Defects In Glucose Homeostasis Research Articles

Disrupted glucose homeostasis and glucagon and insulin secretion defects in Robo βKO mice.

The axon guidance proteins, Roundabout (Robo) receptors play a critical role in morphogenesis of the islets of Langerhans. Mice with a β cell-selective deletion of Robo (Robo βKO), show severely disrupted spatial architecture of their islets, without defects in β cell differentiation or maturity. We have recently shown that Robo βKO mice have reduced synchronous glucose-stimulated β cell calcium oscillations in their islets in vivo, likely disrupting their pulsatile insulin secretion. Here, we analyze whole-body metabolic regulation in Robo βKO mice. We show that Robo βKO mice have mild defects in glucose homeostasis, and altered glucagon and insulin secretion. However, we did not observe any severe whole-body glucoregulatory phenotype following the disruption of islet architecture in Robo βKO. Our data suggest that islet architecture plays only a mild role in overall glucoregulation.

Systemic ablation of vitamin D receptor leads to skeletal muscle glycogen storage disorder in mice.

BackgroundVitamin D deficiency leads to pathologies of multiple organ systems including skeletal muscle. Patients with severe vitamin D deficiency exhibit muscle weakness and are susceptible to frequent falls. Mice lacking a functional vitamin D receptor (VDR) develop severe skeletal muscle atrophy immediately after weaning. But the root cause of myopathies when vitamin D signalling is impaired is unknown. Because vitamin D deficiency leads to metabolic changes as well, we hypothesized that the skeletal muscle atrophy in mice lacking VDR may have a metabolic origin.MethodsWe analysed wild‐type (WT) mice as well as vitamin D receptor null (vdr−/−) mice for skeletal muscle proteostasis, energy metabolism, systemic glucose homeostasis, and muscle glycogen levels. Dysregulation of signalling pathways as well as the glycogen synthesis and utilization machinery were also analysed using western blots. qRT–PCR assays were performed to understand changes in mRNA levels.ResultsSkeletal muscles of vdr−/− exhibited higher expression levels of muscle‐specific E3 ubiquitin ligases and showed increased protein ubiquitination, suggesting up‐regulation of protein degradation. Foxo1 transcription factor was activated in vdr−/− while Foxo3 factor was unaffected. Fasting protein synthesis as well as mTORC1 pathways were severely down‐regulated in vdr−/− mice. Skeletal muscle ATP levels were low in vdr−/− (0.58 ± 0.18 μmol/mL vs. 1.6 ± 0.0.14 μmol/mL, P = 0.006), leading to increased AMPK activity. Muscle energy deprivation was not caused by decreased mitochondrial activity as we found the respiratory complex II activity in vdr−/− muscles to be higher compared with WT (0.29 ± 0.007 mU/μL vs. 0.16 ± 0.005 mU/μL). vdr−/− mice had lower fasting blood glucose levels (95 ± 14.5 mg/dL vs. 148.6 ± 6.1 mg/dL, P = 0.0017) while they exhibited hyperlactataemia (7.42 ± 0.31 nmol/μL vs. 4.95 ± 0.44 nmol/μL, P = 0.0032), suggesting systemic energy deficiency in these mice. Insulin levels in these mice were significantly lower in response to intraperitoneal glucose injection (0.69 ± 0.08 pg/mL vs. 1.11 ± 0.09 pg/mL, P = 0.024). Skeletal muscles of these mice exhibit glycogen storage disorder characterized by increased glycogen accumulation. The glycogen storage disorder in vdr−/− muscles is driven by increased glycogen synthase activity and decreased glycogen phosphorylase activity. Increased glycogenin expression supports higher levels of glycogen synthesis in these muscles.ConclusionsThe results presented show that lack of vitamin D signalling leads to a glycogen storage defect in the skeletal muscles, which leads to muscle energy deprivation. The inability of vdr−/− skeletal muscles to use glycogen leads to systemic defects in glucose homeostasis, which in turn leads to proteostasis defects in skeletal muscles and atrophy.

