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Aim of the study was to explore the gender characteristics of the circadian rhythm of carbohydrate metabolism in men and women with normal body weight. Materials and methods. 15 men and 22 women aged 18 to 56 entered the study and underwent clinical, antropometric, biochemical and hormonal examination. Standard oral glucose tolerance test (OGTT) was also performed in the morning and in the evening. Results and discussion. During OGTT performed in morning time there were no differences in mean baseline blood glucose levels between men and women. However higher glucose levels at 120th minute of the test in men demonstrated relative deceleration of glucose utilization in the morning in this group. Higher glucose levels at 120th minute during OGTT in the evening both in men and women comparing with baseline results, and also higher glucose levels at 120th minute of the test in the evening comparing with morning test, indicate decreased glucose tolerance. Insulin to glucose ratio values in men at all timepoints during OGTT were comparable in the morning and in the evening, but in women they were found to be higher in the evening than in the morning. Conclusion. In evening time both in men and women with normal body weight reduced rate of glucose utilization in peripheral tissues reflects circadian rhythm of carbohydrate metabolism. Gender differences of the circadian rhythm of carbohydrate metabolism consist in reduced glucose tolerance in the morning in men comparing to women that is associated with higher waist to hip circumference ratio in men which in turn is related to cumulation of visceral adipose tissue. Presumably greater amount of visceral adipose tissue in men determines more pronounced manifestations of insulin resistance in the morning.

Метаболический синдром объединяет нарушения метаболизма, приводящие к увеличению массы тела, с сопутствующим системным воспалением. Важным является выявление патогенетических связей между нарушениями обмена глюкозы, липидов, окислительным стрессом, воспалением, увеличением массы тела и молекулярными механизмами циркадианных часов. В обзоре приведены современные данные об обеспечении циркадианных ритмов (ЦР) при участии центрального и периферических пейсмекеров, их молекулярных составляющих и иерархии. Главные факторы нарушений ЦР — изменение продолжительности циклов «свет-темнота», нарушение светового режима, продолжительности сна, употребление еды во второй половине дня. Нарушение ЦР вызывает снижение толерантности к глюкозе, повышение инсулинорезистентности тканей, нарушает всасывание, транспортировку и депонирование липидов в организме и приводит к накоплению излишков энергии. Такие метаболические нарушения происходят параллельно с повышением уровня системного воспаления: выработки провоспалительных хемо- и цитокинов, активации иммунных клеток. Сделан вывод, что нарушения ЦР приводят к метаболическим нарушениям и системному воспалению, что соответствует понятию «метаболического синдрома».

Background The second generation antipsychotic drugs represent the most common form of pharmacotherapy for schizophrenia disorders. It is now well established that most of the second generation drugs cause metabolic side-effects. Risperidone and its active metabolite paliperidone (9-hydroxyrisperidone) are two commonly used antipsychotic drugs with moderate metabolic liability. However, there is a dearth of preclinical data that directly compares the metabolic effects of these two drugs, using sophisticated experimental procedures. The goal of the present study was to compare metabolic effects for each drug versus control animals. Methods Adult female rats were acutely treated with either risperidone (0.1, 0.5, 1, 2, 6 mg/kg), paliperidone (0.1, 0.5, 1, 2, 6 mg/kg) or vehicle and subjected to the glucose tolerance test; plasma was collected to measure insulin levels to measure insulin resistance with HOMA-IR. Separate groups of rats were treated with either risperidone (1, 6 mg/kg), paliperidone (1, 6 mg/kg) or vehicle, and subjected to the hyperinsulinemic euglycemic clamp. Results Fasting glucose levels were increased by all but the lowest dose of risperidone, but only with the highest dose of paliperidone. HOMA-IR increased for both drugs with all but the lowest dose, while the three highest doses decreased glucose tolerance for both drugs. Risperidone and paliperidone both exhibited dose-dependent decreases in the glucose infusion rate in the clamp, reflecting pronounced insulin resistance. Conclusions In preclinical models, both risperidone and paliperidone exhibited notable metabolic side-effects that were dose-dependent. Differences between the two were modest, and most notable as effects on fasting glucose.

Background: Sleep is an important modulator of neuroendocrine function and glucose metabolism. Poor sleep quality is related to metabolic and endocrine alterations, including decreased glucose tolerance, decreased insulin sensitivity, and increased hunger and appetite. Objective: The aim of the present study was to determine the association between sleep quality with metabolic syndrome (MetS) markers, fitness and body fat of women with severe/morbid obesity. Methods: This cross-sectional study included 26 women with severe/morbid obesity. Fasting plasma glucose (FPG), high-density lipids (HDL-c), triglycerides (TGs), and the metabolic outcomes total cholesterol (Tc) and low-density lipids (LDL-c), systolic (SBP) and diastolic blood pressure (DBP), body composition and fitness were measured. Results: Poor sleep quality showed a positive association with body fat (%) ≥ 48.2 (OR; 8.39, 95% CI; 1.13–62.14, p = 0.037), morbid obesity (OR; 8.44, 95% CI; 1.15–66.0, p = 0.036), glucose ≥ 100 mg/dL (OR; 8.44, 95% CI; 1.15–66.0, p = 0.036) and relative handgrip strength ≤ 0.66 (OR; 12.2, 95% CI; 1.79–83.09, p = 0.011). Conclusion: sleep quality is associated with health markers in women with severe/morbid obesity., Universidad de La Frontera, Temuco, Chile Project DI21-0030 and Project FRO 1895

The insulin-like growth factor (IGF) system is responsible for growth, but also affects metabolism and brain function throughout life. New IGF family members (i.e., pappalysins and stanniocalcins) control the availability/activity of IGFs and are implicated in growth. However, how diet and obesity modify this system has been poorly studied. We explored how intake of a high-fat diet (HFD) or commercial control diet (CCD) affects the IGF system in the circulation, visceral adipose tissue (VAT) and hypothalamus. Male and female C57/BL6J mice received HFD (60% fat, 5.1 kcal/g), CCD (10% fat, 3.7 kcal/g) or chow (3.1 % fat, 3.4 kcal/g) for 8 weeks. After 7 weeks of HFD intake, males had decreased glucose tolerance (p &lt, 0.01) and at sacrifice increased plasma insulin (p &lt, 0.05) and leptin (p &lt, 0.01). Circulating free IGF1 (p &lt, 0.001), total IGF1 (p &lt, 0.001), IGF2 (p &lt, 0.05) and IGFBP3 (p &lt, 0.01) were higher after HFD in both sexes, with CCD increasing IGFBP2 in males (p &lt, 0.001). In VAT, HFD reduced mRNA levels of IGF2 (p &lt, 0.05), PAPP-A (p &lt, 0.001) and stanniocalcin (STC)-1 (p &lt, 0.001) in males. HFD increased hypothalamic IGF1 (p &lt, 0.01), IGF2 (p &lt, 0.05) and IGFBP5 (p &lt, 0.01) mRNA levels, with these changes more apparent in females. Our results show that diet-induced changes in the IGF system are tissue-, sex- and diet-dependent.

Obesity is influenced by genetics and diet and has wide ranging comorbidities, including anxiety and depressive disorders. Outbred heterogeneous stock (HS) rats are used for fine-genetic mapping of complex traits and may be useful for understanding gene by diet interactions. In this study, HS rats were fed diets containing 60% kcal from fat (high-fat diet, HFD) or 10% kcal from fat (low-fat diet, LFD) and tested for metabolic ( study 1) and behavioral ( study 2) outcomes. In study 1, we measured glucose tolerance, fasting glucose and insulin, fat pad weights and despair-like behavior in the forced swim test (FST). In study 2, we assessed anxiety-like (elevated plus maze, EPM; open field test, OFT) and despair-like/coping (splash test, SpT; and FST) behaviors. Body weight and food intake were measured weekly in both studies. We found negative effects of HFD on metabolic outcomes, including increased body weight and fat pad weights, decreased glucose tolerance, and increased fasting insulin. We also found negative effects of HFD on despair-like/coping and anxiety-like behaviors. These include increased immobility in the FST, decreased open arm time in the EPM, and increased movement and rest episodes and decreased rearing in the OFT. The diet-induced changes in EPM and OFT were independent of overall locomotion. Additionally, diet-induced changes in OFT behaviors were independent of adiposity, while adiposity was a confounding factor for EPM and FST behavior. This work establishes the HS as a model to study gene by diet interactions affecting metabolic and behavioral health.

