Insulin Resistance In Peripheral Tissues Research Articles

Features of Endocrine Function of the Pancreas with Aging in Nonhuman Primates with Various Types of Adaptive Behavior

An increasing number of studies are devoted to the study of the relationship of mental disorders, such as depression and anxiety, with the risk of developing type 2 diabetes mellitus. However, in the literature there are practically no publications on the study of the relationship of the features of higher nervous activity, in particular, adaptive behavior, in healthy individuals with the risk of developing age-related dysfunction of the pancreatic islet apparatus (PIA). The purpose of this study was to investigate features of the functioning of the PIA during aging in individuals with normal standard behavior (SB), as well as anxiety- and depressive-like behavior (DAB) in experiments on nonhuman primates. 76 physically healthy young mature and old female rhesus monkeys with SB and DAB were used in the experiments. Old animals were divided into subgroups with normal (NW) and excess (EW) body weight. All young animals were characterized by NW. The function of PIA was assessed using a glucose tolerance test. Intergroup differences in the functioning of the PIA in young animals were revealed, which were characterized by signs of impaired early insulin response, apparently due to a decrease in the sensitivity of β-cells of the pancreas to glucose. With aging, the function of the PIA was damaged in all animals, but the features of its changes depended on both the affiliation to a particular behavioral group and the animal's body weight. During aging in animals with SB, the development of relative insulin resistance of peripheral tissues was observed, accompanied by impaired glucose tolerance and a compensatory increase in the secretory activity of the PIA, which were more pronounced in animals with EW. Age-related dysfunction of the PIA in animals with DAB and NW was similar with age-related changes in the PIA function in animals with SB and NW. At the same time, with aging, animals with DAB and EW showed a more significant peak concentration of glucose than that of old animals with SB and EW, accompanied by a minimum «disappearance» rate of glucose from the circulation and significantly lower insulin secretion than this in animals with SB and EW. Thus, age-related dysfunctions of the PIA in primates with SB and DAB are unidirectional with the development of insulin resistance, impaired glucose tolerance and a compensatory increase in insulin secretion, which, however, in old animals with DAB and EW are accompanied by exhaustion of the PIA function, increasing the risk of developing type 2 diabetes mellitus.

Relationship Between Intermittent Hypoxia and Type 2 Diabetes in Sleep Apnea Syndrome.

Sleep apnea syndrome (SAS) is a very common disease involving intermittent hypoxia (IH), recurrent symptoms of deoxygenation during sleep, strong daytime sleepiness, and significant loss of quality of life. A number of epidemiological researches have shown that SAS is an important risk factor for insulin resistance and type 2 diabetes mellitus (DM), which is associated with SAS regardless of age, gender, or body habitus. IH, hallmark of SAS, plays an important role in the pathogenesis of SAS and experimental studies with animal and cellular models indicate that IH leads to attenuation of glucose-induced insulin secretion from pancreatic β cells and to enhancement of insulin resistance in peripheral tissues and cells, such as liver (hepatocytes), adipose tissue (adipocytes), and skeletal muscles (myocytes). In this review, we focus on IH-induced dysfunction in glucose metabolism and its underlying molecular mechanisms in several cells and tissues related to glucose homeostasis.

Diabetes-induced Proteome Changes Throughout Development.

Diabetes Mellitus (DM) is a multisystemic disease involving the homeostasis of insulin secretion by the pancreatic islet beta cells (β-cells). It is associated with hypertension, renal disease, and arterial and arteriolar vascular diseases. The classification of diabetes is identified as type 1 (gene linked β-cell destruction in childhood) and type 2 (late onset associated with β-cell overload and insulin resistance in peripheral tissues. Type 1 diabetes is characterized by insulin deficiency, type 2 diabetes by both insulin deficiency and insulin resistance. The former is a genetically programmed loss of insulin secretion whereas the latter constitutes a disruption of the homeostatic relationship between the opposing activity of β- cell insulin and alpha cell (α-cell) glucagon of the Islets of Langerhans. The condition could also occur in pregnancy, as a prenatal occurring event, possibly triggered by the hormonal changes of pregnancy combined with β-cell overload. This review discusses the molecular basis of the biomolecular changes that occur with respect to glucose homeostasis and related diseases in DM. The underlying link between pancreatic, renal, and microvascular diseases in DM is based on oxidative stress and the Unfolded Protein Response (UPR). Studying proteome changes in diabetes can deepen our understanding of the biomolecular basis of disease and help us acquire more efficient therapies.

