Whole-body Glucose Uptake Research Articles

Association of insulin resistance with hyperglycemia in streptozotocin-diabetic pigs: Effects of metformin at isoenergetic feeding in a type 2–like diabetic pig model

Insulin-mediated glucose metabolism was investigated in streptozotocin (STZ)–treated diabetic pigs to explore if the STZ-diabetic pig can be a suitable model for insulin-resistant, type 2 diabetes mellitus. Pigs (∼40 kg) were meal-fed with a low-fat (5%) diet. Hyperinsulinemic (1, 2, and 8 mU kg −1 min −1) clamps and/or 6,6- 2H-glucose infusion studies were performed in 36 pigs. Diabetic (slow, 30-minute infusion of 130 mg STZ/kg) vs normal pigs were nonketotic, showed fasting hyperglycemia (21.7 ± 1.1 vs 5.3 ± 0.2 mmol/L), comparable plasma insulin (9 ± 7 vs 5 ± 1 mU/L), and elevated triglyceride concentrations (1.0 ± 0.3 vs 0.2 ± 0.1 mmol/L). After a standard meal, plasma triglycerides, cholesterol, and nonesterified fatty acid concentrations were significantly higher in diabetic vs normal pigs (1.2 ± 0.3 vs 0.3 ± 0.1, 2.3 ± 0.2 vs 1.7 ± 0.1, and 1.5 ± 0.5 vs 0.2 ± 0.1 mmol/L, respectively, P < .05). Fasting whole-body glucose uptake, hepatic glucose production, and urinary glucose excretion were increased ( P < .01) in diabetic vs normal pigs (9.1 ± 0.6 vs 4.8 ± 0.4, 11.4 ± 0.6 vs 4.8 ± 0.4, and 2.3 ± 0.2 vs 0.0 ± 0.0 mg kg −1 min −1). During hyperinsulinemic euglycemia (∼6 mmol/L), whole-body glucose uptake was severely reduced ( P < .01) and hepatic glucose production was moderately increased ( P < .05) in diabetic vs normal pigs (6.7 ± 1.3 vs 21.1 ± 2.2 and 1.7 ± 0.5 vs 0.8 ± 0.3 mg kg −1 min −1) despite plasma insulin concentrations of 45 ± 5 vs 24 ± 5 mU/L, respectively. Metformin vs placebo treatment of diabetic pigs (twice 1.5 g/d) for 2 weeks during isoenergetic feeding (1045 kJ/kg body weight 0.75) resulted in a reduction in both fasting and postprandial hyperglycemia (14.7 ± 1.5 vs 19.4 ± 0.6 and 24.9 ± 2.2 vs 35.5 ± 4.9 mmol/L), a reduction in daily urinary glucose excretion (∼250 vs ∼350 g/kg food), and an increase in insulin-stimulated glucose disposal (9.4 ± 2.2 vs 5.8 ± 1.7 mg kg −1 min −1; P < .05), respectively. In conclusion, a slow infusion of STZ (130 mg/kg) in pigs on a low-fat diet induces the characteristic metabolic abnormalities of type 2 diabetes mellitus and its sensitivity to oral metformin therapy. It is therefore a suitable humanoid animal model for studying different aspects of metabolic changes in type 2 diabetes mellitus. Insulin resistance in STZ-diabetic pigs is most likely secondary to hyperglycemia and/or hyperlipidemia and therefore of metabolic origin.

Effect of Rapid Weight-loss Caused by Dehydration on Whole-body Glucose Uptake and Basal Metabolic Conditions

Material arts where athletes are classified by body-weight, the rapid-weight loss procedure has been widely adopted by coaches and athletes to reduce body weight. PURPOSE: To investigate the effect of rapid weight-loss caused by dehydration on whole-body glucose uptake and basal metabolic conditions. METHODS: Twenty-six elite college judo wrestlers (Age: 20.0±0.4yrs; BMI: 24.7±0.9) served as participants. One day prior to the administration of the rapid weight-loss procedure, subjects took an oral glucose tolerance test (OGTT) following an overnight fast. As overnight dehydration and fasting procedure completed (from 9 pm to 9 am), and OGTT was then performed again follow the procedure of the first day. The fasting blood samples of both days were analyzed for blood cholesterol (CHOL), creatine kinase (CK), and uric acid (UA) levels. RESULTS: The body weight of the subjects declined significantly following the 12 hr dehydration and fasting procedure (p < 0.05). However, there were no changes in both whole-body glucose tolerance and insulin sensitivity (p > 0.05), and no changes were observed in blood CHOL and UA levels between pre- and post-tests. But, after overnight dehydration, the blood CK level showed a significant increase (p < 0.05). CONCLUSION: An overnight dehydration and fasting rapid weight-loss procedure could not affect whole-body glucose tolerance and insulin sensitivity. Although the blood CK level was elevated following this weight-loss procedure, it might be caused by the more concentrated blood. This procedure should have no negative influence on the system of carbohydrate substrate uptake and glycogen replenishing in skeletal muscle. The results also support the practical use of this procedure before competitions.