Palmatine ameliorates high fat diet induced impaired glucose tolerance

BackgroundThe impaired glucose tolerance (IGT) is a representative prediabetes characterized by defective glucose homeostasis, and palmatine (PAL) is a natural isoquinoline alkaloid with multiple pharmacological effects. Our study aims to investigate the therapeutic effect of PAL on the impaired glucose tolerance.MethodsMale Sprague–Dawley rats were used to establish an IGT model with high fat diet (HFD). Oral glucose tolerance test (OGTT) and further biochemical analysis were conducted to determine the effect of PAL on glucose intolerance in vivo. Molecular details were clarified in a cellular model of IGT induced by Palmitate (PA) on INS-1 cells.ResultsOur study demonstrated a relief of IGT with improved insulin resistance in HFD induced rats after PAL treatment. Besides, promoted pancreas islets function was validated with significantly increased β cell mass after the treatment of PAL. We further found out that PAL could alleviate the β cell apoptosis that accounts for β cell mass loss in IGT model. Moreover, MAPK signaling was investigated in vivo and vitro with the discovery that PAL regulated the MAPK signaling by restricting the ERK and JNK cascades. The insulin secretion assay indicated that PAL significantly promoted the defective insulin secretion in PA-induced INS-1 cells via JNK rather than ERK signaling. Furthermore, PAL treatment was determined to significantly suppress β cell apoptosis in PA-induced cells. We thus thought that PAL promoted the PA-induced impaired insulin release by inhibiting the β cell apoptosis and JNK signaling in vitro.ConclusionIn summary, PAL ameliorates HFD-induced IGT with novel mechanisms.

TonEBP Promotes β-Cell Survival under ER Stress by Enhancing Autophagy.

The endoplasmic reticulum (ER) stress response and autophagy are important cellular responses that determine cell fate and whose dysregulation is implicated in the perturbation of homeostasis and diseases. Tonicity-responsive enhancer-binding protein (TonEBP, also called NFAT5) is a pleiotropic stress protein that mediates both protective and pathological cellular responses. Here, we examined the role of TonEBP in β-cell survival under ER stress. We found that TonEBP increases β-cell survival under ER stress by enhancing autophagy. The level of TonEBP protein increased under ER stress due to a reduction in its degradation via the ubiquitin–proteasome pathway. In response to ER stress, TonEBP increased autophagosome formations and suppressed the accumulation of protein aggregates and β-cell death. The Rel-homology domain of TonEBP interacted with FIP200, which is essential for the initiation of autophagy, and was required for autophagy and cell survival upon exposure to ER stress. Mice in which TonEBP was specifically deleted in pancreatic endocrine progenitor cells exhibited defective glucose homeostasis and a loss of islet mass. Taken together, these findings demonstrate that TonEBP protects against ER stress-induced β-cell death by enhancing autophagy.

Validity of glucose measurements in the blood by a glucometer reagent strip in critically ill infants

IntroductionHypoglycemia in critically ill infants is a frequent metabolic disorder which is often due to defective glucose homeostasis. If not recognized annotated early, it can result in severe neurological damage with high mortality and morbidity. Today, glucometer is recommended for fast measuring blood glucose. The aim of this study was to evaluate the accuracy of glucometer for early diagnosis of hypoglycemia in the acutely ill infant. Materials and methodsThis study evaluates 130 critically ill infants less than 1year of age who were admitted to Besat hospital – Sanandaj – IRAN. Blood sugar was measured by standard serum method (glucose oxidase) and glucometer reagent strip. ResultsThe overall means of blood sugar were 115.6 ± 1.75 with serum method and 119.1 ± 1.56 with glucometer method. The rates of sensitivity, specificity, positive predictive value and negative predictive value with glucometer method and with serum glucose method were 72%, 53%, 62%, and 77% respectively. The correlation between the two methods was significant (p < 0.001). Kappa statistics for the two methods was 42%. ConclusionsThe results showed that in general, glucometer may be appropriate for rapid screening in emergency situations and when frequent blood glucose monitoring is needed but it cannot be regarded as a very suitable and reliable tool for diagnosis of hypoglycemia in critically ill infants.