Oxidative stress pathways in pancreatic β-cells and insulin-sensitive cells and tissues: importance to cell metabolism, function, and dysfunction.

It is now accepted that nutrient abundance in the blood, especially glucose, leads to the generation of reactive oxygen species (ROS), ultimately leading to increased oxidative stress in a variety of tissues. In the absence of an appropriate compensatory response from antioxidant mechanisms, the cell, or indeed the tissue, becomes overwhelmed by oxidative stress, leading to the activation of intracellular stress-associated pathways. Activation of the same or similar pathways also appears to play a role in mediating insulin resistance, impaired insulin secretion, and late diabetic complications. The ability of antioxidants to protect against the oxidative stress induced by hyperglycemia and elevated free fatty acid (FFA) levels in vitro suggests a causative role of oxidative stress in mediating the latter clinical conditions. In this review, we describe common biochemical processes associated with oxidative stress driven by hyperglycemia and/or elevated FFA and the resulting clinical outcomes: β-cell dysfunction and peripheral tissue insulin resistance.

Estradiol Protects Neuropeptide Y/Agouti-Related Peptide Neurons against Insulin Resistance in Females

When it comes to obesity, men exhibit a higher incidence of metabolic syndrome than women in early adult life, but this sex advantage wanes in postmenopausal women. A key diagnostic of the metabolic syndrome is insulin resistance in both peripheral tissues and brain, especially in the hypothalamus. Since the anorexigenic hormone 17β-estradiol (E₂) regulates food intake in part by inhibiting the excitability of the hypothalamic neuropeptide Y/agouti-related peptide (NPY/AgRP) neurons, we hypothesized that E₂ would protect against insulin resistance in NPY/AgRP neurons with diet-induced obesity (DIO). Therefore, we did whole-cell recordings and single cell quantitative polymerase chain reaction in arcuate NPY^GFP neurons from both female and male mice to test the efficacy of insulin with DIO. The resting membrane potential and input resistance of NPY/AgRP neurons were significantly increased in DIO versus control-diet fed males. Most notably, the efficacy of insulin to activate K_ATP channels in NPY/AgRP neurons was significantly attenuated, although the K_ATP channel opener diazoxide was fully effective in NPY/AgRP neurons from DIO males, indicating that the K_ATP channels were expressed and functional. In contrast, insulin was fully efficacious to activate K_ATP channels in DIO females, and the response was reversed by the K_ATP channel blocker tolbutamide. However, the ability of insulin to activate K_ATP channels was abrogated with ovariectomy but fully restored with E₂ replacement. Insulin resistance in obese males was likely mediated by an increase in suppressor of cytokine signaling-3 (SOCS-3), protein tyrosine phosphatase B (PTP1B) and T-cell protein tyrosine phosphatase (TCPTP) activity, since the expression of all 3 mRNAs were upregulated in the obese males but not in females. As proof of principle, pre-incubation of hypothalamic slices from DIO males with the PTP1B/TCPTP inhibitor CX08005 completely rescued the effects of insulin. Therefore, E₂ protects NPY/AgRP neurons in females against insulin resistance through, at least in part, attenuating phosphatase activity. The neuroprotective effects of E₂ may explain sex differences in the expression of metabolic syndrome that disappears with the loss of E₂ in aging.