Metabolic Aspects of Insulin Resistance in Individuals Born Small for Gestational Age

Numerous studies have shown an association between low weight at birth and being born small for gestational age (SGA) on the one hand and risk of developing insulin resistance and type 2 diabetes on the other. Our studies in twins have indicated a non-genetic age-dependent origin of insulin resistance and type 2 diabetes associated with being born SGA. In order to gain insight into the molecular metabolic defects and mechanisms linking SGA with insulin resistance and type 2 diabetes, we performed a series of experiments in young and elderly twins, and, in particular, in young men (aged 19–23 years) with a weight at birth at term in the lowest 10th percentile with no family history of diabetes. The control group included age-matched men with birth weights at term in the upper normal range. While body mass index and waist-to-hip ratios were similar in the individuals born SGA and controls, dual-energy X-ray absorptiometry studies documented a higher degree of abdominal obesity in the men who had a low weight at birth. Using the gold standard hyperinsulinaemic-euglycaemic clamp technique combined with glucose tracers and studies of forearm glucose uptake, we found an impairment of insulin-stimulated glycolytic flux and reduced forearm (muscle) glucose uptake in the face of normal whole-body glucose uptake. In addition, we found a significantly decreased insulin secretion rate during oral glucose ingestion after correction for insulin action (disposition index), a paradoxical enhanced insulin suppression of hepatic glucose production and lower fasting plasma glycerol levels, suggesting impaired lipolysis. Finally, analysis of skeletal muscle biopsies showed reduced muscle expression of several key proteins involved in insulin signalling and glucose transport, including protein kinase C-ζ, the two subunits of phosphoinositol 3-kinase (i.e., p85α and p110β) and the insulin-sensitive glucose transporter, Glut-4, in individuals of low birth weight. In conclusion, being born SGA and of low birth weight is associated with type 2 diabetes in a non-genetic manner, and programming of muscle insulin action and signalling represents an early mechanism responsible for this association.

Reversal of fructose-induced hypertension and insulin resistance by chronic losartan treatment is independent of AT2 receptor activation in rats

To examine whether angiotensin II type 2 receptors (AT2R) are involved in the reversal of fructose-induced hypertension and insulin resistance after chronic angiotensin II type 1 receptor (AT1R) blockade. Sprague-Dawley rats on fructose-enriched or regular diets were pretreated with losartan, an AT1R antagonist, or vehicle for 2 weeks before two-step glucose and insulin clamp experiments with [3-3H]glucose infusion. The hepatic glucose production (HGP) and whole-body glucose uptake (WBGU) were calculated during basal, euglycemic and euglycemic hyperinsulinemic periods. Blood pressure was measured before and after acute losartan (10 mg/kg, i.v. bolus), alone or in combination of PD123319 (PD, 50 microg/kg per min), an AT2R antagonist, or CGP42112 (2 microg/kg per min), an AT2R agonist, during the clamp study. In rats on a regular diet, acute infusion of losartan alone or in combination with PD, an AT2R blocker, did not alter blood pressure and glucose metabolism during experiments. Fructose feeding for 6 weeks significantly increased blood pressure and attenuated insulin-mediated suppression of HGP and stimulation of WBGU. Both acute and chronic administration of losartan suppressed fructose-induced hypertension. Concomitant treatment with PD and losartan blunted the acute but not chronic losartan-mediated depressor effect. Acute losartan treatment further reduced insulin-induced suppression of HGP, but simultaneously increased insulin-stimulated WBGU. These acute metabolic effects of losartan were eliminated when PD was co-administered with losartan. Conversely, chronic losartan pretreatment significantly enhanced suppression of HGP and increased stimulation of WBGU by insulin, which were not altered when PD or CGP 42112 was superimposed on losartan during the clamp experiments. These results suggest that reversal of high fructose-induced hypertension and insulin resistance by chronic losartan treatment is not dependent on AT2R activation and that functional activation of AT1R plays a major role in the pathogenesis of high fructose-induced hypertension and insulin resistance.