It has been established that Long noncoding RNAs (lncRNAs) play a pivotal role in regulating systemic glucose and lipid homeostasis. Previously, we identified a insulin-resistance (IR) related lncRNA named Gm15441, which was upregualted in skeletal muscle from db/db mice by RNA-sequencing. Here, we explored the relationship between Gm15441 and skeletal muscle function in vitro and in vivo and the possible mechanism involved in that process. Real-time PCR analyses revealed Gm15441 was abundant in skeletal muscle compared to other metabolic tissues. Additionally, Gm15441 expression was observed upregualted in IR cells (pamitate-treated C2C12 myotubes) and mice (db/db, ob/ob and aged mice). Overexpression of Gm15441 by plasmid transfection in C2C12 myotubes decreased Glut4, p-Akt/Akt and p-Irs1/Irs1 protein levels and attenuated glucose uptake capacity by the 2-NBDG method. Gm15441 overexpression also impaired mitochondrial oxygen consumption and Pgc1α expression. Moreover, adeno-associated viral (AAV) vectors to induce Gm15441 expression in skeletal muscles. Six-week-old male mice were administered with AAV-GFP or AAV-Gm15441 vectors followed with or without high-fat diet (HFD) for 14 weeks. Body weight gain and food intake were not different among the groups, but AAV-Gm15441 mice under HFD showed decreased glucose tolerance and insulin sensitivity. These mice exhibited ectopic lipid accumulation in skeletal muscle by HE staining, although no difference was observed in skeletal muscle weights and serum TG. A global mRNA analysis further indicated a possible regulatory role of Pparα-Pgc1α pathway in Gm15441-mediated dysregulation of glucose-lipid metabolism. Collectively, these findings improve our understanding of lncRNAs involved in skeletal muscle glucose-lipid metabolism and represent potential therapeutic targets to IR and associated metabolic diseases. Key words: lncRNA, Gm15441, skeletal muscle, insulin resistance, Pgc1α. Disclosure L. You: None. Y. Zeng: None. N. Gu: None. C. Ji: None.

The CDC states that there has been a dramatic increase in obesity from 1990 to 2010. Type-II diabetes and obesity prevalence are increasing worldwide. Often, obesity and Type-II diabetes are concurrent, and predispose individuals to development of fatty liver disease, referred to as Non-alcoholic fatty liver disease (NAFLD). Perfluorooctane sulfonic acid (PFOS) and perfluorooctanoic acid (PFOA) are two commonly studied perfluorinated compounds (PFC’s) that are considered environmental toxicants that have the potential to elicit diabetic and NAFLD phenotypes. This dissertation presents novel findings of gaps within the literature to date. Traditionally, diabetes and obesity have been discussed in regard with genetics, diet and old age. Now, risk factors that also need to be considered are environmental chemicals. We found that PFOS elicits an insulin-resistant phenotype in adult mice, where they were not utilizing glucose as readily compared to the controls. The effect of PFOS on therapeutic management interventions has not previously been looked at. Here, we show that PFOS interferes with the Metformin-induced decrease in glucose. We also found a vast increase in the hepatic triglycerides with PFOS exposure. In this thesis, PFOS was administered in a sub-chronic low dose (100μg/kg) daily to mice fed ad libitum or placed on caloric restriction (CR) for five weeks. In the cohort we generated, we observed that PFOS exposure increased hepatic lipid content in mature male mice fed ad libitum and dampened the observed CR-induced decrease in hepatic lipids. PFOS administration did not affect glucose tolerance in ad libitum fed mice, but did interfere with CR-induced improvement of glucose tolerance. This was further associated with suppression of IRS-1 mRNA expression in liver. As hepatic lipid content is closely tied to insulin and glucagon signaling for hepatic glucose production, it was determined whether the observed effects in vivo were due to PFOSstimulated hepatic glucose production. Using cultured mouse hepatocytes under low glucose conditions, it was evaluated whether PFOS could enhance glucagonstimulated glucose production. PFOS stimulated hepatocyte glucose production and also enhanced glucagon-induced glucose production. Furthermore, in HEPG2 cells, PFOS exposure (25 and 250 μM) significantly increased glucose output and AiCar, which suppresses glucose production, was ineffective in the presence of PFOS. These findings provide a mechanistic explanation for the decreased glucose tolerance in our in vivo mouse cohort. PFOS increases glucose output from the in vitro models, even when challenged with metformin or AiCar, as well as, decreases the glucose utilization in the in vivo mouse study suggesting that it has a glucagon-like effect. PFOA is a perfluorinated carboxylic acid also commonly found in the environment. According to the EPA, low levels of PFOA are widely distributed in environmental media (Houde et al., 2011; Gewertz et al., 2013) and in the blood of the general United States population. The EPA states that PFOA is a known liver toxicant, development toxicant, and carcinogen in rodents. It has been detected in human liver, kidney and adipose tissue ranging from 0.3 to 3.8ng/g with the highest concentrations within the liver (Maestri et al., 2006). In another study, PFOA is considered an obesogen to mid-aged mice where insulin and leptin levels were altered at a very low concentration (Hines et al., 2009). PFOA is a Potent activator of peroxisomeproliferator activated receptor-alpha (Ppar-α) contributing to oxidative stress and activation of fatty acid oxidation pathways in hepatocytes. Given its persistence, the purpose of this study was to evaluate whether PFOA treatment affects fatty acid oxidation, lipid synthesis, and antioxidant response gene expression in adipose tissue in adult male mice. Utilizing an exposure paradigm characterized by the Environmental Protection Agency, adult male mice were treated with 1.0 or 3.0 mg PFOA ammonium salt/kg for 7 days. Adipose tissue was collected and total RNA was isolated. Analysis of mRNA was completed by quantitative PCR. For the most part, gene expression in adipose tissue from vehicleand PFOA-treated mice was similar. Literature lacks data on PFOA in adipose tissue and in human health, which continue to be discovered. Given its persistence, longer exposure periods and protein expression changes should be examined.

In this study, we observed the effect of D-chiro-inositol (DCI) on glucose consumption in type 2 diabetic db/db mice, and investigated the relevant mechanism. We discovered that the stability of 24-h blood glucose under the nonfasting condition and decreased glucose tolerance were both alleviated after treatment with DCI. Moreover, the content of glycosylated protein and advanced glycation end products in the serum was reduced, the damage in the liver tissue was alleviated, and the synthesis of liver glycogen was significantly promoted. In addition, DCI increased the expression of insulin receptor substrate 2 (IRS2), phosphatidylinositol 3-kinase (PI3K), protein kinase B (AKT), glucose transporters 4 (GLUT4), and phospho-AKT (S473) protein. In contrast, DCI decreased the expression level of glycogen synthase kinase 3β (GSK3β) protein in liver tissue to various degrees, as shown by immunohistochemistry and western blotting. Furthermore, DCI increased the mRNA expression of IRS2, PI3K, AKT, and GLUT4, and reduced that of GSK3β in liver tissue, as demonstrated by polymerase chain reaction. Finally, DCI promoted glucose consumption in high glucose-stimulating HepG2 cells and increased the expression of IRS2 protein in HepG2 cells, as revealed by fluorescence staining and flow cytometry. Our results indicate that DCI can significantly improve glucose metabolism in diabetic mice and HepG2 cells. This effect may be associated with the upregulation of IRS2, PI3K, AKT, and GLUT4 and downregulation of GSK3β.

Metabolic syndrome is a cluster of disorders that increase the risk of cardiovascular disease and diabetes. This study has investigated the responses to rind of yellow mangosteen (Garcinia dulcis), usually discarded as waste, in a rat model of human metabolic syndrome. The rind contains higher concentrations of phytochemicals (such as garcinol, morelloflavone and citric acid) than the pulp. Male Wistar rats aged 8&ndash, 9 weeks were fed either corn starch diet or high-carbohydrate, high-fat diet for 16 weeks, which were supplemented with 5% freeze-dried G. dulcis fruit rind powder during the last 8 weeks. We characterised metabolic, cardiovascular, liver and gut microbiota parameters. High-carbohydrate, high-fat diet-fed rats developed abdominal obesity, hypertension, increased left ventricular diastolic stiffness, decreased glucose tolerance, fatty liver and reduced Bacteroidia with increased Clostridia in the colonic microbiota. G. dulcis fruit rind powder attenuated these changes, improved cardiovascular and liver structure and function, and attenuated changes in colonic microbiota. G. dulcis fruit rind powder may be effective in metabolic syndrome by appetite suppression, inhibition of inflammatory processes and increased fat metabolism, possibly related to changes in the colonic microbiota. Hence, we propose the use of G. dulcis fruit rind as a functional food to ameliorate symptoms of metabolic syndrome.

