Low-grade inflammation in persons with recently diagnosed type 2 diabetes: The role of abdominal adiposity and putative mediators.

AIMS: To determine the magnitude of the association between abdominal adiposity and low-grade inflammation in persons with recently diagnosed type 2 diabetes (T2D) and to determine to what extent this association is mediated by low physical activity level, hyperinsulinaemia, hyperglycaemia, dyslipidaemia, hypertension, and comorbidities. MATERIALS AND METHODS: We measured waist circumference, clinical characteristics, and inflammatory markers i.e. tumour necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and high-sensitivity C-reactive protein (hsCRP), in >9000 persons with recently diagnosed T2D. We applied multiple mediation analysis using structural equation modelling, with adjustment for age and sex. RESULTS: Waist circumference as a proxy for abdominal adiposity was positively associated with all inflammatory markers. Hence, a one-standard deviation (SD) increase in waist circumference (SD = 15 cm) was associated with a 22%, 35%, and 46% SD increase in TNF-α (SD = 1.5 pg/mL), IL-6 (SD = 4.4 pg/mL), and hsCRP (SD = 6.9 mg/L), respectively. The level of hyperinsulinaemia assessed by fasting C-peptide was quantitatively the most important mediator, accounting for 9%-25% of the association between abdominal adiposity and low-grade inflammation, followed by low physical activity (5%-7%) and high triglyceride levels (2%-6%). Although mediation of adiposity-induced inflammation by greater comorbidity and higher glycated haemoglobin levels reached statistical significance, their impact was minor (1%-2%). CONCLUSIONS: In persons with recently diagnosed T2D, there was a clear association between abdominal adiposity and low-grade inflammation. A considerable part (20%-40%) of this association was mediated by other factors, with hyperinsulinaemia as a potentially important driver of adiposity-induced inflammation in T2D.

Skeletal muscle fibre type and enzymatic activity in adult offspring following placental and peripheral malaria exposure in foetal life.

Background: Maternal malaria may restrict foetal growth. Impaired utero-placental blood flow due to malaria infection may cause hypoxia-induced altered skeletal muscle fibre type distribution in the offspring, which may contribute to insulin resistance and impaired glucose metabolism. This study assessed muscle fibre distribution 20 years after placental and/or peripheral in-utero malaria exposure compared to no exposure, i.e., PPM+, PM+, and M-, respectively. Methods: We traced 101 men and women offspring of mothers who participated in a malaria chemosuppression study in Muheza, Tanzania. Of 76 eligible participants, 50 individuals (29 men and 21 women) had skeletal muscle biopsy taken from m. vastus lateralis in the right leg. As previously reported, fasting and 30 min post-oral glucose challenge plasma glucose values were higher, and insulin secretion disposition index was lower, in the PPM+ group. Aerobic capacity (fitness) was estimated by an indirect VO2max test on a stationary bicycle. Muscle fibre sub-type (myosin heavy chain, MHC) distribution was analysed, as were muscle enzyme activities (citrate synthase (CS), 3-hydroxyacyl-CoA dehydrogenase, myophosphorylase, phosphofructokinase, lactate dehydrogenase, and creatine kinase activities. Between-group analyses were adjusted for MHC-I %. Results: No differences in aerobic capacity were found between groups. Despite subtle elevations of plasma glucose levels in the PPM+ group, there was no difference in MHC sub-types or muscle enzymatic activities between the malaria-exposed and non-exposed groups. Conclusion: The current study did not show differences in MHC towards glycolytic sub-types or enzymatic activity across the sub-groups. The results support the notion of the mild elevations of plasma glucose levels in people exposed to placental malaria in pregnancy being due to compromised pancreatic insulin secretion rather than insulin resistance.

FOXO3A-short is a novel regulator of non-oxidative glucose metabolism associated with human longevity.

