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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 was done on a population-based cohort of same-sex elderly monozygotic (MZ) and dizygotic (DZ) twins (n = 297) and singleton control subjects (C) (n = 71) including measures of anthropometry and glucose tolerance. In addition, type 2 diabetes incidence cases in twins (n = 626) and singletons (n = 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 ± SD) (MZ: 6.0 ± 1.0, DZ: 5.8 ± 0.7, C: 5.6 ± 0.3, P = 0.004) and 120-rain post-oral glucose tolerance test plasma glucose levels (in mmol/l) (MZ: 8.6 ± 4.6, DZ: 8.4 ± 3.9, C: 6.8 ± 2.4, P = 0.003) compared with singletons. Importantly, twins had a higher prevalence of type 2 diabetes (MZ: 17.5% [95% CI 14.4-20.6], DZ: 15.7% [13.1-18.3], C: 5.6% [3.0-8.2], P = 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 MZ (0.76 [0.68-0.84]) and DZ (0.71 [0.63-0.78]) 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., Type 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 [...]

The gene encoding calpain-10 (CAPN10) has been identified as a candidate gene for type 2 diabetes. Our aim was to study the impact of genetic (heritability and polymorphisms) and nongenetic (insulin, free fatty acids, and age) factors on CAPN10 mRNA expression in skeletal muscle using two different study designs. Muscle biopsies were obtained before and after hyperinsulinemic-euglycemic clamps from 166 young and elderly monozygotic and dizygotic twins as well as from 15 subjects with normal (NGT) or impaired glucose tolerance (IGT) exposed to an Intralipid infusion. We found hereditary effects on both basal and insulin-exposed CAPN10 mRNA expression. Carriers of the type 2 diabetes-associated single nucleotide polymorphism (SNP)-43 G/G genotype had reduced CAPN10 mRNA levels compared with subjects carrying the SNP-43 A-allele. Age had no significant influence on CAPN10 mRNA levels. Insulin had no significant effect on CAPN10 mRNA levels, neither in the twins nor in the basal state of the Intralipid study. However, after a 24-h infusion of Intralipid, we noted a significant increase in CAPN10 mRNA in response to insulin in subjects with NGT but not in subjects with IGT. In conclusion, we provide evidence that mRNA expression of CAPN10 in skeletal muscle is under genetic control. Glucose-tolerant but not glucose-intolerant individuals upregulate their CAPN10 mRNA levels in response to prolonged exposure to fat., Type 2 diabetes is a complex trait with both environmental and hereditary factors contributing to the overall pathogenesis (1,2). The gene encoding calpain-10 (CAPN10), located on chromosome 2q37, has been [...]

The human transcription factor FOXC2 has recently been shown to protect against diet-induced insulin resistance in transgenic mice. We investigated the expression of FOXC2 in fat and muscle and performed a genetic analysis in human subjects. FOXC2 mRNA levels were increased in visceral compared with subcutaneous fat from obese subjects (12 ± 4-fold; P = 0.0001), and there was a correlation between whole-body insulin sensitivity and FOXC2 mRNA levels in visceral fat (fS-insulin R = -0.64, P = 0.01, and homeostasis model assessment of insulin resistance [HOMA-IR] R = -0.68, P = 0.007) and skeletal muscle (fS-insulin R = -0.57, P = 0.03, and HOMA-IR R = -0.55, P = 0.04). Mutation screening of the FOXC2 gene identified a common polymorphism in the 5' untranslated region (C-512T). The T allele was associated with enhanced insulin sensitivity (HOMA-IR P = 0.007) and lower plasma triglyceride levels in females (P = 0.007). Also, the higher expression of FOXC2 in visceral than in subcutaneous fat was restricted to subjects homozygous for the T allele (P = 0.03 vs. P = 0.7). Our data suggest that increased FOXC2 expression may protect against insulin resistance in human subjects and that genetic variability in the gene may influence features associated with the metabolic syndrome. Diabetes 51:3554-3560, 2002, The metabolic or insulin resistance syndrome (1,2) is a common companion of conditions such as impaired glucose tolerance (IGT) and type 2 diabetes (3). Presence of the syndrome is associated [...]

OBJECTIVE -- The rapid-acting insulin analogs aspart and lispro have now been developed in biphasic formulations. This trial compared the postprandial serum glucose control of biphasic insulin aspart 30 (BlAsp [...]

Several studies have linked low birth weight (LBW) and type 2 diabetes. We investigated hepatic and peripheral insulin action including intracellular glucose metabolism in 40 19-year-old men (20 LBW, 20 [...]

