Glucagon receptor antagonism improves islet function in mice with insulin resistance induced by a high-fat diet

Aims/hypothesis Increased glucagon secretion predicts deterioration of glucose tolerance, and high glucagon levels contribute to hyperglycaemia in type 2 diabetes. Inhibition of glucagon action may therefore be a potential novel target to reduce hyperglycaemia. Here, we investigated whether chronic treatment with a glucagon receptor antagonist (GRA) improves islet dysfunction in female mice on a high-fat diet (HFD). Materials and methods After 8 weeks of HFD, mice were treated with a small molecule GRA (300 mg/kg, gavage once daily) for up to 30 days. Insulin secretion was studied after oral and intravenous administration of glucose and glucagon secretion after intravenous arginine. Islet morphology was examined and insulin secretion and glucose oxidation were measured in isolated islets. Results Fasting plasma glucose levels were reduced by GRA (6.0 ± 0.2 vs 7.4 ± 0.5 mmol/l; p = 0.017). The acute insulin response to intravenous glucose was augmented (1,300 ± 110 vs 790 ± 64 pmol/l; p < 0.001). The early insulin response to oral glucose was reduced in mice on HFD + GRA (1,890 ± 160 vs 3,040 ± 420 pmol/l; p = 0.012), but glucose excursions were improved. Intravenous arginine significantly increased the acute glucagon response (129 ± 12 vs 36 ± 6 ng/l in controls; p < 0.01), notably without affecting plasma glucose. GRA caused a modest increase in alpha cell mass, while beta cell mass was similar to that in mice on HFD + vehicle. Isolated islets displayed improved glucose-stimulated insulin secretion after GRA treatment (0.061 ± 0.007 vs 0.030 ± 0.004 pmol islet⁻¹ h⁻¹ at 16.7 mmol/l glucose; p < 0.001), without affecting islet glucose oxidation. Conclusions/interpretation Chronic glucagon receptor antagonism in HFD-fed mice improves islet sensitivity to glucose and increases insulin secretion, suggesting improvement of key defects underlying impaired glucose tolerance and type 2 diabetes.     

Exercise training reduces fatty acid availability and improves the insulin sensitivity of glucose metabolism

Aims/hypothesis It is not known whether the beneficial effects of exercise training on insulin sensitivity are due to changes in hepatic and peripheral insulin sensitivity or whether the changes in insulin sensitivity can be explained by adaptive changes in fatty acid metabolism, changes in visceral fat or changes in liver and muscle triacylglycerol content. We investigated the effects of 6 weeks of supervised exercise in sedentary men on these variables. Subjects and methods We randomised 17 sedentary overweight male subjects (age 50 ± 2.6 years, BMI 27.6 ± 0.5 kg/m²) to a 6-week exercise programme (n = 10) or control group (n = 7). The insulin sensitivity of palmitic acid production rate (Ra), glycerol Ra, endogenous glucose Ra (EGP), glucose uptake and glucose metabolic clearance rate were measured at 0 and 6 weeks with a two-step hyperinsulinaemic–euglycaemic clamp [step 1, 0.3 (low dose); step 2, 1.5 (high dose) mU kg⁻¹ min⁻¹]. In the exercise group subjects were studied >72 h after the last training session. Liver and skeletal muscle triacylglycerol content was measured by magnetic resonance spectroscopy and visceral adipose tissue by cross-sectional computer tomography scanning. Results After 6 weeks, fasting glycerol, palmitic acid Ra (p = 0.003, p = 0.042) and NEFA concentration (p = 0.005) were decreased in the exercise group with no change in the control group. The effects of low-dose insulin on EGP and of high-dose insulin on glucose uptake and metabolic clearance rate were enhanced in the exercise group but not in the control group (p = 0.026; p = 0.007 and p = 0.04). There was no change in muscle triacylglycerol and liver fat in either group. Conclusions/interpretation Decreased availability of circulating NEFA may contribute to the observed improvement in the insulin sensitivity of EGP and glucose uptake following 6 weeks of moderate exercise. Electronic supplementary material Supplementary material is available in the online version of this article at and is accessible to authorised users.     

Plasma pancreatic polypeptide levels are associated with differences in body fat distribution in human subjects