566-P: Mild Increase of Proinflammatory Macrophages Correlates with Reduction of Nerve Fiber Density in Sural Nerve of Human Type 2 Diabetic Subjects

The dominant infiltration of pro-inflammatory M1 macrophages (M1) compared to anti-inflammatory M2 macrophages (M2) exerts insulin resistance in peripheral tissues of type 2 diabetes (T2DM). This inflammatory reaction is also associated with the pathogenesis and development of diabetic complications including neuropathy (DPN). It is still unclarified, however, regarding macrophage infiltration in human DPN. The aim of this study is to clarify the significance of macrophage infiltration in sural nerve (SN) in subjects with T2DM. SN of autopsy cases was dissected from 2014 to 2016. Eleven cases (Male 6, Female 5) of non-T2DM (nDM) and 11 cases (Male 3, Female 8) of T2DM (T2D) were subjected to the evaluation. Double immunohistochemistry was performed in cross section of SN for CD68 (Pan-macrophage) and CD206 (M2). M1 was defined as CD68+ and CD206- and M2 was as CD206+, respectively. Epon-embedded semithin section was used for morphometrical assessment of SN fibers. In frozen SN, mRNA expression was evaluated by qPCR. Average age and BMI were comparable between 2 groups. HbA1c was significantly greater in T2D (mean±SE) (7.2±0.5%) than nDM (5.5±0.2%) (p<0.05). Pathological evaluation showed 2.4 times M1 in T2D more than that in nDM (p<0.05). On the other hand, M2 was comparable between 2 groups. Expression of iNOS for M1 in T2D was 1.8 times increased compared to that of nDM (p<0.05), whilst, that of CD163 for M2 was comparable between two groups. Correlation analysis between macrophage infiltration and clinical parameters disclosed that the M1 infiltration proportionally correlated with the value of HbA1c (p<0.05), whereas there was no correlation between M2 infiltration and HbA1c. SN fiber density inversely correlated with M1 population (p<0.05). Collectively, mild, but significant pro-inflammatory condition is associated with SN fiber loss, suggesting the pathogenic role of M1 in DPN. Disclosure H. Mizukami: None. S. Osonoi: None. K. Takahashi: None. K. Kudo: None. C. Itabashi: None. S. Yagihashi: None.

310-OR: Integrating Islet and Skeletal Muscle Enhancer RNA Signatures with Diverse Omics Data Enables Fine-Mapping of Diabetes and Related Trait GWAS Loci

Type 2 diabetes (T2D) results from interaction between genetic variation and environmental exposures that influence insulin secretion in pancreatic islets and insulin resistance in skeletal muscle and other peripheral tissues. Genome-wide association studies (GWAS) have identified hundreds of loci that modulate risk for T2D and related insulin traits. These loci mostly occur in non protein-coding regions which makes identification of causal regulatory single nucleotide polymorphisms (SNPs) and their associated mechanisms difficult. Previous studies show that many active enhancers are transcribed into enhancer RNA (eRNA). To identify actively transcribed regulatory elements with high genomic resolution and prioritize SNPs, we generated eRNA profiles using cap analysis of gene expression (CAGE) across 57 islet and 146 skeletal muscle samples and 15 replicates of the human beta cell line EndoC-BH1. We computationally integrated these CAGE profiles with ChIP-seq profiles for five histone marks along with open chromatin ATAC-seq profiles to generate high-resolution cross-tissue chromatin states. We identify multiple CAGE-enriched chromatin states that correspond to actively transcribed promoter or enhancer regions, which are supported by diverse patterns of chromatin activity across an orthogonal set of 127 human epigenome maps. We find 11,856 CAGE+ promoter regions across islets and muscle and 54% are shared across the two tissues, whereas we observe 1,712 CAGE+ eRNA regions and only 7% are shared, indicating the cell-identity nature of these eRNA states. We find significant enrichment for GWAS and eQTL SNPs to overlap these CAGE+ chromatin states. Finally, at a subset of loci, we validate these findings using a modified high-throughput STARR-seq assay where we observe allelic activity. These results provide the highest-resolution epigenome maps for islets and muscle to date, and we are using them to fine-map GWAS SNPs. Disclosure S. Parker: None. A. Varshney: None. Funding American Diabetes Association/Pathway to Stop Diabetes (1-14-INI-07 to S.P.); National Institutes of Health (1R01DK117960)

