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The aim of the study was to investigate, whether type 2 diabetes independently influences adipokines and inflammatory markers in patients with metabolic syndrome.36 patients with metabolic syndrome without type 2 diabetes and 39 patients with metabolic syndrome with type 2 diabetes, carefully matched for age, sex, and BMI, were investigated. Primary outcome measures were circulating adipokines and inflammatory markers (adiponectin, leptin, visfatin, vaspin, resistin, TNF-α, IL-6, monocyte chemoattractant protein-1 (MCP-1), retinol binding protein 4 (RBP-4), growth differentiation factor-15 (GDF-15)). In addition, we determined parameters of glucose and lipid metabolism.Patients with metabolic syndrome and type 2 diabetes had significantly lower levels of plasma total cholesterol, low-density lipoprotein cholesterol and triglycerides (p0.05). They displayed higher GDF-15 concentrations (1,113 ± 135 vs. 656 ± 63 pg/ml, p = 0.005) and lower visfatin concentrations (3.7 ± 0.3 vs. 4.8 ± 0.2 ng/ml, p = 0.009). There were no differences in other adipokines and inflammatory markers between both groups.In patients with metabolic syndrome, type 2 diabetes leads to decreased visfatin and increased GDF-15 serum levels when compared to carefully matched non-diabetic subjects. Whether the increase in GDF-15 is an indicator or a causal factor for the increased cardiovascular risk in diabetic subjects remains to be investigated in further studies.

OBJECTIVE Recent work has shown that insulin stimulates its own secretion in insulin-sensitive humans, suggesting that insulin resistance in the β-cell could cause β-cell dysfunction. We have tested whether insulin exposure and insulin sensitivity modulate β-cell function in subjects with normal glucose tolerance (NGT) and whether they contribute to dysglycemia in impaired glucose regulation (IGR). RESEARCH DESIGN AND METHODS Insulin sensitivity (by euglycemic clamp), insulin-induced secretory response at isoglycemia (IISR) (as C-peptide percent change from basal during the clamp), glucose-induced secretory response (GISR) to an intravenous glucose bolus, and β-cell glucose sensitivity (β-GS) (by oral glucose tolerance test [OGTT] modeling) were measured in 1,151 NGT and 163 IGR subjects from the RISC (Relationship between Insulin Sensitivity and Cardiovascular Disease) study. RESULTS In NGT, IISR was related to both insulin sensitivity and antecedent insulin exposure; GISR was related to insulin exposure. IISR was positively, if weakly, related to β-GS (r= 0.16, P < 0.0001). Both IISR (−23 [39] vs. −9 [2]%, median [interquartile range], P < 0.03) and β-GS (69 [47] vs. 118 [83] pmol ⋅ min–1 ⋅ m–2 ⋅ mmol–1 ⋅ L, P < 0.0001) were decreased in IGR compared with NGT. Insulin sensitivity and β-GS were the major determinants of mean OGTT glucose in both NGT and IGR, with a minor role for IISR. In a multivariate logistic model, IGR was predicted by β-GS (odds ratio 4.84 [95% CI 2.89–8.09]) and insulin sensitivity (3.06 [2.19–4.27]) but not by IISR (1.11 [0.77–1.61]). CONCLUSIONS Pre-exposure to physiological hyperinsulinemia stimulates insulin secretion to a degree that depends on insulin sensitivity. However, this phenomenon has limited impact on β-cell dysfunction and dysglycemia.

BACKGROUNDGrowth differentiation factor-15 (GDF-15) is a stress-responsive cytokine linked to obesity comorbidities such as cardiovascular disease, inflammation, and cancer. GDF-15 also has adipokine properties and recently emerged as a prognostic biomarker for cardiovascular events.METHODSWe evaluated the relationship of plasma GDF-15 concentrations with parameters of obesity, inflammation, and glucose and lipid metabolism in a cohort of 118 morbidly obese patients [mean (SD) age 37.2 (12) years, 89 females, 29 males] and 30 age- and sex-matched healthy lean individuals. All study participants underwent a 75-g oral glucose tolerance test; 28 patients were studied before and 1 year after Roux-en-Y gastric bypass surgery.RESULTSObese individuals displayed increased plasma GDF-15 concentrations (P < 0.001), with highest concentrations observed in patients with type 2 diabetes. GDF-15 was positively correlated with age, waist-to-height ratio, mean arterial blood pressure, triglycerides, creatinine, glucose, insulin, C-peptide, hemoglobin A1c, and homeostatic model assessment insulin resistance index and negatively correlated with oral glucose insulin sensitivity. Age, homeostatic model assessment index, oral glucose insulin sensitivity, and creatinine were independent predictors of GDF-15 concentrations. Roux-en-Y gastric bypass led to a significant reduction in weight, leptin, insulin, and insulin resistance, but further increased GDF-15 concentrations (P < 0.001).CONCLUSIONSThe associations between circulating GDF-15 concentrations and age, insulin resistance, and creatinine might account for the additional cardiovascular predictive information of GDF-15 compared to traditional risk factors. Nevertheless, GDF-15 changes following bariatric surgery suggest an indirect relationship between GDF-15 and insulin resistance. The clinical utility of GDF-15 as a biomarker might be limited until the pathways directly controlling GDF-15 concentrations are better understood.

Background: Because women have been excluded from many study populations in investigations of diabetes care, there is insufficient information on sex-specific differences in glycemic control. Objective: The aim of the present study was to assess whether treatment goals for glycemic and cardiovascular risk factor control are achieved equally in older, Central European, female and male patients with type 2 diabetes mellitus (T2DM). Methods: In a retrospective cross-sectional study, data were analyzed from consecutive older (aged ≥60 years) female and male patients with insulin-treated T2DM who attended a diabetes outpatient clinic between January 2007 and April 2008 at the Medical University of Vienna, Austria. Sex-specific differences in glycosylated hemoglobin (HbA1c) levels were assessed as the primary outcome. LDL-C and HDL-C, as well as systolic and diastolic blood pressure (SBP and DBP, respectively), were assessed as secondary outcomes and were adjusted for age, duration of diabetes, duration of insulin treatment, body mass index, insulin units per kilogram per day, and secondary causes of diabetes. P values were adjusted using the Bonferroni correction. Results: Data were analyzed from 183 female and 209 male patients with insulin-treated T2DM. In multivariate linear regression models, women had significantly higher levels of LDL-C (P = 0.008), HDL-C (P < 0.001), SBP (P < 0.001), and DBP (P = 0.034), but not HbA1c (P = NS). Multivariate logistic regression models revealed that women were significantly less likely to meet treatment goals for blood pressure (SBP, P = 0.044; DBP, P = 0.024), but not for cholesterol or HbA1c levels (P = NS for LDL-C, HDL-C, and HbA1c). Conclusion: In this study of older patients with insulin-treated T2DM, whereas glycemic control was comparable between women and men, a more adverse cardiovascular risk factor profile was observed in female patients.

The first-degree offspring of patients with type 2 diabetes are prone to develop type 2 diabetes, and have both insulin resistance and beta cell impairment. However, it is still unclear whether both pathophysiological features are inseparably combined and which is the outstanding determinant in the offspring.Glucose metabolism, insulin sensitivity (calculated as M value divided by insulin [M/I]) and beta cell function were studied in the offspring of individuals with type 2 diabetes (n = 187; 57% females; age 43.8 +/- 8.1 years; BMI 26.8 +/- 4.5 kg/m(2)) and in individuals without a family history of type 2 diabetes (controls, n = 519, 55% females; age 43.4 +/- 8.2 years; BMI 26.4 +/- 3.7 kg/m(2), no significant differences between the groups for any characteristic) by performance of 75 g OGTT and 2 h hyperinsulinaemic (40 mU min(-1) m(-2))-isoglycaemic clamp tests. Beta cell function was evaluated by calculating insulinogenic index (IGI) from C-peptide AUC:glucose AUC ratios from the first hour of OGTT (IGI[60 min]) and from the total OGTT (IGI[120 min]).During the OGTT, the offspring of individuals with type 2 diabetes showed 4-14% higher plasma glucose from 30 to 120 min (p0.05) and 20-29% higher serum insulin from 90 to 120 min, but decreased IGI(60 min) and IGI(120 min) (p0.05). M/I was 11% lower in the offspring of affected individuals than in controls (p0.01). To study the offspring of patients with type 2 diabetes with insulin sensitivity similar to that of the control group, the offspring of affected patients were divided into M/I quartiles. Those in the third M/I quartile showed M/I values and major anthropometric characteristics similar to those of the controls, but insulin AUC and C-peptide AUC values were lower in the first hour and the total OGTT (p0.05). The third M/I quartile had lower IGI values at 60 min and 120 min: 11% and 14% lower, respectively (p0.02).The first-degree offspring of type 2 diabetic patients show insulin resistance and beta cell dysfunction in response to oral glucose challenge. Beta cell impairment exists in insulin-sensitive offspring of patients with type 2 diabetes, suggesting beta cell dysfunction to be a major defect determining diabetes development in diabetic offspring.