Intronic single-nucleotide polymorphisms (SNPs) in FOXO3A are associated with human longevity. Currently, it is unclear how these SNPs alter FOXO3A functionality and human physiology, thereby influencing lifespan. Here, we identify a primate-specific FOXO3A transcriptional isoform, FOXO3A-Short (FOXO3A-S), encoding a major longevity-associated SNP, rs9400239 (C or T), within its 5' untranslated region. The FOXO3A-S mRNA is highly expressed in the skeletal muscle and has very limited expression in other tissues. We find that the rs9400239 variant influences the stability and functionality of the primarily nuclear protein(s) encoded by the FOXO3A-S mRNA. Assessment of the relationship between the FOXO3A-S polymorphism and peripheral glucose clearance during insulin infusion (Rd clamp) in a cohort of Danish twins revealed that longevity T-allele carriers have markedly faster peripheral glucose clearance rates than normal lifespan C-allele carriers. In vitro experiments in human myotube cultures utilizing overexpression of each allele showed that the C-allele represses glycolysis independently of PI3K signaling, while overexpression of the T-allele represses glycolysis only in a PI3K-inactive background. Supporting this finding inducible knockdown of the FOXO3A-S C-allele in cultured myotubes increases the glycolytic rate. We conclude that the rs9400239 polymorphism acts as a molecular switch which changes the identity of the FOXO3A-S-derived protein(s), which in turn alters the relationship between FOXO3A-S and insulin/PI3K signaling and glycolytic flux in the skeletal muscle. This critical difference endows carriers of the FOXO3A-S T-allele with consistently higher insulin-stimulated peripheral glucose clearance rates, which may contribute to their longer and healthier lifespans.

Independent phenotypic plasticity axes define distinct obesity sub-types.

Studies in genetically 'identical' individuals indicate that as much as 50% of complex trait variation cannot be traced to genetics or to the environment. The mechanisms that generate this 'unexplained' phenotypic variation (UPV) remain largely unknown. Here, we identify neuronatin (NNAT) as a conserved factor that buffers against UPV. We find that Nnat deficiency in isogenic mice triggers the emergence of a bi-stable polyphenism, where littermates emerge into adulthood either 'normal' or 'overgrown'. Mechanistically, this is mediated by an insulin-dependent overgrowth that arises from histone deacetylase (HDAC)-dependent ß-cell hyperproliferation. A multi-dimensional analysis of monozygotic twin discordance reveals the existence of two patterns of human UPV, one of which (Type B) phenocopies the NNAT-buffered polyphenism identified in mice. Specifically, Type-B monozygotic co-twins exhibit coordinated increases in fat and lean mass across the body; decreased NNAT expression; increased HDAC-responsive gene signatures; and clinical outcomes linked to insulinemia. Critically, the Type-B UPV signature stratifies both childhood and adult cohorts into four metabolic states, including two phenotypically and molecularly distinct types of obesity.

Smoking in pregnancy is associated with increased adiposity and retinal arteriolar wall-to-lumen ratio in adolescence: The Copenhagen Child Cohort Study 2000.

PURPOSE: To investigate the association between prenatal exposures and anthropometric data and cardiovascular risk factors including retinal arteriolar wall-to-lumen ratio in adolescence. METHODS: This longitudinal observational study included all 1445 adolescents from the Copenhagen Child Cohort 2000 who attended the 2016-2017 examination. Outcome measures included retinal arteriolar wall-to-lumen ratio, height, body mass index, waist-to-hip ratio, body composition measured by bioimpedance, and blood pressure. Information on prenatal exposures (birth weight, gestational age, maternal smoking during pregnancy) as well as sex, parental age, household income and parental educational levels were obtained from national registries. Associations between exposures and outcome measures were analyzed using general linear models. RESULTS: Maternal smoking during pregnancy was associated with a higher retinal arteriolar wall-to-lumen ratio (0.004 or 1.9%, P = 0.009) at age 16/17 years, an association driven exclusively by the female participants (0.008 or 3.7%, P < 0.0001). Maternal smoking during pregnancy was also associated to higher body-mass index (1.43 kg/m2, P < 0.0001), waist-to-hip ratio (0.02, P < 0.0001) and fat mass index (0.93 kg/m2, P < 0.0001). Birth weight, gestational age, and parental age had no detectable impact on retinal arteriolar wall-to-lumen ratios. CONCLUSION: Prenatal exposure to tobacco smoking is associated with a higher risk of obesity and, predominantly in girls, to a greater retinal arteriolar wall thickness, which suggests that maternal smoking may induce an unfavorable cardiovascular and metabolic risk profile in the child.

