Development Of Glucose Intolerance Research Articles

Pancreatic β-cell hyper-O-GlcNAcylation leads to impaired glucose homeostasis in vivo.

Protein O-GlcNAcylation is a nutrient and stress-sensitive protein post-translational modification (PTM). The addition of an O-GlcNAc molecule to proteins is catalyzed by O-GlcNAc transferase (OGT), whereas O-GlcNAcase (OGA) enzyme is responsible for removal of this PTM. Previous work showed that OGT is highly expressed in the pancreas, and we demonstrated that hypo-O-GlcNAcylation in β-cells cause severe diabetes in mice. These studies show a direct link between nutrient-sensitive OGT and β-cell health and function. In the current study, we hypothesized that hyper-O-GlcNAcylation may confer protection from β-cell failure in high-fat diet (HFD)-induced obesity. To test this hypothesis, we generated a mouse model with constitutive β-cell OGA ablation (βOGAKO) to specifically increase O-GlcNAcylation in β-cells. Under normal chow diet, young male and female βOGAKO mice exhibited normal glucose tolerance but developed glucose intolerance with aging, relative to littermate controls. No alteration in β-cell mass was observed between βOGAKO and littermate controls. Total insulin content was reduced despite an increase in pro-insulin to insulin ratio in βOGAKO islets. βOGAKO mice showed deficit in insulin secretion in vivo and in vitro. When young animals were subjected to HFD, both male and female βOGAKO mice displayed normal body weight gain and insulin tolerance but developed glucose intolerance that worsened with longer exposure to HFD. Comparable β-cell mass was found between βOGAKO and littermate controls. Taken together, these data demonstrate that the loss of OGA in β-cells reduces β-cell function, thereby perturbing glucose homeostasis. The findings reinforce the rheostat model of intracellular O-GlcNAcylation where too much (OGA loss) or too little (OGT loss) O-GlcNAcylation are both detrimental to the β-cell.

Exposure to intrauterine diabetes and post-natal high-fat diet: Effects on the endocrine pancreas of adult rat female pups

AimsTo evaluate the morphological changes in the pancreatic islet cells of adult female pups born to diabetic rats and fed a high-fat diet. Main methodsFemale Sprague-Dawley rats were distributed into four experimental groups (n = 10 animals/group): 1) female pups from non-diabetic dams and fed a standard diet (OC/SD), 2) female pups from non-diabetic dams and fed a high-fat (OC/HFD), 3) female pups from diabetic dams and fed a standard diet (OD/SD) and 4) female pups from diabetic dams and fed a high-fat diet (OD/HFD). In adulthood, the rats were submitted to the oral glucose tolerance test and later euthanized to collect the pancreas for the analysis of pancreatic islets. Key findingsThe OC/HFD and OD/SD groups showed an increased percentage of cells immunostained for insulin and a decreased percentage and intensity of staining for somatostatin. The OD/HFD group showed an increased percentage of cells immunostained for insulin and glucagon and a higher staining intensity for glucagon. There was a progressive increase in blood glucose in the OC/HFD, OD/SD, and OD/HFD groups. SignificanceThe association between maternal diabetes and/or the administration of high-fat diet-induced changes in the pancreatic hormonal triad of female pups in adulthood. In turn, these changes in the pancreatic islets are not capable of causing decreased blood glucose in the offspring, contributing to the development of glucose intolerance in adulthood.

Probiotics in the Prevention and Treatment of Gestational Diabetes Mellitus (GDM): A Review.

Gestational diabetes mellitus (GDM)is one of the most common perinatal pathologies, with a prevalence of 5–20% depending on the population or diagnostic standards. It is diagnosed when glucose intolerance is first detected during pregnancy. In the pathogenesis of GDM, genetic, environmental, and pregnancy-related factors (excessive fat storage and increased adipokine and cytokine secretion) play important roles. A growing amount of scientific data has indicated the role of gut microbiota (GM) dysbiosis in the development of glucose intolerance during pregnancy. Previous studies have indicated that, in comparison to healthy pregnant women, GDM individuals have a greater abundance of bacteria belonging to the genera Ruminococcus, Eubacterium, and Prevotella and a lower number of bacteria belonging to the genera Bacteroides, Parabacteroides, Roseburia, Dialister, and Akkermansia. Recently, many studies have focused on treating GDM with methods targeting GM. Several previous studies have analyzed the effect of probiotics on the course of GDM, but their data are inconclusive. In view of this state, the aim of the study was to collect and comprehensively discuss current knowledge regarding the role of probiotic supplementation in preventing and treating GDM. According to the analyzed data, probiotics have a positive influence on glycemic control and are a promising tool for lowering the frequency of GDM. However, further studies must be conducted to determine the optimal model of probiotic therapy (strain, dose, time of intervention, etc.) in pregnant women with GDM.

