Insulin Sensitivity In Individuals Research Articles

Insulin-sensitive adiposity is associated with a relatively lower risk of diabetes than insulin-resistant adiposity: the Bogalusa Heart Study.

Obesity and insulin resistance are both closely associated with type 2 diabetes mellitus (T2DM). It is, however, not clear whether the role of obesity in the development of T2DM is dependent on insulin resistance. This study aims to assess the hypothesis that insulin-sensitive adiposity is associated with a relatively lower risk of T2DM than insulin-resistant adiposity, and the adiposity-T2DM association is modified by insulin resistance in middle-aged black and white adults. The longitudinal study cohort consisted of 1588 middle-aged normoglycemic black and white adults aged 18-44years at baseline who were followed for 16years on average. Overweight/obesity at baseline was defined as BMI ≥25, and insulin resistance was measured using the homeostasis model assessment of insulin resistance (HOMA). The prevalence of incident pre-diabetes and T2DM was compared between the insulin-sensitive and insulin-resistant adiposity groups. The prevalence of both incident pre-diabetes and T2DM was higher in the insulin-resistant adiposity than in the insulin-sensitive adiposity group (11.5 vs. 7.5%, p=0.023 for pre-diabetes; 16.7 vs. 2.7%, p<0.001 for T2DM). In multivariable logistic analyses, adjusted for baseline age, race, sex, follow-up years, and smoking, baseline insulin-resistant obesity was associated with incident pre-diabetes (odds ratio, OR=2.07, p=0.046) and T2DM (OR=8.19, p<0.001). ORs did not differ between blacks and whites. The ORs for the association of BMI with pre-diabetes and T2DM significantly increased across increasing quartiles of baseline HOMA (p for trend=0.032 for pre-diabetes and <0.001 for T2DM). Slopes of increasing follow-up glucose with baseline BMI, measured as regression coefficients (β), were significantly greater in insulin-resistant than in insulin-sensitive individuals (β=0.86 vs. 0.38, p=0.009 for difference in slopes). These findings suggest that insulin resistance amplifies the obesity-diabetes association and underscore the importance of preventing both adiposity and insulin resistance in young adults.

Differences in Plasma Metabolites in Insulin Resistant and Insulin Sensitive Obese Individuals during a Hyperinsulinemic/Euglycemic Clamp

Although the vast majority of obese adults are insulin resistant (IR), some obese individuals remain relatively insulin sensitive (IS), though the underlying mechanisms for this difference are unclear. The hyperinsulimemic‐euglycemic clamp (HEC) is the gold standard test for insulin sensitivity. However, it is not clear if the differences in insulin‐mediated changes in glucose metabolism between IS and IR obese individuals extend to other key metabolites.In this study, we monitored the dynamics of 49 metabolites in obese IR vs. IS during a HEC. From an original screening of 28 obese adults, twelve non‐diabetic subjects, matched for age, sex, BMI, fat mass and fat‐free mass were divided into the 6 most IS and 6 most IR women based on glucose uptake during a HEC clamp. Mean glucose uptake during the clamp was 7.4±1.2 vs 15.6±2.47 mg/kg FFM/min for IR and IS, respectively (p &lt;0.0001).Serum metabolite levels were measured at 8 time points during the clamp using liquid chromatography‐mass spectrometry (LC‐MS): 2 samples at baseline, immediately prior to insulin infusion, every 20 minutes during the insulin infusion (4 samples), and 2 samples at steady state glucose levels (after ~2h of insulin infusion).Metabolite levels were quantitated by peak area, with stable‐isotope internal standards used to allow absolute quantitation of select metabolites. Statistical differences between IS and IR groups were assessed using t‐tests.Compared with IS, IR individuals had higher baseline levels of valine (p=0.023) and leucine and isoleucine (LI) (combined peak area) (p=0.006). However, the rate of decline in LI in response to insulin was greater in IS compared with IR. At steady‐state glucose infusion (~2 hr of HEC) most metabolites were either unchanged or fell from baseline levels. LI and valine concentrations fell about 50% in response to insulin in both groups, but LI and valine continued to be 40–100% greater in IR compared with IS (p=0.022 and 0.007, respectively). Likewise, threonine, lysine and glutamate levels were greater in IR than IS (all p&lt;0.019) when glucose reached steady‐state during the HEC. No significant differences between IR and IS were found in various fatty acid, TCA cycle intermediates, or lactate levels at baseline or at steady‐state of the HEC.These findings indicate that obese adults, who are seemingly “protected” against a decline in insulin‐mediated glucose uptake, also demonstrate improved response of insulin to lower BCAA and other amino acids that have been associated with and increase risk of development of type 2 diabetes. These results suggest that changes in the plasma level of metabolites associated with risk of type 2 diabetes is driven by insulin resistance and not obesity per se.