Type 2 diabetes remission 1 year after an intensive lifestyle intervention: A secondary analysis of a randomized clinical trial.

AIM: To investigate whether an intensive lifestyle intervention induces partial or complete type 2 diabetes (T2D) remission. MATERIALS AND METHODS: In a secondary analysis of a randomized, assessor-blinded, single-centre trial, people with non-insulin-dependent T2D (duration <10 years), were randomly assigned (2:1, stratified by sex, from April 2015 to August 2016) to a lifestyle intervention group (n = 64) or a standard care group (n = 34). The primary outcome was partial or complete T2D remission, defined as non-diabetic glycaemia with no glucose-lowering medication at the outcome assessments at both 12 and 24 months from baseline. All participants received standard care, with standardized, blinded, target-driven medical therapy during the initial 12 months. The lifestyle intervention included 5- to 6-weekly aerobic and combined aerobic and strength training sessions (30-60 minutes) and individual dietary plans aiming for body mass index ≤25 kg/m2 . No intervention was provided during the 12-month follow-up period. RESULTS: Of the 98 randomized participants, 93 completed follow-up (mean [SD] age 54.6 [8.9] years; 46 women [43%], mean [SD] baseline glycated haemoglobin 49.3 [9.3] mmol/mol). At follow-up, 23% of participants (n = 14) in the intervention and 7% (n = 2) in the standard care group met the criteria for any T2D remission (odds ratio [OR] 4.4, 95% confidence interval [CI] 0.8-21.4]; P = 0.08). Assuming participants lost to follow-up (n = 5) had relapsed, the OR for T2D remission was 4.4 (95% CI 1.0-19.8; P = 0.048). CONCLUSIONS: The statistically nonsignificant threefold increased remission rate of T2D in the lifestyle intervention group calls for further large-scale studies to understand how to implement sustainable lifestyle interventions among people with T2D.

Diagnosing gestational diabetes mellitus in the Danish National Birth Cohort.

INTRODUCTION: The Danish National Birth Cohort (DNBC) contains comprehensive information on diet, lifestyle, constitutional and other major characteristics of women during pregnancy. It provides a unique source for studies on health consequences of gestational diabetes mellitus. Our aim was to identify and validate the gestational diabetes mellitus cases in the cohort. MATERIAL AND METHODS: We extracted clinical information from hospital records for 1609 pregnancies included in the Danish National Birth Cohort with a diagnosis of diabetes during or before pregnancy registered in the Danish National Patient Register and/or from a Danish National Birth Cohort interview during pregnancy. We further validated the diagnosis of gestational diabetes mellitus in 2126 randomly selected pregnancies from the entire Danish National Birth Cohort. From the individual hospital records, an expert panel evaluated gestational diabetes mellitus status based on results from oral glucose tolerance tests, fasting blood glucose and Hb1c values, as well as diagnoses made by local obstetricians. RESULTS: The audit categorized 783 pregnancies as gestational diabetes mellitus, corresponding to 0.89% of the 87 792 pregnancies for which a pregnancy interview for self-reported diabetes in pregnancy was available. From the randomly selected group the combined information from register and interviews could correctly identify 96% (95% CI 80-99.9%) of all cases in the entire Danish National Birth Cohort population. Positive predictive value, however, was only 59% (56-61%). CONCLUSIONS: The combined use of data from register and interview provided a high sensitivity for gestational diabetes mellitus diagnosis. The low positive predictive value, however, suggests that systematic validation by hospital record review is essential not to underestimate the health consequences of gestational diabetes mellitus in future studies.

Parental smoking during pregnancy and the risk of gestational diabetes in the daughter.

