Insulin-mediated Glucose Disposal Research Articles

Similar insulin regulation of splanchnic FFA and VLDL-TG in men with nonalcoholic hepatic steatosis and steatohepatitis

This study aimed to determine whether obese men with nonalcoholic fatty liver disease (NAFLD) display differences between those with simple steatosis versus steatohepatitis (NASH) in splanchnic and hepatic FFA and VLDL-triglycerides (VLDL-TG) balances. The study involved 17 obese men with biopsy-proven NAFLD (9 with NASH and 8 with simple steatosis). We used hepatic vein catheterization in combination with [3H]palmitate and [14C]VLDL-TG tracers to measure splanchnic palmitate and VLDL-TG uptake and release rates during basal and hyperinsulinemic conditions. Indocyanine green was used to measure splanchnic plasma flow. Splanchnic palmitate uptake was similar in the two groups and significantly reduced during hyperinsulinemia (NASH: 62 (48–77) versus 38 (18–58) μmol/min; simple steatosis: 62 (46–78) versus 45 (25–65) μmol/min, mean (95% CI), basal versus clamp periods, respectively, P = 0.02 time-effect). Splanchnic palmitate release was also comparable between groups and nonsignificantly diminished during hyperinsulinemia. The percent palmitate delivered to the liver originating from visceral adipose tissue lipolysis was similar and unchanged by hyperinsulinemia. Splanchnic uptake and release of VLDL-TG were similar between groups. Hyperinsulinemia suppressed VLDL-TG release (P <0.05 time-effect) in both groups. Insulin-mediated glucose disposal was similar in the two groups (P = 0.54). Obese men with NASH and simple steatosis have similar splanchnic uptake and release of FFA and VLDL-TG and a similar proportion of FFA from visceral adipose tissue lipolysis delivered to the liver. These results suggest that FFA and VLDL-TG splanchnic balances are unaffected by NAFLD severity.

Genome-Wide Association Study of Obsessive-Compulsive Symptoms including 33,943 individuals from the general population.

While 1-2% of individuals meet the criteria for a clinical diagnosis of obsessive-compulsive disorder (OCD), many more (~13-38%) experience subclinical obsessive-compulsive symptoms (OCS) during their life. To characterize the genetic underpinnings of OCS and its genetic relationship to OCD, we conducted the largest genome-wide association study (GWAS) meta-analysis of parent- or self-reported OCS to date (N = 33,943 with complete phenotypic and genome-wide data), combining the results from seven large-scale population-based cohorts from Sweden, the Netherlands, England, and Canada (including six twin cohorts and one cohort of unrelated individuals). We found no genome-wide significant associations at the single-nucleotide polymorphism (SNP) or gene-level, but a polygenic risk score (PRS) based on the OCD GWAS previously published by the Psychiatric Genetics Consortium (PGC-OCD) was significantly associated with OCS (Pfixed = 3.06 × 10-5). Also, one curated gene set (Mootha Gluconeogenesis) reached Bonferroni-corrected significance (Ngenes = 28, Beta = 0.79, SE = 0.16, Pbon = 0.008). Expression of genes in this set is high at sites of insulin mediated glucose disposal. Dysregulated insulin signaling in the etiology of OCS has been suggested by a previous study describing a genetic overlap of OCS with insulin signaling-related traits in children and adolescents. We report a SNP heritability of 4.1% (P = 0.0044) in the meta-analyzed GWAS, and heritability estimates based on the twin cohorts of 33-43%. Genetic correlation analysis showed that OCS were most strongly associated with OCD (rG = 0.72, p = 0.0007) among all tested psychiatric disorders (N = 11). Of all 97 tested phenotypes, 24 showed a significant genetic correlation with OCS, and 66 traits showed concordant directions of effect with OCS and OCD. OCS have a significant polygenic contribution and share genetic risk with diagnosed OCD, supporting the hypothesis that OCD represents the extreme end of widely distributed OCS in the population.