Long Working Hours and the Risk of Glucose Intolerance: A Cohort Study.

Long working hours have negative effects on the health of workers. Several studies have reported the association between long working hours and both diabetes and prediabetes. Therefore, we aimed to examine the temporal relationship between long working hours and glucose intolerance. Our cohort study collected data from 25,803 healthy male participants at baseline. To evaluate the risk of incident glucose intolerance, we estimated the hazard ratios (HRs) and 95% confidence intervals (CIs) using the Cox proportional hazards regression analyses. During 77,605.0 person-years of follow-up, 6741 participants developed glucose intolerance. Multivariable-adjusted HRs (95% CI) for weekly working 41–52 and >52 h compared with working 35–40 h, were 1.28 (1.17–1.40) and 2.80 (2.54–3.09), respectively. In the dose-response analyses, long working hours had a nearly linear relationship with the development of glucose intolerance across most working hours per week. The association between long working hours and incident glucose intolerance was stronger in the younger-age subgroups than in the older-age subgroups (p for interaction <0.001). Our large-scale cohort study demonstrated that long working hours were associated with incident glucose intolerance, with a dose-response relationship.

The Roles of Probiotics in the Gut Microbiota Composition and Metabolic Outcomes in Asymptomatic Post-Gestational Diabetes Women: A Randomized Controlled Trial.

Probiotics are widely used as an adjuvant therapy in various diseases. Nonetheless, it is uncertain how they affect the gut microbiota composition and metabolic and inflammatory outcomes in women who have recently experienced gestational diabetes mellitus (post-GDM). A randomized, double-blind, placebo-controlled clinical trial involving 132 asymptomatic post-GDM women was conducted to close this gap (Clinical Trial Registration: NCT05273073). The intervention (probiotics) group received a cocktail of six probiotic strains from Bifidobacterium and Lactobacillus for 12 weeks, while the placebo group received an identical sachet devoid of living microorganisms. Anthropometric measurements, biochemical analyses, and 16S rRNA gene sequencing results were evaluated pre- and post-intervention. After the 12-week intervention, the probiotics group’s fasting blood glucose level significantly decreased (mean difference −0.20 mmol/L; p = 0.0021). The HbA1c, total cholesterol, triglycerides, and high-sensitivity C-reactive protein levels were significantly different between the two groups (p < 0.05). Sequencing data also demonstrated a large rise in the Bifidobacterium adolescentis following probiotic supplementation. Our findings suggest that multi-strain probiotics are beneficial for improved metabolic and inflammatory outcomes in post-GDM women by modulating gut dysbiosis. This study emphasizes the necessity for a comprehensive strategy for postpartum treatment that includes probiotics to protect post-GDM women from developing glucose intolerance.

Transgenerational effects of zinc, selenium and chromium supplementation on glucose homeostasis in female offspring of gestational diabetes rats