BACKGROUND: Fetal exposure to parental smoking may have long-term impact on the development of disease in adulthood. We examined the association of parental smoking during pregnancy with risk of gestational diabetes mellitus (GDM) in the daughter. METHODS: We included 15,665 singleton pregnancies from 10,152 women in the Nurses' Health Study II cohort whose mothers participated in the Nurses' Mothers' Cohort Study. Data on maternal and paternal smoking during pregnancy and associated covariates were recalled by the mothers. GDM diagnosis was self-reported by the daughters and was validated by medical record review in a previous study. We used log-binomial models with generalized estimating equations to estimate relative risks (RRs) and 95% confidence intervals (CIs). RESULTS: We observed a positive association between maternal heavy smoking during pregnancy and risk of GDM in the daughter. The multivariable-adjusted RRs (95% CIs) of GDM among women whose mothers did not smoke during pregnancy, continued smoking 1-14, 15-24, and ≥ 25 cigarettes/day were 1.00 (reference), 1.05 (0.81-1.35), 1.27 (0.95-1.70) and 1.98 (1.18-3.30), respectively (P for trend = 0.01). Further adjustment for the women's perinatal variables, adult-life characteristics and body mass index during various periods of life modestly attenuated the association. No association was observed between paternal smoking during the pregnancy period and risk of GDM in the daughter. CONCLUSIONS: Maternal heavy smoking (≥ 25 cigarettes/day) during pregnancy was associated with higher risk of gestational diabetes in the daughter. Further studies are warranted to confirm our findings and to elucidate the underlying mechanisms.

Head-to-head comparison of intensive lifestyle intervention (U-TURN) versus conventional multifactorial care in patients with type 2 diabetes: protocol and rationale for an assessor-blinded, parallel group and randomised trial.

INTRODUCTION: Current pharmacological therapies in patients with type 2 diabetes (T2D) are challenged by lack of sustainability and borderline firm evidence of real long-term health benefits. Accordingly, lifestyle intervention remains the corner stone in the management of T2D. However, there is a lack of knowledge regarding the optimal intervention programmes in T2D ensuring both compliance as well as long-term health outcomes. Our objective is to assess the effects of an intensive lifestyle intervention (the U-TURN intervention) on glycaemic control in patients with T2D. Our hypothesis is that intensive lifestyle changes are equally effective as standard diabetes care, including pharmacological treatment in maintaining glycaemic control (ie, glycated haemoglobin (HbA1c)) in patients with T2D. Furthermore, we expect that intensive lifestyle changes will decrease the need for antidiabetic medications. METHODS AND ANALYSIS: The study is an assessor-blinded, parallel group and a 1-year randomised trial. The primary outcome is change in glycaemic control (HbA1c), with the key secondary outcome being reductions in antidiabetic medication. Participants will be patients with T2D (T2D duration <10 years) without complications who are randomised into an intensive lifestyle intervention (U-TURN) or a standard care intervention in a 2:1 fashion. Both groups will be exposed to the same standardised, blinded, target-driven pharmacological treatment and can thus maintain, increase, reduce or discontinue the pharmacological treatment. The decision is based on the standardised algorithm. The U-TURN intervention consists of increased training and basal physical activity level, and an antidiabetic diet including an intended weight loss. The standard care group as well as the U-TURN group is offered individual diabetes management counselling on top of the pharmacological treatment. ETHICS AND DISSEMINATION: This study has been approved by the Scientific Ethical Committee at the Capital Region of Denmark (H-1-2014-114). Positive, negative or inconclusive findings will be disseminated in peer-reviewed journals, at national and international conferences. TRIAL REGISTRATION NUMBER: NCT02417012.

Subclinical inflammation during third trimester of pregnancy was not associated with markers of the metabolic syndrome in young adult offspring.