Adipose tissue macrophages: going off track during obesity.

Inflammation originating from the adipose tissue is considered to be one of the main driving forces for the development of insulin resistance and type 2 diabetes in obese individuals. Although a plethora of different immune cells shapes adipose tissue inflammation, this review is specifically focused on the contribution of macrophages that reside in adipose tissue in lean and obese conditions. Both conventional and tissue-specific functions of adipose tissue macrophages (ATMs) in lean and obese adipose tissue are discussed and linked with metabolic and inflammatory changes that occur during the development of obesity. Furthermore, we will address various circulating and adipose tissue-derived triggers that may be involved in shaping the ATM phenotype and underlie ATM function in lean and obese conditions. Finally, we will highlight how these changes affect adipose tissue inflammation and may be targeted for therapeutic interventions to improve insulin sensitivity in obese individuals. Highlights • Macrophages play a significant role in regulating adipose tissue functioning during health and disease• In addition to conventional functions such as clearing cellular debris and participating in tissue immune surveillance, lipid buffering is an important function of ATMs• Obesity-induced inflammation, characterised by an elevated number of proinflammatory macrophages in adipose tissue, has been suggested to contribute to systemic insulin resistance• Their origin, as well as a combination of peripheral changes and adipose tissue-derived stressors, probably contribute to ATM dysfunction and inflammatory traits during obesity• Identification of transcriptional differences between ATMs from lean vs obese adipose tissue at several key points during the development of obesity and insulin resistance may reveal upstream triggers, regulatory factors and intracellular pathways that shape ATM function• Targeting metabolic capacity rather than the inflammatory phenotype of ATMs may hold potential to restore ATM function and adipose tissue homeostasis in obese individuals

Association between insulin dosage and insulin usage time, and coronary artery lesions in patients with type 2 diabetes and coronary heart disease.

Insulin is used in the treatment of type 2 diabetes, with its usage reaching 30–50% in Western countries. The aim of the present study was to determine the association between insulin dosage (ID)/insulin usage time (IT) and coronary artery lesions in patients of type 2 diabetes with coronary heart disease. Based on the insulin using dosage, 353 type 2 diabetes patients were divided into the high-dose (≥0.5 IU/kg) and low-dose (<0.5 IU/kg) group. Selected coronary angiography was performed and the Gensini score was used to determine the degree of the coronary artery lesions. The homeostasis model assessment-insulin sensitivity (HOMA-IS) index was assessed by HOMA2. Data including age, gender, smoking, body mass index (BMI), systolic blood pressure (SBP), diastolic blood pressure (DBP), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), total cholesterol (TC), triglyceride (TG), glucose (Glu), hemoglobin A1c (HbA1c), C-peptide, ID, IT, diabetes duration time (DT), and IT/DT were collected. The association between insulin usage (both dose and time) and the coronary artery lesions in these patients was then determined. Statistical differences for the two groups for factors including C-peptide, HbA1c, ID, IT, DT, IT/DT and the Gensini score values (P<0.05) were identified. By contrast, no significant differences for factors such as gender, smoking history, age, BMI, TC, TG, LDL, HDL, fasting insulin, Glu, SBP and DBP were observed. The coronary artery damage Gensini score in insulin-insensitive individuals was significantly greater than that in the insulin-sensitive individuals. The Spearman analysis revealed that ID and IT, DT and IT/DT were positively correlated with the coronary artery damage Gensini score. The multivariate regression, the interquartile range method and receiver operating characteristic analyses showed that ID, ID/DT, IT had a greater effect on coronary vascular damage compared with DT. In conclusion, the degree of coronary artery lesions were correlated with ID, IT, DT, IT/DT. High doses of insulin or a high IT/DT ratio may aggravate coronary artery damage.

