Insulin-resistant Individuals Research Articles

Dietary support in insulin resistance: An overview of current scientific reports.

Over the past 30 years, a significant increase in the prevalence of insulin resistance (IR) has been observed. It is associated with more frequent occurrence of impaired glucose tolerance, diabetes, excessive weight, cardiovascular diseases, and endocrine disorders. The results of current studies do not indicate a necessity to exclude dairy products from the diet of insulin-resistant individuals. In addition, it has been found that moderate amounts of alcohol as part of a balanced, low-energy diet do not have a negative effect on insulin sensitivity. The authors of recent studies emphasize the importance of reducing the intake of simple sugars, especially from sweet drinks, sweets and excessive fruit juice consuption. Many studies have demonstrated the beneficial effects of consuming complex, low-glycemic-index carbohydrates that are rich in dietary fiber. An insulin-resistant patient's diet should be rich in whole grains and high amounts of non-starchy vegetables and raw fruit. The beneficial effect of the Dietary Approaches to Stop Hypertension (DASH diet) and the Mediterranean diet has been confirmed. The positive correlation between low-carbohydrate and very-low-carbohydrate diets requires confirmation in long-term studies with the participation of insulin-resistant patients. Research shows the benefits of increased calorific intake during the first half of the day, especially from a high-energy and low-glycemic-index breakfast. Furthermore, many researchers indicate that slow and mindful eating is a significant component of an appropriate diet for insulin-resistant individuals.

Metabolic signature of obesity-associated insulin resistance and type 2 diabetes

BackgroundObesity is associated with an increased risk of insulin resistance and type 2 diabetes mellitus (T2DM). However, some obese individuals maintain their insulin sensitivity and exhibit a lower risk of associated comorbidities. The underlying metabolic pathways differentiating obese insulin sensitive (OIS) and obese insulin resistant (OIR) individuals remain unclear.MethodsIn this study, 107 subjects underwent untargeted metabolomics of serum samples using the Metabolon platform. Thirty-two subjects were lean controls whilst 75 subjects were obese including 20 OIS, 41 OIR, and 14 T2DM individuals.ResultsOur results showed that phospholipid metabolites including choline, glycerophosphoethanolamine and glycerophosphorylcholine were significantly altered from OIS when compared with OIR and T2DM individuals. Furthermore, our data confirmed changes in metabolic markers of liver disease, vascular disease and T2DM, such as 3-hydroxymyristate, dimethylarginine and 1,5-anhydroglucitol, respectively.ConclusionThis pilot data has identified phospholipid metabolites as potential novel biomarkers of obesity-associated insulin sensitivity and confirmed the association of known metabolites with increased risk of obesity-associated insulin resistance, with possible diagnostic and therapeutic applications. Further studies are warranted to confirm these associations in prospective cohorts and to investigate their functionality.

Study of insulin resistance in offspring of type 2 diabetes mellitus and obese persons

Introduction: Insulin resistance always associate pancreatic b -cell dysfunction in type 2 diabetes mellitus. Obesity is strongly associated with type 2 diabetes mellitus. Therefore screening to evaluate the status of insulin resistance in offspring of type 2 diabetes mellitus to identify risk of further metabolic complications is important. Aims and objectives: The aim of the study is to find out the correlation between insulin resistance in control with genetic inheritance and obesity. Materials and Methods: It was a Case control Study carried out on 120 apparently healthy, non-diabetic people were included in the study. The age of these people lies between 20 to 40 years. The following anthropometric measurements were done in the above 120 patients. These people were classified depending upon BMI. Body Mass Index (BMI) Categorym 18.5–29.99 Non obese 30.0 Obese Further these people were categorized on the basis of detailed family history of diabetes mellitus to their parents into 4 different groups and each group contain 30 people as a a) Group-I (Control): Includes 30 people who were non-obese, off-springs of non-diabetic persons. b) Group-II (Cases): Includes 30 people who were non-obese, offsprings of type 2 diabetes mellitus patients. c) Group-III (Cases): Includes 30 people who were obese, off-springs of non-diabetic persons. d) Group-IV (Cases): Includes 30 people who were obese, offsprings of type 2 diabetes mellitus. Conclusion: The purpose of our study was to identify insulin resistance individuals even before appearance of diabetes mellitus in the above groups by HOM-IR method. So that they can be targeted for aggressive lifestyle interventions and subsequent morbidity can be prevented. Keywords: Insulin resistance, Obesity

From syndrome X to cardiometabolic risk: clinical and public health implications.