OBJECTIVE: Growing evidence indicates that the metabolic syndrome (MS) is rooted in adverse exposures during fetal life. The aim of this study was to assess the possible associations between biomarkers of inflammation during third trimester of pregnancy and markers of MS in adult offspring. METHODS: High-sensitive C-reactive protein (CRP), tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß) and interleuki-6 (IL-6) were measured in serum samples obtained in gestational week 30. Offspring were clinically examined at age 20 years. Analyses based on 439 mother-offspring dyads were adjusted for maternal smoking during pregnancy, height, prepregnancy body mass index (BMI), education, and offspring's sex. Offspring MS markers included waist circumference, BMI, blood pressure, HOMA insulin resistance, and plasma levels of fasting glucose, triglycerides, cholesterol fractions, insulin, and leptin. RESULTS: The median level was 2.8 (interquartile range = 3.3) µg/ml for CRP, for TNF-α: 5.7 (3.2) pg/ml, for IL-1ß: 0.5 (0.4) pg/ml, and for IL-6: 1.1 (0.7) pg/ml. Concentrations were not significantly associated with MS markers in the offspring. The results remained essentially unchanged after correction for potential confounding. CONCLUSION: Markers for subclinical inflammation in third trimester in healthy women were not associated with components of MS in their adult offspring.

Endothelial function after 10 days of bed rest in individuals at risk for type 2 diabetes and cardiovascular disease.

Physical inactivity is considered to be deleterious to vascular health, and in particular in first-degree relatives to patients with type 2 diabetes (FDR) and persons born with low birth weight (LBW), who may later in life develop cardiovascular disease. A period of imposed physical inactivity could unmask this risk. We hypothesized that the impact of physical inactivity on endothelial function would be more marked in subjects at increased risk for type 2 diabetes and cardiovascular disease (LBW and FDR) compared with a matched control group (CON), all of whom were recruited via advertisements and via the Danish Birth Registry. Twenty LBW, 20 CON and 13 FDR were studied before and after 10 days of bed rest. Forearm blood flow (FBF) was measured by venous occlusion plethysmography during brachial intra-arterial infusion of acetylcholine or adenosine at baseline and with superimposed hyperinsulinaemia. Markers of endothelial activation and inflammation were measured in plasma. Bed rest did not change the vasodilator responses to adenosine or acetylcholine alone in any group, but reduced vasodilator responses to adenosine or acetylcholine during hyperinsulinaemia in LBW. Bed rest impaired insulin-mediated vasodilatation in CON and LBW and increased endothelial activation markers in FDR and LBW but not in CON. Vasodilator responses were very low in FDR prior to bed rest, and did not decrease further during bed rest. Physical inactivity does not impair endothelium-dependent vasodilatation per se, but the vascular vasodilator effect of insulin diminished in CON and LBW after bed rest. In FDR, a further deterioration of FBF with inactivity is not possible.

Impact of metformin versus repaglinide on non-glycaemic cardiovascular risk markers related to inflammation and endothelial dysfunction in non-obese patients with type 2 diabetes.

OBJECTIVE: In patients with type 2 diabetes mellitus (T2DM), biomarkers reflecting inflammation and endothelial dysfunction have been linked to cardiovascular disease (CVD biomarkers) and metabolic regulation. In T2DM patients, metformin and insulin secretagogues have demonstrated equal anti-hyperglycaemic potency. Here, we report the effect of metformin versus an insulin secretagogue, repaglinide, on CVD biomarkers in non-obese T2DM patients. DESIGN AND METHODS: Single-centre, double-masked, double-dummy, crossover study during 2x4 months involving 96 non-obese (body mass index< or =27 kg/m(2)) insulin-naïve T2DM patients. At enrolment, previous oral hypoglycaemic agents were stopped and the patients entered a 1-month run-in on diet-only treatment. Hereafter, patients were randomized to either 2 mg repaglinide thrice daily followed by 1 g metformin twice daily or vice versa each during 4 months with a 1-month washout between interventions. RESULTS: Levels of tumour necrosis factor-alpha, plasminogen activator inhibitor-1 antigen, tissue-type plasminogen activator antigen, von Willebrand factor, soluble intercellular adhesion molecule-1 and soluble E-selectin were significantly lower during metformin versus repaglinide treatments. In contrast, Amadori albumin and heart rate were higher during metformin versus repaglinide. Levels of interleukin-6, fibrinogen, soluble vascular cell adhesion molecule-1, asymmetric dimethylarginine and advanced glycation end products as well as glycaemic levels (previously reported) and 24-h blood pressure were similar between treatments. Adjustment for known macrovascular disease did not affect the between-treatment effects. CONCLUSIONS: In non-obese T2DM patients, metformin was more effective in reducing selected biomarkers reflecting inflammation and endothelial dysfunction compared with repaglinide despite similar glycaemic levels between treatments.

