Hepatic Insulin Resistance Index Research Articles

OR31-6 Insulin Sensitivity and Pancreatic Beta-Cell Function in Patients with Primary Aldosteronism

Insulin sensitivity and pancreatic beta-cell function are primary determinants of glucose tolerance. Primary aldosteronism (PA) is associated with increased risk for glucose intolerance. However, its effects on insulin sensitivity and β-cell function have shown mixed results. In this study, we compared indices of insulin sensitivity and pancreatic β-cell function derived from an oral glucose tolerance test (OGTT) in patients from two cohorts: subjects with PA (n=25) and essential hypertension control (EHC) subjects. The EHC controls (n=25) were similar in age and BMI range, gender composition (female, n=14), and number of subjects with type 2 diabetes (n=3). Group comparisons were performed after adjusting for age, sex, and BMI; data is presented as unadjusted mean ± SD. As expected, the PA group show lower potassium concentrations compared to the EHC group, as well as elevated aldosterone and reduced renin levels. Mean arterial pressure was not significantly different between the groups (PA:100.6 ± 11.7, EHC: 96.7 ± 15.5 mm Hg, p=0.22). The area under the curve (AUC) for insulin during an OGTT, but not glucose, was higher in the PA group (insulin AUC: 14831 ± 9545 vs. 8582 ± 4948, μU/mL∙min, p<0.05). Whole-body and hepatic insulin sensitivity were determined using surrogate indices and oral minimal model (SIMM) analysis. PA individuals were found to be less insulin sensitive compared to EHC subjects (Quantitative insulin sensitivity check index (QUICKI): 0.337 ± 0.035 vs. 0.367 ± 0.062, p<0.001; Matsuda Index: 3.98 ± 2.33 vs. 7.24 ± 6.50, p<0.001; and SIMM: 1.01x10-3 ± 2.01x10-3 vs. 1.87x10-3 ± 2.71x10-3, min-1 per μU/mL, p=0.08). The hepatic insulin resistance index (HIRI) was significantly higher in PA individuals (HIRI: 5.62 ± 4.52 vs. 4.02 ± 2.78, mg/dL∙ μU/mL ∙ 106, p<0.001), suggesting decreased hepatic insulin sensitivity. Insulinogenic index (IGI), a measure of β -cell function is calculated as change in insulin concentrations divided by change in glucose from 0 to 30 min (ΔI0-30/ΔG0-30). IGI was slightly higher in the PA cohort (169 ± 150 vs. 124 ± 122, pmol/mmol, p=0.06). Oral disposition index (DI), a marker of integrated islet β-cell function, is the product of insulin secretion and sensitivity derived from OGTT. DI was similar between the groups (561 ± 434 vs. 605 ± 517, p=0.80). This accounts for the similar glucose tolerance between the groups. In summary, insulin sensitivity is significantly lower in PA and is accompanied by a compensatory increase in β-cell function. These results suggest that excess aldosterone and/or other steroids in the context of PA may negatively affect insulin action without adversely impacting beta-cell function.

OR28-6 Short-Term Mifepristone Treatment Improves Hepatic and Adipose Tissue Insulin Sensitivity in Overweight and Obese Subjects with Glucose Intolerance

Background: Increased tissue cortisol availability and enhanced glucocorticoid action have been implicated in abnormal glucose and fat metabolism in patients with obesity, metabolic syndrome, and type 2 diabetes. Objective: To test the hypothesis that blockade of glucocorticoid receptor (GR) with mifepristone ameliorates insulin resistance in overweight/obese subjects with glucose intolerance. Design: We conducted a randomized, placebo-controlled, double-blind, crossover trial of mifepristone (50 mg orally, every six hr) in overweight/obese subjects (BMI 25-37 kg/m2), with abnormal glucose tolerance (n=16, women=7). Participants (age:56 ± 8 yr) had prediabetes (n=12) or mild type 2 DM (n=4, A1c < 7%) on diet control or stable dose of metformin for 3 months (n=2). Mifepristone or placebo treatment for one week was followed by a 6-8-week washout and crossover to the other arm. At baseline, and after each treatment period, insulin sensitivity was assessed by a frequently sampled intravenous glucose tolerance test (FSIVGTT) and an oral glucose tolerance test (OGTT). Whole body glucose disposal index of insulin sensitivity (SI) was derived using a Minimal model analysis. Adipose tissue-SI, which reflects insulin-induced free fatty acid (FFA) suppression, was estimated by the log-linear slope of FFA levels during the FSIVGTT. Matsuda index, oral glucose insulin sensitivity index (OGIS, ml/min/m2), and hepatic insulin resistance index (HIRI, mg/dL×µU/mL×105) were derived from OGTT. Adipo-IR, a surrogate measure of adipocyte insulin resistance, was calculated by multiplying fasting concentrations of FFA and insulin (mmol×pmol/L). Comparison of various post-treatment parameters was performed using crossover ANOVA. This analysis takes into account specific treatment arm, treatment order, and treatment effects. Thus, we explicitly tested for carryover effects in our crossover study. Results: GR blockade did not affect body weight (p=0.56) or fasting glucose (p=0.67), but significantly decreased fasting insulin levels when compared with placebo [mean (95%CI): -40.7 (-68.53 to -12.91), p=0.007]. Mifepristone administration for one week did not alter whole body glucose disposal indices of insulin sensitivity (FSIVGTT-Si: p=0.52, Matsuda Index: p=0.74; and OGIS: p=0.75). However, GR blockade reduced HIRI [-19.80 (-40.76 to 1.15), p=0.05], Adipo-IR [-15.54 (-31.47 to 0.37), p=0.04], and improved Adipose-SI [-19.75 (-31.41 to -8.08), p=0.003]. Conclusions: In patients with abnormal glucose tolerance, short-term GR blockade improved hepatic and adipose tissue insulin sensitivity without significantly altering whole-body insulin sensitivity. These findings suggest that GR may be a therapeutic target in insulin-resistant states. Unless otherwise noted, all abstracts presented at ENDO are embargoed until the date and time of presentation. For oral presentations, the abstracts are embargoed until the session begins. s presented at a news conference are embargoed until the date and time of the news conference. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.