Clinical studies have demonstrated that maternal gestational diabetes mellitus (GDM) increases the offspring's risk of developing glucose intolerance. Our previous study reported that co-supplementation with zinc, selenium, and chromium improved insulin resistance in diet-induced GDM rats. Here, Transgenerational effects of supplementation with zinc (10 mg/kg.bw), selenium (20 μg/kg.bw), and chromium (20 μg/kg.bw) in F1 female offspring of both zinc, selenium and chromium (ZnSeCr)-treated, and untreated GDM rats daily by gavage from weaning to the postpartum were investigated in the present study. Glucose homeostasis in the F1 female offspring of GDM at different stages were evaluated. Maternal GDM did increase the birth mass of newborn F1 female offspring, as well as the serum glucose and insulin levels. Zinc, selenium and chromium supplementation attenuated the GDM-induced mass gain, increased serum glucose and insulin levels in the female neonates. The high fat and sucrose (HFS) diet-fed GDM-F1 offspring developed GDM, with glucose intolerance, hyperglycemia and insulin resistance during pregnancy. Moreover, endoplasmic reticulum (ER) stress-related protein levels were increased and the activation of insulin signaling pathways were reduced in the liver of HFS-fed GDM-F1 offspring. Whereas glucose homeostasis in parallel with insulin sensitivity was normalized in the female offspring of GDM by supplementation both F0 dams and F1 offspring with zinc, selenium and chromium, not in those either F0 or F1 elements supplemented offspring. Therefore, we speculate that zinc, selenium and chromium supplementation may have a potential beneficial transgenerational effect on the glucose homeostasis in the female offspring of GDM.

Mouse model of NASH that replicates key features of the human disease and progresses to fibrosis stage 3.

Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease in the United States and the world; with no Food and Drug Administration–approved pharmacological treatment available, it remains an area of unmet medical need. In nonalcoholic steatohepatitis (NASH), the most important predictor of clinical outcome is the fibrosis stage. Moreover, the Food and Drug Administration recommends that clinical trials for drugs to treat this disease include patients with fibrosis stage 2 or greater. Therefore, when using animal models for investigating the pathophysiology of NAFLD and for the preclinical evaluation of new drugs, it is important that the animals develop substantial fibrosis. The aim of this study was to develop a mouse model of NAFLD that replicated the disease in humans, including obesity and progressive liver fibrosis. Agouti yellow mutant mice, which have hyperphagia, were fed a Western diet and water containing high‐fructose corn syrup for 16 weeks. Mice became obese and developed glucose intolerance. Their gut microbiota showed dysbiosis with changes that replicate some of the changes described in humans with NASH. They developed NASH with activity scores of 5–6 and fibrosis, which was stage 1 after 16 weeks, and stage 3 after 12 months. Changes in liver gene expression assessed by gene‐set enrichment analysis showed 90% similarity with changes in human patients with NASH. Conclusion: Ay mice, when fed a Western diet similar to that consumed by humans, develop obesity and NASH with liver histology, including fibrosis, and gene expression changes that are highly similar to the disease in humans.

Minor Changes in Daily Rhythms Induced by a Skeleton Photoperiod Are Associated with Increased Adiposity and Glucose Intolerance.

Eating during the rest phase is associated with metabolic syndrome, proposed to result from a conflict between food consumption and the energy-saving state imposed by the circadian system. However, in nocturnal rodents, eating during the rest phase (day-feeding, DF) also implies food intake during light exposure. To investigate whether light exposure contributes to DF-induced metabolic impairments, animals receive food during the subjective day without light. A skeleton photoperiod (SP) is used to entrain rats to a 12:12 cycle with two short light pulses framing the subjective day. DF-induced adiposity is prevented by SP, suggesting that the conflict between light and feeding stimulates fat accumulation. However, all animals under SP conditions develop glucose intolerance regardless of their feeding schedule. Moreover, animals under SP with ad libitum or night-feeding have increased adiposity. SP animals show a delayed onset of the daily rise in body temperature and energy expenditure and shorter duration of nighttime activity, which may contribute to the metabolic disturbances. These data emphasize that metabolic homeostasis can only be achieved when all daily cycling variables are synchronized. Even small shifts in the alignment of different metabolic rhythms, such as those induced by SP, may predispose individuals to metabolic disease.

