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To determine whether the glucagonotropic gut-derived hormone glucagon-like peptide 2 (GLP-2) might be exploited as a safeguard against insulin-induced hypoglycemia, we evaluated the effects of exogenous GLP-2 during hypoglycemia, euglycemia and hyperglycemia. Ten healthy, young men underwent six randomized study days: two insulin-induced hypoglycemic clamps (2.5 mmol/L), two euglycemic clamps, and two hyperglycemic clamps (10 mmol/L). At each glycemic level, double-blinded intravenous infusion with GLP-2 (6 pmol/kg/minfrom −10 to 0 min, and 2 pmol/kg/min from 0 to 90 min) or placebo was given. Compared to placebo, exogenous GLP-2 increased glucagon secretion (assessed by baseline-subtracted area under curve) during euglycemia ([mean ± SD] −141±159 pmol/L×min vs. 261±200 pmol/L×min, P=0.0005), but not during hypo- and hyperglycemia. However, compared to placebo, GLP-2 increased glucagon secretion during the initial 40 minutes of the hypoglycemic clamp (38±81 pmol/L×min vs. 174±82 pmol/L×min, P=0.0007). In conclusion, the glucagonotropic effect of GLP-2 is evident at euglycemia and - to a lesser extent - during hypoglycemia, but not during hyperglycemia; positioning GLP-2 as a potential plasma glucose-stabilizer, which perhaps may be utilized therapeutically as a safeguard against insulin-induced hypoglycemia. Disclosure N. L. Hansen: None. T. Magnussen: None. J. J. Holst: Consultant; Self; Novo Nordisk, Other Relationship; Self; Antag Therapeutics, Bainan Biotech, MSD Corporation, Novo Nordisk, Other Relationship; Spouse/Partner; Antag Therapeutics, Bainan Biotech, Synklino ApS. B. Hartmann: None. M. B. Christensen: None. A. Lund: Speaker’s Bureau; Self; Novo Nordisk, Sanofi. F. K. Knop: Advisory Panel; Self; MSD Corporation, Novo Nordisk A/S, Sanofi, Consultant; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Novo Nordisk A/S, Pharmacosmos, Zealand Pharma A/S, Research Support; Self; Novo Nordisk A/S, Zealand Pharma A/S, Speaker’s Bureau; Self; AstraZeneca, Bayer AG, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, MSD Corporation, Novo Nordisk A/S.

The present study addresses the insulin sensitivity in mice deficient in LXRbeta (LXRbeta(-/-)) as well as in wild type (wt) mice assessed by hyperinsulinemic euglycemic clamp. Wt and LXRbeta(-/-) mice were fed either a normal chow diet or a high fat and high cholesterol diet (HFCD), and insulin sensitivity was assessed by hyperinsulinemic euglycemic clamps. We show that LXRbeta(-/-) mice have reduced insulin clearance during hyperinsulinemic clamps upon feeding both HFCD and a regular chow diet. Moreover we also observed reduced hepatic inflammation in LXRbeta(-/-) mice compared to wt mice upon feeding an HFCD, despite equal levels of hepatic steatosis. In summary, our results indicate that LXRbeta(-/-) mice have reduced insulin clearance during hyperinsulinemic euglycemic clamps and also reduced hepatic inflammation upon feeding an HFCD for 26weeks.

Exercise affects substrate utilisation and insulin sensitivity, which in turn improve blood glucose and lipid levels in subjects with type 2 diabetes (T2D). However, making long-lasting lifestyle-changes might be more realistic if the results were easier to record. Screening for biomarkers reflecting metabolic fitness could thus serve as a tool for maintained motivation. The aim of this study was to test the possibility that metabolomics can be used to identify individuals with improved insulin sensitivity as a result of increased physical activity. Healthy and diabetic subjects were investigated before and after 3 months of exercise to determine various metabolic parameters. Insulin sensitivity was determined by hyperinsulinemic euglycemic clamps and found to be improved in the diabetic men. Plasma was collected during the clamp and analyzed through GC/TOFMS. Healthy subjects could be distinguished from diabetics by means of low molecular-weight compounds (LMC) in plasma independently of gender or exercise, and exercise induced differences in LMC patterns both for healthy and T2D subjects. Forty-four significant metabolites were found to explain differences between LMC patterns obtained from trained and non-trained diabetics. Among these compounds, 17 could be annotated and 5 classified. Inositol-1-phosphate showed the highest correlation to insulin sensitivity in diabetic men, whereas an as yet unknown fatty acid correlated best with insulin sensitivity in women. Both metabolites were better correlated to insulin sensitivity than glucose. Finally, the finding that inostitol-1-phosphate negatively correlates with insulin sensitivity in diabetic men, was validated using samples obtained from a similar training study on diabetic men.

