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...

Numerous studies have shown an association between low weight at birth and being born small for gestational age (SGA) on the one hand and risk of developing insulin resistance and type 2 diabetes on the other. Our studies in twins have indicated a non-genetic age-dependent origin of insulin resistance and type 2 diabetes associated with being born SGA. In order to gain insight into the molecular metabolic defects and mechanisms linking SGA with insulin resistance and type 2 diabetes, we performed a series of experiments in young and elderly twins, and, in particular, in young men (aged 19–23 years) with a weight at birth at term in the lowest 10th percentile with no family history of diabetes. The control group included age-matched men with birth weights at term in the upper normal range. While body mass index and waist-to-hip ratios were similar in the individuals born SGA and controls, dual-energy X-ray absorptiometry studies documented a higher degree of abdominal obesity in the men who had a low weight at birth. Using the gold standard hyperinsulinaemic-euglycaemic clamp technique combined with glucose tracers and studies of forearm glucose uptake, we found an impairment of insulin-stimulated glycolytic flux and reduced forearm (muscle) glucose uptake in the face of normal whole-body glucose uptake. In addition, we found a significantly decreased insulin secretion rate during oral glucose ingestion after correction for insulin action (disposition index), a paradoxical enhanced insulin suppression of hepatic glucose production and lower fasting plasma glycerol levels, suggesting impaired lipolysis. Finally, analysis of skeletal muscle biopsies showed reduced muscle expression of several key proteins involved in insulin signalling and glucose transport, including protein kinase C-ζ, the two subunits of phosphoinositol 3-kinase (i.e., p85α and p110β) and the insulin-sensitive glucose transporter, Glut-4, in individuals of low birth weight. In conclusion, being born SGA and of low birth weight is associated with type 2 diabetes in a non-genetic manner, and programming of muscle insulin action and signalling represents an early mechanism responsible for this association.

Individuals born with low birth weight (LBW) are at risk of developing type 2 diabetes mellitus (T2D), which may be precipitated by physical inactivity. Twenty-two LBW subjects and twenty-three controls were studied before and after bed rest by the hyperinsulinemic euglycemic clamp combined with indirect calorimetry and infusion of stable isotope tracers and preceded by an intravenous glucose tolerance test. LBW subjects had a similar body mass index but elevated abdominal obesity compared with controls. The basal rate of whole body lipolysis (WBL) was elevated in LBW subjects with and without correction for abdominal obesity before and after bed rest (all P ϭ 0.01). Skeletal muscle hormone-sensitive lipase (HSL) protein expression and phosphorylation at Ser565 were similar in the two groups. Bed rest resulted in a decrease in WBL and an increased skeletal muscle HSL Ser565 phosphorylation indicating a decreased HSL activity in both groups. All subjects developed peripheral insulin resistance in response to bed rest (all P Ͻ 0.0001) with no differences between groups. LBW subjects developed hepatic insulin resistance in response to bed rest. In conclusion, increased WBL may contribute to the development of hepatic insulin resistance when exposed to bed rest in LBW subjects. Nine days of bed rest causes severe peripheral insulin resistance and reduced WBL and skeletal muscle HSL activity, as well as a compensatory increased insulin secretion, with no differences in LBW subjects and controls. physical inactivity; insulin resistance; prediabetic subjects PHYSICAL ACTIVITY IS AN IMPORTANT environmental moderator of metabolism, and sedentary lifestyle has been identified as a major risk factor for the metabolic syndrome, including type 2 diabetes mellitus (T2D), hypertension, and dyslipidemia (7,9,12,18,41). Thus there is an urgent need to gain more insight into the impact of physical inactivity on physiological mechanisms involved in the development of T2D and metabolic syndrome (23)(24)(25). Previous studies (28, 29) of physical inactivity in healthy individuals showed that 7 days bed rest diminished whole body glucose uptake as a result of decreased insulin action in inactive muscles. The Dallas Bed Rest and Training Study showed that 3 wk of bed rest caused a decrease in maximal exercise capacity (V O 2 max ) comparable to 30 yr of aging (26,27).An association between low birth weight (LBW) and impairment of glucose homeostasis was first proposed by Hales and Barker in 1991 (17). Since then, several studies have confirmed and elaborated on these findings, thereby highlighting the importance of the intrauterine environment in the development of diseases in adulthood, including hypertension, cardiovascular disease (16), and abnormal glucose tolerance (35,37,43). Accordingly, studies from the UK (2) as well as from our group (19, 20, 30, 31, 34 -36, 39) have provided evidence in favor of an important additional role of an adverse intrauterine environment associated with LBW in the development of insulin resistance,...

In patients with poorly controlled T1DM, at similar glycaemic levels, adjunct metformin therapy during 1 year significantly lowered levels of proatherogenic cholesterolaemia independent of statin therapy.