OBJECTIVE—Statins may exert pleiotropic effects on insulin action that are still controversial. We assessed effects of high-dose simvastatin therapy on peripheral and hepatic insulin sensitivity, as well as on ectopic lipid deposition in patients with hypercholesterolemia and type 2 diabetes. RESEARCH DESIGN AND METHODS—We performed a randomized, double-blind, placebo-controlled, single-center study. Twenty patients with type 2 diabetes received 80 mg simvastatin (BMI 29 ± 4 kg/m2, age 55 ± 6 years) or placebo (BMI 27 ± 4 kg/m2, age 58 ± 8 years) daily for 8 weeks and were compared with 10 healthy humans (control subjects; BMI 27 ± 4 kg/m2, age 55 ± 7 years). Euglycemic-hyperinsulinemic clamp tests combined with d-[6,6-d2]glucose infusion were used to assess insulin sensitivity (M) and endogenous glucose production (EGP). 1H magnetic resonance spectroscopy was used to quantify intramyocellular and hepatocellular lipids. RESULTS—High-dose simvastatin treatment lowered plasma total and LDL cholesterol levels by ∼33 and ∼48% (P < 0.005) but did not affect M, intracellular lipid deposition in soleus and tibialis anterior muscles and liver, or basal and insulin-suppressed EGP. In simvastatin-treated patients, changes in LDL cholesterol related negatively to changes in M (r = −0.796, P < 0.01). Changes in fasting free fatty acids (FFAs) related negatively to changes in M (r = −0.840, P < 0.01) and positively to plasma retinol-binding protein-4 (r = 0.782, P = 0.008). CONCLUSIONS—High-dose simvastatin treatment has no direct effects on whole-body or tissue-specific insulin action and ectopic lipid deposition. A reduction in plasma FFAs probably mediates alterations in insulin sensitivity in vivo.

Context: Recent data suggest that circulating retinol-binding protein (RBP) might be involved in the pathogenesis of insulin resistance. Moreover, protein C inhibitor (PCI), which specifically binds retinoic acid, was found to be increased in myocardial infarction survivors who are also insulin resistant.Objective: The objective of this study was to investigate the association of insulin resistance with RBP factors and PCI active antigen.Design and Setting: This was a clinical study.Patients: Nondiabetic humans with high (IS; n = 20, 14 females, six males, aged 47.2 ± 1.9 yr, body mass index 26 ± 1 kg/m2) and low (IR; n = 20, 14 females, six males, aged 45.5 ± 1.7 yr, body mass index 28 ± 1 kg/m2) insulin-stimulated glucose-disposal (M) participated in this study.Main Outcome Measures: M was measured by 2-h hyperinsulinemic (40 mU·min−1·m−2)-isoglycemic clamp tests. Measurements of RBP were performed using a nephelometric method and validated using quantitative Western blotting.Results: M (80–120 min) was higher in IS (10.9 ± 0.6 mg·min−1·kg−1) than IR (4.0 ± 0.2; P < 10−12). Fasting plasma RBP concentrations were comparable between IS and IR measured by both nephelometry (IS: 4.4 ± 0.3; IR: 4.6 ± 0.3 mg/dl, P = 0.6) and quantitative Western blot (IS 7.9 ± 0.5, IR 8.3 ± 0.6 mg/dl; P = 0.6). Fasting plasma PCI active antigen was similar in both groups. Plasma RBP and PCI were not significantly related to M. RBP was positively correlated with uric acid (r = 0.488, P = 0.003), triglycerides (r = 0.592, P < 0.001), prealbumin (r = 0.63, P < 0.0001), and vitamin A (r = 0.75, P < 10−6).Conclusions: Our data demonstrate that healthy, insulin-resistant humans do not show altered plasma retinol binding factors, such as RBP and PCI. Both do not significantly correlate with insulin sensitivity. Thus, our findings do not support the hypothesis of insulin sensitivity modulation by proteins involved in retinol transport.

Obestatin, a recently discovered 23-amino acid peptide, is involved in the regulation of appetite and body weight in antagonistic fashion to ghrelin, both deriving from a common precursor peptide. Ghrelin was shown to be associated with insulin resistance, which may also affect obestatin. We investigated the association between insulin resistance and plasma concentrations of obestatin and ghrelin in nondiabetic individuals with high (IS; n = 18, 13 females and 5 males, age 47 ± 2 yr, BMI = 25.5 ± 0.9 kg/m2) and low (IR; n = 18, 12 females and 6 males, age 45 ± 2 yr, P = 0.49, BMI = 27.5 ± 1.1 kg/m2, P = 0.17) insulin-stimulated glucose disposal (M), measured by 2-h hyperinsulinemic (40 mU·min−1·m−2) isoglycemic clamp tests. M100–120 min was higher in IS (10.7 ± 0.7) than in IR (4.4 ± 0.2 mg·min−1·kg−1, P < 10−9), whereas insulin-dependent suppression of free fatty acids (FFA) in plasma was reduced in IR (71 ± 6% vs. IS: 82 ± 5%, P < 0.02). In both groups, plasma ghrelin concentrations were comparable at fasting and similarly reduced by 24–28% during insulin infusion. IR had lower fasting plasma obestatin levels (383 ± 26 pg/ml vs. IS: 469 ± 23 pg/ml, P < 0.02). Clamp insulin infusion reduced plasma obestatin to ∼81% of basal values in IS ( P < 0.00002), but not in IR. Fasting plasma obestatin was correlated positively with M ( r = 0.34, P = 0.04), HDL cholesterol ( r = 0.45, P = 0.01), and plasma ghrelin concentrations ( r = 0.80, P < 0.000001) and negatively with measures of adiposity, plasma FFA during clamp ( r = −0.42, P < 0.01), and systolic blood pressure ( r = −0.33, P < 0.05). In conclusion, fasting plasma concentrations of obestatin, but not of ghrelin, are reduced in insulin resistance and are positively associated with whole body insulin sensitivity in nondiabetic humans. Furthermore, plasma obestatin is reduced by insulin in insulin-sensitive but not in insulin-resistant persons.