The aim of this study was to investigate the effect of two different glucose levels on GH response to the combined administration of GHRH+GHRP-6 in patients with type 2 diabetes. GH response to i.v. bolus of GHRH+GHRP-6 (100 mcg, each) was measured in 12 male patients with type 2 diabetes (mean age: 53.9+/-1.59 years; BMI: 25.58+/-0.39 kg/m(2); mean HbA(1c): 8.7+/-0.42%), during a euglycemic (mean glucose: 4.92+/-0.08 mmol) hyperinsulinemic clamp (insulin infusion rate of 100 mU/kg/h) and a hyperglycemic clamp (mean glucose: 12.19+/-0.11 mmol/l). There was no difference in basal GH levels between the hyperglycemic and euglycemic clamps (2.9+/-0.99 mU/l versus 1.48+/-0.44 mU/l; P0.05). Peak GH response to GHRH+GHRP-6 during the hyperglycemic clamp was lower than in the englycemic clamp (112.45+/-14.45 mU/l versus 151.06+/-16.87 mU/l; P0.05). Area under the GH curve was lower in the hyperglycemic than in the euglycemic clamp (6974.49+/-1001.95 mU/l/min versus 9560.75+/-1140.65 mU/l/min; P0.05). It is concluded that hyperglycemia significantly reduces GH response to combined administration of GHRH+GHRP-6 in normal weight patients with type 2 diabetes. It is suggested that ambient glucose levels should be taken into account during interpretation of GH response to combined administration of GHRH+GHRP-6 in patients with type 2 diabetes.

The hyperinsulinemic euglycemic clamp is the gold standard for assessment of insulin resistance and requires frequent, accurate measurements of blood glucose concentrations, typically utilizing the YSI 2300 STAT Plus™ glucose analyzer (YSI, Inc., Yellow Springs, OH). Despite its accuracy, the YSI has several limitations, including its cost, lengthy run time, need for trained personnel, frequent maintenance, and large blood volumes. Simpler hospital-grade hand-held glucose meters are now available but have not been validated for use in pediatric clamp settings. Our objective was to evaluate the accuracy, precision, and reliability of the StatStrip(®) (SS) hospital glucose monitoring system (Nova Biomedical, Waltham, MA) relative to the YSI 2300 STAT glucose analyzer in pediatric hyperinsulinemic euglycemic clamps.Four hundred sixty blood specimens drawn from 11 pediatric patients undergoing hyperinsulinemic euglycemic clamps were simultaneously analyzed by SS and YSI. Outcome measures included SS bias relative to YSI and glucose measurement precision on SS and YSI.The SS showed a slight positive bias of 0.75 ± 2.83 mg/dL versus the YSI. Percentage coefficients of variance for SS and YSI were 9.53% and 9.25%, respectively. Using a Bland-Altman plot, the limits of agreement were ± 5.7 mg/dL. The coefficient of repeatability for SS was 6.63; the coefficient of individual agreement between the YSI and SS was 0.995.The SS is a suitable replacement for the YSI in pediatric hyperinsulinemic euglycemic clamp studies, is easier to use, more cost-effective, and faster, and requires less blood. Future euglycemic clamp studies can consider utilizing this methodology.