Metabolic Interaction of Helicobacter pylori Infection and Gut Microbiota.

As a barrier, gut commensal microbiota can protect against potential pathogenic microbes in the gastrointestinal tract. Crosstalk between gut microbes and immune cells promotes human intestinal homeostasis. Dysbiosis of gut microbiota has been implicated in the development of many human metabolic disorders like obesity, hepatic steatohepatitis, and insulin resistance in type 2 diabetes (T2D). Certain microbes, such as butyrate-producing bacteria, are lower in T2D patients. The transfer of intestinal microbiota from lean donors increases insulin sensitivity in individuals with metabolic syndrome, but the exact pathogenesis remains unclear. H. pylori in the human stomach cause chronic gastritis, peptic ulcers, and gastric cancers. H. pylori infection also induces insulin resistance and has been defined as a predisposing factor to T2D development. Gastric and fecal microbiota may have been changed in H. pylori-infected persons and mice to promote gastric inflammation and specific diseases. However, the interaction of H. pylori and gut microbiota in regulating host metabolism also remains unknown. Further studies aim to identify the H. pylori-microbiota-host metabolism axis and to test if H. pylori eradication or modification of gut microbiota can improve the control of human metabolic disorders.

Tenomodulin promotes human adipocyte differentiation and beneficial visceral adipose tissue expansion

Proper regulation of energy storage in adipose tissue is crucial for maintaining insulin sensitivity and molecules contributing to this process have not been fully revealed. Here we show that type II transmembrane protein tenomodulin (TNMD) is upregulated in adipose tissue of insulin-resistant versus insulin-sensitive individuals, who were matched for body mass index (BMI). TNMD expression increases in human preadipocytes during differentiation, whereas silencing TNMD blocks adipogenesis. Upon high-fat diet feeding, transgenic mice overexpressing Tnmd develop increased epididymal white adipose tissue (eWAT) mass, and preadipocytes derived from Tnmd transgenic mice display greater proliferation, consistent with elevated adipogenesis. In Tnmd transgenic mice, lipogenic genes are upregulated in eWAT, as is Ucp1 in brown fat, while liver triglyceride accumulation is attenuated. Despite expanded eWAT, transgenic animals display improved systemic insulin sensitivity, decreased collagen deposition and inflammation in eWAT, and increased insulin stimulation of Akt phosphorylation. Our data suggest that TNMD acts as a protective factor in visceral adipose tissue to alleviate insulin resistance in obesity.

The Effect of 28 Days of Beta-alanine Supplementation on Exercise Capacity and Insulin Sensitivity in Individuals with Type 2 Diabetes Mellitus: A Randomised, Double-blind and Placebo-controlled Pilot Trial

Objective: To determine the effects of 28 days of BA supplementation on exercise capacity as measured by time to volitional failure during an incremental treadmill test in individuals with T2DM. Methods: Participants undertook a modified Naughton treadmill test to assess exercise capacity and a fasting blood test before and after the supplementation period. Participants consumed four grams of BA (n=7) per day or the equivalent amount of maltodextrin (n=5) for 28 days and maintained their lifestyle habits during the supplementation period. Results: Twenty-eight days of BA supplementation significantly increased the time to volitional failure during the treadmill exercise test by m=135.2, SD=(± 81.3) seconds (21%), p=0.001, as detected by general linear model analysis with repeated measures. There was significant interaction of pre to post by group in fasting blood glucose, p=0.046. A strong negative correlation was found between the changes in the time to volitional failure during exercise testing and the changes in fasting blood glucose in the beta-alanine treatment group, r=− 0.92, p<0.01. Conclusion: This study has provided new evidence that BA supplementation can increase exercise capacity in individuals with T2DM.

Impact of Adiposity on Incident Hypertension Is Modified by Insulin Resistance in Adults: Longitudinal Observation From the Bogalusa Heart Study.