EFFECTS OF LEUCAS CEPHALOTES EXTRACT ON INSULIN RESISTANCE AND ASSOCIATED METABOLIC SYNDROME IN TYPE II DIABETIC RATS

Background: Type II diabetes is the most common metabolic disorder caused by inadequate insulin secretion by pancreatic β-cells to compensate for insulin resistance in peripheral tissues, which leads microvascular and macrovascular complications. Novel treatment strategies for the management of insulin resistance and associated metabolic syndromes, plant based medicines contributing much with minimal side effects like lactic acidosis. Objective: As Insulin resistance and associated metabolic syndrome contributes to the pathogenesis of type 2 diabetes mellitus, we investigated whether methanolic extract of whole plant Leucas cephalotes (MELC) plays any role in preventing type-2 diabetes mellitus and associated metabolic syndrome in streptozotocin (STZ) induced diabetic rats. Materials and Methods: The MELC was prepared by solvent extraction procedure. Rat pups of age 5 days were divided into 4 groups, with 6 animals in each. Group-I pups served as vehicle control and received 1% sodium carboxy methyl cellulose (CMC), Group-II served as diabetic control and was treated only with single dose of streptozotocin (80mg/kg, i.p), Group-III & Group-IV served as test groups were treated with MELC at doses of 150mg/kg and 300mg/kg respectively for about 45 days after single dose administration of STZ (80mg/kg, i.p). On 30th and 45th day, blood samples were collected from all animals and levels of fasting glucose, fasting insulin, uric acid, Hydrogen Sulphide (H2S), triglycerides and total cholesterol levels in plasma were estimated. Results: The plasma fasting glucose levels were found to be significantly (p<0.001) elevated in single dose streptozotocin treated diabetic control than vehicle control. However, in low dose and high dose test groups, fasting glucose levels, fasting insulin levels, insulin resistance, all the biochemical parameters associated with metabolic syndrome such as fasting insulin values, Triglyceride, Total cholesterol, H2S and Uric acid levels were significantly (p<0.01and p<0.001) decreased after chronic administration of MELC for 45 days and the decrease was more prominent with higher dose. Conclusions: The present investigation reveals that MELC administration shows significant effect on insulin resistance and associated metabolic syndrome in a dose dependent manner. So, hereby the beneficial action of MELC on human type-II diabetes may be suggested. Keywords: Leucas cephalotes; Insulin resistance; metabolic syndrome; Streptozotocin; Type-2 Diabetes mellitus.

Molecular Basis of Pathogenesis of Ectopic Fat Deposition in DM2 – An Overview

The presence of fat, beyond physiological limits, in organs, other than the adipose tissue, like the liver, the skeletal muscle, the heart and the pancreas etc is called ectopic fat. It causes specific organ dysfunction in the tissues concerned. The importance of the ectopic fat is that it is connected to peripheral tissue insulin resistance, obesity, metabolic syndrome etc. Though the molecular mechanisms underlying the specific organ dysfunctions are understood, still grey areas exists as to the source of the ectopic fat and how it finds it’s way to the specific sites of the target organs (intra- myocellular in skeletal muscle, hepatocyte cytoplasm of liver, epicardial surface and coronary arteries of heart etc.). The molecular mechanisms involving the actual ectopic deposition fat, are not clear. This article focuses on some of the grey areas in the pathogenesis of the ectopic fat deposition, besides reviewing briefly the facts already known in the literature about ectopic fat deposition.

β-Cell Fate in Human Insulin Resistance and Type 2 Diabetes: A Perspective on Islet Plasticity.