Single Nucleotide Polymorphisms in the Peroxisome Proliferator–Activated Receptor δ Gene Are Associated With Skeletal Muscle Glucose Uptake

The peroxisome proliferator-activated receptors (PPARs) belong to a superfamily of nuclear receptors. It includes PPAR-delta, a key regulator of fatty acid oxidation and energy uncoupling, universally expressed in different tissues. The PPAR-delta gene (PPARD) maps to 6p21.2-p21.1 and has 11 exons and spans 35 kbp. We investigated the effects of single nucleotide polymorphisms (SNPs) of PPARD on whole-body, skeletal muscle, and subcutaneous adipose tissue glucose uptake in 129 healthy individuals using the hyperinsulinemic-euglycemic clamp technique combined with fluorine-18-labeled fluorodeoxyglucose ([18F]FDG) and positron emission tomography (PET). Three of six SNPs of PPARD and their haplogenotypes were significantly associated with whole-body insulin sensitivity. [18F]FDG-PET scanning indicated that SNPs of PPARD primarily affected insulin sensitivity by modifying glucose uptake in skeletal muscle but not in adipose tissue. Our results give evidence that SNPs of PPARD regulate insulin sensitivity particularly in skeletal muscle.

Metabolic and Vascular Effects of Tumor Necrosis Factor-α Blockade with Etanercept in Obese Patients with Type 2 Diabetes

Objective: The pro-inflammatory cytokine tumor necrosis factor-α (TNF-α) impairs insulin action in insulin-sensitive tissues, such as fat, muscle and endothelium, and causes endothelial dysfunction. We hypothesized that TNF-α blockade with etanercept could reverse vascular and metabolic insulin resistance. Method and Results: Twenty obese patients with type 2 diabetes were randomized to etanercept treatment (25 mg subcutaneously twice weekly for 4 weeks) or used as controls in an open parallel study. Forearm blood flow and glucose uptake were measured during intra-arterial infusions of serotonin, sodium nitroprusside and insulin co-infused with serotonin. β-Cell function was assessed with oral and intra-venous glucose tolerance tests and whole-body insulin sensitivity by hyperinsulinemic euglycemic clamps. Plasma levels of C-reactive protein and interleukin-6 decreased significantly with etanercept (C-reactive protein from 9.9 ± 3.1 to 4.8 ± 1.4 mg l^–1, p = 0.04; interleukin-6 from 3.1 ± 0.4 to 1.9 ± 0.2 ng l^–1, p = 0.03). Vasodilatory responses to serotonin and sodium nitroprusside infusions remained unchanged. Insulin effect on vasodilatation and on whole-body and forearm glucose uptake remained unchanged as well. β-Cell function tended to improve. Conclusion: Although short-term etanercept treatment had a significant beneficial effect on systemic inflammatory markers, no improvement of vascular or metabolic insulin sensitivity was observed.

Low 25‐Hydroxyvitamin D Does Not Affect Insulin Sensitivity in Obesity after Bariatric Surgery

A positive correlation between levels of 25-hydroxyvitamin D [25(OH)D] and insulin sensitivity has been shown in healthy subjects. We aimed to test the hypothesis that concentration of 25(OH)D influences insulin sensitivity in obesity before and after weight loss. We investigated the relation between serum 25(OH)D and insulin sensitivity (estimated by euglycemic-hyperinsulinemic clamp) in 116 obese women (BMI > or = 40 kg/m2) evaluated before and 5 and 10 years after biliopancreatic diversion (BPD). Body composition was estimated by the isotope dilution method. Prevalence of hypovitaminosis D was 76% in the obese status and 91% and 89% at 5 and 10 years after BPD, respectively, despite ergocalciferol supplementation. 25(OH)D concentration decreased from 39.2 +/- 22.3 in obesity (p = 0.0001) to 27.4 +/- 16.4 and 25.1 +/- 13.9 nM 5 and 10 years after BPD, respectively. Whole-body glucose uptake increased from 24.27 +/- 4.44 at the baseline to 57.29 +/- 11.56 and 57.71 +/- 8.41 mumol/kg(fat free mass) per minute 5 and 10 years after BPD, respectively (p = 0.0001). Predictor of 25(OH)D was fat mass (R2 = 0.26, p = 0.0001 in obesity; R2 = 0.20, p = 0.02 after BPD). Parathormone correlated with fat mass (R2 = 0.19; p = 0.0001) and BMI (R2 = 0.053; p = 0.01) and inversely with M value (R2 = 0.16; p = 0.0001), but only in obese subjects. A high prevalence of hypovitaminosis D was observed in morbid obesity both before and after BPD. Low 25(OH)D did not necessarily imply increased insulin resistance after BPD, a condition where, probably, more powerful determinants of insulin sensitivity overcome the low circulating 25(OH)D levels. However, the present data cannot exclude some kind of influence of vitamin D status on glucose and insulin metabolism.