Adiposity and insulin resistance are closely associated with hypertension. This study aims to investigate whether the association between adiposity and hypertension is modified by insulin resistance. The cohort consisted of 1624 middle-aged normotensive black and white adults aged 18 to 43 years at baseline who followed for 16 years on average. Overweight/obesity at baseline was defined as body mass index (BMI) ≥25, and insulin resistance was measured using homeostasis model assessment of insulin resistance. Prevalence of incident hypertension was compared between the insulin-sensitive adiposity and insulin-resistant adiposity groups. The prevalence of incident hypertension was higher in the insulin-resistant adiposity than in the insulin-sensitive adiposity group (32.1% versus 22.1%, P<0.001). In multivariable logistic analyses, adjusted for baseline age, race, sex, follow-up years, and smoking, baseline insulin-resistant obesity was associated with incident hypertension (odds ratio, 1.9; P=0.008). Odds ratios did not differ between blacks and whites (P=0.238). Of note, the odds ratios of BMI associated with hypertension significantly increased with increasing quartiles of baseline homeostasis model assessment (odds ratio, 1.3, 1.1, 1.5, and 2.5 in quartiles I, II, III, and IV, respectively; P=0.006 for trend). Slopes of increasing follow-up blood pressure with baseline BMI, measured as regression coefficients (β), were significantly greater in insulin-resistant than in insulin-sensitive individuals (β=0.74 versus β=0.35 for systolic blood pressure, P=0.004 for difference; β=0.51 versus β=0.23 for diastolic blood pressure, P=0.001 for difference). These findings suggest that insulin resistance has a synergistic effect on the obesity-hypertension association in young adults, indicating that the role of adiposity in the development of hypertension is modified by insulin resistance.

Skeletal muscle salt inducible kinase 1 promotes insulin resistance in obesity.

ObjectiveInsulin resistance causes type 2 diabetes mellitus and hyperglycemia due to excessive hepatic glucose production and inadequate peripheral glucose uptake. Our objectives were to test the hypothesis that the proposed CREB/CRTC2 inhibitor salt inducible kinase 1 (SIK1) contributes to whole body glucose homeostasis in vivo by regulating hepatic transcription of gluconeogenic genes and also to identify novel SIK1 actions on glucose metabolism.MethodsWe created conditional (floxed) SIK1-knockout mice and studied glucose metabolism in animals with global, liver, adipose or skeletal muscle Sik1 deletion. We examined cAMP-dependent regulation of SIK1 and the consequences of SIK1 depletion on primary mouse hepatocytes. We probed metabolic phenotypes in tissue-specific SIK1 knockout mice fed high fat diet through hyperinsulinemic-euglycemic clamps and biochemical analysis of insulin signaling.ResultsSIK1 knockout mice are viable and largely normoglycemic on chow diet. On high fat diet, global SIK1 knockout animals are strikingly protected from glucose intolerance, with both increased plasma insulin and enhanced peripheral insulin sensitivity. Surprisingly, liver SIK1 is not required for regulation of CRTC2 and gluconeogenesis, despite contributions of SIK1 to hepatocyte CRTC2 and gluconeogenesis regulation ex vivo. Sik1 mRNA accumulates in skeletal muscle of obese high fat diet-fed mice, and knockout of SIK1 in skeletal muscle, but not liver or adipose tissue, improves insulin sensitivity and muscle glucose uptake on high fat diet.ConclusionsSIK1 is dispensable for glycemic control on chow diet. SIK1 promotes insulin resistance on high fat diet by a cell-autonomous mechanism in skeletal muscle. Our study establishes SIK1 as a promising therapeutic target to improve skeletal muscle insulin sensitivity in obese individuals without deleterious effects on hepatic glucose production.

Hyperinsulinemia in individuals with obesity: Role of insulin clearance.

ObjectiveSeveral studies have shown decreased insulin clearance rate (ICR) in individuals with obesity, but it remains unclear whether this is predominately due to obesity-associated insulin resistance (IR) or obesity itself. We aimed to clarify the complex interrelationship that exists between obesity, IR and ICR.MethodsHealthy volunteers (n = 277) had measurement of IR and ICR using the insulin suppression test (IST). IR was quantified by determining the steady-state plasma glucose (SSPG) during the IST. ICR was estimated by dividing the insulin infusion rate by the steady-state plasma insulin concentration. We performed our analysis by stratifying the experimental population into 4 dichotomous categories, varying in obesity and IR. Obesity was defined as a body mass index (BMI) ≥ 30 kg/m2, and IR was defined as SSPG ≥ 150 mg/dl.ResultsIndividuals with obesity had higher fasting insulin compared with individuals without obesity, regardless of IR. ICR was similar between individuals with and without obesity but was higher in IR individuals compared with insulin sensitive individuals. In multivariate analysis, both fasting insulin and SSPG were significantly associated with ICR. No significant relationships were observed between BMI and ICR.ConclusionsReduced ICR in obesity is secondary to IR, not excess adiposity.

