Abnormalities of carbohydrate metabolism and insulin sensitivity have been reported in estrogen deficiency. Estrogen replacement appears to result in an improvement in these parameters, although progestagens may antagonize these effects. We have examined the effects of transdermal estradiol and oral norethisterone on insulin sensitivity using the hyperinsulinemic euglycemic clamp method by performing a randomized, double blind, placebo-controlled study in 22 healthy women after a surgically induced menopause. After baseline measurements, subjects were randomized to receive either transdermal 17beta-estradiol (50 microg) or matching placebo patches for 6 weeks. The subjects were then further randomized to receive either estradiol in combination with oral norethisterone (1 mg) or a matching oral placebo preparation, crossing over after 6 weeks, with assessment of insulin sensitivity at the end of each treatment. No significant increase in insulin sensitivity was observed after 6 weeks of transdermal 17beta-estradiol treatment (95% confidence interval, -0.54, 1.86; P = 0.27). Addition of norethisterone for a further 6 weeks had no detectable effect on insulin sensitivity (95% confidence interval, -1.65, 1.10; P = 0.65). The results of this study using transdermal estradiol do not support previous reports that unopposed estrogens exert potentially beneficial effects on insulin sensitivity and suggest that the addition of an oral progestagen confers no clinically important risk or benefit. It is therefore unlikely that effects on insulin sensitivity contribute appreciably to the cardioprotective benefits attributed to hormone replacement therapy.

Summary Aims The association of the insertion/deletion polymorphism in the angiotensin‐converting enzyme (ACE) gene with cardiovascular disease and diabetic nephropathy remains a controversial issue. This review aims to give an overview of the research to date assessing the impact of the ACE polymorphism in Type 1 and Type 2 diabetes mellitus (DM). Methods A systematic review of the literature was performed in the databases of MEDLINE, PubMed and EMBASE for the key words ‘diabetes mellitus’, ‘diabetic nephropathy’, ‘ACE polymorphism’ and ‘genotype’ and relevant articles were considered. Results A meta‐analysis assessing the influence of the ACE polymorphism on disease susceptibility demonstrated significant odds ratios in individuals with the DD genotype for coronary heart disease, myocardial infarction and both diabetic and nondiabetic renal disease. No association was found for left ventricular hypertrophy or hypertension in nondiabetic subjects. Conclusions The ACE polymorphism appears to have a significant impact on the progression of diabetic nephropathy and may have therapeutic implications for identifying those individuals resistant to the effects of ACE inhibitors. It also appears to be indicative of an increased vascular risk in diabetic patients; however, larger prospective studies are required to clarify this situation.

1. There is evidence that hyperinsulinaemia increases the aldosterone response to angiotensin II, and that angiotensin-converting enzyme inhibitor drugs enhance peripheral glucose utilization, but the direct effects of angiotensin II on insulin sensitivity have not been reported previously. 2. In a randomized, double-blind, placebo-controlled, cross-over study, 12 healthy male subjects attended on 3 study days for the evaluation of the effects of a subpressor (1 ng min-1kg-1) and pressor (5 ng min-1kg-1) infusion of angiotensin II on whole-body insulin sensitivity using the euglycaemic hyperinsulinaemic clamp. Frequent measurements of blood pressure and heart rate were recorded and blood samples were collected for determination of serum insulin, C-peptide and K+ concentration, plasma renin activity and plasma angiotensin II concentration. 3. Plasma angiotensin II concentrations (means +/- SD) were 11 +/- 5 pg/ml after placebo, and 27 +/- 9 and 125 +/- 28 pg/ml after low and high dose angiotensin II, respectively. The higher dose of angiotensin II was associated with significant increases in blood pressure (e.g. 13 mmHg systolic blood pressure at 150 min) and serum aldosterone concentration. Whole-body insulin sensitivity was 10.5 +/- 2 mg of glucose min-1kg-1 after placebo, and 10.5 +/- 2.2 and 10.9 +/- 3.4 mg of glucose min-1kg-1 after low and high dose angiotensin II (not significant). 4. Angiotensin II had no effect on hyperinsulinaemia-induced reductions in serum potassium and triacylglycerol concentrations. 5. Thus, acute infusion of angiotensin II for 3 h, with or without an increase in blood pressure, has no effect on whole-body insulin sensitivity.

The present studies do not provide evidence for an eNOS-mediated cardioprotective response to estrogen and therefore suggest that additional mechanisms other than the endothelial NO system may have an important role in the cardiovascular effects of estrogen.

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