Aims/hypothesis Pancreatic polypeptide (PP) is produced by the F-cells of the pancreas, and its plasma concentration has been used as a marker of parasympathetic activity. Recent work in rodents suggests that there is both sympathetic and parasympathetic innervation of white adipose tissue and that parasympathetic activity is anabolic resulting in lipid accumulation. We have examined whether in humans increased PP levels are associated with increased intra-abdominal fat (IAF), and thereby insulin resistance. Materials and methods We measured PP levels in 177 non-diabetic subjects (75 male/102 female; age 32–75 years) 3 min after an i.v. glucose bolus during a frequently sampled intravenous glucose tolerance test. IAF and s.c. fat (SCF) areas were measured by CT scan. The insulin sensitivity index (S _I) was quantified using Bergman’s minimal model. Results PP levels were higher in men than in women (96.2 ± 72.2 vs 76.1 ± 55.0 pg/ml, mean ± SD, p = 0.037), as was IAF area (124.7 ± 67.4 vs 83.0 ± 57.7 cm², p < 0.001). While PP levels were significantly associated with IAF (r = 0.16, p = 0.031), WHR (r = 0.30, p < 0.001) and age (r = 0.37, p < 0.01), they were not associated with SCF (r = 0.02, p = 0.829). The association between PP and IAF was not independent of age and/or sex. S _I was negatively associated with PP levels (r = −0.17, p = 0.026) and IAF area (r = −0.65, p < 0.001). The association between S _I and PP disappeared after adjusting for IAF area, indicating that S _I was not a major determinant of PP levels. Conclusions/interpretation In humans, age and sex may modulate the association between plasma PP level and IAF area, suggesting that they may be determinants of parasympathetic activity and thus IAF accumulation.     

Elevated serum levels of visfatin in gestational diabetes: a comparative study across various degrees of glucose tolerance

Aims/hypothesis Concentrations of visfatin are increased in insulin-resistant conditions, but the relationship between visfatin and insulin and/or insulin resistance indices in pregnancy remains unclear. Insulin resistance in pregnancy is further accentuated in women with gestational diabetes mellitus (GDM). Thus we assessed serum levels of visfatin in pregnant women with varying degrees of glucose tolerance. Materials and methods Fasting visfatin levels were measured at 28 weeks of gestation in 51 women divided according to their response to a 50-g glucose challenge test (GCT) and a 75-g OGTT: control subjects (n = 20) had normal responses to both a GCT and an OGTT; the intermediate group (IG; n = 15) had a false-positive GCT, but a normal OGTT; the GDM group (n = 16) had abnormal GCTs and OGTTs. Results There were no age or BMI differences between analysed groups. Across the subgroups there was a progressive increase in glucose and insulin at 120 min of the OGTT (p < 0.01). This was accompanied by an increase in visfatin, from 76.8 ± 14.1 ng/ml in the control subjects, to 84.0 ± 14.7 ng/ml in the IG group and 93.1 ± 12.3 ng/ml in the GDM group (p < 0.01 for GDM vs control subjects). There was a positive correlation between visfatin and fasting insulin (r = 0.38, p = 0.007) and insulin at 120 min of the OGTT (r = 0.39, p = 0.006). Conclusions/interpretation An increase in fasting visfatin, the levels of which correlate with both fasting and post-glucose-load insulin concentrations, accompanies worsening glucose tolerance in the third trimester of pregnancy. However, the significance of these findings, and in particular the role of visfatin in the regulation of insulin sensitivity during pregnancy, remains to be elucidated. Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorised users. G. M. Prelevic and H. S. Randeva are both senior authors.     

Differential effects of fatness,fitness and physical activity energy expenditure on whole-body,liver and fat insulin sensitivity

Aims/hypothesis The relative contributions of fitness (maximal oxygen uptake), physical activity energy expenditure (PAEE) and fatness to whole-body, liver and fat insulin sensitivity is uncertain. The aim of this study was to determine whether fitness and PAEE are associated with whole-body, liver and fat insulin sensitivity independently of body fat. Materials and methods We recruited 25 men (mean [SD] age 53 [6] years). Whole-body (M value) and liver (percentage suppression of endogenous glucose output) insulin sensitivity were estimated using a hyperinsulinaemic–euglycaemic clamp. Insulin sensitivity in fat (insulin sensitivity index for NEFA) was estimated during an OGTT. Total and truncal fat were measured by dual-energy X-ray absorptiometry, fitness by treadmill, and PAEE (n = 21) by 3 day heart rate monitoring and Baecke questionnaire. Results In univariate analyses, fatness was strongly associated with insulin sensitivity (whole-body, liver and fat). Fitness was associated with whole-body (r = 0.53, p < 0.007) and liver (0.42, p = 0.04) insulin sensitivity, while PAEE was associated with liver insulin sensitivity (r = 0.55, p = 0.01). Regression models were established to describe associations between fatness, fitness and physical activity and measures of insulin sensitivity (whole-body, fat and liver) as outcomes. Only fatness was independently associated with whole-body insulin sensitivity (B coefficient −0.01, p = 0.001). Fitness was not associated with any outcome. Only PAEE was independently associated with liver insulin sensitivity (B coefficient 13.5, p = 0.02). Conclusions/interpretation Fatness explains most of the variance in whole-body insulin sensitivity. In contrast, PAEE explains most of the variance in liver insulin sensitivity.     