Altered skeletal muscle fiber composition and size precede whole-body insulin resistance in young men with low birth weight.

CONTEXT: Low birth weight (LBW), a surrogate marker of an adverse fetal milieu, is linked to muscle insulin resistance, impaired insulin-stimulated glycolysis, and future risk of type 2 diabetes. Skeletal muscle mass, fiber composition, and capillary density are important determinants of muscle function and metabolism, and alterations have been implicated in the pathogenesis of insulin resistance. OBJECTIVE: The aim of this study was to investigate whether an adverse fetal environment (LBW) induces permanent changes in skeletal muscle morphology, which may contribute to the dysmetabolic phenotype associated with LBW. DESIGN AND SUBJECTS: Vastus lateralis muscle was obtained by percutaneous biopsy from 20 healthy 19-yr-old men with birth weights at 10th percentile or lower for gestational age (LBW) and 20 normal birth weight controls, matched for body fat, physical fitness, and whole-body glucose disposal. Myofibrillar ATPase staining was used to classify muscle fibers as type I, IIa, and IIx (formerly type IIb), and double immunostaining was performed to stain capillaries (LBW, n=8; normal birth weight, n=12). RESULTS: LBW was associated with increased proportion of type IIx fibers (+66%; P=0.03), at the expense of decreased type IIa fibers (-22%; P=0.003). No significant change was observed in proportion of type I fibers (+16%; P=0.11). In addition, mean area of type IIa fibers was increased (+29%; P=0.01) and tended to be increased for type I fibers as well (+17%; P=0.08). Capillary density was not significantly different between groups. CONCLUSION: Alterations in fiber composition and size may contribute to development of type 2 diabetes in individuals with LBW.

Glycemic control and prevention of microvascular and macrovascular disease in the Steno 2 study.

OBJECTIVE: To review key findings and insights from the Steno 2 trial involving 160 patients with type 2 diabetes in Denmark. METHODS: The Steno 2 study design, with conventional and intensive treatment arms, is described, and the outcomes are summarized. RESULTS: Intensive and target-driven behavior modeling and polypharmacy for 7.8 years induced an absolute risk reduction of 20% in cardiovascular disease events in patients with type 2 diabetes and the metabolic syndrome in comparison with a conventional multifactorial treatment. The relative risk reduction found for microvascular events after 4 years was maintained at a similar level after 7.8 years of intervention: nephropathy 61%, retinopathy 58%, and autonomic neuropathy 63%. CONCLUSION: Improving glycemic control in patients with type 2 diabetes may be as important as, or even more important than, treating hypertension and dyslipidemia for the prevention of both microvascular and macrovascular complications, particularly when aggressive treatment is initiated at an early stage of the disease.

Genetic and nongenetic determinants of skeletal muscle glucose transporter 4 messenger ribonucleic acid levels and insulin action in twins.

CONTEXT: Insulin-stimulated glucose uptake in skeletal muscle is mediated through translocation of the insulin-sensitive glucose transporter 4 (GLUT4)-containing vesicles to the plasma membrane. Thus, skeletal muscle GLUT4 content plays an important role in whole-body insulin sensitivity. OBJECTIVES: The objectives of this study were 1) to examine the relative impact of genetic vs. environmental factors on skeletal muscle GLUT4 mRNA expression using biometric modeling, and 2) to identify factors influencing the expression of GLUT4 and insulin-stimulated whole-body metabolism. DESIGN: We measured GLUT4 mRNA expression in biopsies from young and elderly monozygotic (MZ) and dizygotic (DZ) twins before and during a 2-h hyperinsulinemic euglycemic clamp including 3-(3)H-tritiated glucose and indirect calorimetry. PARTICIPANTS: A random sample of young (22-31 yr; n = 89) and elderly (57-66 yr; n = 69) same sex MZ and DZ twin pairs identified through the Danish Twin Register were studied. RESULTS: We found a major genetic component in the control of basal and insulin-stimulated GLUT4 mRNA expression in young and elderly twins. GLUT4 gene expression increased upon insulin stimulation in both young and elderly twins. Multiple regression analysis revealed that both basal and insulin-stimulated GLUT4 mRNA expressions were positively related to birth weight and total body aerobic capacity and were higher in MZ vs. DZ twins as well as in males vs. females. Both basal and insulin-stimulated expressions of GLUT4 were independently and significantly related to whole-body in vivo insulin action, nonoxidative glucose metabolism, and glucose oxidation. CONCLUSION: We show that skeletal muscle GLUT4 gene expression in twins is significantly and independently related to glucose metabolism and is determined by both genetic and nongenetic factors, including zygosity and birth weight.