KEY POINTS A ketogenic diet is known to lead to weight loss and is considered metabolically healthy; however there are conflicting reports on its effect on hepatic insulin sensitivity. KD fed animals appear metabolically healthy in the fasted state after 3 days of dietary challenge, whereas obesogenic high-fat diet (HFD) fed animals show elevated insulin levels. A glucose challenge reveals that both KD and HFD fed animals are glucose intolerant. Glucose intolerance correlates with increased lipid oxidation and lower respiratory exchange ratio (RER); however, all animals respond to glucose injection with an increase in RER. Hyperinsulinaemic-euglycaemic clamps with double tracer show that the effect of KD is a result of hepatic insulin resistance and increased glucose output but not impaired glucose clearance or tissue glucose uptake in other tissues. ABSTRACT Despite being a relevant healthcare issue and heavily investigated, the aetiology of type 2 diabetes (T2D) is still incompletely understood. It is well established that increased endogenous glucose production (EGP) leads to a progressive increase in glucose levels, causing insulin resistance and eventual loss of glucose homeostasis. The consumption of high carbohydrate, high-fat, western style diet (HFD) is linked to the development of T2D and obesity, whereas the consumption of a low carbohydrate, high-fat, ketogenic diet (KD) is considered healthy. However, several days of carbohydrate restriction are known to cause selective hepatic insulin resistance. In the present study, we compare the effects of short-term HFD and KD feeding on glucose homeostasis in mice. We show that, even though KD fed animals appear to be healthy in the fasted state, they exhibit decreased glucose tolerance to a greater extent than HFD fed animals. Furthermore, we show that this effect originates from blunted suppression of hepatic glucose production by insulin, rather than impaired glucose clearance and tissue glucose uptake. These data suggest that the early effects of HFD consumption on EGP may be part of a normal physiological response to increased lipid intake and oxidation, and that systemic insulin resistance results from the addition of dietary glucose to EGP-derived glucose.

Maternal overnutrition increases the risk of long-term metabolic dysfunction in offspring. Exercise improves metabolism partly by upregulating mitochondrial biogenesis or function, via increased levels of nicotinamide adenine dinucleotide (NAD+). We have shown that the NAD+ precursor, nicotinamide mononucleotide (NMN) can reverse some of the negative consequences of high fat diet (HFD) consumption. To investigate whether NMN can impact developmentally-set metabolic deficits, we compared treadmill exercise and NMN injection in offspring of obese mothers. Five week old lean and obese female C57BL6/J mice were mated with chow fed males. Female offspring weaned onto HFD were given treadmill exercise for 9 weeks, or NMN injection daily for 18 days. Maternal obesity programmed increased adiposity and liver triglycerides, with decreased glucose tolerance, liver NAD+ levels and citrate synthase activity in offspring. Both interventions reduced adiposity, and showed a modest improvement in glucose tolerance and improved markers of mitochondrial function. NMN appeared to have stronger effects on liver fat catabolism (Hadh) and synthesis (Fasn) than exercise. The interventions appeared to exert the most global benefit in mice that were most metabolically challenged (HFD-consuming offspring of obese mothers). This work encourages further study to confirm the suitability of NMN for use in reversing metabolic dysfunction linked to programming by maternal obesity.

Insulin resistance (IR) is the impaired insulin response that causes decreased glucose tolerance. Electrical stimulation (ES) can improve insulin sensitivity in the skeletal muscle. However, the underlying molecular mechanisms remain to be elucidated. In the present study, the effect of ES and diet therapy on IR and the role of the mammalian target of rapamycin (mTOR) pathway in the improvement of IR by ES were investigated. A total of 70 Sprague‑Dawley male rats were divided into five groups: Normal (n=10), IR control (n=15), diet (n=15), ES (n=15) and ES + diet (n=15) groups. An IR rat model was established by high‑fat and high‑carbohydrate diet for 5 weeks and confirmed by measurement of fasting plasma glucose (FPG), insulin, insulin sensitivity index (ISI) and IR index. ES on the Zusanli (ST36), Sanyinjiao (SP 6) and Weiwanxiashu (EX‑B3) acupoints and the low‑fat and low‑carbohydrate diet demonstrated protective effects. The body weight, concentrations of FPG, insulin, triglycerides (TG), free fatty acids (FFA) and total cholesterol (TC) of the rats were detected. Pathologic changes in the liver and pancreatic tissues were assessed. Western blotting and immunohistochemistry were performed to determine the role of PI3K/Akt/mTOR signaling. Results demonstrated that ES and diet therapy significantly increased ISI and reduced FPG, IR index, FFA, TG, TC and weight. Inflammatory cell infiltration in the liver and pancreatic tissues was ameliorated and lipid droplets and cavitation in hepatocyte were decreased after ES and diet therapy. The administration of ES and diet therapy also enhanced glucose transport by the upregulation of glucose transporter 4 and accelerated glycogen synthesis through the suppression of glycogen synthase kinase 3α/β via PI3K/Akt/mTOR signaling. Hence, the present results demonstrated that ES combined with diet therapy improved IR through PI3K/Akt/mTOR signaling. The proposed therapy was superior to the method of diet alone.

Patients with Parkinson’s disease (PD) have a high prevalence of glucose metabolism abnormalities. However, the mechanism underlying these symptoms remains unclear. The hypothalamic-pituitary-adrenal (HPA) axis is the major neuroendocrine axis that regulates homeostasis in mammals, including glucose metabolism. Corticotrophin releasing hormone (CRH), which is synthesized in the paraventricular nucleus (PVN) of the hypothalamus, plays an important role in the regulation of blood glucose levels via the HPA axis. Our previous studies have reported that PVN neurons express numerous dopamine receptors (DRs) and accept direct projections from the substantia nigra (SN). We hypothesize that damage to dopaminergic neurons in the SN might influence the blood glucose level through the HPA system. Rats with bilateral SN lesions induced by 6-hydroxydopamine (6-OHDA) (referred to as 6-OHDA rats) were used to investigate alterations in the levels of blood glucose, CRH, and factors related to the HPA axis and to explore possible mechanisms. Blood glucose levels were detected at different time points after the glucose solution was intraperitoneally administered. CRH and DRs in the PVN were evaluated by immunofluorescence and western blot analysis. Adrenocorticotropic hormone (ACTH) in the pituitary and plasma corticosterone (CORT) was evaluated by radioimmunoassay (RIA). The results showed that 6-OHDA rats exhibited significantly decreased tyrosine hydroxylase (TH) in the SN and decreased glucose tolerance at 6 weeks, but not at 4 weeks. In the PVN, dopamine receptor 2 (D2) was expressed on CRH-positive neurons, and D2-positive neurons were surrounded by TH-positive fibers. Additionally, the expression of CRH was upregulated, whereas the expression of D2 and TH were downregulated in 6-OHDA rats compared with control rats. In D2 knock-out mice, the significantly enhanced expression of CRH and reduced expression of D2 were detected in the PVN. Furthermore, RIA revealed increased ACTH in the pituitary and elevated CORT in the blood. In summary, the present study suggests that the dopaminergic neurons in the SN are involved in the regulation of body glucose metabolism through CRH neurons that express D2 in the hypothalamic PVN. SN lesions decrease glucose tolerance mainly by downregulating D2 and upregulating CRH in the PVN through the HPA neuroendocrine system.

Erythropoietin (EPO), the cytokine that regulates erythropoiesis, contributes to metabolic regulation in rodents. The increase in red blood cell production with EPO treatment in mice was accompanied by improved glycemic control, and by attenuated body weight gain via reducing fat mass in male mice. No change in body weight was observed in mice with EPO receptor restricted to erythroid tissue, suggesting that EPO regulation of body weight is a non-erythroid response. EPO stimulated decrease in fat mass was observed in ovariectomized female mice on high fat diet, but not after estradiol supplementation or in ovariectomized female mice on normal chow, providing evidence for estrogen related gender specific EPO action in metabolic regulation beyond erythropoiesis. Here we determine the contribution of estrogen response in EPO metabolic regulation by assessing EPO treatment in estrogen receptor α knockout (ERαKO) mice. Male and female ERαKO mice exhibit decreased glucose tolerance, increased fat mass and, in female ERαKO mice, increased lean mass compared with WT control mice. Overall, EPO stimulated increase in hematocrit in male and female ERαKO mice on high fat diet was accompanied by improvement in glucose tolerance comparable to that observed in WT control mice treated with EPO. EPO treatment in male ERαKO and WT mice show significantly reduced the increase in fat mass while on high fat diet compared with saline treatment. Similarly, EPO treatment in female ERαKO mice on high fat diet show reduced fat mass gain compared to saline treatment. In contrast, EPO treatment did not affect fat mass in female WT mice on high fat diet. We also observed that on normal chow diet, EPO treatment was able to reduce fat mass in female ERαKO mice, but not in female WT mice, confirming the role of estrogen in mediating the sex-differential effect of EPO in regulating fat mass. These results are evidence of cross talk between EPO and estrogen for metabolic homeostasis and regulation of body mass in female mice. Disclosure J. Lee: None. H. Rogers: None. C.T. Noguchi: None.

