Ian F. Godsland

Insulin resistance in chronic heart failure: relation to severity and etiology of heart failure.

OBJECTIVESnWe attempted to assess insulin sensitivity in patients with chronic heart failure (CHF) and its relation to disease severity.nnnBACKGROUNDnPeripheral muscular changes influence the progression of heart failure. This effect may be due to chronic disturbances of insulin and glucose metabolism that affect the energy status of skeletal and myocardial muscle.nnnMETHODSnWe investigated insulin sensitivity in 79 men-38 patients with CHF, 21 patients with angiographic evidence of coronary artery disease without CHF and 20 healthy control subjects-and assessed its relation to disease severity, etiology and hormonal status (all subjects had a similar age and body mass index). Insulin sensitivity was estimated by minimal modeling analysis of the glucose and insulin and profiles during a 0.5 g/kg body weight intravenous glucose tolerance test.nnnRESULTSnCompared with control subjects, patients with CHF had similar mean fasting glucose but increased insulin levels (67 vs. 29 pmol/liter, p < 0.002) and a 58% reduced mean insulin sensitivity (2.01 vs. 4.84 min-1/pmol/ml x 10(5), p < 0.0001). Peak oxygen consumption (VO2) (r = 0.63), fasting triglycerides (r = -0.62) and age (r = -0.46, all p < 0.001) predicted insulin sensitivity independently. Rest norepinephrine and epinephrine levels, left ventricular ejection fraction and heart failure etiology were not related to insulin sensitivity. Patients with coronary artery disease but no CHF had an intermediate mean insulin sensitivity (3.30 min-1/pmol/ml x 10(5) [-32%, p = 0.042 vs. control subjects; +113%, p = 0.0023 vs. patients with CHF due to ischemic heart disease]). In multivariate analyses of all 79 subjects, age (p = 0.0006), triglycerides (p = 0.0023), fasting insulin (p = 0.0037) and the presence of CHF (p = 0.018) were independent predictors of impaired insulin sensitivity (adjusted joint R2 = 0.53, p < 0.0001).nnnCONCLUSIONSnCHF is associated with marked insulin resistance, characterized by both fasting and stimulated hyperinsulinemia. Advanced heart failure (in terms of reduced peak VO2) is related to increased insulin resistance, but this is not directly mediated through ventricular dysfunction or increased catecholamine levels.

Hormone replacement therapy and the cardiovascular system. Nonlipid effects.

SummaryCoronary heart disease (CHD) is the leading cause of death in women, and the risk of this disease rises markedly after loss of ovarian function. Hormone replacement therapy (HRT) can reduce the incidence of CHD in postmenopausal women by 50%. HRT causes changes in lipids and lipoproteins, but it is now clear that many other effects of gonadal steroid hormones have important influences on the cardiovascular system. These nonlipid effects include a variety of changes in other metabolic risk factors for CHD, as well as direct arterial effects.Insulin resistance and hyperinsulinaemia may be pivotal disturbances in the pathogenesis of CHD. Estradiol reverses the effects of menopause on glucose and insulin metabolism, resulting in an increase in pancreatic insulin secretion and a decrease in insulin resistance, although other types of estrogen may not do this. Androgenic progestogens may oppose this potentially beneficial effect on insulin resistance.Central obesity is linked with many CHD risk factors, and HRT reverses the increased fat distribution that results from loss of ovarian function at the menopause. HRT may also improve the balance between coagulation and fibrinolysis, resulting in a reduction in arterial thrombosis.Finally, estradiol acts directly on the arterial wall, modifying both endothelium-dependent and calcium-dependent processes. These actions result in improved blood flow and reduced blood pressure and, importantly, have the potential to reduce myocardial ischaemia.