Associations between depressive symptoms and insulin resistance: The Hoorn Study

Aims/hypothesis The association between depression and insulin resistance has been investigated in only a few studies, with contradictory results reported. The aim of this study was to determine whether the association between symptoms of depression and insulin resistance varies across glucose tolerance status and between men and women.Subjects and methods Cross-sectional data from a population-based cohort study in Hoorn, a medium-sized town in the Netherlands, were analysed. The study sample consisted of 541 men and women aged 55–75 years, of whom 260 had NGT, 164 had IGT and 117 had established type 2 diabetes mellitus. Main outcome measures were insulin resistance defined by the homeostasis model assessment for insulin resistance (HOMA-IR) and symptoms of depression using the Centre for Epidemiologic Studies Depression Scale (CES-D).Results In the total sample, we found a weak positive correlation between the depressive symptoms CED-D scores and HOMA-IR scores (r _s = 0.156, p < 0.001). Even weaker associations were found in subjects with NGT (r _s = 0.041, p=0.509), in subjects with IGT (r _s = 0.112, p = 0.160) and in subjects with type 2 diabetes (r _s = 0.007, p = 0.942). The association between depressive symptoms and insulin resistance was similar for men and women.Conclusions/interpretation We found only weak associations between depressive symptoms and insulin resistance, which did not differ among different glucose metabolism subgroups or between men and women.     

Tissue specificity of insulin resistance in humans: fat in the liver rather than muscle is associated with features of the metabolic syndrome

Aims/hypothesis The aim of this study was to investigate whether intrahepatic and intramyocellular fat are related to insulin resistance in these respective tissues or to the metabolic syndrome. Methods Hepatic (insulin 1.8 pmol kg⁻¹ min⁻¹ combined with [3-³H]glucose) and muscle (insulin 6.0 pmol kg⁻¹ min⁻¹) insulin sensitivity were measured on separate occasions in 45 non-diabetic men (age 42 ± 1 years, BMI 26.2 ± 0.6 kg/m²) using the euglycaemic–hyperinsulinaemic clamp. Liver fat and intramyocellular lipid (IMCL) were measured by proton magnetic resonance spectroscopy and body composition by magnetic resonance imaging. We also determined fasting serum insulin and adiponectin concentrations, components of the metabolic syndrome and maximal oxygen consumption. Results In participants with high [median 12.0% (interquartile range 5.7–18.5%)] vs low [2.0% (1.0–2.0%)] liver fat, fasting serum triacylglycerols (1.6 ± 0.2 vs 1.0 ± 0.1 mmol/l, p = 0.002) and fasting serum insulin (55 ± 4 vs 32 ± 2 pmol/l, p < 0.0001) were increased and serum HDL-cholesterol (1.26 ± 0.1 vs 1.48 ± 0.1 mmol/l, p = 0.02) and fasting serum adiponectin (9.5 ± 1.2 vs 12.2 ± 1.2 μg/ml, p = 0.05) decreased. In participants with high [19.5% (16.0–26.0%)] vs low [5.0% (2.3–7.5%)] IMCL, these parameters were comparable. Liver fat was higher in participants with [10.5% (3.0–18.0%)] than in those without [2.0% (1.5–6.0%), p = 0.010] the metabolic syndrome, even independently of obesity, while IMCL was comparable. Insulin suppression of glucose rate of appearance and serum NEFA was significantly impaired in the high liver fat group. Conclusions/interpretation Fat accumulation in the liver rather than in skeletal muscle is associated with features of the metabolic syndrome, i.e. increased fasting serum triacylglycerols and decreased fasting serum HDL-cholesterol, as well as with hyperinsulinaemia and low adiponectin.     

Adiposity, inflammation and hyperglycaemia in rural and urban Indian men: Coronary Risk of Insulin Sensitivity in Indian Subjects (CRISIS) Study

Aims/hypothesis The aim of this study was to investigate whether the higher prevalence of insulin resistance and glucose intolerance in urban compared with rural Indian men is related to their higher adiposity (percentage body fat) and the associated inflammatory state. Methods We studied 149 rural, 142 urban slum and 150 urban middle-class male residents (age 30–50 years), who were selected by stratified random sampling. We measured body fat (bioimpedance), waist circumference, glucose tolerance (75 g OGTT), insulin resistance [homeostasis model assessment (HOMA-IR)], beta cell function (insulinogenic index) and inflammatory markers (total leucocyte count, IL-6, TNF-α and C-reactive protein). Results Adiposity, waist circumference, HOMA-IR, insulinogenic index and both fasting and 120 min plasma glucose concentrations increased progressively from rural through to urban slum and urban middle-class men. Inflammatory markers were higher in urban than in rural men. Adiposity was strongly related to HOMA-IR (r = 0.57, p < 0.001) and to insulinogenic index and glycaemic parameters (r = 0.25, p < 0.001 for both). Adiposity explained approximately two thirds of the difference in HOMA-IR between the urban middle-class men and the rural and slum residents, but its contribution to the difference in insulinogenic index and 120 min plasma glucose concentration was not significant. Inclusion of C-reactive protein, IL-6 and total leucocyte count in the models did not further explain these results, nor did the inclusion of waist circumference. There was a significant residual difference after these adjustments. Conclusions/interpretation Adiposity is a major contributor to the difference in insulin resistance between rural and urban Indian men; there was no additional contribution from inflammation or central obesity. Other unmeasured factors also seem to contribute to the metabolic differences between rural and urban men.     