204-OR: An Early Immune Signature in Prediabetes Can Predict Progression to Type 2 Diabetes

Inflammation promotes conversion from metabolically healthy to type 2 diabetes (T2D) in animal models, but convincing demonstrations of this relationship have not been reported in people. We aimed at identifying the cellular and cytokine profile of immune cells, as major sources of inflammation, during progression to T2D. We studied subjects who did or did not convert to T2D in a longitudinal observational cohort study (APT-2D), where drug naïve individuals without T2D at baseline (with normoglycemia or prediabetes) are monitored for disease progression by assessing metabolic function every 6 months for 3 years or until conversion to T2D. Immune cell composition in peripheral blood was studied at baseline and at the point of T2D diagnosis. Correlation analysis was conducted between changes in cell frequency and metabolic parameters: Glycated hemoglobin (HbA1c), Homeostatic Model Assessment of Insulin Resistance (HOMA-IR); fasting insulin (FI); insulin-mediated glucose disposal (M/I); and acute insulin response (AIR). Thirty-two converters aged 49.5 ± 1.6 years with BMI 28.8 ± 0.8 kg/m2 were studied, along with sixty-four non-converters matched for age, gender, and ethnicity. At baseline, our results revealed lower frequencies of classical monocytes and type 2 conventional dendritic cells among converters compared to non-converters, which correlated negatively with HbA1c, HOMA-IR and FI and positively with AIR. At onset of T2D, frequencies of CD8+ and CD4+ naïve T cells, CD19+ B cells, and basophils increased in converters compared to their pre-conversion state and among them CD4+ naïve T cell and CD19+ B cell frequencies correlated negatively with HOMA-IR and FI. Stimulated PBMCs from converters compared to non-converters at baseline produced lower amounts of cytokines (TNFa, IL17A, IL17F, TGFb, IFNg), which did not change after conversion to T2D. Flow cytometric and cytokine profiling thus indicated that changes in immune cell function in prediabetes is linked to T2D conversion. Disclosure S.Baig: None. F.Ginhoux: None. S.Toh: None. N.Aung: None. Y.Hwang: None. C.Tan: None. M.H.Lee: None. D.Ooi: None. M.Shabeer: None. F.Magkos: None. B.Nikolajczyk: None. Funding National Medical Research Council of Singapore (MOHIAFCat1/0048/2016)

Glyphosate potentiates insulin resistance in skeletal muscle through the modulation of IRS-1/PI3K/Akt mediated mechanisms: An in vivo and in silico analysis

Herbicides have been linked to a higher risk of developing diabetes. Certain herbicides also operate as environmental toxins. Glyphosate is a popular and extremely effective herbicide for weed control in grain crops that inhibits the shikimate pathway. It has been shown to negatively influence endocrine function. Few studies have demonstrated that glyphosate exposure results in hyperglycemic and insulin resistance; but the molecular mechanism underlying the diabetogenic potential of glyphosate on skeletal muscle, a primary organ that includes insulin-mediated glucose disposal, is unknown. In this study, we aimed to evaluate the impact of glyphosate on the detrimental changes in the insulin metabolic signaling in the gastrocnemius muscle. In vivo results showed that glyphosate exposure caused hyperglycemia, dyslipidemia, increased glycosylated hemoglobin (HbA1c), liver function, kidney function profile, and oxidative stress markers in a dose-dependent fashion. Conversely, hemoglobin and antioxidant enzymes were significantly reduced in glyphosate-induced animals indicating its toxicity is linked to induce insulin resistance. The histopathology of the gastrocnemius muscle and RT-PCR analysis of insulin signaling molecules revealed glyphosate-induced alteration in the expression of IR, IRS-1, PI3K, Akt, β-arrestin-2, and GLUT4 mRNA. Lastly, molecular docking and dynamics simulations confirmed that glyphosate showed a high binding affinity with target molecules such as Akt, IRS-1, c-Src, β-arrestin-2, PI3K, and GLUT4. The current work provides experimental proof that glyphosate exposure has a deleterious effect on the IRS-1/PI3K/Akt signaling pathways, which in turn causes the skeletal muscle to become insulin resistant and eventually develop type 2 diabetes mellitus.

Abstract #1398611: A High Chemerin: Adiponectin Ratio is Associated with Dysglycemia in Patients with the Polycystic Ovarian Syndrome (PCOS)