OBJECTIVE—Insulin resistance, the underlying pathophysiological mechanism of the metabolic syndrome, can not only predict type 2 diabetes development but also cardiovascular disease. Thus, precise insulin resistance measurement in individuals at risk for metabolic diseases would support clinical risk stratification. However, the gold standard for measuring insulin resistance, the hyperinsulinemic clamp test, is too labor intensive to be performed in large clinical studies/settings. RESEARCH DESIGN AND METHODS—Using plasma glucose and C-peptide concentrations from oral glucose tolerance tests (OGTTs), we developed the novel “clamp-like index” (CLIX) for insulin sensitivity calculation and compared CLIX to clamp glucose infusion rates (GIR) (100–120 min). We evaluated CLIX in 89 nondiabetic subjects (58 female and 31 male, aged 45 ± 1 years, BMI 27.5 ± 0.8 kg/m2) who underwent frequently sampled 3-h 75-g OGTTs and 2-h hyperinsulinemic-isoglycemic clamp (40 mU/min per m2) tests. RESULTS—CLIX, calculated as serum creatinine (×0.85 if male)/(mean AUCglucose × mean AUCC-peptide) × 6,600, was highly correlated (r = 0.670, P < 10−12) with and comparable to clamp GIRs100–120 min. In subgroup analyses, GIRs100–120 min were lower (P < 0.005) in type 2 diabetic offspring (6.2 ± 0.7 mg · min−1 · kg−1) than in sex-, age-, and BMI-matched subjects without a family history of type 2 diabetes (8.6 ± 0.5 mg · min−1 · kg−1), which was also reflected by CLIX (insulin-resistant offspring 6.4 ± 0.6 vs. those without a family history of type 2 diabetes 9.0 ± 0.5; P < 0.002). When compared with normal-weight subjects (GIR 8.8 ± 0.4 mg · min−1 · kg−1; CLIX 9.0 ± 0.5), both GIRs100–120 min and CLIX of obese (5.2 ± 0.9 mg · min −1 · kg−1; 5.7 ± 0.9) and morbidly obese (2.4 ± 0.4 mg · min −1 · kg−1; 3.3 ± 0.5) humans were lower (each P < 0.02). CONCLUSIONS—CLIX, a novel index obtained from plasma OGTT glucose and C-peptide levels and serum creatinine, without inclusion of anthropometrical measures to calculate insulin sensitivity in nondiabetic humans, highly correlates with clamp GIRs and reveals even slight insulin sensitivity alterations over a broad BMI range and is as sensitive as the hyperinsulinemic clamp test.

Aims: We investigated long-term mortality and requirement of renal replacement therapy (RRT) in type 1 diabetes mellitus (T1DM) to study risk factors and late complication incidence of T1DM in a prospective cohort study at Lainz Hospital, Vienna, Austria. Methods: In 1983–1984, T1DM patients [n = 648; 47% females, 53% males; age, 30 ± 11 yr; T1DM duration, 15 ± 9 yr; body mass index, 24 ± 4 kg/m2; glycated hemoglobin (HbA1c), 7.6 ± 1.6%] were stratified into HbA1c quartiles [1st, 5.9 ± 0.5% (range, 4.2–6.5%); 2nd, 6.9 ± 0.3% (6.6–7.4%); 3rd, 7.9 ± 0.3% (7.5–8.4%); and 4th, 9.6 ± 1.3% (8.5–14.8%)]. Twenty years later, both endpoints (death and RRT) were investigated by record linkage with national registries. Results: At baseline, creatinine clearance, blood pressure, and body mass index were comparable among the HbA1c quartiles, whereas albuminuria was more frequent in the 4th quartile (+15%; P < 0.03). After the 20-yr follow-up, 13.0% of the patients had died [rate, 708 per 100,000 person-years (95% confidence interval, 557–859)], and 5.6% had received RRT [311 per 100,000 person-years (95% confidence interval, 210–412)]. Patients with the highest HbA1c values (4th quartile) had a higher mortality rate and a greater incidence of RRT (P < 0.04). In the Cox proportional hazards analysis, age, male gender, increased HbA1c, albuminuria, and reduced creatinine clearance were predictors of mortality (P < 0.05). Predictors of RRT were albuminuria (P < 0.001), reduced creatinine clearance (P < 0.001), and belonging to the 4th HbA1c quartile (P = 0.06). In Kaplan-Meier analysis, mortality was linearly associated with poor glycemia, whereas RRT incidence appeared to rise at a HbA1c threshold of approximately 8.5%. Conclusion/Interpretation: In the Lainz T1DM cohort, 13.0% mortality and 5.6% RRT were directly associated with and more frequently found in poor glycemia, showing that good glycemic control is essential for the longevity and quality of life in T1DM.

OBJECTIVE—In response to hyperglycemia, β-cells release insulin and C-peptide, as well as islet amyloid pancreatic polypeptide, which is involved in glucose homeostasis. After successful pancreas-kidney transplantation (PKT), type 1 diabetic patients may revert to a nondiabetic metabolism without exogenous insulin therapy and re-secrete all β-cell hormones. RESEARCH DESIGN AND METHODS—Using mathematical models, we investigated hormone (amylin, insulin, C-peptide) and metabolite (glucose, free fatty acids) kinetics, β-cell sensitivity to glucose, and oral glucose insulin sensitivity index (OGIS) in 11 nondiabetic type 1 diabetic patients after PKT (BMI 25 ± 1 kg/m2, 47 ± 2 years of age, 4 women/7 men, glucocorticoid-free), 6 matching nondiabetic patients after kidney transplantation (25 ± 1 kg/m2, 50 ± 5 years, 3 women/3 men, on glucocorticoids), and 9 matching nondiabetic control subjects (24 ± 1 kg/m2, 47 ± 2 years, 4 women/5 men) during a 3-h 75-g oral glucose tolerance test (OGTT). RESULTS—PKT patients had higher fasting amylin (19 ± 3 vs. control subjects: 7 ± 1 pmol/l) and insulin (20 ± 2 vs. control subjects: 10 ± 1 μU/ml; each P < 0.01) levels. Kidney transplant subjects showed increased OGTT plasma insulin at 90 min and C-peptide levels (each P < 0.05). In PKT patients, plasma glucose from 90 to 150 min was 9–31% higher (P < 0.05 vs. control subjects). Amylin clearance was comparable in all groups. Amylin’s plasma concentrations and area under the concentration curve were up to twofold higher in PKT patients during OGTT (P < 0.05). OGIS was not significantly different between groups. β-Cell sensitivity to glucose was reduced in PKT patients (−64%, P < 0.009). Fasting plasma amylin was inversely associated with β-cell sensitivity to glucose (r = −0.543, P < 0.004). CONCLUSIONS—After successful PKT, type 1 diabetic patients with nondiabetic glycemia exhibit increased fasting and post–glucose load plasma amylin, which appears to be linked to impaired β-cell function. Thus, higher amylin release in proportion to insulin might also reflect impaired β-cell function in type 1 diabetic patients after PKT.

Endocrine defensive mechanisms provide for energy supply during hypoglycemia. Intramyocellular lipids (IMCL) were recently shown to contribute to energy supply during exercise.The objective of this study was to assess the contribution of IMCL compared with lipolysis and endogenous glucose production (EGP) to insulin-mediated hypoglycemia counterregulation in patients with type 1 diabetes mellitus (T1DM).This was a prospective explorative study performed in a university research facility.Six well-controlled T1DM (age, 29 +/- 4 yr; body mass index, 23.4 +/- 1.0 kg/m2; hemoglobin A1c, 6.3 +/- 0.1%) and six nondiabetic humans (controls; age, 28 +/- 2 yr; body mass index, 23.4 +/- 1.0 kg/m2; hemoglobin A1c, 5.1 +/- 0.1%) were studied.We performed 240-min hypoglycemic (approximately 3 mM)-hyperinsulinemic (0.8 mU/kg x min) clamps on separate days to measure: 1) systemic lipolysis ([2H5]glycerol turnover), EGP ([6,6-(2)H2]glucose), and local lipolysis in abdominal s.c. adipose tissue and gastrocnemius muscle (microdialysis); and 2) IMCL (by 1H nuclear magnetic resonance spectroscopy) in soleus and tibialis anterior muscle.The main outcome measures were changes in IMCL during prolonged hypoglycemia.At baseline, EGP, glycerol turnover, and IMCL were not different between the groups. During hypoglycemia, hormonal counterregulation was blunted in T1DM (peak: glucagon, 68 +/- 4 vs. 170 +/- 37 pg/ml; cortisol, 16 +/- 2 vs. 24 +/- 2 microg/dl; epinephrine, 274 +/- 84 vs. 597 +/- 212 pg/ml; all P0.05 vs. control). T1DM had approximately 50% lower EGP (4.6 +/- 0.6 vs. 10.9 +/- 0.5 micromol/kg x min; P0.005), but approximately 40% higher glycerol turnover (374 +/- 21 vs. 272 +/- 19 micromol/kg x min; P0.01). Glycerol concentrations in muscle (T1DM, 302 +/- 22 control, 346 +/- 17 micromol/liter) and adipose tissue (264 +/- 25 vs. 318 +/- 25 micromol/liter) did not differ between groups. IMCL in soleus and tibialis anterior muscle did not change from baseline during hypoglycemia.In well-controlled T1DM, impaired hypoglycemia counterregulation is associated with decreased glucose production and augmented whole body lipolysis, which cannot be explained by either hydrolysis of muscle triglycerides or increased abdominal s.c. adipose tissue lipolysis.

