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.

Adiponectin isoforms in elderly patients with or without coronary artery disease.

OBJECTIVES: To study the distribution of adiponectin isoforms in a group of very old patients. DESIGN: Cross-sectional. SETTING: Geriatric ambulatory clinic of the Department of Medicine at Policlinico "Tor Vergata." PARTICIPANTS: One hundred eight elderly adults (mean age 85.0+/-3.2) with or without a history of a previous myocardial infarction as proof of established coronary artery disease (CAD) at least 3 months before entry into the study. Accordingly, subjects were divided into CAD positive (CAD+, n=50) and CAD negative (CAD-, n=58). MEASUREMENT: Assessment of adiponectin isoforms along with metabolic, lipid, and inflammatory profiles. RESULTS: CAD+ subjects had significantly higher levels of total adiponectin (Tot-Ad) and low-molecular-weight adiponectin (LMW-Ad) than CAD- subjects (P=.008 for both). LMW-Ad and high-sensitivity C-reactive protein were positively correlated, even after adjustment for waist circumference, sex, glomerular filtration rate, and presence of diabetes mellitus (correlation coefficient (r)=0.25, P=.05). This association was not confirmed when CAD+ subjects were analyzed alone. A positive association was found in CAD+ subjects between brain natriuretic peptide (BNP), high-molecular-weight adiponectin (HMW-Ad), and Tot-Ad (r=0.798 and r=0.795, P<.001 for all) but not LMW-Ad. CONCLUSION: Distribution of adiponectin isoforms differed in populations of elderly subjects according to the presence of coronary atherosclerosis. The data support the hypothesis for a protective role of LMW-Ad during aging, although additional studies are needed to definitively clarify whether LMW-Ad plays a protective role in older people with a history of CAD.

Fish oil supplementation improves endothelial function in normoglycemic offspring of patients with type 2 diabetes.

OBJECTIVE: Offspring of patients with type 2 diabetes (OPDs) exhibits endothelial dysfunction (ED) associated with a chronic inflammatory state. N-3 polyunsaturated fatty acids (n-3 PUFA) may have antioxidant and anti-inflammatory properties that are beneficial for cardiovascular and metabolic health. Therefore, in the present study, we tested the hypothesis that dietary supplementation with fish oil rich in n-3 PUFA may improve ED in otherwise healthy OPDs. METHODS AND DESIGN: A double-blind, placebo-controlled trial was conducted with 50 OPDs. Participants were randomized to treatment with either placebo or n-3 PUFA (2g/day) for 12 weeks. Before and after treatment we evaluated endothelial function (using flow-mediated dilation (FMD) of the brachial artery), circulating inflammatory markers (adiponectin, TNF-alpha, and high sensitivity-CRP), and insulin resistance (QUICKI). RESULTS: No significant changes were observed in study outcomes in subjects treated with placebo. By contrast, when compared with baseline values, subjects treated with n-3 PUFA had significant improvement in FMD (9.1+/-5.8% vs. 11.7+/-4.4%, p=0.02) that was accompanied by decreased plasma triglycerides (117+/-73mg/dl vs. 86+/-44mg/dl, p=0.001) and TNF-alpha levels (8.9+/-2.3pg/ml vs. 6.8+/-2.7pg/ml, p=0.001), and a trend towards increased plasma adiponectin levels (7.8+/-4.5microg/ml vs. 9.5+/-5.1microg/ml, p=0.09). When data were analyzed by multiple regression analysis, decreased TNF-alpha after treatment with n-3 PUFA predicted increased FMD. CONCLUSION: Dietary supplementation with n-3 PUFA significantly improved endothelial function and reduced pro-inflammatory markers in OPDs. Thus, fish oil consumption may have beneficial cardiovascular and metabolic health effects in otherwise healthy subjects predisposed to diabetes and its vascular complications.

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.