Tumor Necrosis Factor-α Induces Skeletal Muscle Insulin Resistance in Healthy Human Subjects via Inhibition of Akt Substrate 160 Phosphorylation

Most lifestyle-related chronic diseases are characterized by low-grade systemic inflammation and insulin resistance. Excessive tumor necrosis factor-alpha (TNF-alpha) concentrations have been implicated in the development of insulin resistance, but direct evidence in humans is lacking. Here, we demonstrate that TNF-alpha infusion in healthy humans induces insulin resistance in skeletal muscle, without effect on endogenous glucose production, as estimated by a combined euglycemic insulin clamp and stable isotope tracer method. TNF-alpha directly impairs glucose uptake and metabolism by altering insulin signal transduction. TNF-alpha infusion increases phosphorylation of p70 S6 kinase, extracellular signal-regulated kinase-1/2, and c-Jun NH(2)-terminal kinase, concomitant with increased serine and reduced tyrosine phosphorylation of insulin receptor substrate-1. These signaling effects are associated with impaired phosphorylation of Akt substrate 160, the most proximal step identified in the canonical insulin signaling cascade regulating GLUT4 translocation and glucose uptake. Thus, excessive concentrations of TNF-alpha negatively regulate insulin signaling and whole-body glucose uptake in humans. Our results provide a molecular link between low-grade systemic inflammation and the metabolic syndrome.

Validation of Insulin Resistance Indexes in a Stable Renal Transplant Population

The purpose of this study was to investigate the validity of established insulin resistance indexes, based on fasting blood parameters, in a stable renal transplant population. Fasting insulin, homeostasis model assessment (HOMA), the quantitative insulin sensitivity check index (QUICKI), and McAuley's index were assessed for correlation and agreement with whole-body glucose uptake (M value) divided by prevailing serum insulin concentrations (I value) assessed during a hyperinsulinemic-euglycemic clamp in 51 stable renal transplant recipients, who were at a median of 7.5 years after transplant. Multivariate linear regression analyses were used to determine independent risk factors for insulin resistance. The M/I value correlated with fasting insulin concentration (r = -0.56), HOMA (r = -0.53), QUICKI (r = 0.52), and McAuley's index (r = 0.61) (all P < 0.01). Linear regression showed agreement between all indexes and insulin resistance. However, McAuley's index showed the strongest agreement irrespective of age, sex, renal allograft function, and obesity. In multivariate analysis, fasting insulin concentration (beta = -0.59, P = 0.002), fasting triglyceride concentration (beta = -0.33, P = 0.04), and BMI (beta = -1.22, P = 0.05) were independently associated with the M/I value. All investigated insulin resistance indexes were valid estimates of insulin resistance in the long-term stable renal transplant population. However, correlation and agreement were strongest for McAuley's index. In addition to fasting insulin and triglyceride concentrations, of which McAuley's index is composed, only BMI seemed to be independently associated with insulin resistance in this population.

Insulin Resistance and Hypertension

Insulin resistance refers to the reduction in insulin-mediated glucose uptake in insulin-sensitive tissues, specifically in skeletal muscle. As a compensatory response, hyperinsulinemia ensues to maintain normal blood glucose levels. In epidemiological studies, fasting insulin level is commonly used as a surrogate marker of insulin resistance. In normoglycemic subjects, fasting insulin correlated well with whole-body glucose uptake ( r =−0.68) as measured by the “gold standard” euglycemic hyperinsulinemic clamp method, although the correlation was lower in individuals with impaired glucose tolerance or type 2 diabetes mellitus.1 Although fasting insulin is a reasonable measure of insulin resistance, it is potentially confounded by variability in insulin secretion. Thus, the indexes derived from fasting insulin and glucose, such as the Homeostasis Model Assessment (HOMA),2 the Quantitative Insulin Sensitivity Check Index (QUICKI),3 and the insulin sensitivity index (ISI) developed by Gutt and coworkers,4 have been more widely used to assess insulin resistance in clinical and population-based studies. See p 1719 Although the role of insulin resistance in the pathophysiology of type 2 diabetes mellitus is well accepted, the relationship between insulin resistance and blood pressure remains controversial. Nearly 40 years ago, Welborn and colleagues5 observed that nondiabetic patients with essential hypertension had significantly higher plasma insulin concentrations than did normotensive individuals. This positive relationship has been confirmed in several longitudinal studies, but the results are not entirely consistent. In some studies, the association between hyperinsulinemia and incident hypertension disappeared after adjustment for body mass index (BMI), suggesting that the association is confounded or mediated through obesity. Therefore, the causal role of insulin resistance/compensatory hyperinsulinemia in the development of hypertension continues to be debated. As reported in this issue of Circulation , Arnlov and colleagues6 investigated the relationship between insulin sensitivity, using ISI, and the 4-year incidence of hypertension and blood …

Could the low level of expression of the gene encoding skeletal muscle mitofusin-2 account for the metabolic inflexibility of obesity?