PCOS is a multifactorial disease, which in turn increases the chance of progression to Type 2 diabetes (T2D) and metabolic syndrome. Since PCOS is now recognized as the ovarian manifestation of metabolic syndrome, identifying potential biomarkers predictive of glucose intolerance in a subset of PCOS could have important implications for the prevention of T2D in this young population. We observed impaired glucose tolerance (IGT) in PCOS to precede impaired fasting glucose (IFG), indicating impaired insulin-mediated peripheral glucose disposal. Two-hour post-glucose plasma glucose (2h-PGPG), the gold standard protocol to detect IGT, has its limitations, i.e., expensive, labor-intensive, and variability issues. Identifying a biomarker is therefore an unmet need for community studies. Chemerin and Adiponectin are two important organokines that are inversely associated with each other in people with metabolic syndrome (MetS). We looked at Chemerin: Adiponectin ratio as a possible biomarker for glucose intolerance in PCOS. Both fasting plasma glucose and 2h-PGPG were measured biochemically by the GOD-POD method. HbA1c level was measured by HPLC. Serum chemerin and adiponectin levels were measured by ELISA using commercial kits from Cusa-Bio. Serum c-peptide level was used to calculate HOMA2IR and HOMA2β, using ELISA kits from G-Biosciences. Subjects with PCOS with glucose intolerance (PCOS-IGT); median (interquartile range), 26.71 (10.19 - 45.09) [n = 44] showed higher serum chemerin: adiponectin ratio (CAR) compared to controls (PCOS-NGT); median (interquartile range), 6.977 (5.470 - 14.06). CAR correlated positively with 2h-PGPG (r = 0.5347, p < 0.01) and negatively with HOMA-2β (r = -0.5029, p < 0.05). A CAR cut-off value of 14.15 on the ROC curve provided the optimum trade-off between sensitivity and specificity (70.59% and 78.95% respectively). The same cut-off value showed sensitivity and specificity of 76.92%, with an AUC of 0.8964 and likelihood ratio of 3.333, in the case of comparison between PCOS-NGT and PCOS subjects having 2h-PGPG in the diabetic range (PCOS-T2D). With a power (1 – β) of 0.9258, CAR could identify 93% of the subjects having peak plasma glucose levels on OGTT ≥ 140 mg/dL. Moreover, CAR correlated strongly with TG: HDLc ratio (r = 0.62, p < 0.0001). These results suggest that CAR may be utilized as a biomarker for dysglycaemia in the study population. CAR could be a surrogate marker of dysglycaemia in PCOS. The strong correlation between CAR and TG: HDLc ratio is consistent with the premise that lipid abnormalities might precede glucose abnormalities in PCOS, like the situation in metabolic syndrome.

Insulin Resistance

The twin epidemic of ‘Diabesity’-diabetes and obesity, all over the world, both in developed and developing countries, has brought the issue of insulin resistance (IR) into new focus of research. Apart from Type 2 diabetes mellitus (DM), IR is implicated in many other clinical syndromes because of its varied metabolic and mitogenic actions. IR has been found to play important pivotal role in pathophysiology of diabesity. IR is defined as when a normal or higher insulin level fails to produce expected biological response; one predominantly affecting insulin mediated glucose disposal 20–30% reduction in the number of insulin receptors on the target cells is observed in majority of Type 2 DM patients but 1/3 of the patients may not manifest loss of number of receptors; therefore, defective post-receptor signalling is considered as the main cause of IR. Main sites of IR are liver, adipose tissue and skeletal muscles. Apart from Type 2 DM, many other clinical and genetic syndromes are associated with IR.

Kaempferol improves glucose uptake in skeletal muscle via an AMPK-dependent mechanism

Insulin resistance is a hallmark of type-2 diabetes (T2D) pathogenesis. Because skeletal muscle (SkM) is the major tissue for insulin-mediated glucose disposal, insulin resistance in SkM is considered a major risk factor for developing T2D. Thus, the identification of compounds that enhance the ability of SkM to take up glucose is a promising strategy for preventing T2D. Our previous work showed that kaempferol, a flavonol present in many foods, improves insulin sensitivity in obese mice, however, the mechanism underlying this beneficial action remains unclear. Here, we show that kaempferol directly stimulates glucose uptake and prevents lipotoxicity-impaired glucose uptake in primary human SkM. Kaempferol stimulates Akt phosphorylation in a time-dependent manner in human SkM cells. The effect of kaempferol on glucose uptake was blunted by inhibition of glucose transporter 4, phosphoinositide 3-kinase (PI3K), or AMPK. In addition, kaempferol induced AMPK phosphorylation, and inhibition of AMPK prevented kaempferol-stimulated Akt phosphorylation. In vivo, kaempferol administration induced rapid glucose disposal accompanied with increased Akt and AMPK phosphorylation in SkM tissue of the mice. Taken together, these findings suggest that kaempferol stimulates glucose uptake in SkM via an AMPK/Akt dependent mechanism, and it may be a viable therapeutic agent for insulin resistance.