Plasma lactate and leukocyte mitochondrial DNA copy number as biomarkers of insulin sensitivity in non-diabetic women.

High plasma lactate levels have been associated with reduced mitochondrial respiratory capacity and increased type 2 diabetes risk, while mitochondrial DNA (mtDNA) copy number has been proposed as a biomarker of mitochondrial function linked to glucose homeostasis. The aim of this study was to evaluate the association between circulating lactate levels and leukocyte mtDNA copy numbers with insulin secretion/sensitivity indexes in 65 Chilean non-diabetic women. mtDNA copy numbers were measured in leukocytes using qPCR and digital-droplet PCR. A 75-g Oral Glucose Tolerance Test (OGTT) was performed to calculate systemic and tissue-specific insulin sensitivity indexes, as well as insulin secretion surrogates based on plasma c-peptide. An intravenous glucose tolerance test (IVGTT; 0.3g/kg) was also carried out. Disposition indexes were calculated as the product of insulin secretion × sensitivity. Plasma levels of leptin, adiponectin, TNF-α, MCP-1, and non-esterified fatty acids were also determined. Fasting plasma lactate shows a significant association with a wide range of insulin sensitivity/resistance indexes based on fasting plasma samples (HOMA-S, adipose IR index, Revised-QUICKI, leptin-adiponectin ratio, TyG index, McAuley index and TG-to-HDL-C ratio), as well as OGTT-based measures such as the Matsuda index, the hepatic insulin resistance index, and the disposition index. Fasting plasma lactate was also positively associated with the circulating adipokines TNF-α and MCP-1. We also detected a direct association between fasting plasma lactate with leukocyte mtDNA copy numbers. The above results support the use of fasting plasma lactate, and possibly leukocyte mtDNA copy numbers, as biomarkers of reduced oxidative mitochondrial capacity, decreased hepatic insulin sensitivity, and future diabetes risk.

Mild Physiologic Hyperglycemia Induces Hepatic Insulin Resistance in Healthy Normal Glucose-Tolerant Participants.

Chronic hyperglycemia worsens skeletal muscle insulin resistance and β-cell function. However, the effect of sustained physiologic hyperglycemia on hepatic insulin sensitivity is not clear. To examine the effect of sustained physiologic hyperglycemia (similar to that observed in patients with type 2 diabetes) on endogenous (primarily reflecting hepatic) glucose production (EGP) in healthy individuals. Volunteers participated in a three-step hyperinsulinemic (10, 20, 40 mU/m2 per minute) euglycemic clamp before and after a 48-hour glucose infusion to increase plasma glucose concentration by ∼40 mg/dL above baseline. EGP was measured with 3-3H-glucose before and after chronic glucose infusion. Sixteen persons with normal glucose tolerance [eight with and eight without a family history (FH) of diabetes] participated in the study. EGP. Basal EGP increased following 48 hours of glucose infusion (from a mean ± SEM of 2.04 ± 0.08 to 3.06 ± 0.29 mg/kgffm⋅ min; P < 0.005). The hepatic insulin resistance index (basal EGP × fasting plasma insulin) markedly increased following glucose infusion (20.1 ± 1.8 to 51.7 ± 6.6; P < 0.005) in both FH+ and FH- subjects. Sustained physiologic hyperglycemia for as little as 48 hours increased the rate of basal hepatic glucose production and induced hepatic insulin resistance in health persons with normal glucose tolerance, providing evidence for the role of glucotoxicity in the increase in hepatic glucose production in type 2 diabetes.

Effects of growth hormone on hepatic insulin sensitivity and glucose effectiveness in healthy older adults.