SNAP-25 Puts SNAREs at Center Stage in Metabolic Disease

Synaptosomal Associated Protein of 25 kD (SNAP-25) is an essential protein contributing 2 out of 4 α-helices in the formation of the core soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex which mediates regulated membrane fusion. Regulated exocytosis is a strictly controlled event in eukaryotic cells mediating important homeostatic processes and cellular communications. Altered release of neurotransmitters or hormones is usually considered as part of the progressing pathophysiology of central neurological or peripheral metabolic disorders. However, the molecular changes which precede and initiate disturbed secretion of neurotransmitters and hormones are still unclear. We have explored an alternative hypothesis; that a minor modification in the machinery mediating regulated exocytosis, instead, may underlie the origin of the diseases associated with altered secretion of neurotransmitters and hormones. Possibly, certain modifications to genes encoding for SNAREs or proteins affecting SNARE function may increase the susceptibility to develop disease and its progression can be accelerated when combined with aging and life style factors. To test this theory, we genetically manipulated the Snap25 gene to express only one of the two alternatively spliced isoforms, SNAP-25a. SNAP-25b-deficient mice demonstrated alterations in synaptic transmission and increased insulin secretion which, with time, spontaneously progressed into a pronounced metabolic disease, including defects in glucose homeostasis, obesity, liver steatosis and perturbations in central homeostatic signaling. Thus, deregulated function of SNAP-25 and possibly other SNAREs or SNARE-interacting proteins, can, by itself, act as risk factors for the development of metabolic disease. Here, we provide an overview of the peripheral and central consequences of the deregulations in core SNARE complex with focus on SNAP-25.

The Role of Gut-brain Axis in Regulating Glucose Metabolism After Acute Pancreatitis.

Objectives:Diabetes has become an epidemic in developed and developing countries alike, with an increased demand for new efficacious treatments. A large body of pre-clinical evidence suggests that the gut–brain axis may be exploited as a potential therapeutic target for defective glucose homeostasis. This clinical study aimed to investigate a comprehensive panel of glucoregulatory peptides, released by both the gut and brain, in individuals after acute pancreatitis.Methods:Fasting levels of glucagon-like peptide-1 (GLP-1), glicentin, oxyntomodulin, peptide YY, ghrelin, cholecystokinin, vasoactive intestinal peptide (VIP), and secretin were studied. Modified Poisson and multivariable linear regression analyses were conducted. Pre-determined concentration ranges were used to categorize each peptide into quartiles.Results:A total of 83 individuals were included, of who 30 (36%) developed abnormal glucose metabolism (AGM) after acute pancreatitis. In individuals with AGM, the highest quartile of oxyntomodulin differed most significantly from the lowest quartile with a prevalence ratio (PR; 95% confidence interval) of 0.50 (0.21, 1.20; P=0.005); of glicentin with a PR of 0.26 (0.13, 0.54; P<0.001); and of VIP with a PR of 0.34 (0.13, 0.89; P=0.043). Peptide YY, GLP-1, cholecystokinin, ghrelin, and secretin were not significantly associated with AGM.Conclusions:Fasting circulating oxyntomodulin, glicentin, and VIP levels are significantly decreased in patients with defective glucose homeostasis after acute pancreatitis. Oxyntomodulin appears to be a promising therapeutic target for future clinical studies on diabetes associated with diseases of the exocrine pancreas.