Muscle Oxidative Stress Plays a Role in Hyperthyroidism-Linked Insulin Resistance

While a low level of ROS plays a role in cellular regulatory processes, a high level can lead to oxidative stress and cellular dysfunction. Insulin resistance (IR) is one of the dysfunctions in which oxidative stress occurs and, until now, the factors underlying the correlation between oxidative stress and IR were unclear and incomplete. This study aims to explore this correlation in skeletal muscle, a tissue relevant to insulin-mediated glucose disposal, using the hyperthyroid rat as a model of oxidative stress. The development of IR in the liver from hyperthyroid animals has been widely reported, whereas data concerning the muscle are quite controversial. Thus, we investigated whether hyperthyroidism induces IR in skeletal muscle and the role of oxidative stress in this process. Particularly, we compared the effects of hyperthyroidism on IR both in the absence and presence of vitamin E (Vit E), acting as an antioxidant. Putative correlations between ROS production, oxidative stress markers, antioxidant capacity and changes in intracellular signalling pathways related to insulin action (AKT) and cellular stress response (EIF2α; JNK; PGC1α; BIP; and NRF1) were investigated. Moreover, we assessed the effects of hyperthyroidism and Vit E on the expression levels of genes encoding for glucose transporters (Slc2a1; Slc2a4), factors involved in lipid homeostasis and insulin signalling (Pparg; Ppara, Cd36), as well as for one of the IR-related inflammatory factors, i.e., interleukin 1b (Il1b). Our results suggest that hyperthyroidism-linked oxidative stress plays a role in IR development in muscle and that an adequate antioxidant status, obtained by vitamin E supplementation, that mitigates oxidative stress, may prevent IR development.

Effect of Intermittent Fasting on Muscle Glycogen Stores in Rats with High-Calorie Diet

Insulin resistance in skeletal muscle is important since it is normally responsible for most of the insulin-mediated glucose disposal and contains the largest glycogen storage regulated by insulin sensitivity. A high-calorie diet is known to be a risk factor for insulin resistance. Lifestyle modification by regulating caloric intake through intermittent fasting (IF) is recommended to prevent insulin resistance. This study aims to analyze the effect of eight weeks of intermittent fasting on skeletal muscle glycogen stores in rats with a four-week high-calorie diet. A total 24 healthy male Wistar rats were divided into four groups, Ad-libitum with a standard diet (AL-SD) Ad-libitum with a high-calorie diet (AL-HCD) IF with a standard diet (IF-SD) IF with a high-calorie diet (IF-HCD). Muscles were obtained and stained with PAS stain to evaluate glycogen expression based on color intensity. The results of the glycogen expression score were obtained as follows, AL-SD=2.113±0.589 AL-HCD=1.827±0.375 IF-SD=2.109±0.499 IF-HCD=1.979±0.334. Although there was no significant difference between groups (p> 0.05), IF can prevent excessive reduction of glycogen stores in subjects with a HCD compared to the AL-HCD group. In conclusion, this study suggests that IF might improve the reduction of glycogen stores in muscles due to a high-calorie diet.

O105 Human adaptation to immobilisation: novel insights of impacts on glucose disposal and fuel utilization

Abstract Introduction Bed-rest (BR) reduces whole-body insulin-stimulated glucose disposal (GD) and alters muscle fuel metabolism. However, little is known about metabolic adaptation from acute to chronic BR, particularly when volunteers are maintained in energy balance. Methods Healthy males (n=10, 24±1.25 years) maintained in energy balance underwent 3 days of BR (acute BR; ABR). A second cohort matched for gender and body mass index (n=20, 34±1.8 years) underwent 56 days of BR (chronic BR; CBR). A hyperinsulinaemic euglycaemic clamp (60 mU/kg lean mass/min) was performed before and after BR. Indirect calorimetry was performed before and during the clamp steady-state to calculate rates of whole-body fuel oxidation. Vastus Lateralis muscle biopsies were taken before and after each clamp. Two-way repeated measures ANOVA was used to detect differences in end-point measures. Results ABR reduced insulin-mediated glucose disposal (GD; p&amp;lt;0.001), which was unchanged in magnitude following CBR (p&amp;lt;0.05). This reduction in GD following both acute and CBR was paralleled by the elimination of a 35% increase in insulin-stimulated muscle glycogen storage seen Pre BR. ABR had no impact on insulin-stimulated carbohydrate (CHO) and lipid oxidation, but CBR reduced CHO oxidation (p&amp;lt;0.05) and blunted the magnitude of insulin-mediated inhibition of lipid oxidation (p&amp;lt;0.05). Neither acute nor CBR increased muscle intramyocellular lipid content. Conclusion ABR suppressed insulin-stimulated GD and glycogen storage, and the extent of suppression increased no further after CBR. However, GD and storage were dissociated from substrate oxidation during CBR. Moreover, the shift in substrate oxidation after CBR was not explained by IMCL accumulation. Take home message Acute bed rest impairs insulin-stimulated glucose disposal and glycogen storage which is the same magnitude as that seen in chronic bed rest.