In obesity the cellular capacity to switch from using lipid to carbohydrate and vice versa as the energy substrate, known as 'metabolic flexibility', is impaired. Mitofusin 2 (MFN2), a mitochondrial membrane protein, seems to contribute to the maintenance and operation of the mitochondrial network, and its expression is reduced in obesity. The aim of this study was to verify whether MFN2 might be implicated in the metabolic inflexibility of obesity. Insulin sensitivity was measured in six morbidly obese women before and 2 years after malabsorptive bariatric surgery (BMI 53.3+/-10.5 vs 30.3+/-4.0 kg/m2). Skeletal muscle MFN2, SLC2A4 (formerly known as GLUT4), COX3 (encoding cytochrome c oxidase subunit III) and CS (encoding citrate synthase) mRNA levels were measured by real-time PCR. Following bilio-pancreatic surgery, significant increases in MFN2 mRNA (from 0.4+/-0.2 to 1.7+/-1.1 arbitrary units [AU], p=0.019) and SLC2A4 mRNA (0.38+/-0.12 to 0.76+/-0.24 AU, p=0.04) were observed, while increases in COX3 mRNA (from 14.2+/-6.4 to 20.2+/-12.5 AU) and CS mRNA (from 0.4+/-0.1 to 0.7+/-0.3 AU) failed to reach statistical significance. Insulin-mediated whole-body glucose uptake significantly (p<0.0001) increased from 21.2+/-4.1 to 52.8+/-5.9 micromol kg fat-free mass(-1) min(-1) and glucose oxidation rose from 11.1+/-2.1 to 37.7+/-4.7 micromol kg fat-free mass(-1) min(-1) (p<0.0001). Levels of MFN2 mRNA were strongly correlated with the absolute values for the glucose oxidation rate, both during fasting (glucose oxidation =3.55 MFN2 mRNA + 3.93; R2=0.92, p<0.0001) and during the clamp (glucose oxidation=18.8 MFN2 mRNA+34.7; R2=0.80, p<0.0001). The percentage changes in MFN2 mRNA were positively correlated with the percentage change in glucose oxidation during the clamp (glucose oxidation percent (%) change=0.3 MFN2 mRNA percent (%) change+153.2; R2=0.61, p<0.001). We propose that the significant increase in MFN2 mRNA levels may explain the increase in glucose oxidation observed in morbid obesity following bariatric surgery.

A Potential Important Role of Skeletal Muscle in Human Counterregulation of Hypoglycemia

During hypoglycemia, systemic glucose uptake (SGU) decreases and endogenous glucose release (EGR) increases. Skeletal muscle appears to be primarily responsible for the reduced SGU and may be important for the increased EGR by providing lactate for gluconeogenesis (GN). The objective of the study was to test the hypothesis that reduced muscle glucose uptake and increased muscle lactate release both make major contributions to glucose counterregulation using systemic isotopic techniques in combination with forearm net balance measurements. The study was conducted at the University of Giessen Clinical Research Center. Nine healthy volunteers participated in the study. A 2-h hyperinsulinemic euglycemic clamp (blood glucose approximately 4.4 mm) was followed by a 90-min hypoglycemic clamp (blood glucose approximately 2.6 mm). Compared with the euglycemic clamp, SGU decreased (21.0 +/- 2.0 vs. 29.6 +/- 1.8 micromol.kg body weight(-1).min(-1); P < 0.001), whereas EGR (11.2 +/- 1.7 vs. 4.9 +/- 1.3 micromol.kg body weight(-1) .min(-1); P < 0.003), arterial lactate concentrations (1051 +/- 162 vs. 907 +/- 115 microm; P < 0.02), systemic lactate release (23.5 +/- 0.9 vs. 17.1 +/- 0.9 micromol.kg body weight(-1).min(-1); P < 0.001), and lactate GN (4.50 +/- 0.60 vs. 2.74 +/- 0.30 micromol.kg body weight(-1).min(-1); P < 0.02) increased during hypoglycemia; the proportion of lactate used for GN remained unchanged (38 +/- 4 vs. 32 +/- 3%; P = 0.27). Whole-body muscle glucose uptake decreased approximately 50% during hypoglycemia (6.4 +/- 1.9 vs. 13.6 +/- 2.9 micromol.kg body weight(-1).min(-1); P < 0.001), which accounted for approximately 85% of the reduction of SGU. Whole-body muscle lactate release increased 6.6 +/- 1.6 micromol.kg body weight(-1). min(-1) (P < 0.01), which could have accounted for all the increase in systemic lactate release and, considering the proportion of lactate used for GN, contributed 1.4 +/- 0.4 micromol.kg body weight(-1).min(-1) (approximately 25%) to the increase in EGR. Reduced muscle glucose uptake and increased muscle lactate release both make major contributions to glucose counterregulation in humans.