Impact of polymorphisms in WFS1 on prediabetic phenotypes in a population-based sample of middle-aged people with normal and abnormal glucose regulation

Aim/hypothesis  Recently, variants in WFS1 have been shown to be associated with type 2 diabetes. We aimed to examine metabolic risk phenotypes of WFS1 variants in glucose-tolerant people and in individuals with abnormal glucose regulation. Methods  The type 2 diabetes-associated WFS1 variant rs734312 (His611Arg) was studied in the population-based Inter99 cohort involving 4,568 glucose-tolerant individuals and 1,471 individuals with treatment-naive abnormal glucose regulation, and in an additional 3,733 treated type 2 diabetes patients. Results  The WFS1 rs734312 showed a borderline significant association with type 2 diabetes with directions and relative risks consistent with previous reports. In individuals with abnormal glucose regulation, the diabetogenic risk A allele of rs734312 was associated in an allele-dependent manner with a decrease in insulinogenic index (p = 0.025) and decreased 30-min serum insulin levels (p = 0.047) after an oral glucose load. In glucose-tolerant individuals the same allele was associated with increased fasting serum insulin concentration (p = 0.019) and homeostasis model assessment of insulin resistance (HOMA-IR; p = 0.026). To study the complex interaction of WFS1 rs734312 on insulin release and insulin resistance we introduced Hotelling’s T ² test. Assuming bivariate normal distribution, we constructed standard error ellipses of the insulinogenic index and HOMA-IR when stratified according to glucose tolerance status around the means of each WFS1 rs734312 genotype level. The interaction term between individuals with normal glucose tolerance and abnormal glucose regulation on the insulinogenic index and HOMA-IR was significantly associated with the traits (p = 0.0017). Conclusions/interpretation  Type 2 diabetes-associated risk alleles of WFS1 are associated with estimates of a decreased pancreatic beta cell function among middle-aged individuals with abnormal glucose regulation. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorised users.     

Effects of peroxisome proliferator-activated receptor (PPAR)-α and PPAR-γ agonists on glucose and lipid metabolism in patients with type 2 diabetes mellitus

Aims/hypothesis The aim of the study was to examine the effects of pioglitazone (PIO), a peroxisome proliferator-activated receptor (PPAR)-γ agonist, and fenofibrate (FENO), a PPAR-α agonist, as monotherapy and in combination on glucose and lipid metabolism. Subjects and methods Fifteen type 2 diabetic patients received FENO (n = 8) or PIO (n = 7) for 3 months, followed by the addition of the other agent for 3 months in an open-label study. Subjects received a 4 h hyperinsulinaemic–euglycaemic clamp and a hepatic fat content measurement at 0, 3 and 6 months. Results Following PIO, fasting plasma glucose (FPG) (p < 0.05) and HbA_1c (p < 0.01) decreased, while plasma adiponectin (AD) (5.5 ± 0.9 to 13.8 ± 3.5 μg/ml [SEM], p < 0.03) and the rate of insulin-stimulated total-body glucose disposal (R _d) (23.8 ± 3.8 to 40.5 ± 4.4 μmol kg⁻¹ min⁻¹, p < 0.005) increased. After FENO, FPG, HbA_1c, AD and R _d did not change. PIO reduced fasting NEFA (784 ± 53 to 546 ± 43 μmol/l, p < 0.05), triacylglycerol (2.12 ± 0.28 to 1.61 ± 0.22 mmol/l, p < 0.05) and hepatic fat content (20.4 ± 4.8 to 10.2 ± 2.5%, p < 0.02). Following FENO, fasting NEFA and hepatic fat content did not change, while triacylglycerol decreased (2.20 ± 0.14 to 1.59 ± 0.13 mmol/l, p < 0.01). Addition of FENO to PIO had no effect on R _d, FPG, HbA_1c, NEFA, hepatic fat content or AD, but triacylglycerol decreased (1.61 ± 0.22 to 1.00 ± 0.15 mmol/l, p < 0.05). Addition of PIO to FENO increased R _d (24.9 ± 4.4 to 36.1 ± 2.2 μmol kg⁻¹ min⁻¹, p < 0.005) and AD (4.1 ± 0.8 to 13.1 ± 2.5 μg/ml, p < 0.005) and reduced FPG (p < 0.05), HbA_1c (p < 0.05), NEFA (p < 0.01), hepatic fat content (18.3 ± 3.1 to 13.5 ± 2.1%, p < 0.03) and triacylglycerol (1.59 ± 0.13 to 0.96 ± 0.9 mmol/l, p < 0.01). Muscle adenosine 5′-monophosphate-activated protein kinase (AMPK) activity did not change following FENO; following the addition of PIO, muscle AMPK activity increased significantly (phosphorylated AMPK:total AMPK ratio 1.2 ± 0.2 to 2.2 ± 0.3, p < 0.01). Conclusions/interpretation We conclude that PPAR-α therapy has no effect on NEFA or glucose metabolism and that addition of a PPAR-α agonist to a PPAR-γ agent causes a further decrease in plasma triacylglycerol, but has no effect on NEFA or glucose metabolism.     

