005 and 0.011 respectively) and systolic and diastolic blood pressures at night (P = 0.002 and 0.004 respectively) in patients with autonomic neuropathy. We found a negative correlation between nocturnal melatonin levels and the degree of systolic blood pressure decrease at night (r = -0.478, P = 0.045). As a conclusion this study has shown that circadian rhythm of melatonin secretion is blunted in type 2 diabetic patients and there is a complex relationship between various components of autonomic nervous system and melatonin secretion at night. Among the patients with autonomic neuropathy those with more preserved HRV and the systolic nondippers (<10% reduction in blood pressure during the night relative to daytime values) have more pronounced melatonin surge at night.