Increased Fat Mass Compensates for Insulin Resistance in Abdominal Obesity and Type 2 Diabetes

To evaluate the relative impact of abdominal obesity and newly diagnosed type 2 diabetes on insulin action in skeletal muscle and fat tissue, we studied 61 men with (n = 31) or without (n = 30) diabetes, subgrouped into abdominally obese or nonobese according to the waist circumference. Adipose tissue depots were quantified by magnetic resonance imaging, and regional glucose uptake was measured using 2-[(18)F]fluoro-2-deoxyglucose/positron emission tomography during euglycemic hyperinsulinemia. Across groups, glucose uptake per unit tissue weight was higher in visceral (20.5 +/- 1.4 micromol . min(-1) . kg(-1)) than in abdominal (9.8 +/- 0.9 micromol min(-1) . kg(-1), P < 0.001) or femoral (12.3 +/- 0.6 micromol . min(-1) . kg(-1), P < 0.001) subcutaneous tissue and approximately 40% lower than in skeletal muscle (33.1 +/- 2.5 micromol . min(-1) . kg(-1), P < 0.0001). Abdominal obesity was associated with a marked reduction in glucose uptake per unit tissue weight in all fat depots and in skeletal muscle (P < 0.001 for all regions). Recent type 2 diabetes per se had little additional effect. In both intra-abdominal adipose (r = -0.73, P < 0.0001) and skeletal muscle (r = -0.53, P < 0.0001) tissue, glucose uptake was reciprocally related to intra-abdominal fat mass in a curvilinear fashion. When regional glucose uptake was multiplied by tissue mass, total glucose uptake per fat depot was similar irrespective of abdominal obesity or type 2 diabetes, and its contribution to whole-body glucose uptake increased by approximately 40% in obese nondiabetic and nonobese diabetic men and was doubled in obese diabetic subjects. We conclude that 1) in abdominal obesity, insulin-stimulated glucose uptake rate is markedly reduced in skeletal muscle and in all fat depots; 2) in target tissues, this reduction is reciprocally (and nonlinearly) related to the amount of intra-abdominal fat; 3) mild, recent diabetes adds little insulin resistance to that caused by abdominal obesity; and 4) despite fat insulin resistance, an expanded fat mass (especially subcutaneous) provides a sink for glucose, resulting in a compensatory attenuation of insulin resistance at the whole-body level in men.

Epicardial Adipose Tissue and Insulin Resistance in Obese Subjects

Epicardial adipose tissue has been recently recognized as a source of bioactive molecules as well as free fatty acids, adiponectin, and inflammatory cytokines. Epicardial fat reflects intraabdominal visceral fat, and the echocardiographic assessment of this tissue is an easy and reliable marker of visceral adiposity. In this study we evaluated whether epicardial adipose tissue is related to insulin sensitivity and glucose metabolism in obese subjects. Thirty obese subjects (20 women and 10 men; mean age, 40.8 +/- 11.5 yr; body mass index, 43 +/- 9.1 kg/m2) were included in this study. No subject was taking drugs or had a history or evidence of metabolic, cardiovascular, respiratory, or hepatic disease. Each subject underwent a transthoracic echocardiogram to evaluate epicardial adipose tissue thickness, a euglycemic hyperinsulinemic clamp to estimate insulin sensitivity, and an oral glucose tolerance test to evaluate glucose tolerance. The thickness of the epicardial adipose tissue on the right ventricle varied between 4 and 17.4 mm. Echocardiographic epicardial adipose tissue was significantly correlated with whole-body glucose uptake index from the clamp and with all indices of insulin resistance and glucose intolerance measured, except the 120-min plasma glucose level after an oral glucose tolerance test. Our study showed that the epicardial fat is significantly related to obesity-related insulin resistance. This finding could be of potential interest in clinical practice and research of obesity-related risk stratification.

A 100-kDa urinary protein is associated with insulin resistance in offspring of type 2 diabetic patients

One-third of normoalbuminuric type 1 diabetic patients show immunoreactive nephrin in urine. Offspring of type 2 diabetic patients are insulin-resistant and susceptible to the development of diabetes. We investigated whether the offspring of type 2 diabetic patients show nephrin in urine and whether possible nephrinuria is associated with insulin resistance. Urinary proteins from timed overnight urine collections from 128 offspring of type 2 diabetic patients and 9 control subjects were analysed by western blotting using an antibody against nephrin. Glucose metabolism was assessed by OGTT and IVGTT and the euglycaemic-hyperinsulinaemic clamp technique. Of the offspring, 12.5% were strongly and 14.1% weakly positive for a 100-kDa urinary protein. All controls were negative. During the first 10 min of an IVGTT, the offspring strongly positive for the urinary protein had a higher insulin response than the offspring without the protein (3,700 vs 2,306 pmol l(-1)min(-1), p=0.007). Insulin sensitivity (the rate of whole-body glucose uptake divided by the steady-state insulin level x 100) was lower among the offspring strongly positive for the urinary protein than among the offspring negative for the protein (11.3 vs 15.8 micromol kg(-1)min(-1)pmol(-1)l(-1), p=0.008). A 100-kDa urinary protein detectable with a nephrin antibody is associated with insulin resistance in offspring of type 2 diabetic patients.