Although the first description of a syndrome defined by the co-existence of atherogenic and diabetogenic metabolic abnormalities is debated in the literature, it was Gerald Reaven who proposed, in his landmark 1988 Banting award lecture, that a significant proportion of individuals (with diabetes or not) were characterised by insulin resistance causing prejudice to cardiovascular health. However, Reaven was influenced by seminal observations made more than 50 years earlier by Himsworth who proposed that there were two forms of diabetes (insulin resistant v. insulin sensitive). Reaven went further in proposing the theory that insulin resistance was the most prevalent cause of CVD associated with metabolic abnormalities that he named syndrome X. Because there was a syndrome X documented in cardiology, the term evolved to insulin resistance syndrome. As Reaven could also find insulin-resistant individuals in non-obese subjects, he did not include obesity as a feature of syndrome X. Imaging studies then revealed that excess adipose tissue in the abdominal cavity, a condition described as visceral obesity, was the form of overweight/obesity associated with insulin resistance and its related abnormalities. As obesity risk assessment and management remain largely based on body weight (BMI) and weight loss, it is proposed that our clinical approaches and public health messages should be revisited. First, patients should be educated about the importance of monitoring their waistline as a crude index of abdominal adiposity. Secondly, public health approaches focussing on 'lifestyle vital signs' including achieving healthy waistlines rather than healthy body weights should be developed.

Comparative DNA methylomic analyses reveal potential origins of novel epigenetic biomarkers of insulin resistance in monocytes from virally suppressed HIV-infected adults

BackgroundCompared to healthy individuals, those with stably repressed HIV experience a higher risk of developing insulin resistance, a hallmark of pre-diabetes and a major determinant for cardiometabolic diseases. Although epigenetic processes, including in particular DNA methylation, appear to be dysregulated in individuals with insulin resistance, little is known about where these occur in the genomes of immune cells and the origins of these alterations in HIV-infected individuals. Here, we examined the genome-wide DNA methylation states of monocytes in HIV-infected individuals (n = 37) with varying levels of insulin sensitivity measured by the homeostatic model assessment of insulin resistance (HOMA-IR).ResultsBy profiling DNA methylation at single-nucleotide resolution using the Illumina Infinium HumanMethylation450 BeadChip in monocytes from insulin-resistant (IR; HOMA-IR ≥ 2.0; n = 14) and insulin-sensitive (IS; HOMA-IR < 2.0; n = 23) individuals, we identified 123 CpGs with significantly different DNA methylation levels. These CpGs were enriched at genes involved in pathways relating to glucose metabolism, immune activation, and insulin-relevant signaling, with the majority (86.2%) being hypomethylated in IR relative to IS individuals. Using a stepwise multiple logistic regression analysis, we observed 4 CpGs (cg27655935, cg02000426, cg10184328, and cg23085143) whose methylation levels independently predicted the insulin-resistant state at a higher confidence than that of clinical risk factors typically associated with insulin resistance (i.e., fasting glucose, 120-min oral glucose tolerance test, Framingham Risk Score, and Total to HDL cholesterol ratio). Interestingly, 79 of the 123 CpGs (64%) exhibited remarkably similar levels of methylation as that of hematopoietic stem cells (HSC) in monocytes from IR individuals, implicating epigenetic defects in myeloid differentiation as a possible origin for the methylation landscape underlying the insulin resistance phenotype. In support of this, gene ontology analysis of these 79 CpGs revealed overrepresentation of these CpGs at genes relevant to HSC function, including involvement in stem cell pluripotency, differentiation, and Wnt signaling pathways.ConclusionAltogether, our data suggests a possible role for DNA methylation in regulating monocyte activity that may associate with the insulin-resistant phenotype. The methylomic landscape of insulin resistance in monocytes could originate from epigenetic dysregulation during HSC differentiation through the myeloid lineage. Understanding the factors involved with changes in the myeloid trajectory may provide further insight into the development of insulin resistance. Furthermore, regulation of specific genes that were implicated in our analysis reveal possible targets for modulating immune activity to ameliorate insulin resistance.

Contribution of Impaired Insulin Signaling to the Pathogenesis of Diabetic Cardiomyopathy.