The study was designed to examine the contribution of direct (substrate-mediated) and indirect (hormone-mediated) effects of amino acids on hepatic glucose metabolism in healthy men.The protocols were: (i) CON+S (n=7): control conditions with somatostatin to inhibit endogenous hormone release resulting in fasting plasma concentrations of amino acids, insulin (approximately 28 pmol/l) and glucagon (approximately 65 ng/l), (ii) AA+S ( n=7): amino acid infusion-fasting insulinaemia-fasting glucagonaemia, (iii) GLUC+S ( n=6): fasting amino acids-fasting insulinaemia-hyperglucagonaemia (approximately 99 ng/l) and (iv) AA-S (n=5): amino acid infusion without somatostatin resulting in amino acid-induced hyperinsulinaemia (approximately 61 pmol/l)-hyperglucagonaemia (approximately 147 ng/l). Net glycogenolysis was calculated from liver glycogen concentrations using (13)C nuclear magnetic resonance spectroscopy. Total gluconeogenesis (GNG) was calculated by subtracting net glycogenolysis from endogenous glucose production (EGP) which was measured with [6,6-(2)H(2)]glucose. Net GNG was assessed with the (2)H(2)O method.During AA+S and GLUC+S, plasma glucose increased by about 50% (p0.01) due to a comparable rise in EGP. This was associated with a 53-% (p0.05) and a 65% increase (p0.01) of total and net GNG during AA+S, whereas net glycogenolysis rose by 70% (p0.001) during GLUC+S. During AA-S, plasma glucose remained unchanged despite nearly-doubled (p0.01) total GNG.Conditions of postprandial amino acid elevation stimulate secretion of insulin and glucagon without affecting glycaemia despite markedly increased gluconeogenesis. Impaired insulin secretion unmasks the direct gluconeogenic effect of amino acids and increases plasma glucose.

Leptin has recently been suggested to play a role in the pathogenesis of hepatic steatosis. Consequently, this study was designed to examine the direct effects of portal leptin on the intrahepatic lipid contents in the postabsorptive state. Rat livers (n = 6 per group) were perfused in a recirculating system and portally infused with leptin (0.5 nmol/L, 5 nmol/L, and 25 nmol/L), insulin (10 nmol/L), leptin (5 nmol/L) plus insulin (10 nmol/L), glucagon (1 nmol/L), or vehicle (control). Intrahepatic contents of triglycerides, free cholesterol, cholesteryl esters, and free fatty acids were determined from the lipid extract of frozen livers by capillary gas chromatography. Short-term leptin infusion increased total triglycerides in a concentration-dependent (0.5 nmol/L: 2.8 ± 0.4 mg/g, 5 nmol/L: 7.0 ± 0.5 mg/g, 25 nmol/L: 8.3 ± 1.0 mg/g) and time-dependent manner. Total triglycerides also rose during exposure to insulin plus leptin (7.2 ± 0.6 mg/g) but fell during glucagon infusion (2.6 ± 0.2 mg/g; control: 4.3 ± 0.3 mg/g;P < .05). Leptin, insulin, and glucagon increased intrahepatic free cholesterol (P < .05). Free fatty acids were also higher during leptin exposure (0.5 nmol/L: 1.28 ± 0.08 mg/g, 5 nmol/L: 0.47 ± 0.01 mg/g, 25 nmol/L: 0.48 ± 0.04 mg/g, control: 0.38 ± 0.03 mg/g; P < .05). In conclusion, hyperleptinemia increases hepatic triglyceride content and may therefore contribute to hepatic steatosis in hyperleptinemic obese patients. (Hepatology 2000;32:1045-1049.)

Big changes are hard. When trying to achieve guideline targets in diabetes and cardiometabolic disorders, patients can lack commitment or suffer despondency. It is much easier to make small changes in lifestyle or treatment, which are less noticeable and easier to manage long-term. Obesity is central to the cardiometabolic disorders, and even small weight losses of 2-5% can improve the cardiometabolic risk profile and substantially reduce the risk of developing type 2 diabetes. Likewise, small increases in physical activity, such as 15-30 min of brisk walking per day, can cut the risk of heart disease by 10%. Lifestyle or treatment changes that lead to small improvements in metabolic parameters also impact patient outcome - for example, a 5 mmHg decrease in blood pressure can translate into significant reductions in the rates of myocardial infarction and cardiovascular mortality. Benefits of small changes can also be seen in health economic outcome models. Implementing change at an individual versus a population level has different implications for overall benefit and patient motivation. Even very small steps taken in trying to reach guideline targets should represent a positive achievement for patients. Patient engagement is essential - only when patients commit themselves to change can benefits be maintained, and physicians should recognise their influence. Small changes in individual parameters can result in significant beneficial effects; however, a major impact can occur when small changes are made together in multiple parameters. More research is required to elucidate the full impact of small changes on patient outcome.

Moderate alcohol consumption is associated with a reduced risk of type 2 diabetes with a stronger effect in women. As the underlying mechanisms remain poorly characterised, we investigated its relationship with insulin resistance, insulin secretion, clearance of insulin and glucagon concentration.One-thousand two-hundred and seventy-six non-diabetic individuals from the RISC (relationship between insulin sensitivity and cardiovascular disease) study without high alcohol consumption were studied; all had a euglycaemic-hyperinsulinaemic clamp and an OGTT with assessment of insulin sensitivity, secretion and clearance.Alcohol consumption was positively associated with insulin sensitivity in women (β = 0.15, p ( trend ) = 0.005) and in men (β = 0.07, p ( trend ) = 0.07) after controlling for age, centre, waist, smoking and physical activity. In women, this association persisted after adjustment for adiponectin but was attenuated after controlling for HDL-cholesterol, suggesting that part of the protection is related to a higher HDL-cholesterol concentration. Higher alcohol consumption was associated with lower basal insulin secretion in women only (β = -0.10, p ( trend ) = 0.004) and this association persisted after adjustment for insulin sensitivity. In men, increasing alcohol consumption was associated with enhanced insulin clearance and increased fasting NEFA concentrations, independently of insulin sensitivity. Fasting glucagon decreased with increasing alcohol in women only (abstainers 9.2 ± 4.4;28 g/week 8.6 ± 4.0; 28-64 g/week 8.1 ± 3.7;64 g/week 7.5 ± 3.1 pmol/l; p ( trend ) = 0.01).Light-to-moderate alcohol consumption was associated in healthy women with enhanced insulin sensitivity, reduced basal insulin secretion rate and lower fasting plasma glucagon concentration, providing consistent mechanisms for the reduced risk of diabetes.