Growth hormone (GH) replacement decreases insulin sensitivity in healthy individuals. However, the effects of GH on organ-specific insulin sensitivity and glucose effectiveness are not well characterized. The purpose of this study was to evaluate the effects of GH administration for 26 weeks on muscle and hepatic insulin sensitivity and glucose effectiveness in healthy older individuals. This report is from a 26-week randomized, double-blind, placebo-controlled parallel-group trial in healthy, ambulatory, community-dwelling older women and men. We compared surrogate indices of insulin sensitivity [quantitative insulin-sensitivity check index (QUICKI), muscle insulin sensitivity index (MISI), hepatic insulin resistance index (HIRI)] and glucose effectiveness [oral glucose effectiveness index (oGE)] derived from oral glucose tolerance tests (OGTTs) in subjects before and after 26 weeks of administration of GH (n = 17) or placebo (n = 15) as an exploratory outcome. GH administration for 26 weeks significantly increased fasting insulin concentrations and HIRI but did not significantly change MISI or oGE compared to placebo. GH administration for 26 weeks in healthy older subjects impairs insulin sensitivity in the liver but not skeletal muscle and does not alter glucose effectiveness.

Predictive Accuracy of Surrogate Indices for Hepatic and Skeletal Muscle Insulin Sensitivity.

Surrogate indices of muscle and hepatic insulin sensitivity derived from an oral glucose tolerance test (OGTT) are frequently used in clinical studies. However, the predictive accuracy of these indices has not been validated. In this cross-sectional study, hyperinsulinemic-euglycemic glucose clamp with tritiated glucose infusion and a 75-g OGTT were performed in individuals (n = 659, aged 18 to 49 years, body mass index of 16 to 64 kg/m2) with varying degrees of glucose tolerance. A calibration model was used to assess the ability of OGTT-derived, tissue-specific surrogate indices [hepatic insulin resistance index (HIRI) and muscle insulin sensitivity index (MISI)] to predict insulin sensitivity/resistance indices derived from the reference glucose clamp [Hepatic-IRbasal, a product of fasting plasma insulin and hepatic glucose production (HGP), Hepatic-IRclamp, reciprocal of the percent suppression of HGP during the insulin clamp corrected for plasma insulin concentration, and Muscle-ISclamp, a measure of peripheral glucose disposal]. Predictive accuracy was assessed by root mean squared error of prediction and leave-one-out, cross-validation-type square root of the mean squared error of prediction. HIRI and MISI were correlated with their respective clamp-derived indices. HIRI was negatively related to Muscle-ISclamp (r = -0.62, P < 0.0001) and MISI correlated with Hepatic-IR derived from the clamp (Hepatic-IRbasal: r = -0.48, P < 0.0001 and Hepatic-IRclamp: r = -0.41, P < 0.0001). However, the accuracy of HIRI and MISI to predict Hepatic-IR (basal or during clamp) was not significantly different. Likewise, the ability of HIRI and MISI to predict Muscle-ISclamp was also similar. Our findings indicate that the surrogate indices derived from an OGTT are accurate in predicting insulin sensitivity but are not tissue specific.

Plasma lipid profiling of tissue-specific insulin resistance in human obesity.

Obesity-associated insulin resistance (IR) may develop in multiple organs, representing different aetiologies towards cardiometabolic diseases. This study aimed to identify distinct plasma lipid profiles in overweight/obese individuals who show muscle-IR and/or liver-IR. Baseline data of the European multicenter DiOGenes project were used (n = 640; 401 women, nondiabetic BMI: 27-45 kg/m2). Muscle insulin sensitivity index (MISI) and hepatic insulin resistance index (HIRI) were derived from a 5-point oral glucose tolerance test. The 140 plasma lipids were quantified by liquid chromatography-mass spectrometry. Linear mixed models were used to evaluate associations between MISI, HIRI and plasma lipids. MISI was comparable between sexes while HIRI and triacylglycerol (TAG) levels were lower in women than in men. MISI was associated with higher lysophosphatidylcholine (LPC) levels (standardized (std)β = 0.126; FDR-p = 0.032). Sex interactions were observed for associations between HIRI, TAG and diacylglycerol (DAG) lipid classes. In women, but not in men, HIRI was associated with higher levels of TAG (44 out of 55 species) and both DAGspecies (stdβ: 0.139-0.313; FDR-p < 0.05), a lower odd-chain/even-chain TAG ratio (stdβ = -0.182; FDR-p = 0.005) and a lower very-long-chain/long-chain TAG ratio (stdβ = -0.156; FDR-p = 0.037). In overweight/obese individuals, muscle insulin sensitivity is associated with higher plasma LPC concentrations. Women have less hepatic IR and lower TAG than men. Nevertheless, hepatic IR is associated with higher plasma TAG and DAG concentrations and a lower abundance of odd-chain and very-long-chain TAG in women, but not in men. This suggests a more pronounced worsening of plasma lipid profile in women with the progression of hepatic IR.