Insulin Signaling and Glucose Uptake in the Soleus Muscle of 30-Month-Old Rats After Calorie Restriction With or Without Acute Exercise.

Exercise and calorie restriction (CR) can each improve insulin sensitivity in older individuals, but benefits of combining these treatments on skeletal muscle insulin signaling and glucose uptake are poorly understood, especially in predominantly slow-twitch muscles (eg, soleus). Accordingly, our purpose was to determine independent and combined effects of prior acute exercise and CR (beginning at 14 weeks old) on insulin signaling and glucose uptake in insulin-stimulated soleus muscles of 30-month-old rats. CR alone (but not exercise alone) versus ad libitum sedentary controls induced greater insulin-stimulated glucose uptake. There was a main effect of diet (CR > ad libitum) for insulin-stimulated Akt(Ser473) and Akt(Thr308) phosphorylation. CR alone versus ad libitum sedentary increased Akt substrate of 160 kDa (AS160) Ser(588) phosphorylation and TBC1D1 Thr(596), but not AS160 Thr(642) phosphorylation or abundance of GLUT4, GLUT1, or hexokinase II proteins. Combined CR and exercise versus CR alone did not further increase insulin-stimulated glucose uptake although phosphorylation of Akt(Ser473), Akt(Thr308), TBC1D1(Thr596), and AMPK(Thr172) for the combined group exceeded values for CR and/or exercise alone. These results revealed that although the soleus was highly responsive to a CR-induced enhancement of insulin-stimulated glucose uptake, the exercise protocol did not elevate insulin-stimulated glucose uptake, either alone or when combined with CR.

Gene expression in WAT from healthy humans and monkeys correlates with FGF21-induced browning of WAT in mice.

Identify a gene expression signature in white adipose tissue (WAT) that reports on WAT browning and is associated with a healthy phenotype. RNA from several different adipose depots across three species were analyzed by whole transcriptome profiling, including 1) mouse subcutaneous white fat, brown fat, and white fat after in vivo treatment with FGF21; 2) human subcutaneous and omental fat from insulin-sensitive and insulin-resistant patients; and 3) rhesus monkey subcutaneous fat from healthy and dysmetabolic individuals. A "browning" signature in mice was identified by cross-referencing the FGF21-induced signature in WAT with the brown adipose tissue (BAT) vs. WAT comparison. In addition, gene expression levels in WAT from insulin-sensitive/healthy vs. insulin-resistant/dysmetabolic humans and rhesus monkeys, respectively, correlated with the gene expression levels in mouse BAT vs. WAT. A subset of 49 genes were identified that were consistently regulated or differentially expressed in the mouse and human data sets that could be used to monitor browning of WAT across species. Gene expression profiles of WATs from healthy insulin-sensitive individuals correlate with those of BAT and FGF21-induced browning of WAT.

Exercise and Weight Loss Improve Muscle Mitochondrial Respiration, Lipid Partitioning, and Insulin Sensitivity After Gastric Bypass Surgery.

Both Roux-en-Y gastric bypass (RYGB) surgery and exercise can improve insulin sensitivity in individuals with severe obesity. However, the impact of RYGB with or without exercise on skeletal muscle mitochondria, intramyocellular lipids, and insulin sensitivity index (SI) is unknown. We conducted a randomized exercise trial in patients (n = 101) who underwent RYGB surgery and completed either a 6-month moderate exercise (EX) or a health education control (CON) intervention. SI was determined by intravenous glucose tolerance test. Mitochondrial respiration and intramyocellular triglyceride, sphingolipid, and diacylglycerol content were measured in vastus lateralis biopsy specimens. We found that EX provided additional improvements in SI and that only EX improved cardiorespiratory fitness, mitochondrial respiration and enzyme activities, and cardiolipin profile with no change in mitochondrial content. Muscle triglycerides were reduced in type I fibers in CON, and sphingolipids decreased in both groups, with EX showing a further reduction in a number of ceramide species. In conclusion, exercise superimposed on bariatric surgery–induced weight loss enhances mitochondrial respiration, induces cardiolipin remodeling, reduces specific sphingolipids, and provides additional improvements in insulin sensitivity.