Although it is well established that type 2 diabetes (T2D) is generally due to the progressive loss of β-cell insulin secretion against a background of insulin resistance, the actual correlation of reduced β-cell mass to its defective function continues to be debated. There is evidence that a compensatory increase in β-cell mass, and the consequent insulin secretion, can effectively cope with states of insulin resistance, until hyperglycemia supervenes. Recent data strongly indicate that the mechanisms by which islets are able to compensate in response to insulin resistance in peripheral tissues is secondary to hyperplasia, as well as the activation of multiple cellular machineries with diverse functions. Importantly, islet cells exhibit plasticity in altering their endocrine commitment; for example, by switching from secretion of glucagon to secretion of insulin and back (transdifferentiation) or from an active secretory state to a nonsecretory quiescent state (dedifferentiation) and back. Lineage tracing (a method used to track each cell though its differentiation process) has demonstrated these potentials in murine models. A limitation to drawing conclusions from human islet research is that most studies are derived from human autopsy and/or organ donor samples, which lack in vivo functional and metabolic profiling. In this review, we specifically focus on evidence of islet plasticity in humans-from the normal state, progressing to insulin resistance to overt T2D-to explain the seemingly contradictory results from different cross-sectional studies in the literature. We hope the discussion on this intriguing scenario will provide a forum for the scientific community to better understand the disease and in the long term pave the way for personalized therapies.

Palmitic acid causes insulin resistance in granulosa cells via activation of JNK.

Obesity is a worldwide health problem with rising incidence and results in reproductive difficulties. Elevated saturated free fatty acids (FFAs) in obesity can cause insulin resistance (IR) in peripheral tissues. The high intra-follicular saturated FFAs may also account for IR in ovarian granulosa cells (GCs). In the present study, we investigated the relationship between saturated FFAs and IR in GCs by the use of palmitic acid (PA). We demonstrated that the glucose uptake in cultured GCs and lactate accumulation in the culture medium were stimulated by insulin, but the effects of insulin were attenuated by PA treatment. Besides, insulin-induced phosphorylation of Akt was reduced by PA in a dose- and time-dependent manner. Furthermore, PA increased phosphorylation of JNK and JNK blockage rescued the phosphorylation of Akt which was downregulated by PA. These findings highlighted the negative effect of PA on GCs metabolism and may partially account for the obesity-related reproductive disorders.

Carbenoxolone ameliorates insulin sensitivity in obese mice induced by high fat diet via regulating the IκB-α/NF-κB pathway and NLRP3 inflammasome

The characteristic feature of obesity and insulin resistance is chronic low-grade inflammation. Nod-Like Receptor Pyrin 3 (NLRP3) inflammasome plays a central role in obesity-induced insulin resistance. However, how does Carbenoxolone (CBX) play its role in ameliorating insulin resistance in peripheral tissues of obese mice induced by high-fat diet (HFD) remains unknown. In our study, we explored the molecular mechanism of CBX in improving insulin resistance in liver and skeletal muscle in mice induced by the HFD. Our results revealed that in the CBX group, a significant decrease in fasting blood glucose, insulin and HOMA-IR score were observed. CBX could attenuate intracellular lipid accumulation and inflammation aggravation in liver and skeletal muscle. Besides, treatment with CBX could significantly reduce expressions of p-IκB-α, p-NF-κB, p-IRS-1, NLRP3 and inflammatory factors, increase expressions of p-PI3K and p-AKT. Therefore, CBX could dramatically improve insulin resistance in liver and skeletal muscle in mice induced by the high-fat diet. In conclusions, we demonstrate that CBX has a significant protective effect on diet-induced obesity in mice. The potential mechanisms include inhibiting IκB-α/NF-κB pathway, restricting the production of NLRP3 inflammasome and other inflammatory factors, reducing the expression of p-IRS-1, increasing the expressions of p-PI3K and p-AKT, thus ameliorating insulin resistance in liver and skeletal muscle of high-fat diet mice. Therefore CBX is an active agent against diet-induced obesity and is given the opportunity for the treatment of obesity related diseases.

