A. Insulin resistance induced by physical inactivity is associated with multiple transcriptional changes in skeletal muscle in young men.

BackgroundDespite intensive insulin treatment, many patients with type-1 diabetes (T1DM) have longstanding inadequate glycaemic control. Metformin is an oral hypoglycaemic agent that improves insulin action in patients with type-2 diabetes. We investigated the effect of a one-year treatment with metformin versus placebo in patients with T1DM and persistent poor glycaemic control.Methodology/Principal FindingsOne hundred patients with T1DM, preserved hypoglycaemic awareness and HaemoglobinA1c (HbA1c) ≥8.5% during the year before enrolment entered a one-month run-in on placebo treatment. Thereafter, patients were randomized (baseline) to treatment with either metformin (1 g twice daily) or placebo for 12 months (double-masked). Patients continued ongoing insulin therapy and their usual outpatient clinical care. The primary outcome measure was change in HbA1c after one year of treatment. At enrolment, mean (standard deviation) HbA1c was 9.48% (0.99) for the metformin group (n = 49) and 9.60% (0.86) for the placebo group (n = 51). Mean (95% confidence interval) baseline-adjusted differences after 12 months with metformin (n = 48) versus placebo (n = 50) were: HbA1c, 0.13% (−0.19; 0.44), p = 0.422; Total daily insulin dose, −5.7 U/day (−8.6; −2.9), p<0.001; body weight, −1.74 kg (−3.32; −0.17), p = 0.030. Minor and overall major hypoglycaemia was not significantly different between treatments. Treatments were well tolerated.Conclusions/SignificanceIn patients with poorly controlled T1DM, adjunct metformin therapy did not provide any improvement of glycaemic control after one year. Nevertheless, adjunct metformin treatment was associated with sustained reductions of insulin dose and body weight. Further investigations into the potential cardiovascular-protective effects of metformin therapy in patients with T1DM are warranted.Trial RegistrationClinicalTrials.gov NCT00118937

These data support and expand previous findings of abnormal glucose metabolism in young men with LBW. In addition, we found that the young, healthy men with LBW exhibited hepatic insulin resistance. However, the study does not support the hypothesis that muscle mitochondrial dysfunction per se is the underlying key metabolic defect that explains or precedes whole body insulin resistance in LBW subjects at risk for developing type 2 diabetes.

OBJECTIVEThe aim of this study was to investigate the impact of 9 days of bed rest on insulin secretion, insulin action, and whole-body glucose and fat metabolism in first-degree relative (FDR) and matched control (CON) subjects.RESEARCH DESIGN AND METHODSA total of 13 FDR and 20 CON subjects participated in the study. All were studied before and after 9 days of bed rest using the clamp technique combined with indirect calorimetry preceded by an intravenous glucose tolerance test. Glucose and glycerol turnover rates were studied using stable isotope kinetics.RESULTSBed rest caused a significant decrease in whole-body insulin sensitivity in both groups. Hepatic insulin resistance was elevated in FDR subjects prior to bed rest and was significantly augmented by bed rest in FDR (P < 0.01) but not in CON (P = NS) subjects. The rate of whole-body lipolysis decreased during bed rest in both FDR and CON subjects, with no significant differences between the groups. Insulin resistance induced by bed rest was fully accounted for by the impairment of nonoxidative glucose metabolism in both groups (overall P < 0.001).CONCLUSIONSWhole-body insulin action in both insulin-resistant FDR and healthy CON subjects deteriorates with 9 days of bed rest, converging toward similar degrees of whole-body insulin resistance. FDR subjects exhibit hepatic insulin resistance (HIR), which, in contrast to CON subjects, deteriorates in response to physical inactivity. FDR subjects exhibit reduced insulin secretion when seen in relation to their degree of HIR but not peripheral insulin resistance.

OBJECTIVE-Genetic susceptibility, low birth weight (LBW), and aging are key etiological factors in the development of type 2 diabetes. LBW is common among twins. It is unknown whether twin status per se is associated with risk of type 2 diabetes, and valid concordance rates of type 2 diabetes in twins on a lifetime perspective are lacking. RESEARCH DESIGN AND METHODS-A clinical study wasdone on a population-based cohort of same-sex elderly monozygotic (MZ) and dizygotic (DZ) twins (n ϭ 297) and singleton control subjects (C) (n ϭ 71) including measures of anthropometry and glucose tolerance. In addition, type 2 diabetes incidence cases in twins (n ϭ 626) and singletons (n ϭ 553) were identified through the National Diabetes Register.RESULTS-Twins were more abdominally obese, insulin resistant, and glucose intolerant, as evidenced by a higher A1C (%) (means Ϯ SD) (MZ: 6.0 Ϯ 1.0, DZ: 5.8 Ϯ 0.7, C: 5.6 Ϯ 0.3, P ϭ 0.004) and 120-min post-oral glucose tolerance test plasma glucose levels (in mmol/l) (MZ: 8.6 Ϯ 4.6, DZ: 8.4 Ϯ 3.9, C: 6.8 Ϯ 2.4, P ϭ 0.003) compared with singletons. Importantly, twins had a higher prevalence of type 2 diabetes (MZ: 17.5% ], DZ: 15.7% [13.1-18.3], C: 5.6% [3.0 -8.2], P ϭ 0.03) together with a 60% higher incidence rate of type 2 diabetes compared with singletons. Cumulative concordance rates of type 2 diabetes to the age of 84 years were similar among elderly ) and ]) twins.CONCLUSIONS-Twin status per se is associated with abdominal obesity, insulin resistance, and increased prevalence of type 2 diabetes in elderly twins. The data support a quantitatively significant impact of the fetal environment as opposed to genetics on risk of type 2 diabetes. Diabetes 58: [1350][1351][1352][1353][1354][1355] 2009 T ype 2 diabetes is a complex disease with a multifactorial etiology. The finding of higher concordance rates among monozygotic (MZ) compared with dizygotic (DZ) twins in some (1-3) but not all (4) twin studies has been considered as strong evidence of a significant genetic component in type 2 diabetes. Further support has been provided by the recent identification of a number of type 2 diabetesassociated genes in the genome-wide association studies (5,6). However, the combined effect of these type 2 diabetes susceptibility genes accounts for Ͻ10% of the population risk of the disease, and even for the most significant type 2 diabetes susceptibility genes, such as the TCF7L2 gene, the predominant proportion of the carriers of risk alleles will not develop type 2 diabetes on a lifetime perspective (5).Low birth weight is another known risk factor for type 2 diabetes and is more common in twins compared with singletons (7). In accordance with the "fetal origin hypothesis" (8 -10), we have demonstrated elevated plasma glucose and insulin profiles during an oral glucose challenge in MZ compared with DZ twins (11). A more recent study of nondiabetic elderly twins (12) provided some mechanistic explanation in such that monozygosity was associated with reduced peripheral insulin sensitivity. F...