MicroRNA-21 promotes pancreatic β cell function through modulating glucose uptake

Pancreatic β cell dysfunction contributes to the pathogenesis of type 2 diabetes. MiR-21 has been shown to be induced in the islets of glucose intolerant patients and type 2 diabetic mice. However, the role of miR-21 in the regulation of pancreatic β cell function remains largely elusive. In the current study, we identify the pathway by which miR-21 regulates glucose-stimulated insulin secretion utilizing mice lacking miR-21 in their β cells (miR-21βKO). We find that miR-21βKO mice develop glucose intolerance due to impaired glucose-stimulated insulin secretion. Mechanistic studies reveal that miR-21 enhances glucose uptake and subsequently promotes insulin secretion by up-regulating Glut2 expression in a miR-21-Pdcd4-AP-1 dependent pathway. Over-expression of Glut2 in knockout islets results in rescue of the impaired glucose-stimulated insulin secretion. Furthermore, we demonstrate that delivery of miR-21 into the pancreas of type 2 diabetic db/db male mice is able to promote Glut2 expression and reduce blood glucose level. Taking together, our results reveal that miR-21 in islet β cell promotes insulin secretion and support a role for miR-21 in the regulation of pancreatic β cell function in type 2 diabetes.

Serum Ferritin in Metabolic Syndrome-Mechanisms and Clinical Applications.

Metabolic syndrome (MS) is a cluster of conditions including central obesity, hypertriglyceridemia, low HDL cholesterol, hyperglycaemia, and hypertension with a prevalence rate of 20–25% of the world’s adult population. Metabolic syndrome is often characterized by insulin resistance, which some have suggested is a major supportive connection between physical inactivity and MS. Various studies suggest that moderately elevated iron and ferritin levels are associated with an increased prevalence of metabolic syndrome and are markers of insulin resistance. Increased body iron stores are associated with the development of glucose intolerance, type 2 diabetes mellitus, and insulin resistance syndrome (IRS). This is a hospital-based cross-sectional observational study, which was conducted in the department of internal medicine of a tertiary care hospital in northern India. The study was conducted from 1 January 2019 to 30 June 2020 and included 100 patients and 100 controls. All subjects in the age group of 35–65 years were enrolled and investigated as per the study design. Metabolic syndrome patients were diagnosed according to the modified National Cholesterol Education Program Adult Treatment Panel-III (NCEP ATP-III) with BMI > 23 kg/m2. All baseline investigations were undertaken, including serum ferritin levels. Insulin resistance (IR) was calculated using the homeostasis model assessment IR (HOMA-IR) formula. We found a positive association between an increase in serum ferritin with the prevalence of metabolic syndrome and its clinical parameter. The serum ferritin level was positively correlated with the level of insulin resistance and inversely correlated with the insulin level of the patients.

Long term high fat diet induces metabolic disorders and aggravates behavioral disorders and cognitive deficits in MAPT P301L transgenic mice.

Most Alzheimer disease (AD) patients present as sporadic late onset AD, with metabolic factors playing an important role in the occurrence and development of AD. Given the link between peripheral insulin resistance and tau pathology in streptozotocin-injected and db/db mouse models of diabetes, we fed high fat diet (HFD) to pR5 mice expressing P301L mutant human tau, with the aim of developing a new model with characteristics of obesity, T2DM and AD to mimic AD patients exacerbated by obesity and T2DM, an increasing trend in modern society. In our study, pR5 and C57BL/6 (WT) mice were randomly allocated to a standard diet (STD) or HFD for 30 weeks starting at 8 weeks of age. Food intake was measured weekly, body weight and fasting glucose levels were measured fortnightly, and a comprehensive behavioral test battery was performed to assess anxiety, depression and cognitive dysfunction. Glucose and insulin tolerance tests were performed after 30 weeks of HFD. We also investigated the effect of long term HFD on tau pathology in the brains of WT and P301L mice by performing western blotting of whole brain homogenates for total tau, phosphorylated tau at Ser396 and Thr231. Our results show that pR5 mice fed with HFD are more vulnerable to diet induced obesity compared to WT, especially with increasing age. In addition, pR5 mice on HFD developed glucose intolerance and insulin resistance. It was identified that long term HFD significantly aggravates depression like behavior and impairs cognitive function in pR5 mice, and also induces anxiety like behavior in both pR5 and WT mice. Long term HFD was also shown to aggravate tau hyperphosphorylation in pR5 transgenic mice, and increase total and hyperphosphorylated tau in WT mice. These results indicate that diet induced obesity of pR5 transgenic mice expressing P301L mutant human tau generates T2DM, and aggravates tau phosphorylation, and is therefore a model useful for investigations that seek to understand the relationships between AD, T2DM and obesity, and the underlying biochemical changes and mechanisms associated with metabolic disorders and AD tauopathy.