SKIN MICROVASCULAR FLOWMOTION IS UNALTERED IN ABDOMINALLY OBESE MEN

Objective: Abdominal obesity represents a systemic metabolic pathology, being related to the development of insulin resistance and cardiovascular diseases. Microvascular dysfunction is multifactorial and alters, among other things, insulin-mediated glucose disposal. We have previously shown that insulin-mediated microvascular recruitment in skeletal muscle is impaired in obese men and that weight loss can reverse this impairment. Our objective was to examine whether impairment of insulin-mediated microvascular function and subsequent reversal by weight loss can be detected in skin as well using flowmotion analyses. Design and method: Twenty-five lean and 53 abdominally obese men (waist circumference 102–110 cm; aged18–65 yrs.; no cardiovascular diseases or type 2 diabetes) were recruited. Following baseline measurements, the obese men were randomized to either an 8-week program of low calorie diet (LCD), or usual diet (control). Skin flowmotion was measured by laser-doppler flowmetry and Fourier analyses resulted in the contribution of five frequency domains: endothelial, 0.01–0.02 Hz; neurogenic, 0.02–0.06 Hz; myogenic, 0.06–0.15 Hz; respiratory, 0.15–0.40 Hz and cardiac, 0.40–1.60 Hz. Flowmotion was measured before and during a hyperinsulinaemic euglycaemic clamp. Results: Baseline flowmotion was not different between lean and obese men. In both lean and obese men, hyperinsulinaemia induced a similar increase in total flowmotion (lean: 6.5% (1.5, 11.5); obese: 3.6% (0.6, 6.6); p = 0.309 vs lean) and the endothelial domain (lean: 12.3% (1.7, 22.9); obese: 8.6% (2.5, 14.7); p = 0.538 vs lean), and a decrease in the neurogenic domain (lean: -14.2% (-24.8, -3.7); obese: -4.6% (-13, 3.8); p = 0.149 vs lean). The LCD intervention did not statistically significantly affect flowmotion. Conclusions: In contrast to insulin-mediated microvascular recruitment in skeletal muscle, skin microvascular flowmotion is unaltered in abdominally obese men versus lean. In addition, a weight loss intervention in the obese men did not affect skin microvascular flowmotion. These findings indicate that the sensitivity of the microvasculature to systemic mediators may differ between tissues.

Effects of Sustained Hyperglycemia on Skeletal Muscle Lipids in Healthy Subjects.

Sustained increases in plasma glucose promote skeletal muscle insulin resistance independent from obesity and dyslipidemia (ie, glucotoxicity). Skeletal muscle lipids are key molecular determinants of insulin action, yet their involvement in the development of glucotoxicity is unclear. To explore the impact of mild physiologic hyperglycemia on skeletal muscle lipids. Single group pretest-posttest. Healthy males and females with normal glucose tolerance. 72-hour glucose infusion raising plasma glucose by ~50 mg/dL. Skeletal muscle lipids, insulin sensitivity, lipid oxidation. Despite impairing insulin-mediated glucose disposal and suppressing fasting lipid oxidation, hyperglycemia did not alter either the content or composition of skeletal muscle triglycerides, diacylglycerides, or phospholipids. Skeletal muscle ceramides decreased after glucose infusion, likely in response to a reduction in free fatty acid concentrations. Our results demonstrate that the major lipid pools in skeletal muscle are unperturbed by sustained increases in glucose availability and suggest that glucotoxicity and lipotoxicity drive insulin resistance through distinct mechanistic pathways.

Mechanisms by Which Skeletal Muscle Myokines Ameliorate Insulin Resistance.