Diabetic cardiomyopathy (DCM) has emerged as a relevant cause of heart failure among the diabetic population. Defined as a cardiac dysfunction that develops in diabetic patients independently of other major cardiovascular risks factors, such as high blood pressure and coronary artery disease, the underlying cause of DCMremains to be unveiled. Several pathogenic factors, including glucose and lipid toxicity, mitochondrial dysfunction, increased oxidative stress, sustained activation of the renin-angiotensin system (RAS) or altered calcium homeostasis, have been shown to contribute to the structural and functional alterations that characterize diabetic hearts. However, all these pathogenic mechanisms appear to stem from the metabolic inflexibility imposed by insulin resistance or lack of insulin signaling. This results in absolute reliance on fatty acids for the synthesis of ATP and impairment of glucose oxidation. Glucose is then rerouted to other metabolic pathways, with harmful effects on cardiomyocyte function. Here, we discuss the role that impaired cardiac insulin signaling in diabetic or insulin-resistant individuals plays in the onset and progression of DCM.

Effects of branched-chain amino acids on glucose metabolism in obese, prediabetic men and women: a randomized, crossover study

Recent studies have shown that circulating branched-chain amino acids (BCAAs) are elevated in obese, insulin-resistant individuals. However, it is not known if supplementation of additional BCAAs will further impair glucose metabolism. The aim of this pilot study was to determine the effects of BCAA supplementation on glucose metabolism in obese, prediabetic individuals. This is a randomized crossover study involving 12 obese individuals with prediabetes. Participants were randomly assigned to receive a daily supplement containing either 20 g BCAA or protein low in BCAAs for 4 wk with a 2-wk washout in between. At each visit, an oral-glucose-tolerance test (OGTT) was performed. Collected blood samples were used to measure glucose, insulin, and insulin resistance-associated biomarkers. BCAA supplementation tended to decrease the plasma glucose area under the curve (AUC) measured by the OGTT (AUC percentage change from supplementation baseline, BCAA: -3.3%±3%; low-BCAA: 10.0%±6%; P=0.08). However, BCAA supplementation did not affect plasma insulin during OGTT challenge (BCAA: -3.9%±8%; low-BCAA: 14.8%±10%; P=0.28). The plasma concentrations of nerve growth factor (BCAA: 4.0±1 pg/mL; low-BCAA: 5.7±1 pg/mL; P=0.01) and monocyte chemoattractant protein-1 (BCAA: -0.4%±9%; low-BCAA: 29.0%±18%; P=0.02) were significantly lowered by BCAA supplementation compared to low-BCAA control. Plasma interleukin 1β was significantly elevated by BCAA supplementation (BCAA: 231.4%±187%; low-BCAA: 20.6%±33%; P=0.05). BCAA supplementation did not affect the circulating concentrations of the BCAAs leucine (BCAA: 9.0%±12%; low-BCAA: 9.2%±11%), valine (BCAA: 9.1%±11%; low-BCAA: 12.0%±13%), or isoleucine (BCAA: 2.5%±11%; low-BCAA: 7.3%±11%). Our data suggest that BCAA supplementation did not impair glucose metabolism in obese, prediabetic subjects. Further studies are needed to confirm the results seen in the present study. This study was registered at clinicaltrials.gov as NCT03715010.

Specific loss of adipocyte CD248 improves metabolic health via reduced white adipose tissue hypoxia, fibrosis and inflammation.

BackgroundA positive energy balance promotes white adipose tissue (WAT) expansion which is characterized by activation of a repertoire of events including hypoxia, inflammation and extracellular matrix remodelling. The transmembrane glycoprotein CD248 has been implicated in all these processes in different malignant and inflammatory diseases but its potential impact in WAT and metabolic disease has not been explored.MethodsThe role of CD248 in adipocyte function and glucose metabolism was evaluated by omics analyses in human WAT, gene knockdowns in human in vitro differentiated adipocytes and by adipocyte-specific and inducible Cd248 gene knockout studies in mice.FindingsCD248 is upregulated in white but not brown adipose tissue of obese and insulin-resistant individuals. Gene ontology analyses showed that CD248 expression associated positively with pro-inflammatory/pro-fibrotic pathways. By combining data from several human cohorts with gene knockdown experiments in human adipocytes, our results indicate that CD248 acts as a microenvironmental sensor which mediates part of the adipose tissue response to hypoxia and is specifically perturbed in white adipocytes in the obese state. Adipocyte-specific and inducible Cd248 knockouts in mice, both before and after diet-induced obesity and insulin resistance/glucose intolerance, resulted in increased microvascular density as well as attenuated hypoxia, inflammation and fibrosis without affecting fat cell volume. This was accompanied by significant improvements in insulin sensitivity and glucose tolerance.InterpretationCD248 exerts detrimental effects on WAT phenotype and systemic glucose homeostasis which may be reversed by suppression of adipocyte CD248. Therefore, CD248 may constitute a target to treat obesity-associated co-morbidities.