Normal secretion and action of the gut incretin hormones glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide in young men with low birth weight.

CONTEXT: Low birth weight (LBW) is associated with increased risk of type 2 diabetes mellitus. An impaired incretin effect was reported previously in type 2 diabetic patients. OBJECTIVE: We studied the secretion and action of glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) in young LBW men (n = 24) and matched normal birth weight controls (NBW) (n = 25). RESULTS: LBW subjects were 5 cm shorter but had a body mass index similar to NBW. LBW subjects had significantly elevated fasting and postprandial plasma glucose, as well as postprandial (standard meal test) plasma insulin and C-peptide concentrations, suggestive of insulin resistance. Insulin secretion in response to changes in glucose concentration ("beta-cell responsiveness") during the meal test was similar in LBW and NBW but inappropriate in LBW relative to insulin sensitivity. Fasting and postprandial plasma GLP-1 and GIP levels were similar in the groups. First- and second-phase insulin responses were similar in LBW and NBW during a hyperglycemic clamp (7 mm) with infusion of GLP-1 or GIP, respectively, demonstrating normal action of these hormones on insulin secretion. CONCLUSION: Reduced secretion or action of GLP-1 or GIP does not explain a relative reduced beta-cell responsiveness to glucose or the slightly elevated plasma glucose concentrations observed in young LBW men.

Dissociation between fat-induced in vivo insulin resistance and proximal insulin signaling in skeletal muscle in men at risk for type 2 diabetes.

The effect of short- (2 h) and long-term (24 h) low-grade Intralipid infusion on whole-body insulin action, cellular glucose metabolism, and proximal components of the insulin signal transduction cascade was studied in seven obese male glucose intolerant first degree relatives of type 2 diabetic patients [impaired glucose tolerance (IGT) relatives] and eight matched control subjects. Indirect calorimetry and excision of vastus lateralis skeletal muscle biopsies were performed before and during hyperinsulinemic euglycemic clamps combined with 3[(3)H]glucose. Clamps were performed after 0, 2, or 24 h Intralipid infusion (0.4 ml.kg(-1).min(-1)). Insulin-stimulated glucose disposal decreased approximately 25% after short- and long-term fat infusion in both IGT relatives and controls. Glucose oxidation decreased and lipid oxidation increased after both short- and long-term fat infusion in both groups. Insulin-stimulated glucose oxidation was higher after long-term as compared with short-term fat infusion in control subjects. Short- or long-term infusion did not affect the absolute values of basal or insulin-stimulated insulin receptor substrate-1 tyrosine phosphorylation, tyrosine-associated phosphoinositide 3-kinase (PI 3-kinase) activity, insulin receptor substrate-1-associated PI 3-kinase activity, or Akt serine phosphorylation in IGT relatives or matched controls. In fact, a paradoxical increase in both basal and insulin-stimulated PI 3-kinase activity was noted in the total study population after both short- and long-term fat infusion. Short- and long-term low-grade Intralipid infusion-induced (or enhanced) whole-body insulin resistance and impaired glucose metabolism in IGT relatives and matched control subjects. The fat-induced metabolic changes were not explained by impairment of the proximal insulin signaling transduction in skeletal muscle.