Antidiabetogenic effects of hydroxychloroquine on insulin sensitivity and beta cell function: a randomised trial.

Hydroxychloroquine (HCQ), an antimalarial drug with anti-inflammatory properties, is employed in rheumatic diseases. In observational studies, patients with rheumatic diseases treated with HCQ have a lower risk of developing diabetes. However, the physiological mechanisms remain unexplained. We hypothesised that HCQ may have favourable effects on insulin sensitivity and/or beta cell function. This was a randomised, double-blind, parallel-arm (placebo vs HCQ 400 mg/day) trial at the University of Pittsburgh. Randomisation was conducted by a computer system with concealment by sealed envelopes. Treatment duration was 13 ± 1 weeks. Randomised participants (HCQ n = 17; placebo n = 15) were non-diabetic volunteers, age >18, overweight or obese, with one or more markers of insulin resistance. All participants were included in intention-to-treat analysis. Outcomes were changes in insulin sensitivity and beta cell function measured by intravenous glucose tolerance tests and minimal model analysis. There was a positive change in insulin sensitivity with HCQ but not placebo (mean ± SEM: +20.0% ± 7.1% vs -18.4% ± 7.9%, respectively; p < 0.01; difference: 38.3% ± 10.6%; 95% CI: 17%, 60%). Improvement in beta cell function was also observed with HCQ but not placebo (+45.4% ± 12.3% vs -19.7% ± 13.6%; p < 0.01; difference: 65% ± 19%; 95% CI: 27%, 103%). There were modest treatment effects on fasting plasma glucose and HbA(1c) (p < 0.05) but circulating markers of inflammation (IL-6, IL-1, TNF-α, soluble intercellular adhesion molecule) were not affected in either group. In contrast, adiponectin levels increased after HCQ treatment but not after placebo (+18.7% vs +0.7%, respectively; p < 0.001). Both low- and high-molecular-weight adiponectin forms accounted for the increase. There were no serious or unexpected adverse effects. HCQ improves both beta cell function and insulin sensitivity in non-diabetic individuals. These metabolic effects may explain why HCQ treatment is associated with a lower risk of type 2 diabetes. An additional novel observation is that HCQ improves adiponectin levels, possibly being a mediator of the favourable effects on glucose metabolism. Our findings suggest that HCQ is a drug with considerable metabolic effects that warrant further exploration in disorders of glucose metabolism. Clinicaltrials.gov NCT01326533 FUNDING: This study was funded by National Institutes of Health no. 5R21DK082878, UL1-RR024153 and UL-1TR000005.

Effects of Ramadan fasting on glucose homeostasis and adiponectin levels in healthy adult males.

BackgroundAdiponectin is a hormone secreted by adipocytes during the fasting phase of the fast-fed cycle. Ramadan fasting involves prolonged fasting for up to twelve hours and thus could lead to increased secretion of adiponectin by adipocytes. However, studies on the role of adiponectin on glucose and body weight homeostasis during Ramadan fasting is still a matter of controversy. Thus the specific aim of this study was to assess the effect of fasting during Ramadan on the adiponectin levels, body weight and glucose homeostasis in healthy male Malaysian subjects.MethodsTwenty healthy male (19–23 years) Muslim subjects were followed up during the fasting month of Ramadan. Anthropometry and blood samples were taken one week before and during the fourth week of fasting. Plasma glucose, insulin and adiponectin were estimated and insulin sensitivity indices were estimated using the Homeostasis Model Assessment.ResultsSubjects experienced a significant decrease in body weight (2.4 %, p < 0.001) and body mass index (5.5 %, p < 0.01). There was also a significant decrease of 12.3 %, 52.8 % and 45.6 % of plasma glucose, insulin and adiponectin respectively (p < 0.01). The drop in adiponectin was positively correlated with the decrease in body weight (r = 0.45, p < 0.05). There was also a significant increase in insulin sensitivity and a decrease in insulin resistance (p < 0.01).ConclusionsThese results indicate that Ramadan fasting in young healthy individuals has a positive impact on the maintenance of glucose homeostasis. It also shows that adiponectin levels dropped along with significant loss in weight. We feel caloric restriction during the Ramadan fasting is in itself sufficient to improve insulin sensitivity in healthy individuals.