The aim of the study was to evaluate the 3 years incidence of cardiometabolic risk factors, such as impaired fasting glucose, reduced high-density lipoprotein (HDL)-cholesterol, increased plasma triglycerides or blood pressure as well as impaired glucose tolerance in overweight or obese (ow/ob) and normal body weight (nbw) subjects metabolically normal at baseline. Subjects from the Relationship between Insulin Sensitivity and Cardiovascular Disease (RISC) study were analyzed. We analyzed 284 nbw and 152 ow/ob subjects who, at baseline, did not show any of the above-mentioned cardiometabolic risk factors. At 3 years, these parameters were re-evaluated. Intima-media thickness (IMT) of the common carotid artery (CCA) was echographically measured. At follow-up, the incidence of one or more cardiometabolic risk factors was 57.2% in ow/ob vs. 31.7% in nbw (P < 0.0001). After adjustment for age, sex, menopause status, lifestyle parameters, insulin sensitivity, and fasting insulinemia, BMI remained significantly linked to the development of one or more cardiometabolic risk factors (P = 0.02). An increased BMI at follow-up was significantly associated with the development of cardiometabolic alterations, in both nbw and ow/ob groups (P = 0.04). Ow/ob subjects who, at 3 years follow-up, remained metabolically normal, showed a less favourable cardiometabolic profile, when compared to nbw counterparts. In ow/ob metabolically normal males and females, intima-media of the common carotid at follow-up was thicker than in nbw (P = 0.03 for males, P = 0.04 for females). In conclusion, metabolically normal obese subjects show a higher incidence of cardiometabolic risk factors, in a short follow-up period. Weight gain is significantly associated with the development of these factors, in both nbw and ow/ob subjects.

OBJECTIVE Recent work has shown that insulin stimulates its own secretion in insulin-sensitive humans, suggesting that insulin resistance in the β-cell could cause β-cell dysfunction. We have tested whether insulin exposure and insulin sensitivity modulate β-cell function in subjects with normal glucose tolerance (NGT) and whether they contribute to dysglycemia in impaired glucose regulation (IGR). RESEARCH DESIGN AND METHODS Insulin sensitivity (by euglycemic clamp), insulin-induced secretory response at isoglycemia (IISR) (as C-peptide percent change from basal during the clamp), glucose-induced secretory response (GISR) to an intravenous glucose bolus, and β-cell glucose sensitivity (β-GS) (by oral glucose tolerance test [OGTT] modeling) were measured in 1,151 NGT and 163 IGR subjects from the RISC (Relationship between Insulin Sensitivity and Cardiovascular Disease) study. RESULTS In NGT, IISR was related to both insulin sensitivity and antecedent insulin exposure; GISR was related to insulin exposure. IISR was positively, if weakly, related to β-GS (r= 0.16, P < 0.0001). Both IISR (−23 [39] vs. −9 [2]%, median [interquartile range], P < 0.03) and β-GS (69 [47] vs. 118 [83] pmol ⋅ min–1 ⋅ m–2 ⋅ mmol–1 ⋅ L, P < 0.0001) were decreased in IGR compared with NGT. Insulin sensitivity and β-GS were the major determinants of mean OGTT glucose in both NGT and IGR, with a minor role for IISR. In a multivariate logistic model, IGR was predicted by β-GS (odds ratio 4.84 [95% CI 2.89–8.09]) and insulin sensitivity (3.06 [2.19–4.27]) but not by IISR (1.11 [0.77–1.61]). CONCLUSIONS Pre-exposure to physiological hyperinsulinemia stimulates insulin secretion to a degree that depends on insulin sensitivity. However, this phenomenon has limited impact on β-cell dysfunction and dysglycemia.

OBJECTIVE Glucose is the major stimulus for insulin release. Time course and amount of insulin secreted after glycemic stimulus are different between type 2 diabetes mellitus (T2DM) patients and healthy subjects. In rodents, it was demonstrated that insulin can modulate its own release. Previous studies in humans yielded contrasting results: Insulin was shown to have an enhancing effect, no effect, or a suppressive effect on its own secretion. Thus, we aimed to evaluate short-term effects of human insulin infusion on insulin secretion during normoglycemia in healthy humans and T2DM subjects of both sex. RESEARCH DESIGN AND METHODS Hyperinsulinemic-isoglycemic clamps with whole-body insulin-sensitivity (M) and C-peptide measurements for insulin secretion modeling were performed in 65 insulin-sensitive (IS) subjects (45 ± 1 year, BMI: 24.8 ± 0.5 kg/m2), 17 insulin-resistant (IR) subjects (46 ± 2 years, 28.1 ± 1.3 kg/m2), and 20 T2DM patients (56 ± 2 years, 28.0 ± 0.8 kg/m2; HbA1c = 6.7 ± 0.1%). RESULTS IS subjects (M = 8.8 ± 0.3 mg · min−1 · kg−1) had higher (P < 0.00001) whole-body insulin sensitivity than IR subjects (M = 4.0 ± 0.2) and T2DM patients (M = 4.3 ± 0.5). Insulin secretion profiles during clamp were different (P < 0.00001) among the groups, increasing in IS subjects (slope: 0.56 ± 0.11 pmol/min2) but declining in IR (−0.41 ± 0.14) and T2DM (−0.87 ± 0.12, P < 0.00002 IR and T2DM vs. IS) subjects. Insulin secretion changes during clamp directly correlated with M (r = 0.6, P < 0.00001). CONCLUSIONS Insulin release during normoglycemia can be modulated by exogenous insulin infusion and directly depends on whole-body insulin sensitivity. Thus, in highly sensitive subjects, insulin increases its own secretion. On the other hand, a suppressive effect of insulin on its own secretion occurs in IR and T2DM subjects.

OBJECTIVE Women with gestational diabetes mellitus (GDM) show reduced insulin sensitivity and markedly elevated glucose excursions. After delivery, GDM mostly reverts to normal glucose tolerance (NGT), although leaving an increased risk of type 2 diabetes. Because gastrointestinal function changes during pregnancy causing vomiting, constipation, or reduced motility, we thought that gut glucose absorption in GDM or pregnancy might be altered to affect circulating glucose excursions. RESEARCH DESIGN AND METHODS By undergoing 180-min oral glucose tolerance tests (OGTTs), pregnant women with GDM (GDMpreg; n = 15, BMI = 32 ± 2 kg/m2, aged 33 ± 1 years) were compared with NGT women (NGTpreg; n = 7, BMI = 28 ± 1 kg/m2, aged 34 ± 2 years), matching for major anthropometric characteristics (each P > 0.2). After delivery (6–7 months later), both groups were studied the same way. We computed and mathematically modeled gut glucose absorption from insulin-mediated glucose disappearance and endogenous glucose production (EGP). Whole-body insulin sensitivity was calculated using the Clamp-like Index. RESULTS GDMpreg showed 16–25% higher plasma glucose concentrations (P < 0.04) during the final 2 h of OGTT, similar EGP, but lower (P < 0.01) insulin sensitivity (2.7 ± 0.2 mg · kg−1 · min−1 vs. NGTpreg: 4.5 ± 0.8 mg · kg−1 · min−1). In GDMpreg, gut glucose absorption rates were ≤52% lower from 30 to 120 min (P < 0.03 vs. conditions after delivery or NGTpreg). In contrast, glucose absorption rates in NGTpreg were comparable during and after pregnancy. None of the studied women developed diabetes after delivery. CONCLUSIONS In GDMpreg, OGTT gut glucose absorption is markedly lower during hyperglycemia, whereas both glycemia and glucose absorption in NGTpreg are comparable between pregnant and postpartum states. Thus, hyperglycemia in GDM does not seem to result from too rapid or increased glucose absorption.

Insulin resistance, an independent risk-factor for cardiovascular disease, precedes type 2 diabetes and is associated with ectopic lipid accumulation in skeletal muscle and liver. Recent evidence indicates that cardiac steatosis plays a central role in the development of diabetic cardiomyopathy. However, it is not known whether insulin resistance as such in the absence of type 2 diabetes is associated with heart steatosis and/or impaired function. We therefore assessed myocardial steatosis and myocardial function in a sample of women with normal insulin sensitivity, insulin resistance, impaired glucose tolerance (IGT) and type 2 diabetes.Magnetic resonance imaging and localised spectroscopy were used to measure left ventricular dynamic variables and myocardial lipid accumulation in interventricular septum of non-diabetic, age- and BMI-matched insulin-sensitive (n = 11, 47 ± 6 years, BMI 25 ± 2 kg/m(2); clamp-like index [CLIX] = 9.7 ± 0.7) and insulin-resistant (n = 10, 48 ± 5 years, 27 ± 4 kg/m(2); CLIX = 4.5 ± 0.4) women with normal glucose tolerance as well as of women with IGT (n = 6, 45 ± 5 years, 28 ± 6 kg/m(2); CLIX = 3.6 ± 1.1) and type 2 diabetes (n = 7, 52 ± 10 years, 27 ± 3 kg/m(2)).Myocardial lipid content was increased in type 2 diabetic women only (insulin-sensitive 0.4 ± 0.2% [means ± SD]; insulin-resistant 0.4 ± 0.1%; IGT 0.5 ± 0.2%; type 2 diabetes 0.7 ± 0.3%; p 0.05). In insulin-resistant and type 2 diabetic women, stroke volume was lower (-15% and -27%, respectively, vs insulin-sensitive) and heart rate was higher (11% and 14%, respectively, vs insulin-sensitive, p 0.05). No other differences in systolic and diastolic function were observed between study groups.In contrast to liver and skeletal muscle, insulin resistance as such is not associated with increased myocardial lipid accumulation.