To determine whether defects in the insulin signal transduction cascade are present in skeletal muscle from prediabetic individuals, we excised biopsies from eight glucose-intolerant male first-degree relatives of patients with type 2 diabetes (IGT relatives) and nine matched control subjects before and during a euglycemic-hyperinsulinemic clamp. IGT relatives were insulin-resistant in oxidative and nonoxidative pathways for glucose metabolism. In vivo insulin infusion increased skeletal muscle insulin receptor substrate-1 (IRS-1) tyrosine phosphorylation (P = 0.01) and phosphatidylinositide 3-kinase (PI 3-kinase) activity (phosphotyrosine and IRS-1 associated) in control subjects (P < 0.02) but not in IGT relatives (NS). The incremental increase in insulin action on IRS-1 tyrosine phosphorylation was lower in IGT relatives versus control subjects (P < 0.05). The incremental defects in signal transduction noted for IRS-1 and PI 3-kinase may be attributed to elevated basal phosphorylation/activity of these parameters, because absolute phosphorylation/ activity under insulin-stimulated conditions was similar between IGT relatives and control subjects. Insulin increased Akt serine phosphorylation in control subjects and IGT relatives, with a tendency for reduced phosphorylation in IGT relatives (P = 0.12). In conclusion, aberrant phosphorylation/activity of IRS-1, PI 3-kinase, and Akt is observed in skeletal muscle from relatives of patients with type 2 diabetes with IGT. However, the elevated basal activity of these signaling intermediates and the lack of a strong correlation between these parameters to glucose metabolism suggests that other defects of insulin signal transduction and/or downstream components of glucose metabolism may play a greater role in the development of insulin resistance in skeletal muscle from relatives of patients with type 2 diabetes., Insulin resistance in skeletal muscle is a hallmark feature of type 2 (non-insulin-dependent) diabetes (1-3). In normal glucose-tolerant relatives of patients with type 2 diabetes, insulin resistance in skeletal muscle [...]

Numerous studies have implicated impaired early growth (low birth weight [LBW]) as a risk factor for the development of obesity (1) and type 2 diabetes (2). Obesity, particularly abdominal obesity, [...]

Elevated plasma free fatty acids (FFA) are considered to play an important role for the development of insulin resistance in Type 2 diabetes. Nevertheless, previous studies investigating the effect of [...]

Individuals with a low birth weight are at increased risk of developing type 2 diabetes; however, the underlying molecular mechanisms are not known. We have shown previously that low birth weight is associated with changes in insulin signaling protein expression in muscle. The current aim was to determine if low birth weight is associated with changes in insulin signaling proteins in adipose tissue. A total of 17 males aged 22 years were recruited from the Danish Medical Birth Registry. Nine had low birth weights (bottom 10th percentile), and eight bad a normal birth weight (50th to 90th percentile). Adipose biopsies were taken from the abdomen using a Bergstrom needle, and protein expression was determined by Western blotting. There were no differences in expression of the insulin receptor, protein kinase C [zeta], glycogen synthase kinase (GSK)-3[alpha], or GSK3[beta] between the two groups. However, there were reductions in expression of GLUT4 (52 [+ or -] 10.9% reduction, P < 0.01), p85[alpha] regulatory subunit of phosphatidylinositol (PI) 3-kinase (45 [+ or -] 9% reduction, P < 0.01), and the p110[beta] subunit of PI 3-kinase (48 [+ or -] 17% reduction, P = 0.06). These findings suggest that low birth weight is associated with reduced expression of important insulin signaling proteins in adipose tissue that may contribute to an increased risk of type 2 diabetes., Susan E. Ozanne, (1) Katie J. Tingey, (1) Louise Grunnet, (2) Heidi Storgaard, (2) Christine Jensen, (2) Allan Vaag (2) From the (1) Department of Clinical Biochemistry, University of Cambridge, [...]

Objectives: Lipodystrophy and insulin resistance are prevalent among human immunodeficiency virus (HIV)-infected patients on combined antiretroviral therapy (HAART). Aiming to provide a detailed description of the metabolic adverse effects of HIV-lipodystrophy, we investigated several aspects of glucose metabolism, lipid metabolism and β-cell function in lipodystrophic HIV-infected patients.Methods: [3-3H]glucose was applied during euglycaemic hyperinsulinaemic clamps in association with indirect calorimetry in 43 normoglycaemic HIV-infected patients (18 lipodystrophic patients on HAART (LIPO), 18 patients without lipodystrophy on HAART (NONLIPO) and seven patients who were naïve to antiretroviral therapy (NAÏVE) respectively). β-cell function was evaluated by an intravenous glucose tolerance test.Results: Compared with NONLIPO and NAÏVE separately, LIPO displayed markedly reduced ratio of limb to trunk fat (RLF; >34%, P< 0.001), hepatic insulin sensitivity (>40%, P< 0.03), incremental glucose disposal (>50%, P< 0.001) and incremental exogenous glucose storage (>50%, P< 0.05). Furthermore, LIPO displayed reduced incremental glucose oxidation (P< 0.01), increased clamp free fatty acids (P< 0.05) and attenuated insulin-mediated suppression of lipid oxidation (P< 0.05) compared with NONLIPO. In combined study groups, RLF correlated with hepatic insulin sensitivity (r= 0.69), incremental glucose disposal (r= 0.71) and incremental exogenous glucose storage (r= 0.40), all P< 0.01. Disposition index (i.e. first-phase insulin response to intravenous glucose multiplied by incremental glucose disposal) was reduced by 46% (P= 0.05) in LIPO compared with the combined groups of NONLIPO and NAÏVE, indicating an impaired adaptation of β-cell function to insulin resistance in LIPO.Conclusion: Our data suggest that normoglycaemic lipodystrophic HIV-infected patients display impaired glucose and lipid metabolism in multiple pathways involving liver, muscle tissue and β-cell function.