Association Between Body Composition and Development of Glucose Intolerance after Allogeneic Hematopoietic Cell Transplantation.

Allogeneic hematopoietic cell transplantation (HCT) recipients have increased risk of developing glucose intolerance and diabetes mellitus (DM). The strongest risk factor for glucose intolerance is being overweight/obese, as determined by body mass index (BMI), which does not account for differences in body composition. We examined the association between body composition measures from pre-HCT CT and early-onset (≤30 days) de novo glucose intolerance after HCT, and determined its impact on nonrelapse mortality (NRM). This study included 749 patients without pre-HCT DM. Skeletal muscle loss [abnormal skeletal muscle gauge (SMG)] and abnormal visceral adiposity (VA) were defined by sex-specific tertiles. Fine-Gray proportional subdistribution HR estimates and 95% confidence intervals (CI) were obtained to determine the association between muscle loss and VA and development of glucose intolerance. 1 year NRM was calculated for patients alive at day 30. Median age at HCT was 50.2 years. By day 30, 8.1% of patients developed glucose intolerance and 731 remained alive. In multivariable analysis, abnormal SMG was associated with increased risk of glucose intolerance in nonoverweight (BMI &lt; 25 kg/m2) patients (HR = 3.00; 95% CI, 1.15-7.81; P = 0.024); abnormal VA was associated with increased risk of glucose intolerance in overweight/obese patients (HR = 2.26; 95% CI, 1.24-4.12; P = 0.008). Glucose intolerance was independently associated with NRM (HR = 1.88; 95% CI, 1.05-3.39; P = 0.035). Abnormal SMG and VA were associated with glucose intolerance in nonoverweight and overweight/obese patients, respectively, which contributed to increased risk of 1 year NRM. This information may guide personalized interventions to decrease the risk of adverse outcomes after HCT. See related commentary by Giri and Williams, p. 2002.

Male and Female Mice Respond Differently to Short‐term Ketogenic Diet

The ketogenic diet (KD) is a high‐fat, low‐carbohydrate diet that results in the elevation of ketone bodies in the blood, known as ketosis. This metabolic consequence has been suggested as a method for treating neurological conditions, improving exercise performance, and facilitating weight loss. Since most research studies primarily use male populations, less information is available regarding potential sex differences in response to various interventions. Therefore, the purpose of this study was to explore the sex differences in physical, metabolic, and motor performance in mice fed the KD. Male (n=29) and female (n=26) C57BL/6 were randomly assigned to KD (90% fat, 1% carbohydrate) or chow (13% fat, 60% carbohydrate) group for 6 weeks. Body weight and food intake were tracked weekly. At baseline and every 2 weeks, the Rotarod performance test assessed motor coordination and activity levels in all mice. After 6 weeks, adipose tissue, quadriceps, and heart were weighed to observe changes in organ mass. Triglyceride (TG) was measured in the heart, liver, and quadriceps. Blood was drawn to measure changes in serum metabolite levels. Final body weights in Male‐KD were similar to Male‐chow; however, Female‐KD mice were significantly higher relative to Female‐chow. Although adipose tissue mass increased significantly in both KD groups, the increase was ~40% higher in Female‐KD. Quadriceps mass was lower in Male‐KD compared to Male‐chow (188±6 vs.169±5 mg, P&lt;0.05) while not statistically different in Female‐KD relative to Female‐chow. In contrast, heart weight to tibia length ratios (HW:TL) were increased in Female‐KD compared to Female‐chow (5.08±0.06 vs.5.58±0.12, P&lt;0.05) with no significant change in Male‐KD. The KD resulted in similar measures of ketosis, glucose intolerance, and hyperlipidemia in Male‐KD and Female‐KD. While cardiac TG content tended to increase in Male‐KD and Female‐KD to a similar extent (P&lt;0.10), the increase in hepatic TG content was ~30% lower in Female‐KD (P&lt;0.05 vs. Male‐KD). Although Rotarod performance was higher in Female‐KD compared to Male‐KD at week 2 (28.6±3.1 vs.15.2±1.6 sec, P&lt;0.05), performance decreased in Female‐KD and increased in Male‐KD over the remaining weeks and was similar at week 6 (25.7±2.0 vs.20.7±2.0 sec). In summary, these data show sex specific differences in weight gain, adiposity, and muscle (i.e., cardiac and skeletal) mass changes in response to a short‐term KD. Moreover, the data suggest that male and female mice on the KD differ in time sensitive adaptation to ketosis and motor activity. Since both males and females increase adiposity, develop glucose intolerance, and hyperlipidemia, this study questions the viability of the KD as a potential tool for weight loss, and importantly, highlights sex differences in the adaptation to the KD.