In 1976, an animal model of type 2 diabetes (T2DM) was described by Cameron et al. using injection of monosodium glutamate (MSG) in KK mice during the neonatal period. Some years later, similar models have been developed by various doses and durations and the main of these models exhibited obesity and features of diabetes mellitus, including glycosuria, hyperglycemia, hyperinsulinemia, decreased glucose tolerance, and insulin sensitivity. Studies indicated that MSG treatment of newborn animals generates necrosis of neuronal cells of the hypothalamic ventromedial nucleus and arcuate nucleus. Neonatal MSG-treatment was related to normoglycemic-normoinsulinemic state at young ages and development of obesity and hyperinsulinemia at adult ages. Following observation of a severe hypertrophy of pancreatic islets due to the proliferation of β-cells in MSG-treated mice, this model has been proposed as a useful animal model of human T2DM. A higher dose of MSG (≥4 mg/g body weight) accompanied by a longer follow-up duration (>6 months) are needed to establish a typical animal model of T2DM.

Hydrogen sulfide (H2S) is involved in the pathophysiology of type 2 diabetes. Inhibition and stimulation of H2S synthesis has been suggested to be a potential therapeutic approach for type 2 diabetes. The aim of this study was therefore to determine the effects of long-term sodium hydrosulfide (NaSH) administration as a H2S releasing agent on carbohydrate metabolism in type 2 diabetic rats. Type 2 diabetes was established using high fat-low dose streptozotocin. Rats were treated for 9 weeks with intraperitoneal injections of NaSH (0.28, 0.56, 1.6, 2.8, and 5.6 mg/kg). Serum glucose was measured weekly for one month and then at the end of the study. Serum insulin was measured before and after the treatment. At the end of the study, glucose tolerance, pyruvate tolerance and insulin secretion were determined and blood pressure was measured. In diabetic rats NaSH at 1.6&ndash, 5.6 mg/kg increased serum glucose (11%, 28%, and 51%, respectively) and decreased serum insulin, glucose tolerance, pyruvate tolerance and in vivo insulin secretion. In controls, NaSH only at 5.6 mg/kg increased serum glucose and decreased glucose tolerance, pyruvate tolerance and insulin secretion. Chronic administration of NaSH in particular at high doses impaired carbohydrate metabolism in type 2 diabetic rats.

Sleep has often been thought of as a “restorative” process for the mind and the body; however, it has been shown that it also directly affects many metabolic and hormonal processes. Sleep which is a key factor in physiological restitution also modulates the metabolic, endocrine, and cardiovascular systems and thus has medical implications which include decreased glucose tolerance and insulin sensitivity. Reduction in the time available for sleep is a hallmark of modern society which has developed during the past few decades with increase in the time available for work and leisure, often viewed as harmless and efficient. In normal, healthy individuals, glucose tolerance varies across the day, with total sleep loss or even a 2-h reduction of sleep/night for 1 week there is increased levels of proinflammatory cytokines and low grade inflammation, a condition known to predispose to insulin resistance and diabetes. Sleep deprivation is associated with disturbances in the secretion of the counter regulatory hormones such as growth hormone and cortisol. Elevated evening cortisol levels can lead to morning insulin resistance, while the sympathetic nervous system inhibits insulin release while the parasympathetic system stimulates it, thus leading to elevated glucose levels. Adults are sleeping less and less in our society. Yet sleep is no longer thought of as strictly a restorative process for the body. The importance of sleep for metabolic function and specifically glucose homeostasis is now widely accepted, as many studies have shown a correlation between sleep deprivation or poor sleep quality and an increased risk of diabetes.

Rats with intrauterine growth retardation and catch-up growth (CG-IUGR) after birth show increased susceptibility to diabetes mellitus in adulthood. The expression of glucose transporter type 4 (GLUT4) decreases in female IUGR offspring rats with seminutrient restriction during pregnancy. However, the male CG-IUGR rats also display an increased susceptibility to diabetes mellitus in adulthood. Whether there is another factor, besides GLUT4, in male CG-IUGR rat that mediates their susceptibility to diabetes mellitus? The male IUGR rats with catch-up growth were selected as the research objects. CG-IUGR rats had an increased fasting blood glucose level, and increased serum total cholesterol, triglyceride and free fatty acid levels. Glucose tolerance test and insulin tolerance test showed higher glucose levels and much higher insulin levels after a glucose load in CG-IUGR. The mRNA and protein expressions of IRS-2 in liver tissue, and IRS-1 and GLUT4 in skeletal muscle in CG-IUGR rats were down-regulated, but only the GLUT4 down-regulation displayed strong negative correlations with the decreased glucose tolerance capability by Pearson's analysis. The methylation patterns of CpG islands in the promoter regions of IRS-1, IRS-2 and GLUT4 in CG-IUGR rats varied, which was not significantly correlated with their expressions. The male CG-IUGR rats showed decreased glucose tolerant capability, suggesting increased susceptibility to diabetes mellitus in adulthood. The GLUT4 down-regulation may play a vital role in the development of decreased glucose tolerance in male CG-IUGR rats. The methylation modification of the promoter region of GLUT4 does not appear to be involved in its expression.

// Cong Tao 1,2,* , Hongyan Ren 1,3,* , Pan Xu 1 , Jia Cheng 1 , Sujuan Huang 1 , Rong Zhou 1 , Yulian Mu 1 , Shulin Yang 1 , Desheng Qi 2 , Yanfang Wang 1 and Kui Li 1 1 State Key Laboratory of Animal Nutrition, Institute of Animal Science, Chinese Academy of Agricultural Sciences, Beijing, China 2 College of Animal Science and Technology, Huazhong Agricultural University, Wuhan, China 3 Key Laboratory of Animal Embryo & Molecular Breeding of Hubei Province, Institute of Veterinary and Animal Science, Hubei Academy of Agricultural Science, Wuhan, China * These authors have contributed equally to this work Correspondence to: Kui Li, email: // Yanfang Wang, email: // Keywords : miR-200b/a/429, insulin resistance, high-fat-diet, knockout, adipose tissue, Pathology Section Received : March 20, 2016 Accepted : September 12, 2016 Published : September 16, 2016 Abstract Growing evidence demonstrates the important role of microRNAs (miRs) in regulating adipogenesis, obesity and insulin resistance. The miR-200b/a/429 cluster has been functionally characterized in mammalian reproduction; however, the potential role of the miR-200 family in adipocytes is poorly understood. The aim of our study was to investigate the physiological function of miR-200b/a/429 in the regulation of whole-body metabolism in terms of the activities and targets of this cluster in adipocytes. We generated adipocyte-specific miR-200b/a/429 knockout (ASKO) mice using a Cre-loxP system in which Cre expression was driven by the aP2 promoter. The ASKO and wild type (WT) littermate were fed a chow diet (CD) or high-fat-diet (HFD), and changes in body composition, metabolic parameters, energy homeostasis, glucose tolerance and insulin sensitivity were analyzed. The miR-200b/a/429 putative target genes were predicted and validated via luciferase reporter assays. We found that the HFD-fed ASKO mice gradually gained more body weight than the WT mice due to the increased adiposity. Decreased glucose tolerance and insulin sensitivity were also observed in the HFD-fed ASKO mice. Notably, the down-regulation of lipolysis-related genes and the decreased response to CL-316,243 stimulation in the HFD-fed ASKO mice suggested that these animals exhibited impaired lipolysis. In addition, the HFD-fed ASKO mice displayed impaired energy expenditure, indicating that the miR-200b/a/429 cluster is essential for developing adaptive responses to stressors such as HFD. For the first time, our studies demonstrated the essential role of miR-200b/a/429 in adipocytes in the regulation of HFD-induced whole-body metabolic changes.