Background:Several epidemiological studies revealed sex-specific differences during oral glucose tolerance tests (OGTTs), such as higher prevalence of glucose intolerance (i.e. increased glucose at the end of the OGTT) in females, which was not yet explained. Thus, we aimed to analyze sex-related distinctions on OGTT glucose metabolism, including gut absorption, in healthy humans.Methods:Females (n = 48) and males (n = 26) with comparable age (females, 45 ± 1 yr; males, 44 ± 2 yr) and body mass index (both, 25 ± 1 kg/m2) but different height (females, 166 ± 1 cm; males, 180 ± 2 cm; P < 0.000001), all normally glucose tolerant, as tested by frequently sampled, 3-h (75-g) OGTTs, underwent hyperinsulinemic [40 mU/(min · m2)] isoglycemic clamp tests with simultaneous measurement of endogenous glucose (d-[6,6-2H2]glucose) production (EGP). EGP and glucose disappearance during OGTT were calculated from logarithmic relationships with clamp test insulin concentrations. After reliable model validation by double-tracer technique (r = 0.732; P < 0.007), we calculated and modeled gut glucose absorption (ABS).Results:Females showed lower (P < 0.05) fasting EGP [1.4 ± 0.1 mg/(kg · min)] than males [1.7 ± 0.1 mg/(kg · min)] but comparable whole-body insulin sensitivity in clamp tests [females, 8.1 ± 0.4 mg/(kg · min); males, 8.3 ± 0.6 mg/(kg · min)]. Plasma glucose OGTT concentrations were higher (P < 0.04) from 30–40 min in males but from 120–180 min in females. Glucose absorption rates were 21–46% increased in the initial 40 min in males but in females by 27–40% in the third hour (P < 0.05). Gut glucose half-life was markedly higher in females (79 ± 2 min) than in males (65 ± 3 min, P < 0.0001) and negatively related to body height (r = −0.481; P < 0.0001).Conclusions:This study in healthy, glucose-tolerant humans shows for the first time different ABS rates during OGTT in women and men and a negative relationship between body height and gut glucose half-life. Prolonged ABS in females might therefore contribute to higher plasma glucose concentrations at the end of OGTT.

OBJECTIVE So far it is unclear whether chronic peripheral hyperinsulinemia per se might contribute to ectopic lipid accumulation and consequently insulin resistance. We investigated the effects of systemic instead of portal insulin release in type 1 diabetic patients after successful pancreas-kidney transplantation (PKT) with systemic venous drainage on the intracellular lipid content in liver and soleus muscle, endogenous glucose production (EGP), and insulin sensitivity. RESEARCH DESIGN AND METHODS In nine PKT patients and nine matching nondiabetic control subjects, intrahepatocellular lipids (IHCLs) and intramyocellular lipids (IMCLs) were measured using 1H nuclear magnetic resonance spectroscopy. Fasting EGP was measured using d-[6,6-2H2]glucose tracer dilution. A 3-h 75-g oral glucose tolerance test (OGTT) allowed us to assess kinetics of glucose, free fatty acids, insulin, and C-peptide concentrations in plasma and to calculate the clamp-like index (CLIX) for insulin sensitivity and the hepatic insulin resistance (HIR) index. RESULTS The PKT patients displayed approximately twofold increased fasting insulin (20 ± 6 vs. 9 ± 3 μU/ml; P < 0.0002) compared with that in nondiabetic control subjects and ∼10% increased fasting glucose (P < 0.02) concentrations, but during the OGTT areas under the concentration curves of C-peptide and insulin were similar. IHCL (PKT, 2.9 ± 2.5%; nondiabetic control subjects, 4.4 ± 6.6%), IMCL (PKT, 1.0 ± 0.4%; nondiabetic control subjects, 1.0 ± 0.5%), CLIX (PKT, 8 ± 2; nondiabetic control subjects, 7 ± 3), HIR (PKT, 25.6 ± 13.2; nondiabetic control subjects, 35.6 ± 20 [mg · min−1 · kg−1] × [μU/ml]), and EGP (PKT, 1.6 ± 0.2; nondiabetic control subjects, 1.7 ± 0.2 mg · min−1 · kg−1) were comparable between PKT patients and nondiabetic control subjects. IHCL was negatively correlated with CLIX in all participants (r = −0.55; P < 0.04). CONCLUSIONS Despite fasting peripheral hyperinsulinemia because of systemic venous drainage, type 1 diabetic patients after PKT show similar IHCL, IMCL, insulin sensitivity, and fasting EGP in comparison with nondiabetic control subjects. These results suggest that systemic hyperinsulinemia per se does not cause ectopic lipid accumulation in liver and skeletal muscle.

Insulin resistance, the underlying pathophysiological mechanism of the metabolic syndrome, can not only predict type 2 diabetes development but also cardiovascular disease. Thus, precise insulin resistance measurement in individuals at risk for metabolic diseases would support clinical risk stratification. However, the gold standard for measuring insulin resistance, the hyperinsulinemic clamp test, is too labor intensive to be performed in large clinical studies/settings.Using plasma glucose and C-peptide concentrations from oral glucose tolerance tests (OGTTs), we developed the novel "clamp-like index" (CLIX) for insulin sensitivity calculation and compared CLIX to clamp glucose infusion rates (GIR) (100-120 min). We evaluated CLIX in 89 nondiabetic subjects (58 female and 31 male, aged 45 +/- 1 years, BMI 27.5 +/- 0.8 kg/m(2)) who underwent frequently sampled 3-h 75-g OGTTs and 2-h hyperinsulinemic-isoglycemic clamp (40 mU/min per m(2)) tests.CLIX, calculated as serum creatinine (x0.85 if male)/(mean AUC(glucose) x mean AUC(C-peptide)) x 6,600, was highly correlated (r = 0.670, P10(-12)) with and comparable to clamp GIRs(100-120 min). In subgroup analyses, GIRs(100-120 min) were lower (P0.005) in type 2 diabetic offspring (6.2 +/- 0.7 mg x min(-1) x kg(-1)) than in sex-, age-, and BMI-matched subjects without a family history of type 2 diabetes (8.6 +/- 0.5 mg x min(-1) x kg(-1)), which was also reflected by CLIX (insulin-resistant offspring 6.4 +/- 0.6 vs. those without a family history of type 2 diabetes 9.0 +/- 0.5; P0.002). When compared with normal-weight subjects (GIR 8.8 +/- 0.4 mg x min(-1) x kg(-1); CLIX 9.0 +/- 0.5), both GIRs(100-120 min) and CLIX of obese (5.2 +/- 0.9 mg x min (-1) x kg(-1); 5.7 +/- 0.9) and morbidly obese (2.4 +/- 0.4 mg x min (-1) x kg(-1); 3.3 +/- 0.5) humans were lower (each P0.02).CLIX, a novel index obtained from plasma OGTT glucose and C-peptide levels and serum creatinine, without inclusion of anthropometrical measures to calculate insulin sensitivity in nondiabetic humans, highly correlates with clamp GIRs and reveals even slight insulin sensitivity alterations over a broad BMI range and is as sensitive as the hyperinsulinemic clamp test.