The skeletal muscle is the largest organ in the body and secretes circulating factors, including myokines, which are involved in various cellular signaling processes. Skeletal muscle is vital for metabolism and physiology and plays a crucial role in insulin-mediated glucose disposal. Myokines have autocrine, paracrine, and endocrine functions, serving as critical regulators of myogenic differentiation, fiber-type switching, and maintaining muscle mass. Myokines have profound effects on energy metabolism and inflammation, contributing to the pathophysiology of type 2 diabetes (T2D) and other metabolic diseases. Myokines have been shown to increase insulin sensitivity, thereby improving glucose disposal and regulating glucose and lipid metabolism. Many myokines have now been identified, and research on myokine signaling mechanisms and functions is rapidly emerging. This review summarizes the current state of the field regarding the role of myokines in tissue cross-talk, including their molecular mechanisms, and their potential as therapeutic targets for T2D.

Is calorie restriction beneficial for normal-weight individuals? A narrative review of the effects of weight loss in the presence and absence of obesity.

Calorie restriction regimens are popular for their purported health-promoting effects. However, it is unclear whether chronic reduction in energy intake and subsequent weight loss have beneficial effects in the absence of obesity. To this end, the results of studies that examined the effects of the same diet-induced weight loss in individuals with and without obesity were reviewed. The contribution of lean mass to the total amount of weight lost is greater in participants without obesity than in those with obesity, but the reductions in resting, nonresting, and total energy expenditure are of similar magnitude. Both in the presence as well as in the absence of obesity, weight loss decreases visceral adipose tissue and liver fat, increases insulin sensitivity in skeletal muscle (insulin-mediated whole-body glucose disposal rate) and in adipose tissue (meal-induced or insulin-induced suppression of plasma free fatty acid concentration), and augments insulin clearance rate, without affecting pancreatic insulin secretion. These effects are of similar magnitude in participants with and without obesity and result in reductions in fasting plasma glucose and insulin concentrations. These data suggest that the same degree of calorie restriction and the same amount of weight loss have multiple beneficial effects on health outcomes in individuals without obesity, similar to those observed in individuals with obesity.

Role of Pterostilbene in Metabolic Diseases through SIRT1 pathway- A Review

Pterostilbene (PTE) (3-5 dimethoxy-4-hydroxy-trans-stilbenes) is an analogue of resveratrol. It is extracted and isolated from a natural source of the heartwood of Pterocarpus marsupium Roxb., red grape skin, and blueberries (Vaccinium spp.). Substantial evidence suggested that PTE displayed numerous preventive and therapeutic properties in many metabolic disorders such as diabetes and obesity. Metabolic diseases result in Insulin resistance (IR) which advances to impaired sensitivity to insulin-mediated glucose disposal. The prominent role of SIRT (silent information regulator proteins) is now getting emphasized in metabolic disorders. SIRT1 represses Uncoupling protein 2 (UCP2) expressions which are further responsible for improving synthesis of ATP from glucose. This results in improving glucose utilization and insulin secretion, thus preventing IR. SIRT1 also exhibits prominent role in facilitating fatty acid mobilization thereby inhibiting adiposity. Metabolic disorders are therefore the consequences of SIRT1 downregulation. Pterostilbene, being a SIRT1 activator, increases insulin sensitivity reduces adiposity, therefore can prove to be beneficial in diabetes as well as obesity. The review summarizes therapeutic effects portrayed by Pterostilbene via the SIRT1 pathway in metabolic diseases.

Characterizing skeletal muscle dysfunction in women with polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is the most common endocrine condition affecting women. It has traditionally been viewed as a primarily reproductive disorder; however, it is increasingly recognized as a lifelong metabolic disease. Women with PCOS are at increased risk of insulin resistance (IR), type 2 diabetes mellitus, non-alcoholic fatty liver disease and cardiovascular disease. Although not currently a diagnostic criterion, IR is a cardinal pathophysiological feature and highly prevalent in women with PCOS. Androgens play a bidirectional role in the pathogenesis of IR, and there is a complex interplay between IR and androgen excess in women with PCOS. Skeletal muscle has a key role in maintaining metabolic homeostasis and is also a metabolic target organ of androgen action. Skeletal muscle is the organ responsible for the majority of insulin-mediated glucose disposal. There is growing interest in the relationship between skeletal muscle, androgen excess and mitochondrial dysfunction in the pathogenesis of metabolic disease in PCOS. Molecular mechanisms underpinning defects in skeletal muscle dysfunction in PCOS remain to be elucidated, but may represent promising targets for future therapeutic intervention. In this review, we aim to explore the role of skeletal muscle in metabolism, focusing particularly on perturbations in skeletal muscle specific to PCOS as observed in recent molecular and in vivo human studies. We review the possible role of androgens in the pathophysiology of skeletal muscle abnormalities in PCOS, and identify knowledge gaps, areas for future research and potential therapeutic implications. Despite increasing interest in the area of skeletal muscle dysfunction in women with PCOS, significant challenges and unanswered questions remain, and going forward, novel innovative approaches will be required to dissect the underlying mechanisms.