Insulin, Intact and Split Proinsulin, and Coronary Artery Disease in Young Men

BACKGROUNDnGlucose intolerance and hyperinsulinemia are common disturbances in nondiabetic men with premature coronary artery disease (CAD). To investigate the relation between insulin-like molecules and severity of coronary atherosclerosis, 62 consecutive nondiabetic men presenting with a first myocardial infarction before the age of 45 were studied along with 41 healthy, age-matched, male, population-based control subjects.nnnMETHODS AND RESULTSnSpecific two-site immunoradiometric assays were used to distinguish intact proinsulin, (des 31,32) proinsulin, and true insulin in fasting plasma and during an oral glucose tolerance test (OGTT). Global coronary atherosclerosis and number and severity of distinct stenoses were determined in the patients in 15 proximal coronary arterial segments by use of separate semiquantitative classification systems. The patients had a two- to threefold increase in insulin and insulin propeptide concentrations in the fasting state as well as during the OGTT. Severity of coronary atherosclerosis correlated significantly (P < .05 to P < .01) with basal proinsulin (r = .40) and the proinsulin area under the curve (AUC) (r = .34), basal insulin (r = .31), basal C peptide (r = .30), and the glucose AUC (r = .30). In multiple stepwise regression analysis including insulin-like molecules, major plasma lipoproteins, and lipoprotein subfractions, basal proinsulin (increase in R2 = .09) and dense LDL triglycerides (increase in R2 = .10) predicted 19% of the variation of the global coronary atherosclerosis score after adjustment for age, body mass index, fasting insulin concentration, and VLDL triglycerides.nnnCONCLUSIONSnThis study shows that young, nondiabetic, male survivors of myocardial infarction are truly hyperinsulinemic during an OGTT and suggests a close association between proinsulin and coronary atherosclerosis.

Safety evaluation of modern oral contraceptives: Effects on lipoprotein and carbohydrate metabolism

An ideal oral contraceptive should either be neutral as regards metabolic risk markers for arterial disease or should only change them in directions that would be expected to reduce risk. Depending on their formulation, modern low dose oral contraceptives affect systems such as hemostasis, lipoprotein metabolism, and glucose and insulin metabolism. Some of these actions would be expected to decrease the risk of arterial disease and some might be expected to increase risk. Despite these associations there is at present no justification for widespread metabolic screening as a strategy to further improve oral contraceptive safety. Recent developments in atherosclerosis research support the introduction of progestogens such as desogestrel that allow the estrogenic increase in high density lipoprotein levels to persist and that may cause less of an elevation in plasma insulin responses to glucose. The predicted benefit of these formulations in terms of arterial disease is difficult to demonstrate in an epidemiological setting because of the rarity of the disease in young women.

Relationships between blood pressure, oral contraceptive use and metabolic risk markers for cardiovascular disease

Data from a previous study, designed to compare metabolic risk markers for cardiovascular disease in non-users and oral contraceptive (OC) users, were analysed to evaluate the influence of OC composition on blood pressure. Healthy, female volunteers (1189 women) either not using OC (non-users) or currently using one of six different combined formulations (users) were compared. Combinations studied contained 30-40 micrograms ethinyl estradiol combined with the progestins levonorgestrel, norethindrone (at two and three different doses, respectively) or desogestrel. After statistical standardisation to account for the significantly greater age of the non-users and longer duration of OC use amongst the levonorgestrel combination users, mean blood pressure was higher, compared with non-users, in users of monophasic or triphasic levonorgestrel combinations (systolic: +4.3 mmHg (p < 0.001) and +2.7 mmHg (p < 0.001), respectively; diastolic: +2.6 mmHg (p < 0.001) and +2.3 mmHg (p < 0.05), respectively). Blood pressures in users of monophasic norethindrone and desogestrel combinations were not significantly raised and there was no increase in the proportion of women with abnormal values. Diastolic and systolic blood pressures were positively associated with oral glucose tolerance test insulin response (r = 0.11 (p < 0.01) and r = 0.15 (p < 0.001), respectively) in users but not in non-users. Currently used OC containing norethindrone or desogestrel progestins have little impact on blood pressure. Their correlated reduction in impact on insulin concentrations, though small, suggests common mechanisms through which OC affect blood pressure and insulin.

Effects of a low-estrogen desogestrel-containing oral contraceptive on lipid and carbohydrate metabolism.