An Isogenic Human ESC Platform for Functional Evaluation of Genome-wide-Association-Study-Identified Diabetes Genes and Drug Discovery

Genome-wide association studies (GWASs) have increased our knowledge of loci associated with arange of human diseases. However, applying such findings to elucidate pathophysiology and promote drug discovery remains challenging. Here, we created isogenic human ESCs (hESCs) with mutations in GWAS-identified susceptibility genes for type 2 diabetes. In pancreatic beta-like cells differentiated from these lines, we found that mutationsinCDKAL1, KCNQ1, and KCNJ11 led to impaired glucose secretion invitro and invivo, coinciding with defective glucose homeostasis. CDKAL1 mutant insulin+ cells were also hypersensitive to glucolipotoxicity. A high-content chemical screen identified a candidate drug that rescued CDKAL1-specific defects invitro and invivo by inhibiting theFOS/JUN pathway. Our approach of a proof-of-principle platform, which uses isogenic hESCs for functional evaluation of GWAS-identified loci and identification of a drug candidate that rescues gene-specific defects, paves the way for precision therapy of metabolic diseases.

PCSK1 Mutations and Human Endocrinopathies: From Obesity to Gastrointestinal Disorders.

Prohormone convertase 1/3, encoded by the PCSK1 gene, is a serine endoprotease that is involved in the processing of a variety of proneuropeptides and prohormones. Humans who are homozygous or compound heterozygous for loss-of-function mutations in PCSK1 exhibit a variable and pleiotropic syndrome consisting of some or all of the following: obesity, malabsorptive diarrhea, hypogonadotropic hypogonadism, altered thyroid and adrenal function, and impaired regulation of plasma glucose levels in association with elevated circulating proinsulin-to-insulin ratio. Recently, more common variants in the PCSK1 gene have been found to be associated with alterations in body mass index, increased circulating proinsulin levels, and defects in glucose homeostasis. This review provides an overview of the endocrinopathies and other disorders observed in prohormone convertase 1/3-deficient patients, discusses the possible biochemical basis for these manifestations of the disease, and proposes a model whereby certain missense mutations in PCSK1 may result in proteins with a dominant negative action.

Genome-wide association of polycystic ovary syndrome implicates alterations in gonadotropin secretion in European ancestry populations.

Polycystic ovary syndrome (PCOS) is a common, highly heritable complex disorder of unknown aetiology characterized by hyperandrogenism, chronic anovulation and defects in glucose homeostasis. Increased luteinizing hormone relative to follicle-stimulating hormone secretion, insulin resistance and developmental exposure to androgens are hypothesized to play a causal role in PCOS. Here we map common genetic susceptibility loci in European ancestry women for the National Institutes of Health PCOS phenotype, which confers the highest risk for metabolic morbidities, as well as reproductive hormone levels. Three loci reach genome-wide significance in the case–control meta-analysis, two novel loci mapping to chr 8p32.1 and chr 11p14.1, and a chr 9q22.32 locus previously found in Chinese PCOS. The same chr 11p14.1 SNP, rs11031006, in the region of the follicle-stimulating hormone B polypeptide (FSHB) gene strongly associates with PCOS diagnosis and luteinizing hormone levels. These findings implicate neuroendocrine changes in disease pathogenesis.

Effects of vitamins C and D in type 2 diabetes mellitus

Effects of vitamins C and D in type 2 diabetes mellitus Darshika J Christie-David,1,2 Christian M Girgis,2&ndash;4 Jenny E Gunton1&ndash;4 1Department of Endocrinology and Diabetes, Westmead Hospital, 2Faculty of Medicine, University of Sydney, 3Westmead Millennium Institute, 4Garvan Institute of Medical Research, Sydney, NSW, Australia Abstract: Scurvy and rickets are largely considered historical diseases in developed countries. However, deficiencies in vitamins C and D are re-emerging due to increased consumption of processed foods and reduced fresh foods in the Western diet, as well as to an indoor sedentary lifestyle away from sun exposure. These dietary and lifestyle factors also predispose one to diabetes and metabolic syndrome. Our understanding of the potential roles of vitamin C (an antioxidant) and vitamin D (a biologically active hormone) in disease is increasing. In this review, we present observational, interventional, and mechanistic studies that examine the potential links between vitamins C and D in reversing defects in glucose homeostasis and the prevention of type 2 diabetes. Studies suggest an association between vitamin C deficiency and diabetes. An association between vitamin D and insulin resistance has been well described; however, the role of vitamin C and D supplementation in diabetes and its prevention requires further controlled trials. Keywords: glucose homeostasis, diabetes, insulin resistance, vitamin C, vitamin D

Diacylglycerol Signaling Pathway in Pancreatic β-Cells: An Essential Role of Diacylglycerol Kinase in the Regulation of Insulin Secretion.