Beneficial effects of a plant-fish oil, slow carbohydrate diet on cardio-metabolic health exceed the correcting effects of metformin-pioglitazone in diabetic pigs fed a fast-food diet.

BackgroundLifestyle influences endocrine, metabolic and cardiovascular homeostasis. This study investigated the impact of diet and oral anti-diabetic medication on cardio-metabolic health in human-sized diabetic pigs.MethodsAfter a growing pre-phase from ~30 to ~69 kg during which domestic pigs were fed either a low fat, low sucrose diet (group A) or a fast food-type diet elevated in lard (15%) and sucrose (40%) (group B), the pigs were subdivided in 5 groups (n = 7–8 pigs per group). Group 1, normal pigs from group A on a low fat, low sugar (L) pig diet and group 2, normal pigs from group B on a high lard (25%), sucrose-fructose (40%), cholesterol (1%) fast food-type (F) diet. Diabetes (D) was induced in group B pigs by streptozotocin and group 3 received the F diet (DF), group 4 received the F diet with Anti-diabetic medication metformin (2 g.day-1)-pioglitazone (40 mg.day-1) (DFA) and group 5 switched to a Plant-Fish oil (25%), Slowly digestible starch (40%) diet (DPFS). The F and PFS diets were identical for fat, carbohydrate and protein content but only differed in fat and carbohydrate composition. The 5 pig groups were followed up for 7 weeks until reaching ~120 kg.ResultsIn normal pigs, the F diet predisposed to several abnormalities related to metabolic syndrome. Diabetes amplified the inflammatory and cardiometabolic abnormalities of the F diet, but both oral FA medication and the PFS diet partially corrected these abnormalities (mean±SEM) as follows: Fasting plasma TNF-ɑ (pg.ml-1) and NEFA (mmol.l-1) concentrations were high (p<0.02) in DF (193±55 and 0.79±0.16), intermediate in DFA (136±40 and 0.57±012) and low in DPFS pigs (107±31 and 0.48±0.19). Meal intolerance (response over fasting) for glucose and triglycerides (area under the curve, mmol.h-1) and for lactate (3-h postprandial, mmol.l-1) was high (p<0.03) in DF (489±131, 8.6±4.8 and 2.2±0.6), intermediate in DFA (276±145, 1.4±1.1 and 1.6±0.4) and low in DPFS (184±62, 0.7±1.8 and 0.1±0.1). Insulin-mediated glucose disposal (mg.kg-1.min-1) showed a numerical trend (p = NS): low in DF (6.9±2.2), intermediate in DFA (8.2±1.3) and high in DPFS pigs (10.4±2.7). Liver weight (g.kg-1 body weight) and liver triglyceride concentration (g.kg-1 liver) were high (p<0.001) in DF (23.8±2.0 and 69±14), intermediate in DFA (21.1±2.0 and 49±15) and low in DPFS pigs (16.4±0.7 and 13±2.0). Aorta fatty streaks were high (p<0.01) in DF (16.4±5.7%), intermediate in DFA (7.4±4.5%) and low in DPFS pigs (0.05±0.02%).ConclusionThis translational study using pigs with induced type 2 diabetes provides evidence that a change in nutritional life style from fast food to a plant-fish oil, slowly digestible starch diet can be more effective than sole anti-diabetic medication.

Exploring the Role of Skeletal Muscle in Insulin Resistance: Lessons from Cultured Cells to Animal Models.

Skeletal muscle is essential to maintain vital functions such as movement, breathing, and thermogenesis, and it is now recognized as an endocrine organ. Muscles release factors named myokines, which can regulate several physiological processes. Moreover, skeletal muscle is particularly important in maintaining body homeostasis, since it is responsible for more than 75% of all insulin-mediated glucose disposal. Alterations of skeletal muscle differentiation and function, with subsequent dysfunctional expression and secretion of myokines, play a key role in the pathogenesis of obesity, type 2 diabetes, and other metabolic diseases, finally leading to cardiometabolic complications. Hence, a deeper understanding of the molecular mechanisms regulating skeletal muscle function related to energy metabolism is critical for novel strategies to treat and prevent insulin resistance and its cardiometabolic complications. This review will be focused on both cellular and animal models currently available for exploring skeletal muscle metabolism and endocrine function.

