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The cardiac effects of exogenously administered insulin for the treatment of diabetes (DM) have recently attracted much attention. In particular, it has been questioned whether insulin is the appropriate treatment for patients with type 2 diabetes mellitus and heart failure. While several old and some new studies suggested that insulin treatment has beneficial effects on the heart, recent observational studies indicate associations of insulin treatment with an increased risk of developing or worsening of pre-existing heart failure and higher mortality rates. However, there is actually little evidence that the associations of insulin administration with any adverse outcomes are causal. On the other hand, insulin clearly causes weight gain and may also cause serious episodes of hypoglycemia. Moreover, excess of insulin (hyperinsulinemia), as often seen with the use of injected insulin, seems to predispose to inflammation, hypertension, dyslipidemia, atherosclerosis, heart failure, and arrhythmias. Nevertheless, it should be stressed that most of the data concerning the effects of insulin on cardiac function derive from in vitro studies with isolated animal hearts. Therefore, the relevance of the findings of such studies for humans should be considered with caution. In the present review, we summarize the existing data about the potential positive and negative effects of insulin on the heart and attempt to answer the question whether any adverse effects of insulin or the consequences of hyperglycemia are more important and may provide a better explanation of the close association of DM with heart failure.

Context/Objective:Acute pharmacological inhibition of 11β-hydroxysteroid-dehydrogenase 1 (11β-HSD1), which converts cortisone into the much more potent cortisol in peripheral tissues, results in reduction of total, visceral, and liver fat but not insulin resistance. We now investigated whether lifelong alterations of 11β-HSD1 activity similarly affect these cardiometabolic risk parameters by studying single-nucleotide polymorphisms (SNPs) in the 11β-HSD1-coding gene (HSD11B1).Design/Methods:Liver fat content was measured by 1H-magnetic resonance spectroscopy and total and visceral fat mass by 1H-magnetic resonance tomography in 327 subjects. Insulin sensitivity (IS) was estimated during an oral glucose tolerance test and the euglycemic, hyperinsulinemic clamp (n = 219). Nine SNPs covering the whole HSD11B1gene were genotyped.Results:After correction for multiple testing, liver fat content strongly correlated with three SNPs, rs2235543, rs12565406, and rs4844880 (P= .0002, P= .001, and P= .0009, respectively), independently of gender and age. There was a nominal association of these SNPs with hepatic IS but only of rs4844880 with whole-body IS. Subjects homozygous for the major allele had an adjusted odds ratio of 2.16 (95% confidence interval [CI] 1.23–3.90) for rs2235543, 2.06 (95% CI 1.08–4.13) for rs12565406, and 1.95 (95% CI 1.13–3.49) for rs4844880 for having nonalcoholic fatty liver disease compared with carriers of the minor allele. Less strong associations of these SNPs with visceral fat mass were observed. In liver biopsies, carriers of the minor alleles of rs2235543 and rs12565406 had significantly lower HSD11B1mRNA expression (n = 105, P= .034 and P= .0086, respectively).Conclusions:11β-HSD1 may be an important enzyme in the pathogenesis of fatty liver and visceral obesity and a promising target for their treatment.

The prevalence of non-alcoholic fatty liver disease is increasing worldwide and an effective and safe pharmacological treatment is needed. We investigated whether inhibition of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1, also known as HSD11B1) by RO5093151 could safely and effectively decrease liver-fat content in patients with this disorder.

Lifestyle intervention is not always effective for improving arterial hypertension and other cardiovascular risk factors, and the parameters determining the outcome are not known. Because high cardiorespiratory fitness (CRF) protects from cardiovascular disease and mortality, we determined whether CRF at baseline predicts the improvement of blood pressure and other cardiovascular risk factors during a lifestyle intervention.

AbstractIncreased total body fat and fat accumulation in the visceral compartment are important determinants of insulin resistance. In addition, particularly accumulation of fat outside adipose tissue – ectopic fat – in muscle and the liver, has been found to impair insulin signaling in these insulin-sensitive tissues. Therefore, ectopic fat has become an important marker and an interesting target in the prevention and treatment of Type 2 diabetes and cardiovascular disease. While studying the pathogenesis of fat accumulation in skeletal muscle and the liver, more effort is needed to understand in greater detail the mechanisms of ectopic fat-induced insulin resistance.

Increased total body fat and fat accumulation in the visceral compartment are important determinants of insulin resistance. In addition, particularly accumulation of fat outside adipose tissue –– ectopic fat –– in muscle and the liver, has been found to impair insulin signaling in these insulin-sensitive tissues. Therefore, ectopic fat has become an important marker and an interesting target in the prevention and treatment of Type 2 diabetes and cardiovascular disease. While studying the pathogenesis of fat accumulation in skeletal muscle and the liver, more effort is needed to understand in greater detail the mechanisms of ectopic fat-induced insulin resistance.

Objective: In humans, low plasma adiponectin concentrations precede a decrease in insulin sensitivity and predict type 2 diabetes independently of obesity. However, it is possible that the contribution of adiponectin to insulin sensitivity is not equally strong over the whole range of obesity. Research Methods and Procedures: We investigated the cross‐sectional association between plasma adiponectin levels and insulin sensitivity in different ranges of body fat content [expressed as percentage of body fat (PFAT)] in a large cohort of normal glucose‐tolerant subjects (n= 900). All individuals underwent an oral glucose tolerance test (OGTT), and 299 subjects additionally a euglycemic hyperinsulinemic clamp. In longitudinal analyses, the association of adiponectin at baseline with change in insulin sensitivity was investigated in a subgroup of 108 subjects. Results: In cross‐sectional analyses, the association between plasma adiponectin and insulin sensitivity, adjusted for age, gender, and PFAT, depended on whether subjects were lean or obese [pfor interaction adiponectin × PFAT = <0.001 (OGTT) and 0.002 (clamp)]. Stratified by quartiles of PFAT, adiponectin did not correlate significantly with insulin sensitivity in subjects in the lowest PFAT quartile (R2= 0.10, p= 0.13, OGTT; and R2= 0.10, p= 0.57, clamp), whereas the association in the upper PFAT quartile was rather strong (R2= 0.36, p< 0.0001, OGTT; and R2= 0.48, p= 0.003, clamp). In longitudinal analyses, plasma adiponectin at baseline preceded change in insulin sensitivity in obese (n= 54, p= 0.03) but not in lean (n= 54, p= 0.68) individuals. Discussion: These data suggest that adiponectin is especially critical in sustaining insulin sensitivity in obese subjects. Thus, interventions to reduce insulin resistance by increasing adiponectin concentrations may be effective particularly in obese, insulin‐resistant individuals.

Although obese individuals are at high risk of being insulin resistant and developing type 2 diabetes mellitus, as well as having atherosclerosis, it is possible that a phenotype exists with a metabolically benign fat distribution that protects such individuals from type 2 diabetes or cardiovascular disease. In an attempt to identify subjects with metabolically benign obesity, the investigators used magnetic resonance (MR) tomography to measure total body, visceral, and subcutaneous fat, and proton (1H)–MR spectroscopy to determine fat deposition in ectopic tissues (liver and skeletal muscle). The oral glucose tolerance test was used to estimate insulin resistance.