Mild Physiologic Hyperglycemia Induces Hepatic Insulin Resistance in Healthy Normal Glucose Tolerant Subjects–Role of Glucagon and Gluconeogenic Substrates

The aim of the present study was to evaluate the effect of a physiologic increase in plasma glucose concentration on endogenous glucose production (EGP) in healthy NGT individuals. 16 NGT subjects [8 with and 8 without family history of T2DM (9M/7F, age = 44± 3 years, BMI = 26 ± 1 kg/m2)] participated in a 3-step hyperinsulinemic (10, 20, 40 mU/m2 min) euglycemic clamp before and after a 48 hour glucose infusion to increase plasma glucose conc by ∼45 mg/dl above baseline (89±4 to 136±4.9 mg/dl). EGP was measured with [3-3H] glucose and gluconeogenic rate was measured following administration of deuterated water. Plasma FFA, glucagon, lactate, glycerol and alanine concentrations also were measured. Following 48 hours of glucose infusion basal EGP increased from 2.05±0.09 to 3.06±0. mg/kg min (p=0.003) and hepatic insulin resistance index (EGP X Fasting Plasma Insulin) increased markedly and similarly (25.1±1.0 vs. 48.3± 3.2, p&amp;lt;0.005). The baseline plasma glucagon concentration tended to be higher following 48 hours of glucose infusion (64±3 vs. 77± 8 pg/ml, p=0.2) while the product of the plasma glucagon and insulin concentrations was markedly increased (540 ± 56 vs. 1336 ± 262, p=0.004). Although the baseline plasma FFA concentration was markedly reduced following 48 hours of glucose infusion (0.482 ±0.to 0.055± 0.01mM), there was no difference in plasma glycerol concentration (13.4±1.2 vs. 13.3 ± 2.2 mg/L p=ns). There were small increases in both the plasma lactate and alanine concentrations. Total body insulin sensitivity declined from 8.75±2.1 to 6.92± 6 mg.kg/min (p&amp;lt;0.05). Conclusion: Chronic (48 hr) physiologic hyperglycemia to levels seen in T2DM increases basal hepatic glucose production and induces hepatic and skeletal muscle insulin resistance in healthy NGT subjects. These results demonstrate, for the first time that glucotoxicity causes resistance to the suppressive effect of insulin on hepatic glucose production. Disclosure D. Tripathy: None. A. Merovci: None. E.R. Maldonado Corchado: None. R. Basu: Research Support; Self; AstraZeneca. R.A. DeFronzo: Speaker-s Bureau; Self; AstraZeneca, Novo Nordisk Inc.. Advisory Panel; Self; AstraZeneca, Novo Nordisk Inc., Janssen Pharmaceuticals, Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Elcelyx Therapeutics, Inc., Intarcia Therapeutics, Inc.. Research Support; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Janssen Pharmaceuticals, Inc., Takeda Pharmaceuticals U.S.A., Inc..

The potential role of the osteopontin\u2013osteocalcin\u2013osteoprotegerin triad in the pathogenesis of prediabetes in humans

AimsTo examine the relationship between hormones involved in bone remodeling and glucose metabolism alterations in prediabetes.MethodsIndividuals (n = 43) with NGT (BMI = 31.1 ± 1.1 kg/m2) and individuals (n = 79) with impaired glucose regulation (IGR) (BMI = 31.9 ± 1.2 kg/m2) including subjects with IFG, IGT, and IFG-IGT underwent OGTT and DXA. Osteopontin (OPN), osteocalcin (OCN), osteoprotegerin (OPG), and PTH levels were measured at fasting. Beta-cell function was calculated using C-peptide deconvolution. Dynamic indexes of insulin sensitivity were calculated from OGTT. A subgroup underwent to a euglycemic hyperinsulinemic clamp with 3-3H-glucose to estimate the endogenous glucose production (EGP) and insulin-mediated body glucose disposal (TGD/SSPI).ResultsOPN was higher in IGR compared to NGT (5.3 ± 0.5 vs. 3.3 ± 0.2 μg/mL; p = 0.008) and in isolated IGT compared to IFG and IFG-IGT (6.3 ± 0.5 vs. 4.5 ± 0.3 and 5.4 ± 0.5 μg/mL; p = 0.02). OCN was similar in IFG and NGT but lower in IGT and IFG-IGT compared to NGT (7.2 ± 0.3 and 5.4 ± 0.2 vs. 8.3 ± 0.3 ng/mL; p < 0.01). OPN was positively correlated with HbA1c, fasting and 2 h plasma glucose and PTH. OCN was negatively correlated with body fat, 2 h plasma glucose, insulin and positively correlated with Stumvoll index. OPG correlated with TGD/SSPI (r = − 0.29; p < 0.05), EGP, and hepatic insulin resistance index in IGR (r = 0.51, r = 0.43; p < 0.01). There was no correlation between PTH and insulin sensitivity or Beta-cell function parameters.ConclusionsIn prediabetes, hormones known to be involved in bone remodeling may affect glucose metabolism before overt T2DM occurs with tissue-specific mechanisms.

Metabolic disturbances of non-alcoholic fatty liver resemble the alterations typical for type 2 diabetes.