Diacylglycerol (DAG) is a lipid signal messenger and plays a physiological role in β-cells. Since defective glucose homeostasis increases de novo DAG synthesis, DAG may also contribute to β-cell dysfunction in type 2 diabetes. Although the primary function of DAG is to activate protein kinase C (PKC), the role of PKC in insulin secretion is controversial: PKC has been reported to act as both a positive and negative regulator of insulin secretion. In addition to the PKC pathway, DAG has also been shown to mediate other pathways such as the Munc-13-dependent pathway in β-cells. The intracellular levels of DAG are strictly regulated by diacylglycerol kinase (DGK); however, the role of DGK in β-cells and their involvement in β-cell failure in type 2 diabetes remain to be fully elucidated. We have recently reported the roles of type I DGK, DGKα and γ, in insulin secretion from β-cells. DGKα and γ were activated by glucose or high K(+) stimulation in β-cells, and the inhibition of the DGKs by a type I DGK inhibitor or by knockdown with small interfering RNA (siRNA) decreased insulin secretion. Thus, DGKα and γ are suggested to be activated in response to elevated [Ca(2+)]i in β-cells and to act as positive regulators of insulin secretion. In this article, we review the current understanding of the roles of DAG and DGK in β-cell function and their involvement in the development of β-cell dysfunction in type 2 diabetes.

Metabolic dysfunction in obstructive sleep apnea: A critical examination of underlying mechanisms.

It has recently become clear that obstructive sleep apnea (OSA) is an independent risk factor for the development of metabolic syndrome, a disorder of defective energy storage and use. Several mechanisms have been proposed to explain this finding, drawing upon the characteristics that define OSA. In particular, intermittent hypoxia, sleep fragmentation, elevated sympathetic tone, and oxidative stress - all consequences of OSA - have been implicated in the progression of poor metabolic outcomes in OSA. In this review we examine the evidence to support each of these disease manifestations of OSA as a unique risk for metabolic dysfunction. Tissue hypoxia and sleep fragmentation are each directly connected to insulin resistance and hypertension, and each of these also may increase sympathetic tone, resulting in defective glucose homeostasis, excessive lipolysis, and elevated blood pressure. Oxidative stress further worsens insulin resistance and in turn, metabolic dysfunction also increases oxidative stress. However, despite many studies linking each of these individual components of OSA to the development of metabolic syndrome, there are very few reports that actually provide a coherent narrative about the mechanism underlying metabolic dysfunction in OSA.

Primary cilia in pancreatic development and disease.

Primary cilia and their anchoring basal bodies are important regulators of a growing list of signaling pathways. Consequently, dysfunction in proteins associated with these structures results in perturbation of the development and function of a spectrum of tissue and cell types. Here, we review the role of cilia in mediating the development and function of the pancreas. We focus on ciliary regulation of major pathways involved in pancreatic development, including Shh, Wnt, TGF-β, Notch, and fibroblast growth factor. We also discuss pancreatic phenotypes associated with ciliary dysfunction, including pancreatic cysts and defects in glucose homeostasis, and explore the potential role of cilia in such defects.

The Wnt signaling pathway effector TCF7L2 controls gut and brain proglucagon gene expression and glucose homeostasis.