Influence of gestational diabetes on the long-term control of glucose tolerance

Aims/hypothesis Gestational diabetes (GDM) carries a high risk of subsequent diabetes. We asked what impact prior GDM has on beta cell function and insulin action in women who maintain normal glucose tolerance (NGT) for a long time. Methods Ninety-one women with NGT (aged 41 ± 8 years, mean±SD) were studied (by mathematical modelling of the C-peptide response to an OGTT) 7 [6] years (median [interquartile range]) after the index pregnancy, during which 52 had GDM (pGDM) and 39 had NGT (pNGT). In all women an OGTT had also been performed at 29 ± 3 weeks of the index pregnancy. Results Women with pGDM were matched with women with pNGT for age, familial diabetes, time and weight gain since index pregnancy, parity, BMI (25.4 ± 3.9 vs 26.8 ± 6.4 kg/m²), and fasting (4.64 ± 0.56 vs 4.97 ± 0.46 mmol/l) and 2 h plasma glucose levels (5.91 ± 1.14 vs 5.91 ± 1.21 mmol/l). Nonetheless, fasting (49 [29] vs 70 [45] pmol min⁻¹ m⁻², p < 0.001) and total insulin secretion (32 [17] vs 48 [21] nmol m⁻², p < 0.0001) and beta cell glucose sensitivity (slope of the insulin secretion/plasma glucose concentration–response function) (95 [71] vs 115 [79] pmol min⁻¹ m⁻² (mmol/l)⁻¹, p = 0.025) were reduced in the pGDM group compared with the pNGT group, while insulin sensitivity was preserved (424 [98] vs 398 [77] ml min⁻¹ m⁻²). At index pregnancy, women with pGDM and those with pNGT had similar age and BMI. However, both insulin sensitivity (359 [93] vs 417 [92] ml min⁻¹ m⁻², p = 0.0012) and the insulin/glucose incremental area ratio (an empirical index of beta cell function; 98 [74] vs 138 [122] pmol/mmol, p = 0.028) were reduced in women with pGDM. Conclusions Even in women who maintain normal insulin sensitivity, impaired beta cell function is carried over into the NGT status several years after a GDM pregnancy.     

Omitting breakfast and lunch after injection of different long-acting insulin preparations at bedtime: a prospective study in patients with type 2 diabetes

Aims/hypothesis  The aim of this prospective trial was to compare the effect of different long-acting insulin preparations injected at bedtime on glucose concentrations in patients with type 2 diabetes omitting breakfast and lunch the next day. Methods  Twenty patients (ten women) with type 2 diabetes who were on an intensified insulin therapy participated. Mean (±SD) age was 63 ± 10 years, diabetes duration 18 ± 9 years, BMI 32.5 ± 5 kg/m², and HbA_1c 7.3 ± 0.7%. Patients received neutral protamine Hagedorn (NPH) insulin, insulin detemir or insulin glargine for at least 2 months; doses were adjusted to achieve morning blood glucose levels of <7 mmol/l. At the end of the respective treatment period, the long-acting insulin was injected at bedtime (at 22:45 hours) as usual but patients refrained from breakfast and lunch the next day; glucose was measured by a continuous glucose monitoring system (CGMS). Results   Comparable glucose target ranges were reached at midnight (5.8 to 6.1 mmol/l) and at 07:00 hours (6.7 to 6.9 mmol/l) with all three insulin preparations, using mean doses of 29 ± 10 U (NPH insulin), 33 ± 13 U (insulin detemir), and 32 ± 12 U (insulin glargine). Glucose levels between midnight and 07:00 hours were not significantly different for the three insulin preparations. Symptomatic hypoglycaemia did not occur from 08:00 to 16:00 hours; glucose concentrations during this time were slightly lower with NPH insulin than with insulin detemir (p = 0.012) and insulin glargine (p = 0.049). Conclusions/interpretation  Following bedtime injection of NPH insulin or of the analogues insulin detemir or insulin glargine, fasting glucose <7 mmol/l was achieved in the morning, without subsequent hypoglycaemia when participants continued to fast during the day.     