Metabolic Abnormalities of Chronic High-Dose Glucocorticoids Are Not Mediated by Hypothalamic AgRP in Male Mice

Glucocorticoids are potent and widely used medicines but often cause metabolic side effects. A murine model of corticosterone treatment resulted in increased hypothalamic expression of the melanocortin antagonist AgRP in parallel with obesity and hyperglycemia. We investigated how these adverse effects develop over time, with particular emphasis on hypothalamic involvement. Wild-type and Agrp−/− male mice were treated with corticosterone for 3 weeks. Phenotypic, biochemical, protein, and mRNA analyses were undertaken on central and peripheral tissues, including white and brown adipose tissue, liver, and muscle, to determine the metabolic consequences. Corticosterone treatment induced hyperphagia within 1 day in wild-type mice, which persisted for 3 weeks. Despite this early increase in food intake, the body weight only started to increase after 10 days. Hyperinsulinemia occurred at day 1. Also, although after 2 days, alterations were present in the genes often associated with insulin resistance in several peripheral tissues, hyperglycemia only developed at 3 weeks. Throughout, sustained elevation in hypothalamic Agrp expression was present. Mice with Agrp deleted [using clustered regularly interspaced short palindromic repeats (CRISPR)–Cas9, Agrp−/−] were partially protected against corticosterone-induced hyperphagia. However, Agrp−/− mice still had corticosterone-induced increases in body weight and adiposity similar to those of the Agrp+/+ mice. Loss of Agrp did not diminish corticosterone-induced hyperinsulinemia or correct changes in hepatic gluconeogenic genes. Chronic glucocorticoid treatment in mice mimics many of the metabolic side effects seen in patients and leads to a robust increase in Agrp. However, AgRP does not appear to be responsible for most of the glucocorticoid-induced adverse metabolic effects.

PHYSIOLOGY SYMPOSIUM: Effects of heat stress during late gestation on the dam and its calf12.

Heat stress during late gestation in cattle negatively affects the performance of the dam and its calf. This brief exposure to an adverse environment before parturition affects the physiological responses, tissue development, metabolism, and immune function of the dam and her offspring, thereby limiting their productivity. During the dry period of a dairy cow, heat stress blunts mammary involution by attenuating mammary apoptosis and autophagic activity and reduces subsequent mammary cell proliferation, leading to impaired milk production in the next lactation. Dairy cows in early lactation that experience prepartum heat stress display reduced adipose tissue mobilization and lower degree of insulin resistance in peripheral tissues. Similar to mammary gland development, placental function is impaired by heat stress as evidenced by reduced secretion of placental hormones (e.g., estrone sulfate) in late gestation cows, which partly explains the reduced fetal growth rate and lighter birth weight of the calves. Compared with dairy calves born to dams that are exposed to evaporative cooling during summer, calves born to noncooled dry cows maintain lower BW until 1 yr of age, but display a stronger ability to absorb glucose during metabolic challenges postnatally. Immunity of the calves, both passive and cell-mediated immune function, is also impaired by prenatal heat stress, resulting in increased susceptibility of the calves to diseases in their postnatal life. In fact, dairy heifers born to heat-stressed dry cows without evaporative cooling have a greater chance leaving the herd before puberty compared with heifers born to dry cows provided with evaporative cooling (12.2% vs. 22.7%). Dairy heifers born to late-gestation heat-stressed dry cows have lower milk yield at maturity during their first and second lactations. Emerging evidence suggests that late-gestation heat stress alters the mammary gland microstructure of the heifers during the first lactation and exerts epigenetic alterations that might explain, in part, their impaired productivity.