Non-alcoholic fatty liver (NAFL) is an independent risk factor for the development of type 2 diabetes (T2DM). We examined metabolic perturbations in patients with NAFL, patients with T2DM, and control (CON) subjects with normal intrahepatic lipid (IHL) content.A two-step (10 mU/m2 /min; 40 mU/m2/min) hyperinsulinemic-euglycemic clamp was performed in 11 NAFL, 13 T2DM, and 11 CON subjects, all matched for BMI, and aerobic fitness. IHL content was measured using proton magnetic resonance spectroscopy. Because of high IHL content variability in T2DM patients, this group was separated into a high IHL content group (IHL ≥ 5.0%, T2DM+NAFL) and a normal IHL content group (IHL < 5.0%, T2DM-non-NAFL) for further analysis.IHL content was increased in NAFL and T2DM+NAFL subjects (P<0.050 versus CON and T2DM-non-NAFL subjects). Adipose tissue insulin sensitivity index (Adipo-IRi) was higher in NAFL (P<0.050 versus CON and T2DM-non-NAFL subjects) and in T2DM+NAFL subjects (P=0.055 versus CON subjects, P<0.050 versus T2DM-non-NAFL subjects). Suppression of plasma-free fatty acids (P=0.046) was lower in NAFL compared with CON subjects, with intermediate values for T2DM-non-NAFL, and T2DM+NAFL subjects. Suppression of endogenous glucose production (EGP) and insulin-stimulated glucose disposal (ΔRd) was comparable between NAFL, T2DM-non-NAFL, and T2DM+NAFL subjects (all P>0.05), and was lower in comparison with CON subjects (all P<0.01). Metabolic flexibility was lower in T2DM-non-NAFL subjects (P=0.047) and NAFL subjects (P=0.059) compared with CON subjects. Adipo-IRi (r=0.652, P<0.001), hepatic insulin resistance index (HIRi) (r=0.576, P=0.001), and ΔRd (r=-0.653, P<0.001) correlated with IHL content.Individuals with NAFL suffer from metabolic perturbations to a similar degree as T2DM patients. NAFL is an important feature leading to severe insulin resistance and should be viewed as a serious health threat for the development of T2DM. ClinicalTrials.gov: NCT01317576.

High Dietary Magnesium Intake is Significantly and Independently Associated with Higher Insulin Sensitivity in a Mexican-Mestizo Population: A Brief Cross-Sectional Report.

Magnesium acts as a cofactor in many intracellular reactions including phosphorylation of the insulin receptor; therefore, its imbalance can potentially cause insulin resistance. Low serum magnesium concentration has been associated with the development of metabolic syndrome and type 2 diabetes mellitus. To study the association between the daily dietary magnesium intake and insulin resistance estimated by the homeostatic model assessment of insulin resistance and homeostatic model assessment 2, as well as insulin sensitivity estimated by the Matsuda index. In a university affiliated medical center, 32 participants (22 women, 10 men) that had an indication for testing for type 2 diabetes mellitus with an oral glucose tolerance test were enrolled in this cross-sectional, comparative study. Clinical and biochemical evaluations were carried out including an oral glucose tolerance test. Hepatic insulin resistance index, homeostatic model assessment 2, homeostatic model assessment of insulin resistance, and Matsuda insulin sensitivity were calculated for each participant. They were asked to recall their food ingestion (24 hours) of three days of the past week, including a weekend day; magnesium intake was calculated according to the food nutritional information. The low dietary magnesium intake group (< 4.5 mg/kg/day) had a higher two-hour insulin concentration after an oral glucose tolerance test compared to those with high dietary magnesium (119.5 [73.0-190.6] vs. 63.5 [25.4-114.2]; p = 0.008), and insulin sensitivity assessed by the Matsuda index was higher in the high dietary magnesium intake group (4.3 ± 3.1 vs. 2.4 ± 1.5; p = 0.042). In multiple linear regression analysis a higher dietary magnesium intake was independently associated (β = 4.93; p = 0.05) with a better insulin sensitivity estimated by the Matsuda index. Our results suggest that higher magnesium intake is independently associated with better insulin sensitivity in patients at risk for type 2 diabetes mellitus.

Gamma-glutamyltransferase, fatty liver index and hepatic insulin resistance are associated with incident hypertension in two longitudinal studies.

We hypothesized that liver markers and the fatty liver index (FLI) are predictive of incident hypertension and that hepatic insulin resistance plays a role. The association between liver markers and incident hypertension was analysed in two longitudinal studies of normotensive individuals, 2565 from the 9-year data from an epidemiological study on the insulin resistance cohort and the 321 from the 3-year 'Relationship between Insulin Sensitivity and Cardiovascular disease' cohort who had a measure of endogenous glucose production. The FLI is calculated from BMI, waist circumference, triglycerides and gamma-glutamyltransferase (GGT) and the hepatic insulin resistance index from endogenous glucose production and fasting insulin. The incidence of hypertension increased across the quartiles groups of both baseline GGT and alanine aminotransferase. After adjustment for sex, age, waist circumference, fasting glucose, smoking and alcohol intake, only GGT was significantly related with incident hypertension [standardized odds ratio: 1.21; 95% confidence interval (1.10-1.34); P = 0.0001]. The change in GGT levels over the follow-up was also related with an increased risk of hypertension, independently of changes in body weight. FLI analysed as a continuous value, or FLI at least 60 at baseline were predictive of incident hypertension in the multivariable model. In the RISC cohort, the hepatic insulin resistance index was positively related with the risk of 3-year incident hypertension [standardized odds ratio: 1.54 (1.07-2.22); P = 0.02]. Baseline GGT and FLI, as well as an increase in GGT over time, were associated with the risk of incident hypertension. Enhanced hepatic insulin resistance predicted the onset of hypertension and may be a link between liver markers and hypertension.