Effects of long-term calorie restriction and endurance exercise on glucose tolerance,insulin action,and adipokine production

Calorie restriction (CR) slows aging and is thought to improve insulin sensitivity in laboratory animals. In contrast, decreased insulin signaling and/or mild insulin resistance paradoxically extends maximal lifespan in various genetic animal models of longevity. Nothing is known regarding the long-term effects of CR on glucose tolerance and insulin action in lean healthy humans. In this study we evaluated body composition, glucose, and insulin responses to an oral glucose tolerance test and serum adipokines levels in 28 volunteers, who had been eating a CR diet for an average of 6.9 ± 5.5 years, (mean age 53.0 ± 11 years), in 28 age-, sex-, and body fat-matched endurance runners (EX), and 28 age- and sex-matched sedentary controls eating Western diets (WD). We found that the CR and EX volunteers were significantly leaner than the WD volunteers. Insulin sensitivity, determined according to the HOMA-IR and the Matsuda and DeFronzo insulin sensitivity indexes, was significantly higher in the CR and EX groups than in the WD group (P = 0.001). Nonetheless, despite high serum adiponectin and low inflammation, ∼40% of CR individuals exhibited an exaggerated hyperglycemic response to a glucose load. This impaired glucose tolerance is associated with lower circulating levels of IGF-1, total testosterone, and triiodothyronine, which are typical adaptations to life-extending CR in rodents.     

Cortisol clearance and associations with insulin sensitivity, body fat and fatty liver in middle-aged men

Aims/hypothesis The regulation of cortisol metabolism in vivo is not well understood. We evaluated the relationship between cortisol metabolism and insulin sensitivity, adjusting for total and regional fat content and for non-alcoholic fatty liver disease. Materials and methods Twenty-nine middle-aged healthy men with a wide range of BMI were recruited. We measured fat content by dual-energy X-ray absorptiometry and magnetic resonance imaging (MRI), liver fat by ultrasound and MRI, the hypothalamic-pituitary-adrenal axis by adrenal response to ACTH_1-24, unconjugated urinary cortisol excretion, corticosteroid-binding globulin, and cortisol clearance by MS. We assessed insulin sensitivity by hyperinsulinaemic-euglycaemic clamp and by OGTT. Results Cortisol clearance was strongly inversely correlated with insulin sensitivity (M value) (r = −0.61, p = 0.002). Cortisol clearance was increased in people with fatty liver compared with those without (mean±SD: 243 ± 10 vs 158 ± 36 ml/min; p = 0.014). Multiple regression modelling showed that the relationship between cortisol clearance and insulin sensitivity was independent of body fat. The relationship between fatty liver and insulin sensitivity was significantly influenced by body fat and cortisol clearance. Conclusions/interpretation Cortisol clearance is strongly associated with insulin sensitivity, independently of the amount of body fat. The relationship between fatty liver and insulin sensitivity is mediated in part by both fatness and cortisol clearance. Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorised users.     

Impaired fasting glycaemia vs impaired glucose tolerance: similar impairment of pancreatic alpha and beta cell function but differential roles of incretin hormones and insulin action

Aims/hypothesis The impact of strategies for prevention of type 2 diabetes in isolated impaired fasting glycaemia (i-IFG) vs isolated impaired glucose tolerance (i-IGT) may differ depending on the underlying pathophysiology. We examined insulin secretion during OGTTs and IVGTTs, hepatic and peripheral insulin action, and glucagon and incretin hormone secretion in individuals with i-IFG (n = 18), i-IGT (n = 28) and normal glucose tolerance (NGT, n = 20). Methods Glucose tolerance status was confirmed by a repeated OGTT, during which circulating insulin, glucagon, glucose-dependent insulinotrophic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) levels were measured. A euglycaemic–hyperinsulinaemic clamp with [3–³H]glucose preceded by an IVGTT was performed. Results Absolute first-phase insulin secretion during IVGTT was decreased in i-IFG (p = 0.026), but not in i-IGT (p = 0.892) compared with NGT. Hepatic insulin sensitivity was normal in i-IFG and i-IGT individuals (p ≥ 0.179). Individuals with i-IGT had peripheral insulin resistance (p = 0.003 vs NGT), and consequently the disposition index (DI; insulin secretion×insulin sensitivity) during IVGTT (DI_IVGTT)) was reduced in both i-IFG and i-IGT (p < 0.005 vs NGT). In contrast, the DI during OGTT (DI_OGTT) was decreased only in i-IGT (p < 0.001), but not in i-IFG (p = 0.143) compared with NGT. Decreased levels of GIP in i-IGT (p = 0.045 vs NGT) vs increased levels of GLP-1 in i-IFG (p = 0.013 vs NGT) during the OGTT may partially explain these discrepancies. Basal and post-load glucagon levels were significantly increased in both i-IFG and i-IGT individuals (p ≤ 0.001 vs NGT). Conclusions/interpretation We propose that differentiated preventive initiatives in prediabetic individuals should be tested, targeting the specific underlying metabolic defects.     