Leptin pulsatility in formerly obese women

Plasma leptin and growth hormone (GH) profile and pulsatility have been studied in morbidly obese subjects before and 14 months after bilio-pancreatic diversion (BPD), a bariatric technique producing massive lipid malabsorption. The maximum leptin diurnal variation (acrophase) decreased (10.27+/-1.70 vs. 22.60+/-2.79 ng x ml(-1); P=0.001), while its pulsatility index (PI) increased (1.084+/-0.005 vs. 1.050+/-0.004 ng x ml(-1) x min(-1); P=0.02) after BPD. Plasma GH acrophase increased (P=0.0001) from 0.91+/-0.20 to 4.58+/-0.80 microg x l(-1) x min(-1) after BPD as well as GH PI (1.70+/-0.13 vs. 1.20+/-0.04 microg x l(-1) x min(-1); P=0.024). Whole-body glucose uptake (M), assessed by euglycemic-hyperinsulinemic clamp, almost doubled after BPD (from 0.274+/-0.022 to 0.573+/-0.027 mmol x kgFFM(-1) x min(-1); P<0.0001), while 24 h lipid oxidation was significantly (P<0.0001) reduced (131.94+/-35.58 vs. 44.56+/-15.10 g). However, the average lipid oxidation was 97.2+/-3.1% (P<0.01) of the metabolizable lipid intake after the bariatric operation, while it was 69.2+/-8.5% before. After the operation, skeletal muscle ACC2 mRNA decreased (P<0.0001) from 452.82+/-76.35 to 182.45+/-40.69% of cyclophilin mRNA as did the malonyl-CoA (from 0.28+/-0.02 to 0.16+/-0.01 nmol x g(-1); P<0.0001). Leptin changes negatively correlated with M changes (R2=0.69, P<0.001). In a stepwise regression (R2=0.87, P=0.0055), only changes in 24 h free fatty acids (B=0.105+/-0.018, P=0.002) and glucose/insulin ratio (B=0.247+/-0.081, P=0.029) were the best predictors of leptin variations. In conclusion, the reversion of insulin resistance after BPD might allow reversal of leptin resistance, restoration of leptin pulsatility, and consequent inhibition of ACC2 mRNA expression, translating to a reduced synthesis of malonyl-CoA, which, in turn, results in increased fatty acid oxidation. Finally, since leptin inhibits GH secretion, a reduction of circulating leptin levels might have produced an increase in GH secretion, as observed in our series.

Effect of Laparoscopic Colon Resection on Postoperative Glucose Utilization and Protein Sparing

Using a stable isotope method to quantify postoperative changes in glucose and protein metabolism, patients undergoing laparoscopic-assisted colon resection and receiving 4 mg . kg(-1) . min(-1) of dextrose intravenously will (1) have more pronounced suppression of endogenous glucose production, leading to (2) a greater reduction in whole-body protein breakdown. Randomized protocol study. Tertiary health care center in Montreal, Quebec. Twelve patients scheduled for colonic resection were randomly allocated to undergo either laparoscopic (n = 6) or open (n = 6) surgery. Patients underwent a 6-hour stable isotope infusion study (3 hours fasted and 3 hours fed with dextrose infusion) on postoperative day 2. Whole-body protein breakdown and synthesis, amino acid oxidation, and endogenous glucose production and clearance were measured during the postabsorptive state using L-[1-(13)C]leucine and [6,6-(2)H(2)]glucose. Gas exchange and plasma concentrations of metabolites and hormones were also measured. Endogenous glucose production and whole-body protein breakdown during the fasted and fed states. In the fasted state, laparoscopy did not affect protein and glucose metabolism. Dextrose infusion suppressed endogenous glucose production in both groups, with the greatest extent in the laparoscopic group (P = .01). Higher respiratory quotients (P = .001) in the latter group also indicated increased exogenous glucose oxidation. Neither surgical approach nor nutrition affected aspects of protein metabolism. Laparoscopy for colon resection facilitates whole-body glucose uptake and utilization and oxidation of exogenous glucose with no protein-sparing effect. The laparoscopic approach modulates gluconeogenesis, although it is not sufficient in the presence of exogenous energy to promote nitrogen retention.