Plasma acylcarnitine profiling indicates increased fatty acid oxidation relative to tricarboxylic acid cycle capacity in young, healthy low birth weight men.

We hypothesized that an increased, incomplete fatty acid beta‐oxidation in mitochondria could be part of the metabolic events leading to insulin resistance and thereby an increased type 2 diabetes risk in low birth weight (LBW) compared with normal birth weight (NBW) individuals. Therefore, we measured fasting plasma levels of 45 acylcarnitine species in 18 LBW and 25 NBW men after an isocaloric control diet and a 5‐day high‐fat, high‐calorie diet. We demonstrated that LBW men had higher C2 and C4‐OH levels after the control diet compared with NBW men, indicating an increased fatty acid beta‐oxidation relative to the tricarboxylic acid cycle flux. Also, they had higher C6‐DC, C10‐OH/C8‐DC, and total hydroxyl‐/dicarboxyl‐acylcarnitine levels, which may suggest an increased fatty acid omega‐oxidation in the liver. Furthermore, LBW and NBW men decreased several acylcarnitine levels in response to overfeeding, which is likely a result of an upregulation of fatty acid oxidation due to the dietary challenge. Moreover, C10‐OH/C8‐DC and total hydroxyl‐/dicarboxyl‐acylcarnitine levels tended to be negatively associated with the serum insulin level, and the total hydroxyl‐/dicarboxyl‐acylcarnitine level additionally tended to be negatively associated with the hepatic insulin resistance index. This indicates that an increased fatty acid omega‐oxidation could be a compensatory mechanism to prevent an accumulation of lipid species that impair insulin signaling.

A common variation of the PTEN gene is associated with peripheral insulin resistance

AimPhosphatase and tensin homologue (PTEN) reduces insulin sensitivity by inhibiting the phosphatidylinositol 3-kinase (PI3K)/v-akt murine thymoma viral oncogene homologue (Akt) pathway. This study investigated how a common single nucleotide polymorphism near PTEN, previously associated with fasting levels of plasma insulin and glucose, influences in vivo glucose metabolism and insulin signalling. The primary outcome measure was the gene variant's association with peripheral glucose disposal rate and, secondarily, whether this association was explained by altered activities of PTEN targets PI3K and Akt. MethodsA total of 183 normoglycaemic Danes, including 158 twins and 25 singletons, were genotyped for PTEN rs11202614, which is in complete linkage disequilibrium with rs2142136 and rs10788575, which have also been reported in association with glycaemic traits and type 2 diabetes (T2D). Hepatic and peripheral insulin sensitivity was measured using tracer and euglycaemic–hyperinsulinaemic clamp techniques; insulin secretion was assessed by intravenous glucose tolerance test; and muscle biopsies were taken during insulin infusion from 150 twins for measurement of PI3K and Akt activities. ResultsThe minor G allele of PTEN rs11202614 was associated with elevated fasting plasma insulin levels and a decreased peripheral glucose disposal rate, but not with the hepatic insulin resistance index or insulin secretion measured as the first-phase insulin response and disposition index. The single nucleotide polymorphism was not associated with either PI3K or Akt activities. ConclusionA common PTEN variation is associated with peripheral insulin resistance and subsequent risk of developing T2D. However, the association with insulin resistance is not explained by decreased proximal insulin signalling in skeletal muscle.

Hepatic insulin resistance in NAFLD: relationship with markers of atherosclerosis and metabolic syndrome components.