We recently reported that stressed adipocytes release extracellular vesicles (EVs) that act as "find-me" signals to promote macrophage migration and activation. In this study, we performed a comprehensive characterization of stressed adipocyte-derived EVs, assessing their antigenic composition, lipidomics, and RNA profiles. Perilipin A was identified as one of the adipose-specific proteins and studied as a potential novel biomarker to detect adipocyte-derived EVs in circulation. Circulating EVs were significantly increased in mice with diet-induced obesity (DIO) and in obese humans with metabolic syndrome compared to lean controls. This increase was associated with decreased glucose tolerance in the DIO mice and metabolic dysfunction, elevated insulin, and homeostatic model assessment of insulin resistance (HOMA-IR) in the obese humans. EVs from both DIO mice and obese humans were enriched in perilipin A, a central gatekeeper of the adipocyte lipid storehouse and a marker of adipocyte differentiation. In obese humans, circulating levels of EVs enriched in perilipin A were dynamic, decreasing 35% (p

Benefits of exercise have been documented for many diseases with a chronic progression, including obesity, diabetes mellitus, cardiovascular diseases, neurodegenerative diseases, certain types of cancers, and overall mortality. Low-grade systemic inflammation is a key component of these pathologies and it has been demonstrated that can be prevented by performing regularly physical exercise. The aim of this study was to examine the effect of lipopolysaccharide (LPS)-induced inflammation on glucose and insulin tolerance, exercise performance, production of urinary neopterin and striatal neurotransmitters levels in adult male C57BL/6 mice. Increased blood glucose clearance and insulin sensitivity were observed after a single administration of glucose (2 g/kg, p.o.) or insulin (0.5 U/kg, i.p.). However, the repeated injection of LPS (0.33 mg/kg/day, i.p.) decreased glucose tolerance and increase urinary neopterin levels, pointing to systemic inflammation. In parallel to the urinary-increased neopterin, it was observed a significant reduction in the striatal dopamine levels and an increase in the serotonin/dopamine ratio. While a single LPS injection (0.33 mg/kg, i.p.) showed impaired performance in the incremental loading test (10 m/min, with 2 m/min increment every 3 min, at 9% grade), a moderate physical exercise protocol (treadmill for three weeks; 5 sessions/week; up to 50 min/day) prevented the exacerbation of immune system activation and preserved mitochondrial activity in skeletal muscle from mice with continuous LPS infusion (infusion pumps: 0.83 mg/kg/day, i.p.). In conclusion, the peripheral-induced inflammation elicited metabolic alterations that provoked impairment in striatal dopamine metabolism. The moderate exercise prevented the increase of urinary neopterin and preserved mitochondrial activity under LPS-induced inflammatory conditions.

MicroRNAs (miRNAs) are known to contribute to many metabolic diseases, including diabetes. In this study, we investigated the role of miR199a-5p in the regulation of hepatic insulin sensitivity. Ad-anti-miR199a-5p adenoviruses were injected into male C57BL/6J WT mice fed a high-fat diet to inhibit miR199a-5p expression before the glucose levels and insulin resistance were assessed. Similarly, Ad-miR199a-5p adenoviruses were injected into male C57BL/6J WT mice to cause the overexpression of miR199a-5p. To investigate the roles of autophagy-related protein 14 (ATG14) and miR199a-5p in the regulation of insulin sensitivity, we injected Ad-miR199a-5p with or without Ad-ATG14 viruses into WT C57BL/6J mice before performing functional assays. Moreover, we infected HepG2 cells or primary hepatocytes with Ad-anti-miR199a-5p or Ad-miR199a-5p viruses to determine the effect of miR199a-5p on insulin resistance in vitro. Finally, we explored the clinical relevance of miR199a-5p by examining the expression level of miR199a-5p in liver samples derived from diabetes patients. We first demonstrated that knocking down miR199a-5p led to decreased glucose tolerance and clearance in vivo, whereas the overexpression of miR199a-5p had the opposite effect. We further identified ATG14 as the target of miR199a-5p, and ATG14 partially rescued miR199a-5p-potentiated glucose and insulin tolerance. In addition, transmission electron microscopy data and western blot data regarding ATG14, LC3 and BECLIN1 illustrated that miR199a-5p regulates autophagy via ATG14. Knocking down miR199a-5p in primary hepatocytes and HepG2 cells suppressed the insulin-stimulated phosphorylation of insulin receptor β, glycogen synthase kinase 3β and protein kinase B, whereas the overexpression of miR199a-5p further potentiated their phosphorylation. Finally, we detected upregulated miR199a-5p levels, which were correlated with reduced ATG14 mRNA levels and downregulated autophagy in liver samples obtained from diabetes patients. Our study uncovered a novel biological role of miR199a-5p in the regulation of hepatic insulin sensitivity via ATG14-mediated autophagy.

Free fatty acid receptor 2 (FFA2) is expressed on enteroendocrine L cells that release glucagon-like peptide 1 (GLP-1) and peptide YY (PYY) when activated by short-chain fatty acids (SCFAs). Functionally GLP-1 and PYY inhibit gut transit, increase glucose tolerance, and suppress appetite; thus, FFA2 has therapeutic potential for type 2 diabetes and obesity. However, FFA2-selective agonists have not been characterized in vivo. Compound 1 (Cpd 1), a potent FFA2 agonist, was tested for its activity on the following: GLP-1 release, modulation of intestinal mucosal ion transport and transit in wild-type (WT) and FFA2−/− tissue, and food intake and glucose tolerance in lean and diet-induced obese (DIO) mice. Cpd 1 stimulated GLP-1 secretion in vivo, but this effect was only detected with dipeptidyl peptidase IV inhibition, while mucosal responses were PYY, not GLP-1, mediated. Gut transit was faster in FFA2−/− mice, while Cpd 1 slowed WT transit and reduced food intake and body weight in DIO mice. Cpd 1 decreased glucose tolerance and suppressed plasma insulin in lean and DIO mice, despite FFA2−/− mice displaying impaired glucose tolerance. These results suggest that FFA2 inhibits intestinal functions and suppresses food intake via PYY pathways, with limited GLP-1 contribution. Thus, FFA2 may be an effective therapeutic target for obesity but not for type 2 diabetes.

Hypertension, decreased glucose tolerance, adverse lipid profiles and low physical activity levels are associated with increased type 2 diabetes mellitus (T2DM) and cardiovascular disease (CVD) risk. High intensity interval training (HIIT), a low volume, reduced time, high intensity programme, may be a useful alternative to current government guidelines which specify a minimum of 150 minutes of physical activity per week. We describe a personalised programme of high intensity exercise which provides significant improvements in CVD risk markers. Healthy volunteers undertook 6 weeks of HIIT. T2DM and CVD risk predictors including glucose tolerance, VO2max , blood pressure (BP), and lipids were measured before and after HIIT. HIIT training was associated with beneficial changes in a range of predictors of blood flow and cardiovascular risk. There was a heterogeneous response to HIIT, with some subjects responding with favourable changes and others being non-responders to HIIT. In responders, HIIT was associated with a statistically significant (p = 0.023) increase in VO2max , from 45.4 (38.4,52.5) to 56.9 (51.2,65.7) (median (interquartile range)(ml/min/kg)). In responders HIIT resulted in a decrease in systolic BP from 127 (126,129) to 116 (106,122) (mmHg) with p = 0.026 and a decrease is diastolic blood pressure from 72 (69,74) to 57 (56,66) with p = 0.026. There was also some evidence of a beneficial change in blood lipid and glucose concentrations with HIIT. In conclusion, personalised HIIT has potential as an intervention to improve blood flow and cardiovascular health.

The aim of this study was to understand whether high folic acid (HFA) exposure during the perigestational period induces metabolic dysfunction in the offspring, later in life. To do this, female Sprague–Dawley rats (G0) were administered a dose of folic acid (FA) recommended for pregnancy (control, C, 2 mg FA/kg of diet,n=5) or a high dose of FA (HFA, 40 mg FA/kg of diet,n=5). Supplementation began at mating and lasted throughout pregnancy and lactation. Body weight and food and fluid intake were monitored in G0 and their offspring (G1) till G1 were 13 months of age. Metabolic blood profiles were assessed in G1 at 3 and 13 months of age (3M and 13M respectively). Both G0 and G1 HFA females had increased body weight gain when compared with controls, particularly 22 (G0) and 10 (G1) weeks after FA supplementation had been stopped. G1 female offspring of HFA mothers had increased glycemia at 3M, and both female and male G1 offspring of HFA mothers had decreased glucose tolerance at 13M, when compared with matched controls. At 13M, G1 female offspring of HFA mothers had increased insulin and decreased adiponectin levels, and G1 male offspring of HFA mothers had increased levels of leptin, when compared with matched controls. In addition, feeding of fructose to adult offspring revealed that perigestational exposure to HFA renders female progeny more susceptible to developing metabolic unbalance upon such a challenge. The results of this work indicate that perigestational HFA exposure the affects long-term metabolic phenotype of the offspring, predisposing them to an insulin-resistant state.