2046-P: NS-0200 (Leucine-Metformin-Sildenafil) Reduces Weight in Obese Subjects: A 24-Week Randomized Trial

We previously showed leucine to activate the SIrt1/AMPK/NO pathway and to synergize with other activators of this pathway, and developed NS-0200 (leucine-metformin-sildenafil combination) to treat diseases of energy dysregulation. During a previous trial of NS-0200 of nonalcoholic fatty liver disease we noted significant weight loss induced by NS-0200. Accordingly, we have conducted a 24-week placebo-controlled double-blind trial in 258 weight-stable obese subjects to evaluate the effects of leucine (1.1 g) + sildenafil (1 or 4 mg) with or without metformin (500 mg) administered b.i.d. on weight loss in the absence of lifestyle modification; data presented are for the 202 per-protocol completers. Leu/Met/Sil 1.0 or 4.0 mg and Leu/Sil 4.0 mg produced significant weight loss, while LeuSil 1.0 mg did not. Leu/Met/Sil 1.0 mg exerted the greatest effect (2% placebo-adjusted weight loss, p&amp;lt;0.01), with a greater effect in subjects with BMI&amp;lt;40 (2.9% weight loss, 23% of subjects achieved ≥ 5% weight loss). Markedly greater effects were found in African-American (AA) subjects (6% weight loss, p&amp;lt;0.01) and those with BMI 35-39.9 (4.2% weight loss, p&amp;lt;0.001). These sub-group differences were explained, in part, by differences in baseline insulin and insulin resistance. 71% of AA had insulin ≥ 8 mU/L and HOMAIR&amp;gt;2, vs. 42% in Caucasians, and Leu/Met/Sil 1.0 resulted in a 61% decrease in both insulin and HOMAIR(p&amp;lt;0.009) in AA. Similarly, treated subjects with BMI 35-39.9 had ∼two-fold elevations in insulin and HOMAIR vs. those with BMI&amp;lt;35, and 77% had insulin ≥ 8 mU/L and HOMAIR&amp;gt;2 (p=0.017); those with elevated insulin at baseline lost ∼twice as much weight as those with lower insulin (-3.8 vs. -1.8%), and 30% of this subgroup achieved 5% weight loss vs. 6% of placebo. These data indicate NS-0200 results in significant 6-month weight loss, especially in insulin-resistant subjects, and suggest therapeutic utility for obese insulin-resistant individuals. Disclosure M.B. Zemel: Board Member; Self; NuSirt Biopharma, Inc. Employee; Self; NuSirt Biopharma, Inc. Stock/Shareholder; Self; NuSirt Biopharma, Inc. O.G. Kolterman: Advisory Panel; Spouse/Partner; Intarcia Therapeutics, Inc. Advisory Panel; Self; Zafgen, Inc. Board Member; Self; American Diabetes Association, GlySens Incorporated, Viacyte, Inc. Consultant; Self; ADOCIA, Cirius Therapeutics Inc, DiaVacs Inc, JDRF, Nanoprecisionmedical, NuSirt Biopharma, Inc., Renova Therapeutics, Sensulin, LLC. Employee; Self; Whole Biome Inc. Stock/Shareholder; Self; Corcept Therapeutics, GI Therapeutics, Xeris Pharmaceuticals, Inc. Other Relationship; Spouse/Partner; American Diabetes Association. O. Flores: None. G. Fleming: Advisory Panel; Self; ADOCIA, Biocon. Consultant; Self; Enanta Pharmaceuticals, Inc., InsuLine Medical Ltd., Intarcia Therapeutics, Inc., Lexicon Pharmaceuticals, Inc., Merck KGaA, Oramed Pharmaceuticals, Orgenesis Ltd., Sanofi. Employee; Self; Tolerion, Inc. F.L. Greenway: Advisory Panel; Self; BAROnova, Gelesis, Jenny Craig - Curves, Novartis Pharmaceuticals Corporation, NuSirt Biopharma, Inc., Zafgen, Inc. Consultant; Self; Academic Technology Ventures, Basic Research, General Nutrition Corporation, Melior Discoveries. Research Support; Self; Microbiome Therapeutics. Stock/Shareholder; Self; Plensat, Slim Health Nutrition. Other Relationship; Self; Neuroquest. Funding NuSirt Biopharma, Inc.