The nutrient-sensitive kinase mammalian target of rapamycin (mTOR) and its downstream target S6 kinase (S6K) are involved in amino acid-induced insulin resistance. Whether the mTOR/S6K pathway directly modulates glucose metabolism in humans is unknown. We studied 11 healthy men (29 years old, BMI 23 kg/m(2)) twice in random order after oral administration of 6 mg rapamycin, a specific mTOR inhibitor, or placebo. An amino acid mixture was infused to activate mTOR, and somatostatin-insulin-glucose clamps created conditions of low peripheral hyperinsulinemia (approximately 100 pmol/l, 0-180 min) and prandial-like peripheral hyperinsulinemia (approximately 450 pmol/l, 180-360 min). Glucose turnover was assessed using d-[6,6-(2)H(2)]glucose infusion (n = 8). Skeletal muscle biopsies were performed at baseline and during prandial-like peripheral hyperinsulinemia (n = 3). At low peripheral hyperinsulinemia, whole-body glucose uptake was not affected by rapamycin. During prandial-like peripheral hyperinsulinemia, rapamycin increased glucose uptake compared with placebo by 17% (R(d 300-360 min), 75 +/- 5 vs. 64 +/- 5 micromol x kg(-1) x min(-1), P = 0.0008). Rapamycin affected endogenous glucose production neither at baseline nor during low or prandial-like peripheral hyperinsulinemia. Combined hyperaminoacidemia and prandial-like hyperinsulinemia increased S6K phosphorylation and inhibitory insulin receptor substrate-1 (IRS-1) phosphorylation at Ser312 and Ser636 in the placebo group. Rapamycin partially inhibited this increase in mTOR-mediated S6K phosphorylation and IRS-1 Ser312 and Ser636 phosphorylation. In conclusion, rapamycin stimulates insulin-mediated glucose uptake in man under conditions known to activate the mTOR/S6K pathway.

In response to hyperglycemia, beta-cells release insulin and C-peptide, as well as islet amyloid pancreatic polypeptide, which is involved in glucose homeostasis. After successful pancreas-kidney transplantation (PKT), type 1 diabetic patients may revert to a nondiabetic metabolism without exogenous insulin therapy and re-secrete all beta-cell hormones.Using mathematical models, we investigated hormone (amylin, insulin, C-peptide) and metabolite (glucose, free fatty acids) kinetics, beta-cell sensitivity to glucose, and oral glucose insulin sensitivity index (OGIS) in 11 nondiabetic type 1 diabetic patients after PKT (BMI 25 +/- 1 kg/m2, 47 +/- 2 years of age, 4 women/7 men, glucocorticoid-free), 6 matching nondiabetic patients after kidney transplantation (25 +/- 1 kg/m2, 50 +/- 5 years, 3 women/3 men, on glucocorticoids), and 9 matching nondiabetic control subjects (24 +/- 1 kg/m2, 47 +/- 2 years, 4 women/5 men) during a 3-h 75-g oral glucose tolerance test (OGTT).PKT patients had higher fasting amylin (19 +/- 3 vs. control subjects: 7 +/- 1 pmol/l) and insulin (20 +/- 2 vs. control subjects: 10 +/- 1 microU/ml; each P0.01) levels. Kidney transplant subjects showed increased OGTT plasma insulin at 90 min and C-peptide levels (each P0.05). In PKT patients, plasma glucose from 90 to 150 min was 9-31% higher (P0.05 vs. control subjects). Amylin clearance was comparable in all groups. Amylin's plasma concentrations and area under the concentration curve were up to twofold higher in PKT patients during OGTT (P0.05). OGIS was not significantly different between groups. beta-Cell sensitivity to glucose was reduced in PKT patients (-64%, P0.009). Fasting plasma amylin was inversely associated with beta-cell sensitivity to glucose (r = -0.543, P0.004).After successful PKT, type 1 diabetic patients with nondiabetic glycemia exhibit increased fasting and post-glucose load plasma amylin, which appears to be linked to impaired beta-cell function. Thus, higher amylin release in proportion to insulin might also reflect impaired beta-cell function in type 1 diabetic patients after PKT.

GW501516, an agonist of peroxisome proliferator-activated receptor-delta (PPAR-delta), increases lipid combustion and exerts antidiabetic action in animals, effects which are attributed mainly to direct effects on skeletal muscle. We explored such actions further in isolated rat skeletal muscle.Specimens of rat skeletal muscle were pretreated with GW501516 (0.01-30 mumol/l) for 0.5, 4 or 24 h and rates of fuel metabolism were then measured. In addition, effects on mitochondrial function were determined in isolated rat liver mitochondria.At concentrations between 0.01 and 1 mumol/l, GW501516 dose-dependently increased fatty acid oxidation but reduced glucose utilisation in isolated muscle. Thus after 24 h of preincubation with 1 mumol/l GW501516, palmitate oxidation increased by +46+/-10%, and the following decreased as specified: glucose oxidation -46+/-8%, glycogen synthesis -42+/-6%, lactate release -20+/-2%, glucose transport -15+/-6% (all p0.05). Reduction of glucose utilisation persisted independently of insulin stimulation or muscle fibre type, but depended on fatty acid availability (the effect on glucose transport in the absence of fatty acids was an increase of 30+/-9%, p0.01), suggesting a role for the glucose-fatty acid cycle. At higher concentrations, GW501516 uncoupled oxidative phosphorylation by direct action on isolated mitochondria.GW501516-induced activation of PPAR-delta reduces glucose utilisation by skeletal muscle through a switch in mitochondrial substrate preference from carbohydrate to lipid. High concentrations of GW501516 induce mitochondrial uncoupling independently of PPAR-delta.

Decreased skeletal muscle glucose disposal and increased endogenous glucose production (EGP) contribute to postprandial hyperglycemia in type 2 diabetes, but the contribution of hepatic glycogen metabolism remains uncertain. Hepatic glycogen metabolism and EGP were monitored in type 2 diabetic patients and nondiabetic volunteer control subjects (CON) after mixed meal ingestion and during hyperglycemic-hyperinsulinemic-somatostatin clamps applying 13C nuclear magnetic resonance spectroscopy (NMRS) and variable infusion dual-tracer technique. Hepatocellular lipid (HCL) content was quantified by 1H NMRS. Before dinner, hepatic glycogen was lower in type 2 diabetic patients (227 +/- 6 vs. CON: 275 +/- 10 mmol/l liver, P < 0.001). After meal ingestion, net synthetic rates were 0.76 +/- 0.16 (type 2 diabetic patients) and 1.36 +/- 0.15 mg x kg(-1) x min(-1) (CON, P < 0.02), resulting in peak concentrations of 283 +/- 15 and 360 +/- 11 mmol/l liver. Postprandial rates of EGP were approximately 0.3 mg x kg(-1) x min(-1) (30-170 min; P < 0.05 vs. CON) higher in type 2 diabetic patients. Under clamp conditions, type 2 diabetic patients featured approximately 54% lower (P < 0.03) net hepatic glycogen synthesis and approximately 0.5 mg x kg(-1) x min(-1) higher (P < 0.02) EGP. Hepatic glucose storage negatively correlated with HCL content (R = -0.602, P < 0.05). Type 2 diabetic patients exhibit 1) reduction of postprandial hepatic glycogen synthesis, 2) temporarily impaired suppression of EGP, and 3) no normalization of these defects by controlled hyperglycemic hyperinsulinemia. Thus, impaired insulin sensitivity and/or chronic glucolipotoxicity in addition to the effects of an altered insulin-to-glucagon ratio or increased free fatty acids accounts for defective hepatic glycogen metabolism in type 2 diabetic patients.