Timing of food intake associates with body weight regulation, insulin sensitivity and glucose tolerance. However, the mechanism is unknown. The aim of this study was to investigate the effects of changes in meal timing on energy-expenditure, glucose-tolerance and circadian-related variables. Thirty-two women (aged 24±4 years and body mass index 22.9±2.6 kg m−2) completed two randomized, crossover protocols: one protocol (P1) including assessment of resting-energy expenditure (indirect-calorimetry) and glucose tolerance (mixed-meal test) (n=10), the other (P2) including circadian-related measurements based on profiles in salivary cortisol and wrist temperature (Twrist) (n=22). In each protocol, participants were provided with standardized meals (breakfast, lunch and dinner) during the two meal intervention weeks and were studied under two lunch-eating conditions: Early Eating (EE; lunch at 13:00) and Late Eating (LE; lunch 16:30). LE, as compared with EE, resulted in decreased pre-meal resting-energy expenditure (P=0.048), a lower pre-meal protein-corrected respiratory quotient (CRQ) and a changed post-meal profile of CRQ (P=0.019). These changes reflected a significantly lower pre-meal utilization of carbohydrates in LE versus EE (P=0.006). LE also increased glucose area under curve above baseline by 46%, demonstrating decreased glucose tolerance (P=0.002). Changes in the daily profile of cortisol and Twrist were also found with LE blunting the cortisol profile, with lower morning and afternoon values, and suppressing the postprandial Twrist peak (P

Although there is good evidence showing that diets rich in medium chain fatty acids (MCFAs) have less marked obesogenic and diabetogenic effects than diets rich in long chain fatty acids (LCFAs), the role of the pro-inflammatory, medium chain fatty acid receptor (GPR84) in the aetiology of obesity and glucose intolerance is not well characterised. We set out to determine whether GPR84 expression influences obesity and glucose intolerance susceptibility in MCFA and LCFA rich diet fed mice. Wild type (WT) and GPR84 knockout (KO) mice were fed a control, MCFA or LCFA diet, and body mass, heart, liver and epididymal fat mass was assessed, as well as glucose tolerance and adipocyte size. LCFA diets increased body mass and decreased glucose tolerance in both WT and GPR84 KO animals while MCFA diets had no effect on these parameters. There were no differences in body weight when comparing WT and GPR84 KO mice on the respective diets. Glucose tolerance was also similar in WT and GPR84 KO mice irrespective of diet. Liver mass was increased following LCFA feeding in WT but not GPR84 KO mice. Hepatic triglyceride content was increased in GPR84 KO animals fed MCFA, and myocardial triglyceride content was increased in GPR84 KO animals fed LCFA. GPR84 deletion had no effects on body weight or glucose tolerance in mice fed either a high MCFA or LCFA diet. GPR84 may influence lipid metabolism, as GPR84 KO mice had smaller livers and increased myocardial triglyceride accumulation when fed LCFA diets, and increased liver triglyceride accumulation in responses to increased dietary MCFAs.

Previous studies have shown that sleep restriction-induced environmental stress is associated with abnormal metabolism, but the underlying mechanism is poorly understood. In the current study, we investigated the possible lipid and glucose metabolism patterns in chronically sleep-restricted rat. Without changes in food intake, body weight was decreased and energy expenditure was increased in sleep-restricted rats. The effects of chronic sleep disturbance on metabolites in serum were examined using ¹H NMR metabolomics and GC-FID/MS analysis. Six metabolites (lipoproteins, triglycerides, isoleucine, valine, choline, and phosphorylcholine) exhibited significant alteration, and all the fatty acid components were decreased, which suggested fatty acid metabolism was impaired after sleep loss. Moreover, increased blood glucose, reduced serum insulin, decreased glucose tolerance, and impaired glucose-stimulated insulin secretion of islets were also observed in sleep-restricted rats. The islet function of insulin secretion could be partially restored by increasing dietary fat to sleep-disturbed rats suggested that a reduction in circulating fatty acids was related to islet dysfunction under sleep deficiency-induced environmental stress. This study provides a new perspective on the relationship between insufficient sleep and lipid/glucose metabolism, which offers insights into the role of stressful challenges in a healthy lifestyle.

Hepatocyte growth factor (HGF) is a mitogen required for β-cell replication during pregnancy. To determine whether HGF/c-Met signaling is required for β-cell regeneration, we characterized mice with pancreatic deletion of the HGF receptor, c-Met (PancMet KO mice), in two models of reduced β-cell mass and regeneration: multiple low-dose streptozotocin (MLDS) and partial pancreatectomy (Ppx). We also analyzed whether HGF administration could accelerate β-cell regeneration in wild-type (WT) mice after Ppx. Mouse islets obtained 7 days post-Ppx displayed significantly increased c-Met, suggesting a potential role for HGF/c-Met in β-cell proliferation in situations of reduced β-cell mass. Indeed, adult PancMet KO mice displayed markedly reduced β-cell replication compared with WT mice 7 days post-Ppx. Similarly, β-cell proliferation was decreased in PancMet KO mice in the MLDS mouse model. The decrease in β-cell proliferation post-Ppx correlated with a striking decrease in D-cyclin levels. Importantly, PancMet KO mice showed significantly diminished β-cell mass, decreased glucose tolerance, and impaired insulin secretion compared with WT mice 28 days post-Ppx. Conversely, HGF administration in WT Ppx mice further accelerated β-cell regeneration. These results indicate that HGF/c-Met signaling is critical for β-cell proliferation in situations of diminished β-cell mass and suggest that activation of this pathway can enhance β-cell regeneration. © 2014 by the American Diabetes Association., This work was supported in part by grants from the National Institutes of Health (DK-067351 and DK-077096) and the Juvenile Diabetes Research Foundation (1-2007-3) to A.G.-O. S.E. was the recipient of a postdoctoral fellowship from the National Institutes of Health T32 Research Training grant (T32DK-07052-32). C.D. was the recipient of a research fellowship from the Lawson Wilkins Pediatric Endocrine Society.

Objective The increasing prevalence of obesity and related metabolic disorders coincides with increasing exposure to light at night. Previous studies report that mice exposed to dim light at night (dLAN) develop symptoms of metabolic syndrome. This study investigated whether mice returned to dark nights after dLAN exposure recover metabolic function. Design and Methods Male Swiss-Webster mice were assigned to either: [1] standard light-dark (LD) conditions for 8 weeks (LD/LD), [2] dLAN for 8 weeks (dLAN/dLAN), [3] LD for 4 weeks followed by 4 weeks of dLAN (LD/dLAN), and [4] dLAN for 4 weeks followed by 4 weeks of LD (dLAN/LD). Results After 4 weeks in their respective lighting conditions both groups initially placed in dLAN increased body mass gain compared to LD mice. Half of the dLAN mice (dLAN/LD) were then transferred to LD and vice versa (LD/dLAN). Following the transfer dLAN/dLAN and LD/dLAN mice gained more weight than LD/LD and dLAN/LD mice. At the conclusion of the study dLAN/LD mice did not differ from LD/LD mice with respect to weight gain and had lower fat pad mass compared to dLAN/dLAN mice. Compared to all other groups dLAN/dLAN mice decreased glucose tolerance as indicated by an intraperitoneal glucose tolerance test at week 7, indicating that dLAN/LD mice recovered glucose metabolism. dLAN/dLAN mice also increased MAC1 mRNA expression in peripheral fat as compared to both LD/LD and dLAN/LD mice, suggesting peripheral inflammation is induced by dLAN, but not sustained after return to LD. Conclusion These results suggest that re-exposure to dark nights ameliorates metabolic disruption caused by dLAN exposure.

Obesity and impaired glucose homeostasis in older adults place these individuals at risk for diabetes. Dehydration, glucose homeostasis, and insulin resistance are related; while aging and dehydration are associated with decreased glucose tolerance, weight loss can improve glycemia. For older adults following hypocaloric diets, additional water consumption may lead to greater weight loss. Further more, research sug- gests an association between insulin resistance and the body water retention hormone, arginine vasopressin (AVP). Analysis of the association between plasma copeptin (an AVP derivative) and fasting glucose, insulin, and homeostasis model assessment of insulin resistance (HOMA- IR) may provide further insight into the rela- tionship between dehydration and diabetes risk. Our objective was to investigate the possibility that increased water consumption among older adults (n = 29, BMI = 31 ± 1 kg/m², age = 62 ± 1 years) could improve glucose homeostasis be- yond that observed with weight loss, as well as associations between plasma copeptin and dia- betes risk. This retrospective analysis utilized data from a previous investigation, in which obese/overweight older adults were assigned to one of two groups: 1) Water: consume 500 ml of water prior to three daily meals over a 12-week hypocaloric diet intervention, or 2) Non-water: hypocaloric diet alone. In the present analysis, fasting plasma glucose and insulin, HOMA-IR, and plasma copeptin were evaluated, and com- pared to urinary specific gravity (USG), drinking water consumption, and body weight. Analyses performed using group assignment, volume of drinking water consumed or among a subgroup pair-matched for weight loss and sex did not reveal significant differences between groups. However in the full sample, plasma insulin concentration was associated with USG (r = 0.512, P < 0.01) and copeptin (r = 0.389, P < 0.05), and HOMA-IR was associated with USG (r = 0.530, P < 0.01) at week 12. Improvements in fasting insulin for water group participants (−8.5 +/− 4 pmol/L) were also detected. Associations be- tween hydration and insulin resistance support the need for future investigations addressing hydration status and diabetes risk.