High-intensity interval training reduces monocyte activation in obese adults

Alterations in the distribution and activation of monocyte subsets are frequently observed in individuals with obesity and their participation in the pathological complications of obesity is proposed. High-intensity interval training (HIIT) can be a time-efficient alternative to counteract the inflammatory outcomes of obesity, but so far, its effects on monocytes in obesity has not been fully explored. In this study, we investigated whether 8 weeks of HIIT can modify the distribution and activation of the three monocyte subsets (classical, intermediate and non-classical monocytes) in individuals with obesity. Our data show that individuals with obesity have a higher percentage of non-classical monocytes compared to control, lean individuals, and consequently an imbalance among the CD16+ monocyte subsets. Also, the expression of HLA-DR by intermediate monocytes is higher in insulin-resistant obese individuals, which indicates monocyte activation in obesity. After 8 weeks of HIIT, the percentage of non-classical monocytes was reduced in individuals with obesity, restoring the balance among the CD16+ monocytes. Also, the expression of HLA-DR by intermediate monocytes in insulin-resistant obese subjects was lower after HIIT. Both findings indicate that monocyte activation in individuals with obesity was reduced by HIIT. These modifications were observed in the absence of changes in weight and body composition, although they were accompanied by the improvement in the metabolic status (reduced insulin levels). Our findings indicate that HIIT can be considered a time-efficient strategy to manage obesity-related monocyte alterations and strengthen the immunomodulatory potential of HIIT.

Longitudinal multi-omics of host\u2013microbe dynamics in prediabetes

Type 2 diabetes mellitus (T2D) is a growing health problem, but little is known about its early disease stages, its effects on biological processes or the transition to clinical T2D. To understand the earliest stages of T2D better, we obtained samples from 106 healthy individuals and individuals with prediabetes over approximately four years and performed deep profiling of transcriptomes, metabolomes, cytokines, and proteomes, as well as changes in the microbiome. This rich longitudinal data set revealed many insights: first, healthy profiles are distinct among individuals while displaying diverse patterns of intra- and/or inter-personal variability. Second, extensive host and microbial changes occur during respiratory viral infections and immunization, and immunization triggers potentially protective responses that are distinct from responses to respiratory viral infections. Moreover, during respiratory viral infections, insulin-resistant participants respond differently than insulin-sensitive participants. Third, global co-association analyses among the thousands of profiled molecules reveal specific host–microbe interactions that differ between insulin-resistant and insulin-sensitive individuals. Last, we identified early personal molecular signatures in one individual that preceded the onset of T2D, including the inflammation markers interleukin-1 receptor agonist (IL-1RA) and high-sensitivity C-reactive protein (CRP) paired with xenobiotic-induced immune signalling. Our study reveals insights into pathways and responses that differ between glucose-dysregulated and healthy individuals during health and disease and provides an open-access data resource to enable further research into healthy, prediabetic and T2D states.

Genes Involved in Oxidative Stress Pathways Are Differentially Expressed in Circulating Mononuclear Cells Derived From Obese Insulin-Resistant and Lean Insulin-Sensitive Individuals Following a Single Mixed-Meal Challenge.

Background: Oxidative stress induced by nutritional overload has been linked to the pathogenesis of insulin resistance, which is associated with metabolic syndrome, obesity, type 2 diabetes and diabetic vascular complications. Postprandial changes in expression of oxidative stress pathway genes in obese vs. lean individuals, following intake of different types of meals varying in macronutrient composition have not been characterized to date. Here we aimed to test whether/how oxidative stress responses in obese vs. lean individuals are modulated by meal composition.Methods: High-carbohydrate (HC), high-fat (HF), or high-protein (HP) liquid mixed meals were administered to study subjects (lean insulin-sensitive, n = 9 and obese insulin-resistant, n = 9). Plasma levels of glucose and insulin, lipid profile, urinary F2-isoprostanes (F2-IsoP), and expression levels of genes of oxidative stress pathways were assessed in mononuclear cells (MNC) derived from fresh peripheral blood, at baseline and up to 6-h postprandial states. Differences in these parameters were compared between insulin-sensitive/resistant groups undergoing aforementioned meal challenges.Results: Obese individuals exhibited increased pro-oxidant (i.e., CYBB and CYBA) and anti-oxidant (i.e., TXN RD1) gene expression in the postprandial state, compared with lean subjects, regardless of meal type (P interaction for group × time < 0.05). By contrast, lean subjects had higher expression of NCF-4 gene (pro-oxidant) after HC meal and SOD1 gene (anti-oxidant) after HC and HF meals (P interaction for group × meal < 0.05). There was an increase in postprandial level of urinary F2-IsoP in the obese (P < 0.05) but not lean group.Conclusions: These findings may represent an adaptive oxidative response to mitigate increased stress induced by acute nutritional excess. Further, the results suggest an increased predisposition of obese subjects to oxidative stress. Chronic nutritional excess resulting in increases in body weight and adiposity might lead to decompensation leading to worsening insulin resistance and its sequel. Insights from this study could impact on nutritional recommendations for obese subjects at high-risk of cardiovascular diseases.