Neuron-Keratinocyte Communication in the Epidermis in Painful Diabetic Neuropathy

Painful diabetic neuropathy (PDN) is one of the most common and intractable complications of diabetes. PDN is characterized by small-fiber degeneration, which can progress to complete loss of cutaneous innervation and is accompanied by neuropathic pain. Uncovering the mechanisms underlying axonal degeneration in PDN remains a major challenge to finding effective and disease-modifying therapies. Sensory nerve afferents normally extend into the epidermis in close juxtaposition to keratinocytes but degenerate in diabetic skin. Our aim is to identify the changes in gene expression profiles and the interactions between dorsal root ganglion (DRG) neurons and keratinocytes to explore the mechanisms by which keratinocytes communicate with cutaneous afferents and how this communication impacts axonal degeneration underlying neuropathic pain in PDN. We used a mouse model of PDN where mice were fed a regular diet (RD, 11% fat) or a high-fat diet (HFD, 42% fat) for 10 weeks during which these mice develop glucose intolerance, mechanical allodynia, small fiber neuropathy. Using a single-cell RNA (scRNA-seq) sequencing approach we captured DRG and keratinocytes gene expression profiles and generated interactome maps. scRNA-seq identified both neuronal and non-neuronal clusters and several differentially expressed genes between RD and HFD from the DRG. We were able to identify several clusters of immune cells and keratinocytes at different stages of differentiation. scRNA-seq results were validated using RNAscope on DRG and skin frozen sections. Moreover, we generated interactome maps between DRG neurons and the peripheral cells to highlight ligand-receptor interactions and we looked to identify genes that were differentially expressed in these interactions. Taken together our data highlights the importance of studying neurons in conjunction with the cells in the tissues with which they interact to identify ligand-receptor interactions that may lead to the identification of neuron signaling in a chronic pain state such as PDN. Grant support from 1R01AR77691-01. Painful diabetic neuropathy (PDN) is one of the most common and intractable complications of diabetes. PDN is characterized by small-fiber degeneration, which can progress to complete loss of cutaneous innervation and is accompanied by neuropathic pain. Uncovering the mechanisms underlying axonal degeneration in PDN remains a major challenge to finding effective and disease-modifying therapies. Sensory nerve afferents normally extend into the epidermis in close juxtaposition to keratinocytes but degenerate in diabetic skin. Our aim is to identify the changes in gene expression profiles and the interactions between dorsal root ganglion (DRG) neurons and keratinocytes to explore the mechanisms by which keratinocytes communicate with cutaneous afferents and how this communication impacts axonal degeneration underlying neuropathic pain in PDN. We used a mouse model of PDN where mice were fed a regular diet (RD, 11% fat) or a high-fat diet (HFD, 42% fat) for 10 weeks during which these mice develop glucose intolerance, mechanical allodynia, small fiber neuropathy. Using a single-cell RNA (scRNA-seq) sequencing approach we captured DRG and keratinocytes gene expression profiles and generated interactome maps. scRNA-seq identified both neuronal and non-neuronal clusters and several differentially expressed genes between RD and HFD from the DRG. We were able to identify several clusters of immune cells and keratinocytes at different stages of differentiation. scRNA-seq results were validated using RNAscope on DRG and skin frozen sections. Moreover, we generated interactome maps between DRG neurons and the peripheral cells to highlight ligand-receptor interactions and we looked to identify genes that were differentially expressed in these interactions. Taken together our data highlights the importance of studying neurons in conjunction with the cells in the tissues with which they interact to identify ligand-receptor interactions that may lead to the identification of neuron signaling in a chronic pain state such as PDN. Grant support from 1R01AR77691-01.

