QTc and autonomic neuropathy in diabetes: effects of acute hyperglycaemia and n-3 PUFA.

BACKGROUND AND AIMS: Autonomic function is also regulated by glycaemia and exerts a crucial role in the control of blood pressure and cardiac function. The disruption of this physiological mechanism impacts deeply on cardiovascular mortality in diabetes. We investigated the influence of autonomic dysfunction on QTc interval and on sympatho-vagal balance (LF/HF), in response to acute hyperglycaemia and to membrane electrical stabilization (n-3 PUFA). METHODS AND RESULTS: Twenty-four type 2 diabetic patients, without (N-: n=13) or with (N+: n=11) autonomic neuropathy and 13 healthy subjects (C) underwent BP and ECG monitoring during a 24-h period and during a 2-h hyperglycaemic clamp. Delta QTc during the night was blunted in diabetics (0.5+/-2.5 vs. C: 2.9+/-2.5%, p=0.001), and Delta LF/HF was decreased in N+ (-2.8+/-38.2 vs. C=34.8+/-28.1%, p=0.02). During hyperglycaemia, QTc increased in C; LF/HF significantly increased in C and N-. A 6-month treatment with n-3 PUFA partially restored Delta LF/HF and Delta QTc (2.1+/-1.40, p=0.04 vs. basal) only in N-. CONCLUSION: Hyperglycaemia increases QTc interval and sympathetic activity; electrical membrane stabilization improves autonomic function only in the absence of overt autonomic neuropathy. Strategies to prevent the disruption of autonomic function with newer approaches, other than just glucose control, should be implemented.

Relationship between autonomic dysfunction, insulin resistance and hypertension, in diabetes.

Sympathovagal imbalance and insulin resistance are the common underlying disorders linking hypertension and diabetes. The role of hyperinsulinemia, however, on sympathovagal balance and blood pressure has never been clearly dissected from that of hyperglycemia. Nevertheless, the study of animal models of hypertension showed that hypertension does not invariably result in the onset of insulin resistance. This suggests that insulin resistance precedes the onset of hypertension and (possibly) contributes to its pathogenesis, mainly through sympathetic activation. To examine this hypothesis, recent studies investigated the relationship between insulin sensitivity and sympathetic activity in subjects with insulin resistance but free of overt hyperglycemia and obesity, i.e., insulin-resistant offspring of type 2 diabetic patients, demonstrating a prevalence of sympathetic over vagal activity. Therefore insulin resistance and sympathovagal imbalance come before hypertension, but a clear causative role cannot be demonstrated since other mechanisms, including an inappropriate lifestyle, must be taken into account to determine clinical hypertension. Finally, several experiments in human healthy volunteers suggest that the modulation of autonomic regulation at the forearm level can regulate insulin sensitivity, tempting us to speculate that it is the primary autonomic imbalance, through vasoconstriction, that results in both insulin resistance and hypertension. In conclusion, the close relationship between autonomic imbalance, insulin resistance and hypertension is unquestionable; although logical hypothesis can be constructed, which of the three is the earliest event is still not understood, and further research is required.

The Arg972 variant in insulin receptor substrate-1 is associated with an atherogenic profile in offspring of type 2 diabetic patients.

The insulin receptor substrate-1 (IRS-1) gene has been considered a candidate for insulin resistance, type 2 diabetes, and coronary artery disease. To investigate the relationship between the common Gly(972)Arg IRS-1 variant and the presence of cardiovascular risk factors, 153 glucose-tolerant, unrelated offspring of type 2 diabetic patients were studied. There were no differences between Arg(972) IRS-1 carriers and noncarriers in age, gender, body mass index, waist/hip ratio, body composition, fasting glucose and insulin levels, and glucose or insulin levels during the oral glucose tolerance test. Insulin sensitivity, assessed by hyperinsulinemic-euglycemic clamp, was significantly reduced in carriers of Arg(972) IRS-1 (P < 0.03). Carriers of Arg(972) IRS-1 displayed many features of the insulin resistance syndrome, including higher values for serum triglycerides (P < 0.01), total/high density lipoprotein cholesterol ratio (P < 0.01), free fatty acid levels (P < 0.04), systolic blood pressure (P < 0.04), microalbuminuria (P < 0.003), and intima-media thickness (P < 0.02). These results suggest that the Arg(972) IRS-1 variant could contribute to the risk for atherosclerotic cardiovascular diseases associated with type 2 diabetes by producing a cluster of insulin resistance-related metabolic abnormalities.

Early autonomic dysfunction in glucose-tolerant but insulin-resistant offspring of type 2 diabetic patients.

In type 2 diabetes, both insulin resistance and hyperglycemia are considered responsible for autonomic dysfunction, but the specific role of these two abnormalities is not clear. To test the specific role of insulin resistance on autonomic dysfunction, we studied 69 glucose-tolerant offspring of type 2 diabetic patients, comparing the most insulin-resistant tertile (IR) with the most insulin-sensitive tertile (IS) and comparable control subjects, all undergoing the oral glucose tolerance test, impedentiometry, 24-hour blood pressure and ECG monitoring, and an intravenous glucose tolerance test (IVGTT) followed by a euglycemic hyperinsulinemic clamp, with continuous blood pressure and ECG measurements. Sympathovagal balance was evaluated as low- to high-frequency ratio (LF:HF) by spectral analysis on R-R intervals. The change of systolic and diastolic blood pressure was calculated as [(day-night/d)]x100. In IR, the changes of systolic and diastolic blood pressure were significantly lower versus IS (9.2+/-5.0% versus 12.4+/-3.6%, P<0.02; 13.2+/-6.5% versus 17.4+/-5.2%, P<0.02). During the night, LF:HF fall was reduced in IR (43.1+/-21.0 versus 61.4+/-16.9, P<0.02). Hyperinsulinemia (IVGTT) rapidly and significantly increased LF:HF in IR (4.9+/-3.3 versus basal: 2.3+/-1.4, P=0.03) but not in IS. In offspring of type 2 diabetic patients with normal glucose tolerance and normal blood pressure values, insulin resistance is associated with abnormal control of blood pressure and sympathetic activation. Insulin resistance may therefore be responsible for some early derangements of the autonomic nervous tone control and thus contributes to increase the incidence of arterial hypertension and/or diabetes.