Fasting serum lipids, lipoproteins and apolipoproteins, and fasting plasma glucose, insulin and C-peptide were measured in 107 non-users and 83 users of an oral contraceptive containing the progestin desogestrel, combined with 20 micrograms ethinyl estradiol. Plasma glucose, insulin and C-peptide concentrations during an oral glucose tolerance test (OGTT) were measured in a subgroup of 69 non-users and 39 users. Compared with non-users, users had higher concentrations of total, high density lipoprotein (HDL), HDL subfraction 3 and very low density lipoprotein (VLDL) cholesterol, total triglycerides, VLDL triglycerides, apolipoproteins AI and AII and fasting plasma insulin. There were no differences in HDL subfraction 2, low density lipoprotein cholesterol and apolipoprotein B. OGTT glucose was 60% higher in the users and OGTT insulin response 19% higher. The OGTT C-peptide response did not differ. The effects of 20 micrograms ethinyl estradiol combined with 150 micrograms desogestrel on lipid, lipoprotein, glucose and insulin metabolism are similar to those described previously with a 30 micrograms ethinyl estradiol combination containing the same dose of desogestrel. The relatively favourable metabolic profile associated with the higher estrogen dose desogestrel combination is maintained at the lower dose.

Interaction of oral contraceptive use with the effects of age, exercise habits and other cardiovascular risk modifiers on metabolic risk markers

An analysis was undertaken to determine whether combined oral contraceptive (OC) use interacts with the effects of potential cardiovascular risk modifiers (age, body mass index, cigarette smoking, alcohol intake, exercise habit, family histories of heart disease or diabetes, number of pregnancies and duration of OC use) on blood pressure and lipid, lipoprotein, glucose and insulin risk markers for cardiovascular disease. Relationships between risk modifiers and risk markers were compared between non-users (n = 418) and users of low-estrogen dose OC (n = 925, categorised according to progestin content as monophasic levonorgestrel, triphasic levonorgestrel, norethindrone or desogestrel). OC use diminished the adverse effects of age on glucose tolerance. Aerobic exercise had a particularly beneficial effect on triglyceride levels and OGTT insulin response in OC users. The rise in HDL and HDL2 cholesterol concentrations with alcohol intake seen in non-users was diminished in OC users. Increasing duration of use of a desogestrel combination was associated with increasing HDL cholesterol concentrations. No adverse effects of risk modifiers on metabolic risk markers and blood pressure were augmented by OC use, and some were even diminished.

Lipid and carbohydrate metabolic risk markers for coronary heart disease and blood pressure in healthy non-obese premenopausal women of different racial origins in the United Kingdom.

Metabolic risk markers for coronary heart disease (CHD) were determined in apparently healthy females of differing racial origins residing in the United Kingdom. The females were of black (n=122), Oriental (n=144), South Asian (n=128), and white (n=271) origin, premenopausal, non-obese, and aged 16-45 years. In comparison to whites, South Asians had lower serum high-density lipoprotein (HDL) cholesterol and HDL2 cholesterol and higher fasting and oral glucose tolerance test plasma insulin responses. Black females had higher fasting plasma and oral glucose tolerance test insulin and lower serum triglyceride and glucose compared with white females. Orientals differed from whites in having higher fasting and oral glucose tolerance test insulin concentrations. Resting systolic or diastolic blood pressures, total serum cholesterol, HDL3 cholesterol, and low-density lipoprotein (LDL) cholesterol did not differ between groups. Whereas previous studies have demonstrated similar differences in representative samples from different ethnic communities, our results clearly demonstrate that differences also exist in young healthy females, individuals considered to have the least risk of CHD.

Insulin propeptides in conditions associated with insulin resistance in humans and their relevance to insulin measurements

Routine insulin assays measure not only biologically active insulin but also the relatively inactive propeptides, proinsulin and desdipeptide proinsulin. Such measurements may be misleading if insulin propeptide levels are increased, as has been reported in patients with non-insulin-dependent diabetes mellitus (NIDDM). Inferences regarding insulin resistance, based on hyperinsulinemia, could thus be invalidated where routine insulin assays have been used. We have measured plasma insulin levels using a routine assay, together with measurements of the major circulating insulin propeptides, intact proinsulin and des 31,32proinsulin, in various clinical situations associated with apparently increased insulin levels and insulin resistance. Major increases of insulin propeptide levels relative to insulin levels were not seen in obese subjects or in patients taking oral contraceptives or danazol, or in obese subjects compared with non-obese controls. Although the insulinemic responses observed with routine radioimmunoassay in these situations associated with insulin resistance are not confounded by major changes in the proportion of circulating insulin propeptides, further studies will be necessary to validate investigations in other insulin-resistant states.