Leptin has been shown to regulate feed intake and energy expenditure. Insulin stimulates leptin secretion in rodents, but its action on leptin secretion is still obscure in ruminants. If insulin stimulates leptin secretion in ruminants, circulating leptin concentrations may change during exposure to cold, because of fluctuating insulin secretion and action in the cold environment. The present experiment was designed to determine whether feeding or exogenous administration of insulin affects circulating leptin levels in sheep exposed to thermoneutral and cold environments. Suffolk rams that were shorn and fed a diet once daily were subjected to a thermoneutral (20 degrees C) or cold (0 degrees C) environment for at least 1 week. Overall mean concentrations of plasma leptin in the feeding experiment were lower (P

to the editor: Recently, we reported that fat tissue receives not only sympathetic but also parasympathetic innervation ([5][1]). Using microsurgery, transneuronal retrograde tracing, and hyperinsulinemic euglycemic clamps, we demonstrated that parasympathetic innervation of fat tissue has an

We have read with interest the article in the July issue of Diabetes Care by Tam et al. (1) in which they define a cutoff point for having insulin resistance and provide classification trees for predicting insulin resistance from clinical and biochemical markers. We appreciate the authors’ effort to translate detailed phenotypic data into clinical usefulness; however, defining a cutoff point is always challenging, and the study raises a number of questions. Whether the overall aim of setting a cutoff point for insulin resistance is to guide treatment in patients with type 2 diabetes or to prevent or delay the development of diabetes in the general population, the rationale for determining insulin resistance should be clearly defined in order for the cutoff point to …

The euglycemic-hyperinsulinemic clamp is the gold standard for evaluating insulin sensitivity. As such, it is extremely helpful in evaluating the effect of an intervention or in comparing insulin sensitivities between two or more groups. What remains a challenge is to decide the values above which …

This study addressed the controversial question of whether a negative—insulin-feedback loop exists in vivo. We utilized prehepatic insulin production, calculated by computerized deconvolution analysis of peripheral C-peptide concentration, as a measure of endogenous insulin secretion. Prehepatic insulin production was determined in 10 normal men who randomly underwent a control study and two additional studies involving different insulin infusion rates that achieved circulating insulin concentrations within the physiologic range during euglycemic clamps. The results demonstrate a dose-dependent suppression of prehepatic insulin production from 5.8 ± 1.4 mU/min during the control study to 4.0 ± 1.2 and 3.2 ± 0.9 mU/min during plasma insulin levels of 34 ± 4 and 61 ± 6 μU/ml, respectively (P < .05). Therefore, in contrast to recently reported results in vitro, insulin inhibits its own secretion in humans.

Seven endurance-trained subjects [maximal O2 consumption (VO2max) 64 +/- 1 (SE) ml.min-1.kg-1] underwent sequential hyperinsulinemic euglycemic clamps on three occasions: 1) in the “habitual state” 15 h after the last training bout (C), 2) after 60 min of bicycle exercise at 72 +/- 3% of VO2max performed in the habitual state (E), and 3) 5 days after the last ordinary training session (detrained, DT). Sensitivity for insulin-mediated whole-body glucose uptake was not affected by acute exercise [insulin concentrations eliciting 50% of maximal insulin-mediated glucose uptake being 44 +/- 2 (C) vs. 46 +/- 3 (E) microU/ml] but was decreased after detraining (54 +/- 2 microU/ml, P less than 0.05) to levels comparable to those found in untrained subjects [Am. J. Physiol. 254 (Endocrinol. Metab. 17): E248-E259, 1988]. Near-maximal insulin-mediated glucose uptake (responsiveness) was higher than in untrained subjects and not influenced by acute exercise or detraining [13.4 +/- 1.2 (C), 12.2 +/- 0.9 (E), and 12.2 +/- 0.3 (DT) mg.min-1.kg-1]. Calculated by indirect calorimetry, the glucose-to-glycogen conversion was not influenced by E but was reduced during detraining (P less than 0.05) yet remained higher than previously found in untrained subjects (P less than 0.05). However, only on E days did muscle glycogen increase during insulin infusion. Glycogen synthase activity was increased on E and decreased on DT compared with C days.(ABSTRACT TRUNCATED AT 250 WORDS)