Fat accumulation in the liver and in the muscle results in hepatic and muscle insulin resistance and has been associated with increased cardiovascular risk. It is unclear whether the individual role of hepatic and muscle insulin resistance in the onset of dyslipidaemia is observed in nonalcoholic fatty liver disease (NAFLD) patients and whether this association is mediated through traditional risk factors. The aim of this study was to assess hepatic and muscle insulin resistance in NAFLD and its relationship with carotid artery intima-media thickness (IMT) and the apoB/apoAI ratio as markers of atherosclerosis. We studied 132 patients with a non-invasive diagnosis of NAFLD stratified into two groups according to the severity of steatosis at ultrasound scan. In all subjects, we measured hepatic insulin resistance (H-IR) and muscle insulin sensitivity index (MISI) by oral glucose tolerance test as proposed by DeFronzo, IMT, apoB/apoAI and the components of the metabolic syndrome (MS) as defined by ATP III. H-IR was significantly higher in moderate/severe steatosis than in the mild steatosis group (p<0.0001). By contrast, MISI did not differ between the two groups. There was a significant correlation between H-IR, MISI and all of the components of MS. H-IR was significantly correlated with carotid IMT (r=0.35; p<0.0001) and the apoB/apoAI ratio (r=0.43; p<0.0001). Otherwise, a significant correlation was observed only between MISI and apoB/apoAI ratio. Multivariate analysis revealed that H-IR is related to early markers of atherosclerosis independent of MS components. In our study population, NAFLD was positively associated with carotid IMT, and this association is independent of MS components, but strictly related to H-IR that might contribute to the development of atherosclerosis through an impairment of the lipid profile in terms of the apoB/apoAI ratio. By contrast, no significant relation was observed between MISI and carotid IMT.

The insulin resistance phenotype (muscle or liver) interacts with the type of diet to determine changes in disposition index after 2years of intervention: the CORDIOPREV-DIAB randomised clinical trial.

The aim of the study was to determine whether basal insulin resistance (IR) phenotype (muscle and/or liver) determines the effect of long-term consumption of a Mediterranean diet or a low-fat diet on tissue-specific IR and beta cell function. The study was performed in 642 patients included in The effect of an olive oil rich Mediterranean diet on type 2 diabetes mellitus risk and incidence study (CORDIOPREV-DIAB). A total of 327 patients were randomised to a Mediterranean diet (35% fat; 22% from monounsaturated fatty acids) and 315 to a low-fat diet (<28% fat). At baseline, the patients were classified into four phenotypes according to the type of IR: (1) no IR; (2) muscle IR; (3) liver IR; (4) muscle + liver IR. The hepatic insulin resistance index (HIRI), muscular insulin sensitivity index (MISI) and disposition index were analysed at baseline and after 2years of follow-up. At baseline, 322 patients presented no IR, 106 presented muscle IR, 109 presented liver IR, and 105 presented muscle + liver IR. With both dietary interventions, HIRI decreased in all patients (p < 0.001) and MISI increased in muscle IR and muscle + liver IR patients (p < 0.01). Long-term intake of the Mediterranean diet increased the disposition index and insulinogenic index in the muscle IR patients (p = 0.042 and p = 0.044, respectively) and the disposition index in the muscle + liver IR patients (p = 0.048), whereas the low-fat diet increased the disposition index in the liver IR patients (p = 0.017). Although both diets improve insulin sensitivity, there are differences based on basal IR phenotypes. Moreover, according to insulinogenic and disposition index data, a low-fat diet might be more beneficial to patients with liver IR, whereas patients with muscle IR and muscle + liver IR might benefit more from a Mediterranean diet. Trial registration ClinicalTrials.gov NCT00924937 FUNDING: The study was supported by the Ministerio de Economia y Competitividad (AGL2012/39615) and by the Ministerio de Ciencia e Innovacion (PIE14/00005 and PI13/00023).

A Single 60 mg Dose of Denosumab Might Improve Hepatic Insulin Sensitivity in Postmenopausal Nondiabetic Severe Osteoporotic Women.

Background. The RANKL/RANK/OPG signaling pathway is crucial for the regulation of osteoclast activity and bone resorption being activated in osteoporosis. The pathway has been also suggested to influence glucose metabolism as observed in chronic low inflammation. Aim. To test whether systemic blockage of RANKL by the monoclonal antibody denosumab influences glucose metabolism in osteoporotic women. Study Design. This is a prospective study on the effect of a subcutaneously injected single 60 mg dose of denosumab in 14 postmenopausal severe osteoporotic nondiabetic women evaluated at baseline and 4 and 12 weeks after their first injection by an oral glucose tolerance test. Results. A single 60 mg dose of denosumab efficiently inhibited serum alkaline phosphatase while it did not exert any significant variation in fasting glucose, insulin, or HOMA-IR at both 4 and 12 weeks. No changes could be detected in glucose response to the glucose load, Matsuda Index, or insulinogenic index. Nonetheless, 60 mg denosumab induced a significant reduction in the hepatic insulin resistance index at 4 weeks and in HbA1c levels at 12 weeks. Conclusions. A single 60 mg dose of denosumab might positively affect hepatic insulin sensitivity though it does not induce clinical evident glucose metabolic disruption in nondiabetic patients.

Liver steatosis is associated with insulin resistance in skeletal muscle rather than in the liver in Japanese patients with non-alcoholic fatty liver disease.