Analysis of Fatty Acid Esters of Hydroxyl Fatty Acid in Selected Plant Food.

Metabolic syndrome, characterized by obesity, low-grade inflammation, insulin resistance, hyperglycemia, dyslipidemia and hypertension, is a major risk factor for cardiovascular mortality. Preclinical studies on recently discovered classes of lipids - fatty acid esters of hydroxy fatty acids (FAHFA) have revealed their anti-inflammatory and insulin-sensitizing potential. The FAHFA levels are significantly decreased in insulin-resistant individuals, their application exhibited anti-inflammatory effects and restoring the glucose-insulin homeostasis. The aim of our research was to analyze the overall FAHFA composition in a common diet, as only a partial FAHFA composition has been revealed so far (only the PAHSA subclass was analyzed in a few foods). A new approach to the FAHFAs analysis includes nano-LC and post-column modifier followed by negative ion mass spectrometry, in order to obtain maximum sensitivity. Analysis of different foods - oat (whole grain, coarse flakes and fine flakes), apple, clementine, lemon, strawberry, blueberry, mango, kiwi, avocado, pineapple, banana, onion, garlic, cherry tomato, carrot, parsley root, pepper and radish - exhibited wide inter-food variation in the FAHFA profiles. Sixteen analyzed FAHFAs (palmitic, oleic, palmitoleic and stearic hydroxy-esters) showed microgram to low nanogram levels (0.165ng/g - 32μg/g FW), with the highest abundancy in oat, clementine, garlic and pineapple. Stearic acid hydroxy stearic acid (SAHSA) was the most abundant FAHFA, especially in the food with antioxidative, anti-inflammatory and beneficial metabolic effects. In contrary, the PAHSA - previously proven to have the strongest antihyperglycemic and insulin-sensitizing effects, was not present in some foods (radish, avocado, mango, lemon, cherry tomato, kiwi). Our study proves the importance of overall FAHFA analysis in food (especially in a functional food), because of their potential metabolic benefits and possible future incorporation in special diets.

Association between HOMA-IR and Frailty among U.S. Middle-aged and Elderly Population

Previous literatures revealed that homeostasis model assessment-estimated insulin resistance (HOMA-IR) was one of the cardio-metabolic risk factors. This study was conducted to access the association between HOMA-IR and frailty in the United States of America (U.S.) middle-aged and elderly high-risk insulin-resistant population. In the National Health and Nutrition Examination Survey (NHANES III) from 1988 to 1994, the study included 3,893 participants. In order to exam the association between HOMA-IR and frailty in the middle-aged and elderly population through the regression model adjusted for multiple covariates, we divided the participants into middle aged group (Age <65 years) and elderly group (Age > = 65 years) in this study. Each group was then divided into tertiles depending on their HOMA-IR levels. Higher level of HOMA-IR was significantly associated with frailty in the elderly group, but this association was not seen in the middle-aged population. These results demonstrated that the HOMA-IR level can be a novel risk assessment of frailty in elderly high-risk insulin-resistant individuals (Age > = 65 years).

Effects of Light Therapy on Mood and Insulin Sensitivity in Patients With Type 2 Diabetes and Depression: Results From a Randomized Placebo-Controlled Trial.