Molecular Liver Fingerprint Reflects the Seasonal Physiology of the Grey Mouse Lemur (Microcebus murinus) during Winter.

Grey mouse lemurs (Microcebus murinus) are primates that respond to environmental energetic constraints through strong physiological seasonality. They notably fatten during early winter (EW), and mobilize their lipid reserves while developing glucose intolerance during late winter (LW), when food availability is low. To decipher how the hepatic mechanisms may support such metabolic flexibility, we analyzed the liver proteome of adult captive male mouse lemurs, whose seasonal regulations are comparable to their wild counterparts. We highlight profound hepatic changes that reflect fat accretion in EW at the whole-body level, without triggering an ectopic storage of fat in the liver, however. Moreover, molecular regulations are consistent with the decrease in liver glucose utilization in LW, and therefore with reduced tolerance to glucose. However, no major regulation was seen in insulin signaling/resistance pathways. Fat mobilization in LW appeared possibly linked to the reactivation of the reproductive system while enhanced liver detoxification may reflect an anticipation to return to summer levels of food intake. Overall, these results show that the physiology of mouse lemurs during winter relies on solid molecular foundations in liver processes to adapt fuel partitioning while opposing the development of a pathological state despite large lipid fluxes.

To Evaluate the Association of Serum Adiponectin with Fasting and Postprandial Plasma Glucose and Fasting Lipids in Control, IGT and T2DM Subjects

Background: Association of adiponectin with insulin resistance occurs early in obesity development; however it remains unclear if this association is of further importance in prediabetes and early stages of type 2 diabetes and remains the same through all glucose intolerance development stages. The present study was undertaken to evaluate the association of dysglycemia and dyslipidemia with adiponectin in prediabetic subjects as well as in T2DM subjects. Objective: The objective of our study was to evaluate adiponectin level in subjects with pre-diabetes and to compare it with the levels in newly diagnosed type 2 diabetes and healthy (normal glucose tolerance) subjects. Method: It was an observational analytic study with a group compare design. The study was conducted in the Biomedical Research Group and Department of Biochemistry &amp; Cell Biology of the Bangladesh Institute of Research and Rehabilitation in Diabetes, Endocrine and Metabolic Disorders (BIRDEM), Dhaka. This study was done during the period of July 2012 to June 2013. Results: Bivariate Spearman’s correlation analyses were performed for adiponectin with clinical, anthropometrical and other biochemical variables in the Control, IGT and T2DM groups. Postprandial glucose (p=0.023) and age (p=0.011) had a positive correlation with adiponectin in control subjects. A negative correlation was observed between adiponectin and BMI in IGT subjects (p=0.004). A positive correlation with adiponectin and serum HDL (p=0.03) and a negative correlation with serum LDL (p=0.03) were found in T2DM subjects. Conclusion: From our study we can conclude that, BMI has a negative association with adiponectin in IGT subjects. Serum LDL has a negative association and HDL has a positive association with adiponectin in IGT and T2DM subjects.

Effect of artemisinin on improving islet function in rats fed with maternal high-fat diet

Background Maternal high-fat diet (HFD) is a detrimental factor in developing glucose intolerance, obesity, and islet dysfunction. However, the effect of artemisinin on maternal HFD and whether it is related to the alterations of islet function is seldom studied since artemisinin treatments not only attenuate insulin resistance (IR) and restore islet ß cell function in Diabetes mellitus type 2. Methods Female rats were randomly fed a HFD (45% kcal from fat), HFD + artemisinin, or a regular chow diet (RCD) before pregnancy and during gestation. Glucose metabolism and the β cell phenotypes were assessed. Results Maternal HFD increased islet load in female rats, proliferation of pancreatic β cells, increased insulinogen, and decreased insulin secretion response to high glucose stimulation with delayed insulin release, increased fasting glucose, and glucose area under the curve compared with the general diet group. HFD inhibited expression of Foxo1 and PAX6 in female rats. Under the effect of both HFD and pregnancy, islet load was further increased, insulinogen was further increased, and fasting insulin level and fasting glucose were higher than RCD fed general-pregnancy group. ALDH1a3 transdifferentiation and PAX6, Foxo1, and PDX1 expression were increased in islets of high-fat pregnant rats. When adding artemisinin in HFD treated pregnant rats, islet function was significantly improved. Conclusions Intervention with artemisinin in maternal HFD resulted in reduced islet size, decreased number of β-cells and improved islet microcirculation, insulin processing shear process, decreased insulinogen/insulin ratio, and restored islet function through increased expression of PC1/3.