Insulin-mediated muscle microvascular perfusion and its phenotypic predictors in humans

Insulin increases muscle microvascular perfusion and enhances tissue insulin and nutrient delivery. Our aim was to determine phenotypic traits that foretell human muscle microvascular insulin responses. Hyperinsulinemic euglycemic clamps were performed in 97 adult humans who were lean and healthy, had class 1 obesity without comorbidities, or controlled type 1 diabetes without complications. Insulin-mediated whole-body glucose disposal rates (M-value) and insulin-induced changes in muscle microvascular blood volume (ΔMBV) were determined. Univariate and multivariate analyses were conducted to examine bivariate and multivariate relationships between outcomes, ΔMBV and M-value, and predictor variables, body mass index (BMI), total body weight (WT), percent body fat (BF), lean body mass, blood pressure, maximum consumption of oxygen (VO2max), plasma LDL (LDL-C) and HDL cholesterol, triglycerides (TG), and fasting insulin (INS) levels. Among all factors, only M-value (r = 0.23, p = 0.02) and VO2max (r = 0.20, p = 0.047) correlated with ΔMBV. Conversely, INS (r = − 0.48, p ≤ 0.0001), BF (r = − 0.54, p ≤ 0.001), VO2max (r = 0.5, p ≤ 0.001), BMI (r = − 0.40, p < 0.001), WT (r = − 0.33, p = 0.001), LDL-C (r = − 0.26, p = 0.009), TG (r = − 0.25, p = 0.012) correlated with M-value. While both ΔMBV (p = 0.045) and TG (p = 0.03) provided significant predictive information about M-value in the multivariate regression model, only M-value was uniquely predictive of ΔMBV (p = 0.045). Thus, both M-value and VO2max correlated with ΔMBV but only M-value provided unique predictive information about ΔMBV. This suggests that metabolic and microvascular insulin responses are important predictors of one another, but most metabolic insulin resistance predictors do not predict microvascular insulin responses.

Myeloid‐Specific Inhibition of GHS‐R on Metabolic Dysregulation in Skeletal Muscle During Experimental Type 2 Diabetes

Skeletal muscle plays a significant role in insulin-stimulated glucose disposal, which is a focal point in type 2 diabetes (T2D) research.The complex and highly regulated relationship between insulin secretion and insulin-mediated glucose disposal continue to be debated in the literature.Emerging evidence suggests that chronic-low grade inflammation and its associated inflammatory responses play important roles in T2D pathophysiology.Macrophages are a major source of inflammatory cytokines and have been demonstrated to be responsible for the inflammation of many tissues. Growth Hormone Secretagogue receptor (GHS-R), the known receptor of hormone ghrelin, has roles in both glucose homeostasis and inflammation. Insulin resistance is a major risk factor for T2D and muscle is a key tissue associated with insulin resistance. Little is known whether macrophage GHS-R affects the metabolic dysregulation of skeletal muscle in T2D. METHODS This study utilized a high fat diet and multiple low dose streptozotocin injections to generate a T2D model to evaluate the effects of myeloid-specific inhibition of GHS-R (LysM-Cre;Ghsrf/f) on signaling pathways associated with metabolic dysregulation in skeletal muscle.Gastrocnemius muscles were examined for common markers of insulin signaling and protein anabolism.Gene expression and phosphorylation state of proteins were measured using Western blotting. RESULTS Our data indicate that the GHS-R deficiency in myeloid cells resulted in an increase of mTORC1 activity, showing a suppression of phosphorylation on AKT at Ser473 (â25%; p<0.05).AKT is phosphorylated at Ser473 by mTORC2, and the formation/activity of mTORC2 activity is generally suppressed by mTORC1.Although not statistically significant, mTORC1 activity appeared to be elevated, supported by downstream targets of mTORC1 of higher phosphorylation ratios in both S6K ribosomal at Ser235/236 (P=0.11) and 4EBP1 at Thr37/46 (P=0.18).It is to note that upstream canonical AKT activation was not affected by treatment based on the phosphorylation of its substrate GSK3B (P=0.99).In addition, the knockout model also showed a lower phosphorylation of P-ACC suggesting a lower activity of AMPK, an insulin-independent pathway of glucose uptake known to suppresses mTORC1 activity. CONCLUSION Results from the present study suggests that a myeloid-specific knockout of GHSR1a plays a role in the metabolic shift of skeletal muscle towards significant decrease in mTORC2, likely due to augmented mTORC1 activity.