Antidiabetic and hepatoprotective activity of the roots of Calanthe fimbriata Franch

BackgroundCalanthe fimbriata is a Tujia ethnic medicine with various medicinal value and it is traditionally used for the treatment of gastric ulcer, chronic hepatitis, pharyngitis, and so on. ObjectiveThe current study was conducted to evaluate the antidiabetic activity of C. fimbriata methanol extract (CfME) in oral glucose tolerance test (OGTT) mice and in streptozotocin (STZ)-induced diabetic mice. MethodsExperimental diabetes was induced by intraperitoneal injection of STZ (60 mg/kg) for three consecutive days in mice. OGTT in mice and α-glucosidase inhibition assay were also adopted to investigate the activity and elucidate the mechanism of action. Gliclazide and metformin were used as standard drugs in OGTT mice and in STZ-induced diabetic mice experiments, respectively. Blood glucose, total cholesterol (TC), triglyceride (TG), alanine aminotransferase (ALT), aspartate aminotransferase (AST), and hepatic glycogen were measured in plasma or in livers. ResultsCfME exerted potently antihyperglycemic activity in OGTT mice and in STZ-induced diabetic mice and decreased ALT, AST and TG levels, improved hepatomegaly, and increased hepatic glycogen content, however, CfME failed to modify the normal blood glucose in normoglycemic mice and exhibited weakly inhibitory activity on intestinal α-glucosidase. ConclusionThe present study demonstrated that CfME exerted potently antidiabetic activity by restoring the liver function to increase the synthesis of hepatic glycogen and by improving insulin resistance of peripheral tissues to enhance the uptake and utilization of glucose.

Spotlight on epigenetics as a missing link between obesity and type 2 diabetes.

Type 2 diabetes (T2D) is a complex disorder that is caused by a combination of genetic, epigenetic, and environmental factors. β-cell failure and insulin resistance in peripheral tissues that are induced by lipid overload are main hallmarks of T2D. The mechanisms that link obesity-driven alterations of lipid metabolism and T2D are still elusive, thereby impeding the development of effective prevention and treatment strategies. Although genetic variants that have been identified in high-throughput studies comprise an appreciable proportion of the genetic component of T2D, they explain < 20% of the estimated heritability of T2D. A growing body of evidence suggests an intrinsic role for epigenetic modifications in the pathogenesis of T2D. The epigenetic regulation of gene expression in tissues that play a key role in the obesity-related development of T2D has been demonstrated, including PDX1 in pancreatic islets, PPARGC1A in skeletal muscles, ADIPOQ in adipose tissue, and TXNIP in the liver. The present review summarizes our current knowledge of crosstalk between the epigenetic control of gene expression, particularly via DNA methylation, toxic lipid mediators, and the pathogenesis of obesity-related T2D.

Evaluation of the effect of Lactobacillus reuteri V3401 on biomarkers of inflammation, cardiovascular risk and liver steatosis in obese adults with metabolic syndrome: a randomized clinical trial (PROSIR)

BackgroundObesity is characterized by increased fat mass and is associated with the development of insulin resistance syndrome (IRS), usually known as metabolic syndrome. The alteration of the intestinal microbiota composition has a role in the development of IRS associated with obesity, and probiotics, which are live microorganisms that confer a health benefit to the host, contribute to restore intestinal microbiota homeostasis and lower peripheral tissue insulin resistance. We aim to evaluate the effects of the probiotic strain Lactobacillus reuteri (L. reuteri) V3401 on the composition of intestinal microbiota, markers of insulin resistance and biomarkers of inflammation, cardiovascular risk, and hepatic steatosis in patients with overweight and obesity exhibiting IRS.Methods/designWe describe a randomized, double-blind, crossover, placebo-controlled, and single-centre trial. Sixty participants (aged 18 to 65 years) diagnosed with IRS will be randomized in a 1:1 ratio to receive either a daily dose of placebo or 5 × 109 colony-forming units of L. reuteri V3401. The study will consist of two intervention periods of 12 weeks separated by a washout period of 6 weeks and preceded by another washout period of 2 weeks. The primary outcome will be the change in plasma lipopolysaccharide (LPS) levels at 12 weeks. Secondary outcomes will include anthropometric parameters, lipid profile, glucose metabolism, microbiota composition, hepatic steatosis, and inflammatory and cardiovascular biomarkers. Blood and stool samples will be collected at baseline, at the midpoint (only stool samples) and immediately after each intervention period. Luminex technology will be used to measure interleukins. For statistical analysis, a mixed ANOVA model will be employed to calculate changes in the outcome variables.DiscussionThis is the first time that L. reuteri V3401 will be evaluated in patients with IRS. Therefore, this study will provide valuable scientific information about the effects of this strain in metabolic syndrome patients.Trial registrationThe trial has been retrospectively registered in ClinicalTrials.gov on the 23rd November 2016 (ID: NCT02972567), during the recruitment phase.