Adipocyte GPX4 protects against inflammation, hepatic insulin resistance and metabolic dysregulation.

Metabolic inflammation is a hallmark of obesity and related disorders, afflicting substantial morbidity and mortality to individuals worldwide. White visceral and subcutaneous adipose tissue not only serves as energy storage but also controls metabolism. Adipose tissue inflammation, commonly observed in human obesity, is considered a critical driver of metabolic perturbation while molecular hubs are poorly explored. Metabolic stress evoked by e.g. long-chain fatty acids leads to oxidative perturbation of adipocytes and production of inflammatory cytokines, fuelling macrophage infiltration and systemic low-grade inflammation. Glutathione peroxidase 4 (GPX4) protects against lipid peroxidation, accumulation of oxygen-specific epitopes and cell death, collectively referred to as ferroptosis. Here, we explore the function of adipocyte GPX4 in mammalian metabolism. We studied the regulation and function of GPX4 in differentiated mouse adipocytes derived from 3T3-L1 fibroblasts. We generated two conditional adipocyte-specific Gpx4 knockout mice by crossing Gpx4fl/fl mice with Adipoq-Cre+ (Gpx4-/-AT) or Fabp4-Cre+ (Gpx4+/-Fabp4) mice. Both models were metabolically characterized by a glucose tolerance test and insulin resistance test, and adipose tissue lipid peroxidation, inflammation and cell death were assessed by quantifying oxygen-specific epitopes, transcriptional analysis of chemokines, quantification of F4/80+ macrophages and TUNEL labelling. GPX4 expression was induced during and required for adipocyte differentiation. In mature adipocytes, impaired GPX4 activity spontaneously evoked lipid peroxidation and expression of inflammatory cytokines such as TNF-α, interleukin 1β (IL-1β), IL-6 and the IL-8 homologue CXCL1. Gpx4-/-AT mice spontaneously displayed adipocyte hypertrophy on a chow diet, which was paralleled by the accumulation of oxygen-specific epitopes and macrophage infiltration in adipose tissue. Furthermore, Gpx4-/-AT mice spontaneously developed glucose intolerance, hepatic insulin resistance and systemic low-grade inflammation, when compared to wildtype littermates, which was similarly recapitulated in Gpx4+/-Fabp4 mice. Gpx4-/-AT mice exhibited no signs of adipocyte death. Adipocyte GPX4 protects against spontaneous metabolic dysregulation and systemic low-grade inflammation independent from ferroptosis, which could be therapeutically exploited in the future.

The Roles and Associated Mechanisms of Adipokines in Development of Metabolic Syndrome.

Metabolic syndrome is a cluster of metabolic indicators that increase the risk of diabetes and cardiovascular diseases. Visceral obesity and factors derived from altered adipose tissue, adipokines, play critical roles in the development of metabolic syndrome. Although the adipokines leptin and adiponectin improve insulin sensitivity, others contribute to the development of glucose intolerance, including visfatin, fetuin-A, resistin, and plasminogen activator inhibitor-1 (PAI-1). Leptin and adiponectin increase fatty acid oxidation, prevent foam cell formation, and improve lipid metabolism, while visfatin, fetuin-A, PAI-1, and resistin have pro-atherogenic properties. In this review, we briefly summarize the role of various adipokines in the development of metabolic syndrome, focusing on glucose homeostasis and lipid metabolism.

Young Adult LEW.1WR1 Rats Have Reduced Beta Cell Area and Develop Glucose Intolerance

Young Adult LEW.1WR1 Rats Have Reduced Beta Cell Area and Develop Glucose Intolerance