Aims/IntroductionTo examine the association between liver histological features and organ-specific insulin resistance indices calculated from 75-g oral glucose tolerance test data in patients with non-alcoholic fatty liver disease.Materials and MethodsLiver biopsy specimens were obtained from 72 patients with non-alcoholic fatty liver disease, and were scored for steatosis, grade and stage. Hepatic and skeletal muscle insulin resistance indices (hepatic insulin resistance index and Matsuda index, respectively) were calculated from 75-g oral glucose tolerance test data, and metabolic clearance rate was measured using the euglycemic hyperinsulinemic clamp method.ResultsThe degree of hepatic steatosis, and grade and stage of non-alcoholic steatohepatitis were significantly correlated with Matsuda index (steatosis r = −0.45, P < 0.001; grade r = −0.54, P < 0.001; stage r = −0.37, P < 0.01), but not with hepatic insulin resistance index. Multiple regression analyses adjusted for age, sex, body mass index and each histological score showed that the degree of hepatic steatosis (coefficient = −0.22, P < 0.05) and grade (coefficient = −0.40, P < 0.01) were associated with Matsuda index, whereas the association between stage and Matsuda index (coefficient = −0.07, P = 0.593) was no longer significant. A similar trend was observed for the association between steatosis and metabolic clearance rate (coefficient = −0.62, P = 0.059).ConclusionsLiver steatosis is associated with insulin resistance in skeletal muscle rather than in the liver in patients with non-alcoholic fatty liver disease, suggesting a central role of fatty liver in the development of peripheral insulin resistance and the existence of a network between the liver and skeletal muscle.

Resistance training improves indices of muscle insulin sensitivity and β-cell function in overweight/obese, sedentary young men.

We examined the effects of RT on oral glucose tolerance test (OGTT)-derived indices of muscle insulin sensitivity, hepatic insulin resistance, β-cell function, and skeletal muscle proteins related to glucose transport in overweight/obese, sedentary young men. Twenty-eight participants [median body mass index (BMI) 30.9 kg/m(2); age 22 yr] completed 12 wk of RT (3 sessions/wk) and were assessed for changes in OGTT-derived indices, resting metabolic rate, body composition, serum adipokines, and skeletal muscle protein content [hexokinase 2 (HK2), glucose transporter type 4 (GLUT4), RAC-β serine/threonine-protein kinase (AKT2), glycogen synthase kinase 3β, and insulin receptor substrate 1]. Individualized responses to RT were also evaluated. RT significantly improved insulin and glucose area under the curve (both P < 0.03). With the use of OGTT indices of insulin action, we noted improved muscle insulin sensitivity index (mISI; P = 0.03) and oral disposition index (P = 0.03). BMI, lean body mass (LBM), and relative strength also increased (all P < 0.03), as did skeletal muscle protein content of HK2, GLUT4, and AKT2 (26-33%; all P < 0.02). Hepatic insulin resistance index, adiponectin, leptin, and total amylin did not change. Further analysis demonstrated the presence of highly individualized responsiveness to RT for glucose tolerance and other outcomes. RT improved oral indices of muscle insulin sensitivity and β-cell function but not hepatic insulin resistance in overweight/obese young men. In addition to the increase in LBM, the improvements in insulin action may be due, in part, to increases in key insulin signaling proteins.

One Day of Mixed Meal Overfeeding Reduces Hepatic Insulin Sensitivity and Increases VLDL Particle But Not VLDL-Triglyceride Secretion in Overweight and Obese Men

The exact mechanisms responsible for increased plasma triglyceride (TG) concentration in obese people are unclear, and it is not known whether excess energy intake per se is involved in the pathophysiology of this abnormality. The purpose of our study was to examine how excess energy intake from a balanced diet for 1 day affects very-low-density lipoprotein (VLDL)-TG kinetics and its putative regulators hepatic insulin sensitivity and plasma free fatty acid availability. We used stable isotope-labeled tracer methods to evaluate glucose and lipid kinetics in 8 overweight and obese men (age, 38 ± 3 years; body mass index, 33.7 ± 1.7 kg/m(2); means ± SEM) on 2 occasions (randomized crossover design): once, the day after they consumed a balanced diet that provided an amount of energy that matched their energy expenditure, and another time, the day after they consumed a balanced diet that provided 30% excess calories. Eight healthy, lean men (34 ± 1 years; 22.5 ± 0.6 kg/m(2)) were studied under isocaloric conditions only to provide a reference for normal lipid kinetics. VLDL-TG and VLDL-apolipoprotein B-100 (apoB-100) concentrations and secretion rates were significantly greater (P < .01) in overweight/obese compared with lean men. Hypercaloric, compared with isocaloric, feeding in overweight/obese men increased glucose rate of appearance in plasma (904 ± 21 vs 873 ± 26 μmol/min), the hepatic insulin resistance index (10.9 ± 2.2 vs 8.3 ± 1.8), and VLDL-apoB-100 concentration and secretion rate (1.91 ± 0.24 vs. 1.53 ± 0.13 nmol/min), whereas VLDL-apoB-100 plasma clearance rate, VLDL-TG secretion and plasma clearance rates, and free fatty acid rate of appearance in plasma were not affected by overfeeding. One day of moderate overfeeding (30% excess energy intake) stimulates hepatic glucose and VLDL-apo B-100 secretion rates but has no effect on hepatic and adipose tissue fatty acid metabolism in overweight/obese men.