Activation of the Liver X Receptor by Agonist TO901317 Improves Hepatic Insulin Resistance via Suppressing Reactive Oxygen Species and JNK Pathway.

Activation of Liver X receptors (LXRs), key transcriptional regulators of glucose metabolism, normalizes glycemia and improves insulin sensitivity in rodent models with insulin resistance. However, the molecular mechanism is unclear. This study is aimed to elucidate the mechanism of LXRs-mediated liver glucose metabolic regulation in vitro and in vivo. Db/db mice were used as an in vivo model of diabetes; palmitate (PA)-stimulated HepG2 cells were used as an in vitro cell model with impairment of insulin signaling. TO901317 (TO) was chosen as the LXRs agonist. We demonstrated that TO treatment for 14 days potently improved the hepatic glucose metabolism in db/db mice, including fasting blood glucose, fasting insulin level, and HOMA-IR. TO had no effect on the glucose metabolism in normal WT mice. TO-mediated activation of hepatic LXRs led to strong inhibition of ROS production accompanied by inactivation of JNK pathway and re-activation of Akt pathway. TO also suppressed the expression of gluconeogenic genes such as PEPCK and G-6-pase in db/db mice, but not in WT mice. In HepG2 cells, TO almost completely restored PA-induced Akt inactivation, and suppressed PA-stimulated ROS production and JNK activation. Interestingly, basal level of ROS was also inhibited by TO in HepG2 cells. TO significantly inhibited PA-stimulated expressions of gluconeogenic genes. Finally, we found that anti-oxidative genes, such as Nrf2, were up-regulated after LXRs activation by TO. These results strongly support the notion that activation of LXRs is critical in suppression of liver gluconeogenesis and improvement of insulin sensitivity in diabetic individuals. At molecular levels, the mode of action appears to be as fellows: under diabetic condition, ROS production is increased, JNK is activated, and Akt activity is inhibited; TO-mediated LXR activation potently inhibits ROS production, increases anti-oxidative gene expressions, suppresses JNK activation, and restores Akt activity. Our data provide new evidence to support LXRs as promising therapeutic targets for anti-diabetic drug development.

Health benefits of konjac glucomannan with special focus on diabetes

Diabetes mellitus (DM) is one of the most common non-communicable diseases worldwide. The incidence and prevalence of type 2 diabetes is on rise due to population growth, aging, urbanization, and well-known risk factors like obesity, smoking, unhealthy dietary habits and physical inactivity. Effective dietary strategies have an influence on decreasing postprandial plasma glucose burden, including the use of high fiber and low glycemic index diets. Dietary fiber has the ability to improve insulin sensitivity in individuals with type 2 diabetes. Soluble fiber improves satiety by providing bulk and increasing digestion time to slow postprandial glucose uptake, thereby producing lower blood glucose and insulin levels. Glucomannan, a soluble fiber derived from Amorphophallus konjac increases transit time of food and prolongs gastric emptying time, which increases satiety, reduces body weight, decreases the ingestion of foods that increase cholesterol and glucose concentrations, reduces the postprandial rise in plasma glucose, suppresses hepatic cholesterol synthesis, and increases the fecal elimination of cholesterol containing bile acids. The aim of the present study was to review the role of dietary fiber in treatment of diabetes with special focus on konjac glucomannan (KGM) to provide readers with a comprehensive understanding of the health benefits of KGM.

Metabolic and hormonal effects of 'catch-up' sleep in men with chronic, repetitive, lifestyle-driven sleep restriction.