Background Estrogen-progestogen combined oral contraceptive (OC) use has been associated with increased cardiometabolic risk factors, including glucose dysregulation, dyslipidemia, hypertension, and pro-inflammatory state. However, the effect of a high-salt diet on these risk factors during OC use is not yet investigated. We therefore hypothesized that a high-salt diet would increase cardiometabolic risk factors in female rats treated with a combination of OC steroids, levonorgestrel (L) and ethinylestradiol (EE), and that elevated plasma levels of pro-inflammatory markers are associated with the cardiometabolic effects. Methods Female Wistar rats were given ( p.o. ) vehicle, high-dose (1.0μg EE plus 5.0μgL) or low-dose (0.1μg EE plus 0.5μgL) OC with or without a high-salt diet (8%) daily for 8 weeks. Insulin resistance (IR) was estimated using the homeostatic model of assessment (HOMA). Results Results showed that OC treatment or high salt diet led to significant increases in insulin resistance, plasma insulin, total cholesterol (TC), triglyceride (TG), TC/HDL-cholesterol, uric acid levels, and decreased glucose tolerance. OC treatment but not a high-salt diet resulted in increased plasma C-reactive protein and TG/HDL-cholesterol. However, a high-salt diet did not aggravate the effects of OC treatment. Conclusion The results from the present study indicate that glucose dysfunction and dyslipidemia induced by OC use, but not those induced by increased dietary salt are associated with elevated plasma C-reactive protein. Besides, increased dietary salt does not worsen abnormal cardiometabolic impact of OC use.

Insulin resistance is frequently associated with hypertension and type 2 diabetes. The cytochrome P450 (CYP) arachidonic acid epoxygenases (CYP2C, CYP2J) and their epoxyeicosatrienoic acid (EET) products lower blood pressure and may also improve glucose homeostasis. However, the direct contribution of endogenous EET production on insulin sensitivity has not been previously investigated. In this study, we tested the hypothesis that endogenous CYP2C-derived EETs alter insulin sensitivity by analysing mice lacking CYP2C44, a major EET producing enzyme, and by testing the association of plasma EETs with insulin sensitivity in humans. We assessed insulin sensitivity in wild-type (WT) and Cyp2c44 −/− mice using hyperinsulinaemic–euglycaemic clamps and isolated skeletal muscle. Insulin secretory function was assessed using hyperglycaemic clamps and isolated islets. Vascular function was tested in isolated perfused mesenteric vessels. Insulin sensitivity and secretion were assessed in humans using frequently sampled intravenous glucose tolerance tests and plasma EETs were measured by mass spectrometry. Cyp2c44 −/− mice showed decreased glucose tolerance (639 ± 39.5 vs 808 ± 37.7 mmol/l × min for glucose tolerance tests, p = 0.004) and insulin sensitivity compared with WT controls (hyperinsulinaemic clamp glucose infusion rate average during terminal 30 min 0.22 ± 0.02 vs 0.33 ± 0.01 mmol kg−1 min−1 in WT and Cyp2c44 −/− mice respectively, p = 0.003). Although glucose uptake was diminished in Cyp2c44 −/− mice in vivo (gastrocnemius Rg 16.4 ± 2.0 vs 6.2 ± 1.7 μmol 100 g−1 min−1, p

Objective: Monosodium glutamate (MSG) is one of the commonest food additives inthe world and it is a commonly used flavor enhancer. In recent years MSGconsumption has increased as flavoring in cooking. Interestingly, little is knownabout its effects on oxidative stress and some metabolic changes. Aim of the study:The aim of this study was to elucidate the effect of oral ingestion of MSG on somebiochemical changes in the brain and blood of experimental rats to demonstrate theadverse effects of that widely used flavor enhancer. Materials and methods: Thisstudy was carried out on 50 white albino rats which were divided into two equalgroups; control group and MSG treated group. All groups were subjected toestimation of serum lipid profile, free fatty acids (FFs) and malondialdehyde (MDA)levels. Also brain tissue levels of L-glutamate, gamma amino butyric acid (GABA)and MDA were measured for all groups. Results: The present study showed that oralfeeding of MSG significantly increased final body weight, visceral fat weight,impaired glucose tolerance and a state of dyslipidemia with an increased serum freefatty acid level. Significant increase of both serum and brain MDA tissue levels werealso documented. MSG-treated group also showed significant increase of brain L.glutamate and significant decrease of brain gamma amino butyric acid (GABA) levelsas compared to the control. Conclusion: On the basis of these results it could beconcluded that MSG may be an inductive factor of several biochemical and metabolicalterations taking place in healthy subjects, which clearly must contribute to thedevelopment of obesity, decreased glucose tolerance and some excitotoxic effects.Recommendations: The present findings are alarming, and throw doubts upon theunscrupulousness of current use of the flavoring agent MSG in fast processed andcanned foods. Much work is still to be performed to determine other adverse effectson other organs.

Aims/hypothesis Obesity and type 2 diabetes are among the most serious health pathologies worldwide. Stress has been proposed as a factor contributing to the development of these health risk factors; however, the underlying mechanisms that link stress to obesity and diabetes need to be further clarified. Here, we study in mice how chronic stress affects dietary consumption and how that relationship contributes to obesity and diabetes. Methods C57BL/6J mice were subjected to chronic variable stress (CVS) for 15 days and subsequently fed with a standard chow or high-fat diet. Food intake, body weight, respiratory quotient, energy expenditure and spontaneous physical activity were measured with a customised calorimetric system and body composition was measured with nuclear magnetic resonance. A glucose tolerance test was also applied and blood glucose levels were measured with a glucometer. Plasma levels of adiponectin and resistin were measured using Lincoplex kits. Results Mice under CVS and fed with a high-fat diet showed impaired glucose tolerance associated with low plasma adiponectin:resistin ratios. Conclusions/interpretation This study demonstrates, in a novel mouse model, how post-traumatic stress disorder enhances vulnerability for impaired glucose metabolism in an energy-rich environment and proposes a potential adipokine-based mechanism.

Background Sleep disturbance attributable to circadian rhythm abnormalities frequently occurs in previously healthy children and adolescents who often complain of gastrointestinal discomfort after meals. Methods Glucose metabolism, autonomic function, and human clock gene expression in whole blood cells were investigated in 18 adolescent patients with circadian rhythm sleep disorder. Results Glucose tolerance was significantly lower in the patients than in normal controls: the mean sigma blood glucose level was significantly higher (P

A decreased receptive sexual behaviour was found in female F2-offspring of Streptozotocin-treated maternal grandmothers. These F2-offspring are characterized by decreased glucose tolerance and increased diabetes susceptibility, their metabolic situation being comparable to that of Type II prediabetes. The observed phenomena were associated with permanent hypoplasia of the hypothalamic ventromedial nucleus (HVN). It is hypothesized that there could be a causal relationship between these morphological changes in the HVN and impaired sexual behaviour in female prediabetic rats.

Milk intake of suckling rats was controlled by adjusting litter size at birth to maximum three (small litter, overnutrition), ten (normal litter, normal nutrition) or about 19 (large litter, undernutrition) pups. After weaning all animals received the same diet ad libitum. Overnutrition before weaning resulted in an early postnatal hyperinsulinaemia, decreased glucose tolerance and increased susceptibility to streptozotocin-induced diabetes in adulthood. However, the preweaning undernutrition seemed to have no preventive effect on diabetes susceptibility in adulthood. The study suggested that early postnatal overnutrition, which is associated with an early postnatal hyperinsulinemia, can increase diabetes susceptibility in adult life

High Cyclosporin A doses (50 mg/kg b.w.) were given male Wistar rats either homozygous for RT1a or RT1u. Both rat strains are characterized by a similar diminished body weight gain. Cyclosporin A exerted in both strains an increased fed plasma glucose, decreased glucose tolerance and diminished pancreatic insulin content, however, the Wistar rat strain with the MHC RT1u was more sensitive to the effect of Cyclosporin A, indicated by a more marked alteration of pancreatic B-cells and a delayed recovery after drug withdrawal. We concluded that the MHC modulated either the Cyclosporin A metabolism (degradation) or the pancreatic B-cell sensitivity to toxic damage.