Energy metabolism of white adipose tissue and insulin resistance in humans.

Insulin resistance not only occurs in obesity, but also in lipodystrophy. Although adipose tissue mass affects metabolic fluxes and participates in interorgan crosstalk, the role of energy metabolism within white adipose tissue for insulin resistance is less clear. A Medline search identified invivo studies in humans on energy and lipid metabolism in subcutaneous (SAT) and visceral adipose tissue (VAT). Studies in adipocyte cultures and transgenic animal models were included for the better understanding of the link between abnormal energy metabolism in adipose tissue and insulin resistance. The current literature indicates that higher lipolysis and lower lipogenesis in VAT compared to SAT enhance portal delivery of lipid metabolites (glycerol and fatty acids) to the liver. Thus, the lower lipolysis and higher lipogenesis in SAT favour storage of excess lipids and allow for protection of insulin-sensitive tissues from lipotoxic effects. In insulin-resistant humans, enhanced lipolysis and impaired lipogenesis in adipose tissue lead to release of cytokines and lipid metabolites, ultimately promoting insulin resistance. Adipose tissue of insulin-resistant humans also displays lower expression of proteins involved in mitochondrial function. In turn, this leads to lower availability of mitochondria-derived energy sources for lipogenesis in adipose tissue. Abnormal mitochondrial function in human white adipose tissue likely contributes to the secretion of lipid metabolites and lactate, which are linked to insulin resistance in peripheral tissues. However, the relevance of adipose tissue energy metabolism for the regulation of human insulin sensitivity remains to be further elucidated.

Fetal undernutrition, placental insufficiency, and pancreatic β-cell development programming in utero.

The prevalence of obesity and type 2 (T2D) diabetes is a major health concern in the United States and around the world. T2D is a complex disease characterized by pancreatic β-cell failure in association with obesity and insulin resistance in peripheral tissues. Although several genes associated with T2D have been identified, it is speculated that genetic variants account for only <10% of the risk for this disease. A strong body of data from both human epidemiological and animal studies shows that fetal nutrient factors in utero confer significant susceptibility to T2D. Numerous studies done in animals have shown that suboptimal maternal environment or placental insufficiency causes intrauterine growth restriction (IUGR) in the fetus, a critical factor known to predispose offspring to obesity and T2D, in part by causing permanent consequences in total functional β-cell mass. This review will focus on the potential contribution of the placenta in fetal programming of obesity and TD and its likely impact on pancreatic β-cell development and growth.

Basic and clinical study of stem cell treatment for diabetes mellitus in China

Pancreatic islet beta cell dysfunction and insulin resistance are the main mechanisms underlying the development of diabetes mellitus. The current anti-diabetic treatments only alleviate symptoms and may delay the progression of the disease, but cannot cure the disease. Stem cells improve the function of islet beta cells by promoting in situ regeneration and repair mechanisms that improve autophagy of islet beta cells and modulate macrophage function. They also ameliorate the insulin resistance in peripheral tissues by activating the IRS-1-AKT-GLUT4 signaling pathway in skeletal muscle, fat, and liver. Stem cell therapy has provided a new direction for the precise treatment of diabetes. Researchers in China have carried out a series of experiments on different sources of stem cell therapy for diabetes mellitus using different infusion methods, and they have achieved good clinical effects without serious adverse reactions. These results have provided a basis for the clinical application of stem cells in the treatment of diabetes mellitus.