The type 2 diabetes risk gene TCF7L2 is the effector of the Wnt signaling pathway. We found previously that in gut endocrine L-cell lines, TCF7L2 controls transcription of the proglucagon gene (gcg), which encodes the incretin hormone glucagon-like peptide-1 (GLP-1). Whereas peripheral GLP-1 stimulates insulin secretion, brain GLP-1 controls energy homeostasis through yet-to-be defined mechanisms. We aim to determine the metabolic effect of a functional knockdown of TCF7L2 by generating transgenic mice that express dominant-negative TCF7L2 (TCF7L2DN) specifically in gcg-expressing cells. The gcg-TCF7L2DN transgenic mice showed reduced gcg expression in their gut and brain, but not in pancreas. Defects in glucose homeostasis were observed in these mice, associated with attenuated plasma insulin levels in response to glucose challenge. The defect in glucose disposal was exacerbated with high-fat diet. Brain Wnt activity and feeding-mediated hypothalamic AMP-activated protein kinase (AMPK) repression in these mice were impaired. Peripheral injection of the cAMP-promoting agent forskolin increased brain β-cat Ser675 phosphorylation and brain gcg expression and restored feeding-mediated hypothalamic AMPK repression. We conclude that TCF7L2 and Wnt signaling control gut and brain gcg expression and glucose homeostasis and speculate that positive cross-talk between Wnt and GLP-1/cAMP signaling is an underlying mechanism for brain GLP-1 in exerting its metabolic functions.

Implications of microRNAs in the pathogenesis of diabetes

Diabetes is a complex metabolic disease with an etiology that includes genetic, epigenetic and environmental factors that lead to several different defects of glucose homeostasis, primarily in the pancreatic β-cells, liver, muscle, and adipose tissues. MicroRNAs (miRNAs) have recently emerged as important regulators in post-transcriptional gene expression. Although the target genes and biological functions of individual miRNAs remain largely unknown, previous studies have shown them to be important regulators of diverse biological processes, in both normal and pathological states. In the past decade, an increasing number of studies have focused on the regulatory roles of miRNAs in metabolism; thus, miRNAs play an important role in the pathogenesis of diabetes. This review summarizes recent findings related to the roles of miRNAs in diabetes. The information presented herein might be useful for the future development of miRNAs as diagnostic and therapeutic targets in diabetes.

Glucose Tolerance in Mice is Linked to the Dose of the p53 Transactivation Domain

Aim. To test the transactivation domain-mediated control of glucose homeostasis by the tumor suppressor p53. Background. The tumor suppressor p53 has a critical role in maintenance of glucose homeostasis. Phosphorylation of Ser18 in the transaction domain of p53 controls the expression of Zpf385a, a zinc finger protein that regulates adipogenesis and adipose function. This results suggest that the transactivation domain of p53 is essential to the control of glucose homeostasis. Materials and Methods. Mice with mutations in the p53 transactivation domain were examined for glucose homeostasis as well as various metabolic parameters. Glucose tolerance and insulin tolerance tests were performed on age matched wild type and mutant animals. In addition, mice expressing increased dosage of p53 were also examined. Results. Mice with a mutation in p53Ser18 exhibit reduced Zpf385a expression in adipose tissue, adipose tissue-specific insulin resistance, and glucose intolerance. Mice with relative deficits in the transactivation domain of p53 exhibit similar defects in glucose homeostasis, while “Super p53” mice with an increased dosage of p53 exhibit improved glucose tolerance. Conclusion. These data support the role of an ATM—p53 cellular stress axis that helps combat glucose intolerance and insulin resistance and regulates glucose homeostasis.

Zinc Transporter ZIP14 Functions in Hepatic Zinc, Iron and Glucose Homeostasis during the Innate Immune Response (Endotoxemia)