Fifty-two middle-aged patients with essential hypertension were treated for five months with 25 mg mefruside as the only antihypertensive drug. Blood pressure, heart rate, fasting blood glucose, cholesterol, triglycerides, uric acid, electrolytes and weight were controlled regularly before and during treatment. Blood pressure normalized in 43 cases (82.7%). The decrease was more marked in the females and their maximal response appeared later. No significant changes were seen in cholesterol and triglycerides. Serum uric acid levels increased significantly in both sexes (p < 0.001) but no patient developed gout. A significant decrease (p < 0.001) in serum potassium was seen; only one male, with heredity for diabetes mellitus, showed a decreased glucose tolerance.

Body composition, age at onset of obesity, adipose tissue cellularity and metabolic variables have been determined in 137 obese subjects and controls. Weight stability in 34 of the patients could also be judged by a repeated examination after about 10 months. Fat cell number correlated strongly with body fat, while fat cell size increased only within the control range of body fat. Above approximately 30 kg body fat, the fat cell enlargement was equally pronounced at all degrees of obesity. A cross-sectional analysis of the obese men and women indicated that fat cell size was larger at 30–40 years of age than before and after this age. Cell number was elevated but did not increase with age in the obese group. Groups of younger and older obese women did not differ in adipose tissue cellularity factors. This had the consequence that, in comparisons with age- and sex-matched control groups, obesity depending primarily on enlargement of fat cells seemed to be more frequent in the younger age groups, while in older obese subjects cell number seemed to be a more important factor for contribution to obesity. Fat cell number correlated positively with body cell mass. The earlier the onset of obesity the more fat cells, particularly when obesity could be traced to infancy. Obesity starting at adult age was characterized by larger fat cells. Two types of obesity can be distinguished. One is a hypercellular severe obesity with an early onset and an elevated body cell mass. The fat cells may be enlarged or not. The other type of obesity is characterized by fat cell hypertrophy, moderately increased body fat and a later onset. There is no increase in body cell mass. Plasma insulin was dependent on weight stability. Hypertriglyceridemia in obesity was associated with a decreased glucose tolerance, somewhat elevated insulin values, and elevated serum uric acid.

The effects of continuous ambulatory peritoneal dialysis (CAPD) on glucose tolerance and serum immunoreactive insulin and glucagon responses to oral glucose over the first year of therapy were studied in 13 uremic patients. Oral glucose tolerance tests were performed before treatment started, and again after 3 and 12 months on CAPD. Before CAPD, the patients showed decreased glucose tolerance. However, neither fasting blood glucose and serum insulin and glucagon levels nor the insulin and glucagon levels during the tests were significantly different from results obtained in 13 healthy controls. During CAPD, the mean intraperitoneal supply of glucose from the dialysates varied between 121 and 245 g/day and did not change during the study period. Glucose tolerance and hormone responses to glucose did not change during the study period. No patient developed manifest diabetes mellitus. We conclude that glucose intolerance in uremia persists during CAPD, but despite the continuous peritoneal absorption of 100-200 g of glucose during CAPD, the treatment had no effect on glucose tolerance and insulin secretory response.

In order to observe the effect of increased serum resistin on glucose metabolism, insulin sensitivity, and hepatic insulin resistance (IR), mice were intravenously injected with recombinant adenovirus carrying the resistin gene (Adv-resistin-EGFP). Changes in hepatic glucose metabolism were observed using the Periodic Acid-Schiff method. Hepatic AMP-activated protein kinase (AMPK) activation was assessed by Western blot analysis, and glucose-6-phosphatase (G6Pase) and phosphoenolpyruvate carboxykinase (PEPCK) mRNA expression was determined using real-time RT-PCR. Although no effect on fasting blood glucose was detected, increased fasting insulin levels, decreased glucose tolerance and insulin sensitivity, and reduced hepatic glycogen levels and AMPK activation were seen in the Adv-resistin-EGFP mice. Finally, elevated G6Pase and PEPCK mRNA expression levels were detected upon overexpression of resistin. Resistin may inhibit hepatic AMPK activity, which results in elevated expression of gluconeogenic enzymes thereby affecting glucose metabolism and leading to decreased glycogen storage that contributes to the development of hepatic IR.

Glucose intolerance in C57Bl/6 mice has been associated with mutations in the nicotinamide nucleotide transhydrogenase (Nnt) gene. It has been proposed that the absence of NNT from mitochondria leads to increased mitochondrial reactive oxygen species production and subsequent activation of uncoupling protein 2 (UCP2). Activation of UCP2 has been suggested to uncouple electron transport from ATP synthesis in pancreatic beta cell mitochondria thereby decreasing glucose tolerance due to decreased insulin secretion through lower ATP/ADP ratios. The hypothesis tested in this paper is that UCP2 function is required for the dysregulation of glucose homeostasis observed in NNT ablated mice. Single and double Nnt and Ucp2 knockout mouse lines were used to measure glucose tolerance, whole animal energy balance and biochemical characteristics of mitochondrial uncoupling. As expected, glucose tolerance was diminished in mice lacking NNT. This was independent of UCP2 as it was observed either in the presence or absence of UCP2. The range of metabolic parameters examined in the mice and the proton conductance of isolated mitochondria remained unaltered in this double NNT and UCP2 knockout model. Ablation of UCP2 did not itself affect glucose tolerance and therefore previous observations of increased glucose tolerance of mice lacking UCP2 were not confirmed. We conclude that the decreased glucose tolerance in Nnt knockout mice observed in our experiments does not require UCP2.

Sleep is an important modulator of neuroendocrine function and glucose metabolism in children as well as in adults. In recent years, sleep curtailment has become a hallmark of modern society with both children and adults having shorter bedtimes than a few decades ago. This trend for shorter sleep duration has developed over the same time period as the dramatic increase in the prevalence of obesity. There is rapidly accumulating evidence from both laboratory and epidemiological studies to indicate that chronic partial sleep loss may increase the risk of obesity and weight gain. The present article reviews laboratory evidence indicating that sleep curtailment in young adults results in a constellation of metabolic and endocrine alterations, including decreased glucose tolerance, decreased insulin sensitivity, elevated sympathovagal balance, increased evening concentrations of cortisol, increased levels of ghrelin, decreased levels of leptin, and increased hunger and appetite. We also review cross-sectional epidemiological studies associating short sleep with increased body mass index and prospective epidemiological studies that have shown an increased risk of weight gain and obesity in children and young adults who are short sleepers. Altogether, the evidence points to a possible role of decreased sleep duration in the current epidemic of obesity.

To determine whether plasma leptin concentrations and glucose tolerance are affected by changes in energy balance, nine healthy Shetland ponies were fed at 140% followed by 75% of their maintenance requirements for 13 days in each of the two periods. Bodyweight was recorded every three days. Blood samples were taken every two days and analysed for leptin and cortisol. An oral glucose tolerance test was performed on day 7 of each period. Serial blood samples were analysed for glucose and insulin. Although bodyweight was not affected, plasma leptin concentrations increased (P0.001) initially during overfeeding, but returned to previous values after 7 days. During underfeeding, plasma leptin concentrations decreased (P0.001). Underfeeding was associated with a higher AUC for plasma glucose (P=0.02) and plasma insulin (P=0.05) resulting in a decreased glucose tolerance (AUC glucose/AUC insulin; P=0.008), probably due to a plasma cortisol increase caused by the reduced feed intake. It is concluded that changes in energy balance, without altering bodyweight, can influence plasma leptin concentrations in ponies.

Hystricomorph rodents have a divergent insulin molecule with only 1-10% of the biological activity in comparison to other mammalian species. In this study, we used the subterranean rodent Ctenomys talarum as a model and performed blood glucose tolerance tests (GTTs) with trained and untrained individuals to evaluate blood glucose regulation and the possible role of physical activity as a compensatory mechanism. Additionally, we evaluated the variations in blood glucose during acute and chronic stress and gathered data in the field to evaluate natural-occurring variations in blood glucose levels. The GTTs showed that C. talarum have a diminished capacity of regulating blood glucose levels in comparison to other mammals and suggest that unexplored differences in the compensatory mechanisms, insulin structure and/or glucose transporters exist within species of hystricomorph rodents. However, blood glucose levels in the field stayed within the normal mammalian range. Physical activity did not prove to be a compensatory mechanism for blood glucose regulation. The individuals did not display important increases in blood glucose after acute stressors and managed to adequately regulate blood glucose during chronic stress. We suggest that the species may not face a selective pressure favoring a more tightly, mammalian like, capacity of regulating blood glucose levels.