Evidence that autonomic mechanisms contribute to the adaptive increase in insulin secretion during dexamethasone-induced insulin resistance in humans

Aims/hypothesis This study examined whether autonomic mechanisms contribute to adaptively increased insulin secretion in insulin-resistant humans, as has been proposed from studies in animals. Methods Insulin secretion was evaluated before and after induction of insulin resistance with or without interruption of neural transmission. Insulin resistance was induced by dexamethasone (15 mg given over 3 days) in nine healthy women (age 67 years, BMI 25.2 ± 3.4 kg/m², fasting glucose 5.1 ± 0.4 mmol/l, fasting insulin 46 ± 6 pmol/l). Insulin secretion was evaluated as the insulin response to intravenous arginine (5 g) injected at fasting glucose and after raising glucose to 13 to15 mmol/l or to >28 mmol/l. Neural transmission across the ganglia was interrupted by infusion of trimethaphan (0.3–0.6 mg kg⁻¹ min⁻¹). Results As an indication of insulin resistance, dexamethasone increased fasting insulin (to 75 ± 8 pmol/l, p < 0.001) without significantly affecting fasting glucose. Arginine-induced insulin secretion was increased by dexamethasone at all glucose levels (by 64 ± 12% at fasting glucose, by 80 ± 19% at 13–15 mmol glucose and by 43 ± 12% at >28 mmol glucose; p <0.001 for all). During dexamethasone-induced insulin resistance, trimethaphan reduced the insulin response to arginine at all three glucose levels. The augmentation of the arginine-induced insulin responses by dexamethasone-induced insulin resistance was reduced by trimethaphan by 48 ± 6% at fasting glucose, 61 ± 8% at 13–15 mmol/l glucose and 62 ± 8% at >28 mmol/l glucose (p < 0.001 for all). In contrast, trimethaphan did not affect insulin secretion before dexamethasone was given. Conclusions/interpretations Autonomic mechanisms contribute to the adaptative increase in insulin secretion in dexamethasone-induced insulin resistance in healthy participants.     

Brothers of women with polycystic ovary syndrome are characterised by impaired glucose tolerance,reduced insulin sensitivity and related metabolic defects

Aims/hypothesis Since it has been shown that polycystic ovary syndrome (PCOS) is highly inherited and characterised by insulin resistance, we hypothesised that male siblings of PCOS women would also be insulin resistant. Thus, our aim was to assess insulin sensitivity and metabolic parameters in brothers of women with PCOS and male control individuals. Methods Seventeen brothers of PCOS women and 28 male control volunteers were assessed with 75 g OGTTs and euglycaemic–hyperinsulinaemic clamps. PCOS index women were identified using criteria developed at the 1990 National Institutes of Health conference. Results Brothers and control individuals were similar in terms of BMI, waist circumference, percentage body fat and BP. However, brothers had increased triacylglycerol (p = 0.02), plasminogen activator inhibitor-1 (PAI-1; p = 0.02), factor VIII (p = 0.02), 2 h glucose (p < 0.001), AUC_glucose (p < 0.001) and AUC_insulin (p < 0.001). Insulin sensitivity was reduced by 38% in brothers (p < 0.001), and this was primarily due to a 65% decrease in insulin-stimulated non-oxidative carbohydrate metabolism (p < 0.001). These differences remained significant after adjustment for age and BMI, except for triacylglycerol, PAI-1 and fasting glucose. The main findings also persisted after excluding individuals with impaired glucose tolerance or diabetic siblings. Significant interactions with BMI status were found for sex hormone-binding globulin, androstenedione, PAI-1 and AUC_insulin, which were significantly altered only in obese brothers (vs control individuals). Conclusions/interpretation Brothers of PCOS women are characterised by decreased insulin sensitivity and glucose tolerance, as well as hypercoagulability, independently of obesity. Therefore, brothers of PCOS women may have inherited the insulin resistance and metabolic syndrome typical of PCOS.     

Insulin sensitivity, insulin release and glucagon-like peptide-1 levels in persons with impaired fasting glucose and/or impaired glucose tolerance in the EUGENE2 study

Aims/hypothesis We examined the phenotype of individuals with impaired fasting glucose (IFG) and/or impaired glucose tolerance (IGT) with regard to insulin release and insulin resistance. Methods Non-diabetic offspring (n = 874; mean age 40 ± 10.4 years; BMI 26.6 ± 4.9 kg/m²) of type 2 diabetic patients from five different European Centres (Denmark, Finland, Germany, Italy and Sweden) were examined with regard to insulin sensitivity (euglycaemic clamps), insulin release (IVGTT) and glucose tolerance (OGTT). The levels of glucagon-like peptide-1 (GLP-1) and gastric inhibitory polypeptide (GIP) were measured during the OGTT in 278 individuals. Results Normal glucose tolerance was found in 634 participants, while 110 had isolated IFG, 86 had isolated IGT and 44 had both IFG and IGT, i.e. about 28% had a form of reduced glucose tolerance. Participants with isolated IFG had lower glucose-corrected first-phase (0–10 min) and higher second-phase insulin release (10–60 min) during the IVGTT, while insulin sensitivity was reduced in all groups with abnormal glucose tolerance. Similarly, GLP-1 but not GIP levels were reduced in individuals with abnormal glucose tolerance. Conclusions/interpretation The primary mechanism leading to hyperglycaemia in participants with isolated IFG is likely to be impaired basal and first-phase insulin secretion, whereas in isolated IGT the primary mechanism leading to postglucose load hyperglycaemia is insulin resistance. Reduced GLP-1 levels were seen in all groups with abnormal glucose tolerance and were unrelated to the insulin release pattern during an IVGTT.     