The gastric peptide ghrelin augments and the adipocyte-derived hormone leptin reduces appetite and food intake. In the central nervous system, insulin directly decreases hunger sensation but could also act indirectly by modulating ghrelin and leptin secretion. This study examines dose-dependent effects of insulin on plasma ghrelin and leptin concentrations during hyperinsulinemic (1, 2, and 4 mU · kg−1 · min−1)-euglycemic clamp tests in six nondiabetic (control subjects) and six type 2 diabetic patients. Type 2 diabetic patients were studied before and after prolonged (12-h and 67-h) variable intravenous insulin treatment aiming at near-normoglycemia (115 ± 4 mg/dl). Nondiabetic subjects were also studied during saline infusion, which did not affect ghrelin but decreased leptin by 19 ± 6% (P < 0.03). In control subjects, plasma ghrelin decreased at all clamp steps (−17 ± 1, −27 ± 6, and −33 ± 4%, respectively; P < 0.006 vs. baseline), whereas leptin increased by 35 ± 11% (P < 0.05). In type 2 diabetic patients without insulin treatment, ghrelin decreased by 18 ± 7% (P < 0.05) only after 4 mU · kg−1 · min−1 insulin infusion and leptin increased by 19 ± 6% (P < 0.05). After prolonged insulin treatment and near-normoglycemia, ghrelin and leptin remained unchanged in type 2 diabetic patients during the clamps. In conclusion, insulin reduces plasma ghrelin in nondiabetic patients and, to a lesser extent, in type 2 diabetic patients before insulin therapy. These findings indicate an indirect effect of insulin via ghrelin on the suppression of hunger sensation and appetite.

Insulin resistance is frequently associated with increased lipid content in muscle and liver. Insulin excess stimulates tissue lipid accumulation. To examine the effects of insulin and improved glycemia on insulin sensitivity and intracellular lipids, we performed stepped (1, 2, and 4 mU · min−1 · kg−1) hyperinsulinemic-euglycemic clamps in eight type 2 diabetic and six nondiabetic control subjects at baseline and after 12 and 67 h of insulin-mediated near-normoglycemia (118 ± 7 mg/dl). Intrahepatocellular lipids (IHCLs) and intramyocellular lipids (IMCLs) of soleus (IMCL-S) and tibialis anterior muscle (IMCL-TA) were measured with 1H nuclear magnetic resonance spectroscopy. At baseline, nondiabetic subjects had an approximate twofold higher insulin sensitivity (P < 0.02) and lower IHCLs than diabetic patients (5.8 ± 1.2 vs. 18.3 ± 4.2%, P < 0.03), in whom IMCL-TA negatively correlated with insulin sensitivity (r = −0.969, P < 0.001). After a 67-h insulin infusion in diabetic patients, IMCL-S and IHCLs were increased (P < 0.05) by ∼36 and ∼18%, respectively, and correlated positively with insulin sensitivity (IMCL-S: r = 0.982, P < 0.0005; IHCL: r = 0.865, P < 0.03), whereas fasting glucose production, measured with d-[6,6-2H2]glucose, decreased by ∼10% (P < 0.04). In conclusion, these results indicate that IMCLs relate to insulin resistance in type 2 diabetic patients at baseline and that insulin-mediated near-normoglycemia for ∼3 days reduces fasting glucose production but stimulates lipid accumulation in liver and muscle without affecting insulin sensitivity.

Leptin has both insulin-like and insulin-antagonistic effects on glucose metabolism. To test whether leptin interferes directly with insulin signaling, we perfused isolated rat livers with leptin (0.1, 0.5, 5, and 25 nmol/liter), leptin + insulin (5 nmol/liter + 10 nmol/liter), insulin (10 nmol/liter), or vehicle (control). Leptin reduced L-lactate-(10 mmol/liter)-stimulated glucose production by 39-66% (P0.006 vs. control) and phosphoenolpyruvate carboxykinase (PEPCK) activity by 22-52% (P0.001). Physiological leptin concentrations (0.1-5 nmol/liter) stimulated the tyrosine phosphorylation (pY) of insulin receptor substrate-2 (IRS-2) (280-954%; P0.05) and its associated phosphatidylinositol-3 kinase activity (122-621%; P0.003). Leptin (0.5-25 nmol/liter) inhibited IRS-1 pY and its associated phosphatidylinositol-3 kinase activity (20-89%; P0.03) but stimulated janus kinase-2 pY (272-342%; P0.001). Leptin also down-regulated its short receptor isoform in a time- and concentration-dependent manner (28-54%; P0.05). Exposure to leptin + insulin additively reduced glucose production and PEPCK activity (approximately 50%; P0.001 vs. control) and doubled IRS-2 pY (P0.01 vs. insulin). However, leptin + insulin decreased IRS-1 pY by 57% (P0.01 vs. insulin). Insulin alone (P0.01), but not leptin, increased autophosphorylation of nonreceptor tyrosine kinases (pp59(Lyn) + pp125(Fak)). In conclusion, leptin both alone and in combination with insulin reduces hepatic glucose production by decreasing the synthesis of the key enzyme of gluconeogenesis, PEPCK, which results mainly from the stimulation of the IRS-2 pathway.

Plasma concentrations of amino acids are frequently elevated in insulin-resistant states, and a protein-enriched diet can impair glucose metabolism. This study examined effects of short-term plasma amino acid (AA) elevation on whole-body glucose disposal and cellular insulin action in skeletal muscle. Seven healthy men were studied for 5.5 h during euglycemic (5.5 mmol/l), hyperinsulinemic (430 pmol/l), fasting glucagon (65 ng/l), and growth hormone (0.4 microg/l) somatostatin clamp tests in the presence of low (approximately 1.6 mmol/l) and increased (approximately 4.6 mmol/l) plasma AA concentrations. Glucose turnover was measured with D-[6,6-(2)H(2)]glucose. Intramuscular concentrations of glycogen and glucose-6-phosphate (G6P) were monitored using (13)C and (31)P nuclear magnetic resonance spectroscopy, respectively. A approximately 2.1-fold elevation of plasma AAs reduced whole-body glucose disposal by 25% (P < 0.01). Rates of muscle glycogen synthesis decreased by 64% (180--315 min, 24 plus minus 3; control, 67 plus minus 10 micromol center dot l(-1) center dot min(-1); P < 0.01), which was accompanied by a reduction in G6P starting at 130 min (DeltaG6P(260--300 min), 18 plus minus 19; control, 103 plus minus 33 micromol/l; P < 0.05). In conclusion, plasma amino acid elevation induces skeletal muscle insulin resistance in humans by inhibition of glucose transport/phosphorylation, resulting in marked reduction of glycogen synthesis.

AIMS/HYPOTHESIS: Recent evidence suggests a link between myocardial steatosis and diabetic cardiomyopathy. Insulin, as a lipogenic and growth-promoting hormone, might stimulate intramyocardial lipid (MYCL) deposition and hypertrophy. Therefore, the aim of the present study was to investigate the short-term effects of insulin therapy (IT) on myocardial lipid content and morphology in patients with T2DM. METHODS: Eighteen patients with T2DM were recruited (age 56 ± 2 years; HbA1c: 10.5 ± 0.4%). In 10 patients with insufficient glucose control under oral medication IT was initiated due to secondary failure of oral glucose lowering therapy (IT-group), while 8 individuals did not require additional insulin substitution (OT-group). In order to assess MYCL and intrahepatic lipid (IHLC) content as well as cardiac geometry and function magnetic resonance spectroscopy (MRS) and imaging (MRI) examinations were performed at baseline (IT and OT) and 10 days after initiation of IT. Follow up measurements took place 181 ± 49 days after IT. RESULTS: Interestingly, basal MYCLs were 50% lower in IT- compared to OT-group (0.41 ± 0.12 vs. 0.80 ± 0.11% of water signal; p = 0.034). After 10 days of IT, an acute 80%-rise in MYCL (p = 0.008) was observed, while IHLC did not change. Likewise, myocardial mass (+13%; p = 0.004), wall thickness in end-diastole (+13%; p = 0.030) and concentricity, an index of cardiac remodeling, increased (+28%; p = 0.026). In the long-term MYCL returned to baseline, while IHCL significantly decreased (-31%; p = 0.000). No acute changes in systolic left ventricular function were observed. CONCLUSIONS/INTERPRETATION: The initiation of IT in patients with T2DM was followed by an acute rise in MYCL concentration and myocardial mass.