Haplotypes of PPARGC1A are associated with glucose tolerance, body mass index and insulin sensitivity in offspring of patients with type 2 diabetes

Decreased expression of the peroxisomal proliferator activated receptor gamma coactivator 1 alpha gene (PPARGC1A) is found in patients with type 2 diabetes, and variants in this gene have been linked with type 2 diabetes. Therefore, we investigated the effects of single nucleotide polymorphisms in PPARGC1A on body composition and glucose tolerance and on insulin sensitivity and secretion. Non-diabetic offspring (n=156, age 34.9+/-0.5 years [mean+/-SEM], BMI 26.2+/-0.4 kg/m2) underwent an OGTT and an IVGTT and the hyperinsulinaemic-euglycaemic clamp. The promoter and coding regions of PPARGC1A were sequenced. Two haplotype blocks in PPARGC1A were observed, one in the promoter region (G-1774A, A-1679G, T-1422C, A-1278G, C-543A) and one in the coding region and 3' regions (Thr394Thr, Asp475Asp, Gly482Ser, Thr528Thr, Thr612Met, G+2381A). The coding region haplotype carrying the rare allele in codons 482 and 528 was associated with elevated glucose levels in an OGTT (p=0.024, adjusted for age, sex and BMI) and a haplotype carrying the rare alleles in codons 394 and 475 was associated with low BMI (p=0.033), high rates of whole-body glucose uptake (p=0.045) and low glucose levels in the OGTT (p=0.037). We conclude that PPARGC1A is likely to contribute to the risk of diabetes in offspring of patients with type 2 diabetes.

Effects of Metformin and Rosiglitazone Treatment on Insulin Signaling and Glucose Uptake in Patients With Newly Diagnosed Type 2 Diabetes

The effect of metformin or rosiglitazone monotherapy versus placebo on insulin signaling and gene expression in skeletal muscle of patients with newly diagnosed type 2 diabetes was determined. A euglycemic-hyperinsulinemic clamp, combined with skeletal muscle biopsies and glucose uptake measurements over rested and exercised muscle, was performed before and after 26 weeks of metformin (n = 9), rosiglitazone (n = 10), or placebo (n = 11) treatment. Insulin-mediated whole-body and leg muscle glucose uptake was enhanced 36 and 32%, respectively, after rosiglitazone (P < 0.01) but not after metformin or placebo treatment. Insulin increased insulin receptor substrate 1 (IRS-1) tyrosine phosphorylation, IRS-1-associated phosphatidylinositol (PI) 3-kinase activity, and phosphorylation of Akt Ser473 and AS160, a newly described Akt substrate that plays a role in GLUT4 exocytosis, approximately 2.3 fold before treatment. These insulin signaling parameters were unaltered after metformin, rosiglitazone, or placebo treatment. Expression of selected genes involved in glucose and fatty acid metabolism in skeletal muscle was unchanged between the treatment groups. Low-intensity acute exercise increased insulin-mediated glucose uptake but was without effect on insulin signaling. In conclusion, the insulin-sensitizing effects of rosiglitazone are independent of enhanced signaling of IRS-1/PI 3-kinase/Akt/AS160 in patients with newly diagnosed type 2 diabetes.

Insulin resistance induced by sucrose feeding in rats is due to an impairment of the hepatic parasympathetic nerves

A considerable proportion of whole-body insulin-stimulated glucose uptake is dependent upon the hepatic insulin-sensitising substance (HISS) in a pathway mediated by the hepatic parasympathetic nerves (HPNs). We tested the hypothesis that a high-sucrose diet leads to the impairment of the HPN-dependent component of insulin action. We quantified insulin sensitivity using the rapid insulin sensitivity test, a modified euglycaemic clamp. Quantification of the HPN-dependent component was achieved by administration of a muscarinic receptor antagonist (atropine, 3 mg/kg). Insulin sensitivity was higher in standard-fed than in sucrose-fed Wistar rats (305.6+/-34.1 vs 193.9+/-13.7 mg glucose/kg body weight; p<0.005) and Sprague-Dawley rats (196.4+/-5.9 vs 95.5+/-16.3 mg glucose/kg body weight; p<0.01). The HPN-independent component was similar in the two diet groups. Insulin resistance was entirely due to an impairment of the HPN-dependent component in both Wistar rats (164.3+/-28.1 [standard-fed] vs 26.5+/-7.5 [sucrose-fed] mg glucose/kg body weight; p<0.0001) and Sprague-Dawley rats (111.7+/-9.5 vs 35.3+/-21.4 mg glucose/kg body weight; p<0.01). Furthermore, HPN-dependent insulin resistance in Sprague-Dawley rats was already evident after 2 weeks of a high-sucrose diet (28.5+/-7.6 [2 weeks], 35.3+/-21.4 [6 weeks], 17.9+/-5.4 [9 weeks] mg glucose/kg body weight) and was independent of the nature of sucrose supplementation (12.3+/-4.7 [solid] and 17.9+/-5.4 [liquid] mg glucose/kg body weight). Our results support the hypothesis that insulin resistance caused by sucrose feeding is due to an impairment of the HPN-dependent component of insulin action, leading to a dysfunction of the HISS pathway.