Insulin resistance and coronary artery disease

Summary The purpose of the present study was to quantitate insulin-mediated glucose disposal in normal glucose tolerant patients with angiographically documented coronary artery disease (CAD) and to define the pathways responsible for the insulin resistance. We studied 13 healthy, normal weight, normotensive subjects with angiographically documented CAD and 10 age-, weight-matched control subjects with an oral glucose tolerance test and a 2-h euglycaemic insulin (40 mU · m⁻²· min⁻¹) clamp with tritiated glucose and indirect calorimetry. Lean body mass was measured with tritiated water. All CAD and control subjects had a normal oral glucose tolerance test. Fasting plasma insulin concentration (66 ± 6 vs 42 ± 6 pmol/l, p < 0.05) and area under the plasma insulin curve following glucose ingestion (498 ± 54 vs 348 ± 42 pmol · l⁻¹· min⁻¹, p < 0.001) were increased in CAD vs control subjects. Insulin-mediated whole body glucose disposal (27.8 ± 3.9 vs 38.3 ± 4.4 μmol · kg fat free mass (FFM)⁻¹· min⁻¹, p < 0.01) was significantly decreased in CAD subjects and this was entirely due to diminished non-oxidative glucose disposal (8.9 ± 2.8 vs 20.0 ± 3.3 μmol · kg FFM⁻¹· min⁻¹, p < 0.001). The magnitude of insulin resistance was positively correlated with the severity of CAD (r = 0.480, p < 0.05). In the CAD subjects basal and insulin-mediated rates of glucose and lipid oxidation were normal and insulin caused a normal suppression of hepatic glucose production. In conclusion, subjects with angiographically documented CAD are characterized by moderate-severe insulin resistance and hyperinsulinaemia and should be included in the metabolic and cardiovascular cluster of disorders that comprise the insulin resistance syndrome or ’syndrome X'. [Diabetologia (1996) 39: 1345–1350] Received: 6 February 1996 and in revised form: 29 May 1996     

Effect of short-term ACE inhibitor treatment on peripheral insulin sensitivity in obese insulin-resistant subjects

Aims/hypothesis This study was designed to investigate the effect of short-term ACE inhibitor treatment on insulin sensitivity and to examine possible underlying metabolic and haemodynamic effects in obese insulin-resistant subjects.Methods A randomised, double-blind placebo-controlled trial was performed in 18 obese insulin-resistant men (age, 53 ± 2 years; BMI, 32.6 ± 0.8 kg/m²; homeostasis model assessment of insulin resistance, 5.6 ± 0.5; systolic blood pressure [SBP], 140.8 ± 3.2; diastolic blood pressure [DBP], 88.8 ± 1.6 mmHg), who were free of any medication. The aim was to examine the effects of 2 weeks of ACE inhibitor treatment (ramipril, 5 mg/day) on insulin sensitivity, forearm blood flow, substrate fluxes across the forearm, whole-body substrate oxidation and intramuscular triacylglycerol (IMTG) content.Results Ramipril treatment decreased ACE activity compared with placebo (−22.0 ± 1.7 vs 0.2 ± 1.1 U/l, respectively, p < 0.001), resulting in a significantly reduced blood pressure (SBP, −10.8 ± 2.1 vs −2.7 ± 2.0 mmHg, respectively, p = 0.01; DBP, −10.1 ± 1.3 vs −4.2 ± 2.1 mmHg, respectively, p = 0.03). Ramipril treatment had no effect on whole-body insulin-mediated glucose disposal (before: 17.9 ± 2.0, after: 19.1 ± 2.4 μmol kg body weight⁻¹ min⁻¹, p = 0.44), insulin-mediated glucose uptake across the forearm (before: 1.82 ± 0.39, after: 1.92 ± 0.29 μmol 100 ml forearm tissue⁻¹ min⁻¹, p = 0.81) and IMTG content (before: 45.4 ± 18.8, after: 48.8 ± 27.5 μmol/mg dry muscle, p = 0.92). Furthermore, the increase in carbohydrate oxidation (p < 0.001) and forearm blood flow (p < 0.01), and the decrease in fat oxidation (p < 0.001) during insulin stimulation were not significantly different between treatments.Conclusions/interpretation Short-term ramipril treatment adequately reduced ACE activity and blood pressure, but had no significant effects on insulin sensitivity, forearm blood flow, substrate fluxes across the forearm, whole-body substrate oxidation and IMTG content in obese insulin-resistant subjects.