SummaryObjectiveAcutely restricting sleep worsens insulin sensitivity in healthy individuals whose usual sleep is normal in duration and pattern. The effect of recovery or weekend ‘catch‐up’ sleep on insulin sensitivity and metabolically active hormones in individuals with chronic sleep restriction who regularly ‘catch‐up’ on sleep at weekends is as yet unstudied.Design19 men (mean ± SEM age 28·6 ± 2·0 years, BMI 26·0 ± 0·8 kg/m2) with at least 6 months’ history (5·1 ± 0·9 years) of lifestyle‐driven, restricted sleep during the working week (373 ± 6·6 min/night) with regular weekend ‘catch‐up’ sleep (weekend sleep extension 37·4 ± 2·3%) completed an in‐laboratory, randomized, crossover study comprising two of three conditions, stratified by age. Conditions were 3 weekend nights of 10 hours, 6 hours or 10 hours time‐in‐bed with slow wave sleep (SWS) suppression using targeted acoustic stimuli.MeasurementsInsulin sensitivity was measured in the morning following the 3rd intervention night by minimal modelling of 19 samples collected during a 2‐h oral glucose tolerance test. Glucose, insulin, c‐peptide, leptin, peptide YY (PYY), ghrelin, cortisol, testosterone and luteinizing hormone (LH) were measured from daily fasting blood samples; HOMA‐IR, HOMA‐β and QUICKI were calculated.ResultsInsulin sensitivity was higher following three nights of sleep extension compared to sustained sleep restriction. Fasting insulin, c‐peptide, HOMA‐IR, HOMA‐β, leptin and PYY decreased with ‘catch‐up’ sleep, QUICKI and testosterone increased, while morning cortisol and LH did not change. Targeted acoustic stimuli reduced SWS by 23%, but did not alter insulin sensitivity.ConclusionsThree nights of ‘catch‐up’ sleep improved insulin sensitivity in men with chronic, repetitive sleep restriction. Methods to improve metabolic health by optimizing sleep are plausible.

Hypothalamic inflammation in the control of metabolic function.

Diet-induced obesity leads to devastating and common chronic diseases, fueling ongoing interest in determining new mechanisms underlying both obesity and its consequences. It is now well known that chronic overnutrition produces a unique form of inflammation in peripheral insulin target tissues, and efforts to limit this inflammation have met with some success in preserving insulin sensitivity in obese individuals. Recently, the activation of inflammatory pathways by dietary excess has also been observed among cells located in the mediobasal hypothalamus, a brain area that exerts central control over peripheral glucose, fat, and energy metabolism. Here we review progress in the field of diet-induced hypothalamic inflammation, drawing key distinctions between metabolic inflammation in the hypothalamus and that occurring in peripheral tissues. We focus on specific stimuli of the inflammatory response, the roles of individual hypothalamic cell types, and the links between hypothalamic inflammation and metabolic function under normal and pathophysiological circumstances. Finally, we explore the concept of controlling hypothalamic inflammation to mitigate metabolic disease.

Defects in Mitochondrial Efficiency and H2O2 Emissions in Obese Women Are Restored to a Lean Phenotype With Aerobic Exercise Training

The notion that mitochondria contribute to obesity-induced insulin resistance is highly debated. Therefore, we determined whether obese (BMI 33 kg/m2), insulin-resistant women with polycystic ovary syndrome had aberrant skeletal muscle mitochondrial physiology compared with lean, insulin-sensitive women (BMI 23 kg/m2). Maximal whole-body and mitochondrial oxygen consumption were not different between obese and lean women. However, obese women exhibited lower mitochondrial coupling and phosphorylation efficiency and elevated mitochondrial H2O2 (mtH2O2) emissions compared with lean women. We further evaluated the impact of 12 weeks of aerobic exercise on obesity-related impairments in insulin sensitivity and mitochondrial energetics in the fasted state and after a high-fat mixed meal. Exercise training reversed obesity-related mitochondrial derangements as evidenced by enhanced mitochondrial bioenergetics efficiency and decreased mtH2O2 production. A concomitant increase in catalase antioxidant activity and decreased DNA oxidative damage indicate improved cellular redox status and a potential mechanism contributing to improved insulin sensitivity. mtH2O2 emissions were refractory to a high-fat meal at baseline, but after exercise, mtH2O2 emissions increased after the meal, which resembles previous findings in lean individuals. We demonstrate that obese women exhibit impaired mitochondrial bioenergetics in the form of decreased efficiency and impaired mtH2O2 emissions, while exercise effectively restores mitochondrial physiology toward that of lean, insulin-sensitive individuals.