Depression is common in patients with type 2 diabetes and adversely affects quality of life and diabetes outcomes. We assessed whether light therapy, an antidepressant, improves mood and insulin sensitivity in patients with depression and type 2 diabetes. This randomized, double-blind, placebo-controlled trial included 83 patients with depression and type 2 diabetes. The intervention comprised 4 weeks of light therapy (10,000 lux) or placebo light therapy daily at home. Primary outcomes included depressive symptoms (Inventory of Depressive Symptomatology [IDS]) and insulin sensitivity (M-value derived from the results of a hyperinsulinemic-euglycemic clamp). Secondary outcomes were related psychological and glucometabolic measures. Intention-to-treat analysis showed that light therapy was not superior to placebo in reducing depressive symptoms (-3.9 IDS points [95% CI -9.0 to 1.2]; P = 0.248) and had no effect on insulin sensitivity (0.15 mg/kg*min [95% CI -0.41 to 0.70]; P = 0.608). Analyses incorporating only those participants who accurately adhered to the light therapy protocol (n = 51) provided similar results, but did suggest positive effects of light therapy on depression response rates (≥50% reduction in IDS points) (26% more response; P = 0.031). Prespecified analysis showed effect moderation by baseline insulin sensitivity (P = 0.009) and use of glucose-lowering medication (P = 0.023). Light therapy did not affect depressive symptoms in participants with higher insulin sensitivity or those who use only oral glucose-lowering medication or none at all, but it did produce a relevant effect in participants with lower insulin sensitivity (-12.9 IDS points [95% CI -21.6 to -4.2]; P = 0.017) and a trend toward effectiveness in those using insulin (-12.2 IDS points [95% CI -21.3 to -3.1]; P = 0.094). Light therapy was well tolerated. Although this trial is essentially inconclusive, secondary analyses indicate that light therapy might be a promising treatment for depression among a subgroup of highly insulin-resistant individuals with type 2 diabetes.

Intermuscular adipose tissue directly modulates skeletal muscle insulin sensitivity in humans.

Intermuscular adipose tissue (IMAT) is negatively related to insulin sensitivity, but a causal role of IMAT in the development of insulin resistance is unknown. IMAT was sampled in humans to test for the ability to induce insulin resistance in vitro and characterize gene expression to uncover how IMAT may promote skeletal muscle insulin resistance. Human primary muscle cells were incubated with conditioned media from IMAT, visceral (VAT), or subcutaneous adipose tissue (SAT) to evaluate changes in insulin sensitivity. RNAseq analysis was performed on IMAT with gene expression compared with skeletal muscle and SAT, and relationships to insulin sensitivity were determined in men and women spanning a wide range of insulin sensitivity measured by hyperinsulinemic-euglycemic clamp. Conditioned media from IMAT and VAT decreased insulin sensitivity similarly compared with SAT. Multidimensional scaling analysis revealed distinct gene expression patterns in IMAT compared with SAT and muscle. Pathway analysis revealed that IMAT expression of genes in insulin signaling, oxidative phosphorylation, and peroxisomal metabolism related positively to donor insulin sensitivity, whereas expression of macrophage markers, inflammatory cytokines, and secreted extracellular matrix proteins were negatively related to insulin sensitivity. Perilipin 5 gene expression suggested greater IMAT lipolysis in insulin-resistant individuals. Combined, these data show that factors secreted from IMAT modulate muscle insulin sensitivity, possibly via secretion of inflammatory cytokines and extracellular matrix proteins, and by increasing local FFA concentration in humans. These data suggest IMAT may be an important regulator of skeletal muscle insulin sensitivity and could be a novel therapeutic target for skeletal muscle insulin resistance.

The effect of 8-week resistance training on IRS-1 gene expression in gastrocnemius muscle and glycemic profile in diabetes rats

Background: The insulin receptor substrate-1 (IRS-1) has an important role in insulin signaling pathways in the target tissue of obese or insulin-resistant individuals. This study aimed to assess the effect of resistance training on fasting glucose, insulin resistance, and IRS-1 gene expression in gastrocnemius muscle in male Wister rats with type 2 diabetes (T2D). Materials and Methods: For this purpose, T2D induced by high- fat diet (8 weeks) and STZ in fourteen male Wistar rats (220 ± 10 g) and then assigned into exercise (resistance training, 8 weeks, 5 days/weekly, n = 7) and control (no-training, n = 7) by randomly. Fasting blood samples were obtained for measuring glucose, insulin, and calculating insulin resistance (HOMA-IR). Also, the IRS-1 gene expression in gastrocnemius muscle was measured 48 hours after the last training session of both cases and controls. Results: Compared to control, IRS-1 gene expression in gastrocnemius muscle increased significantly by resistance training in exercise groups (p = 0.001). Fasting glucose (p < 0.001) and insulin resistance (p = 0.007) were reduced in the exercise rats compared to the control group. Conclusion: Based on the results, improved fasting glucose and insulin function after resistance training in T2D diabetes could be attributed to enhancing IRS-1 expression in gastrocnemius muscle by training.