ZIP14 (slc39A14) is a zinc transporter induced in response to pro-inflammatory stimuli. ZIP14 induction accompanies the reduction in serum zinc (hypozincemia) of acute inflammation. ZIP14 can transport Zn2+ and non-transferrin-bound Fe2+ in vitro. Using a Zip14−/− mouse model we demonstrated that ZIP14 was essential for control of phosphatase PTP1B activity and phosphorylation of c-Met during liver regeneration. In the current studies, a global screening of ZIP transporter gene expression in response to LPS-induced endotoxemia was conducted. Following LPS, Zip14 was the most highly up-regulated Zip transcript in liver, but also in white adipose tissue and muscle. Using ZIP14−/− mice we show that ZIP14 contributes to zinc absorption from the gastrointestinal tract directly or indirectly as zinc absorption was decreased in the KOs. In contrast, Zip14−/− mice absorbed more iron. The Zip14 KO mice did not exhibit hypozincemia following LPS, but do have hypoferremia. Livers of Zip14−/− mice had increased transcript abundance for hepcidin, divalent metal transporter-1, ferritin and transferrin receptor-1 and greater accumulation of iron. The Zip14−/− phenotype included greater body fat, hypoglycemia and higher insulin levels, as well as increased liver glucose and greater phosphorylation of the insulin receptor and increased GLUT2, SREBP-1c and FASN expression. The Zip14 KO mice exhibited decreased circulating IL-6 with increased hepatic SOCS-3 following LPS, suggesting SOCS-3 inhibited insulin signaling which produced the hypoglycemia in this genotype. The results are consistent with ZIP14 ablation yielding abnormal labile zinc pools which lead to increased SOCS-3 production through G-coupled receptor activation and increased cAMP production as well as signaled by increased pSTAT3 via the IL-6 receptor, which inhibits IRS 1/2 phosphorylation. Our data show the role of ZIP14 in the hepatocyte is multi-functional since zinc and iron trafficking are altered in the Zip14−/− mice and their phenotype shows defects in glucose homeostasis.

Autoimmune-mediated glucose intolerance in a mouse model of systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by the production of autoantibodies against self-antigens such as double-stranded DNA and phospholipids. Classical comorbidities of SLE include glomerulonephritis, infection, cardiovascular disease, arthritis, skin disorders, and neurological disease. In addition to these classical comorbidities, there is emerging evidence that SLE patients are at higher risk of developing insulin resistance and other components of the metabolic syndrome. Visceral adipose tissue inflammation is a central mediator of insulin resistance in the obese setting, but the mechanism behind the pathogenesis of metabolic disease in the SLE patient population is unclear. We hypothesize that lupus-associated changes in the adaptive immune system are associated with disruption in glucose homeostasis in the context of SLE. To test this hypothesis, we assessed the metabolic and immunological phenotype of SLE-prone B6.SLE mice. B6.SLE mice fed a low-fat diet had significantly worsened glucose tolerance, increased adipose tissue insulin resistance, increased β-cell insulin secretion, and increased adipocyte size compared with their respective B6 controls. Independently of diet, B cells isolated from the white adipose tissue of B6.SLE mice were skewed toward IgG production, and the level of IgG1 was elevated in the serum of SLE-prone mice. These data show that B6.SLE mice develop defects in glucose homeostasis even when fed a low-fat diet and suggest that B cells may play a role in this metabolic dysfunction.

Molecular pathways for glucose homeostasis, insulin signaling and autophagy in hepatitis C virus induced insulin resistance in a cellular model

Chronic HCV infection induces insulin resistance (IR). We studied this in a persistently infected cell line with defects in glucose homeostasis resulting from the phosphorylation of glycogen synthase (GS Ser641) and GS kinase isoform 3β (GSK 3βSer9). Reversal of these effects in cells cured of HCV with interferon supports viral specificity. Insulin signaling was disrupted by IRS-1 Ser312 phosphorylation and dysregulation of the Akt pathway. In infected cells, active autophagy was revealed by the formation of LC3 puncta or by increased levels (50–200%) of the markers Beclin 1 and conjugated Atg5/Atg12. Inhibition of autophagy by 3-methyl-adenine (3-MA) reduced Beclin1 levels, inhibited IRS-1 Ser312 or GS Ser641 phosphorylation and decreased viral load. Furthermore, IRS-1 Ser312 and Beclin1 were co-immunoprecipitated suggesting that they interact. It thus appears that HCV infection disturbs glucose homeostasis or insulin signaling to induce IR and also elicits autophagy that may contribute to this process.