Effects of interval exercise in the improvement of glycemic control of obese adults with insulin resistance

Background: physical exercise presents evidence for the treatment of insulin resistance. However, it is necessary to deepen this knowledge. Objective: to compare the effectiveness of a high intensity interval training program (HIIT) with one of resistance training (RT) to improve biochemical parameters of insulin/basal glycemia and post-load. Material and methods: twenty-eight (36 ± 13 years old) non-medicated insulin-resistant individuals (age 36 ± 13 years) were studied. Two groups were randomly formed: RT group (n = 14) and HIIT group (n = 14). Each group participated in 12 weeks of intervention (three sessions/week). Both groups were homogeneous (p > 0.05) in terms of age, weight, height and BMI. Basal glycemia/insulinemia and post-load were evaluated, pre and post intervention. Results: after the intervention there were significant decreases in both groups in: fat (%) HIIT (Pre = 40.20 ± 7.31 vs Post = 36.49 ± 7.28%, p = 0.006), RT (Pre: 39.04 ± 8.52 vs Post: 34.91 ± 8.80%, p = 0.002); fasting insulin, HIIT (Pre: 20.64 ± 9.44 vs. Post: 15.20 ± 6.47uIU/ml, p = 0.0006), RT (Pre: 18.50 ± 8.24, vs Post: 13.59 ± 6.11 uIU/ml, p = 0.015); insulin post load, HIIT (Pre: 127.57 ± 71.73 vs Post: 69.25 ± 39.42 uIU/ml, p < 0.0001), RT (Pre: 125.78 ± 59.85 vs Post: 63.45 ± 36.44uIU/ml, p < 0.0001); and fasting glycemia, HIIT (Pre: 92.86 ± 11.39 vs Post: 87.36 ± 8.00, p = 0.031), RT (Pre: 90.79 ± 11.26 vs Post: 85.26 ± 7.88 mg/dl, p = 0.045). In relation to post-load glycemia only the HIIT group decreased significantly (Pre: 128.57 ± 26.90 vs Post: 103.47 ± 12.70 mg/dl, p < 0.001), reporting differences with the RT group (p < 0.042). Conclusion: both programs showed similar results for the treatment of insulin resistance.

Insulin induces Thr484 phosphorylation and stabilization of SIK2 in adipocytes

Aims/hypothesisSalt-inducible kinase 2 (SIK2) is downregulated in adipose tissue from obese or insulin-resistant individuals and inhibition of SIK isoforms results in reduced glucose uptake and insulin signalling in adipocytes. However, the regulation of SIK2 itself in response to insulin in adipocytes has not been studied in detail. The aim of our work was to investigate effects of insulin on various aspects of SIK2 function in adipocytes. MethodsPrimary adipocytes were isolated from human subcutaneous and rat epididymal adipose tissue. Insulin-induced phosphorylation of SIK2 and HDAC4 was analyzed using phosphospecific antibodies and changes in the catalytic activity of SIK2 with in vitro kinase assay. SIK2 protein levels were analyzed in primary adipocytes treated with the proteasome inhibitor MG132. ResultsWe have identified a novel regulatory pathway of SIK2 in adipocytes, which involves insulin-induced phosphorylation at Thr484. This phosphorylation is impaired in individuals with a reduced insulin action. Insulin stimulation does not affect SIK2 catalytic activity or cellular activity towards HDAC4, but is associated with increased SIK2 protein levels in adipocytes. Conclusion/interpretationOur data suggest that downregulation of SIK2 in the adipose tissue of insulin-resistant individuals can partially be caused by impaired insulin signalling, which might result in defects in SIK2 expression and function.

Salt-inducible kinase 2 regulates TFEB and is required for autophagic flux in adipocytes

Dysregulation of autophagy has been observed in obesity and type 2 diabetes. Salt-inducible kinase 2 (SIK2), a member of the AMPK-related kinase family, is downregulated in adipocytes from obese or insulin resistant individuals and was previously demonstrated to regulate autophagy in cancer and normal cell lines. The aim of this study was thus to investigate a potential role of SIK2 in the regulation of adipocyte autophagy. To do so, SIK2 siRNA silencing or SIKs pharmacological inhibition of SIK2 was employed in murine differentiated 3T3-L1 adipocytes and autophagic flux was monitored. Our data indicate that SIK2 is required for both autophagic flux and expression of TFEB, the transcription factor that regulates autophagy, in adipocytes. The effect of SIK2 on autophagic flux occurs before the regulation of TFEB protein levels, suggesting different mechanisms whereby SIK2 stimulates autophagy. This study broadens the current knowledge on autophagy regulation and SIK2 function in adipocytes.