Dysregulation Of Glucose Homeostasis Research Articles

Dietary pattern, colonic microbiota and immunometabolism interaction: new frontiers for diabetes mellitus and related disorders.

In this review, the numerous possible mechanisms that provide supportive evidence for how colonic dysbiosis denotes metabolic dysfunction, dysregulates glucose homeostasis and leads to diabetes mellitus and related metabolic disorders are defined. Information was gathered from articles identified by systematic reviews and searches using Google, PubMed and Scopus. The composition of the colonic microbiota plays an integral role in maintaining host homeostasis by affecting both metabolic activities and underlying functional gene transcription in individuals with diabetes and related metabolic disorders. Increased colonic microbiome-derived concentrations of lipopolysaccharides, also known as 'metabolic endotoxaemia', as well as alterations in bile acid metabolism, short-chain fatty acids, intestinal hormones and branched-chain amino acid secretion have been associated with the diverse production of pro-inflammatory cytokines and the recruitment of inflammatory cells. It has been shown that changes to intestinal bacterial composition are significant even in early childhood and are associated with the pathogenesis of both types of diabetes. We hope that an improved understanding of related mechanisms linking the colonic microbiome with glucose metabolism might provide for innovative therapeutic approaches that would bring the ideal intestinal ecosystem to a state of optimal health, thus preventing and treating diabetes and related metabolic disorders.

Manipulation of Dietary Amino Acids Prevents and Reverses Obesity in Mice Through Multiple Mechanisms That Modulate Energy Homeostasis.

Reduced activation of energy metabolism increases adiposity in humans and other mammals. Thus, exploring dietary and molecular mechanisms able to improve energy metabolism is of paramount medical importance because such mechanisms can be leveraged as a therapy for obesity and related disorders. Here, we show that a designer protein-deprived diet enriched in free essential amino acids can 1) promote the brown fat thermogenic program and fatty acid oxidation, 2) stimulate uncoupling protein 1 (UCP1)-independent respiration in subcutaneous white fat, 3) change the gut microbiota composition, and 4) prevent and reverse obesity and dysregulated glucose homeostasis in multiple mouse models, prolonging the healthy life span. These effects are independent of unbalanced amino acid ratio, energy consumption, and intestinal calorie absorption. A brown fat-specific activation of the mechanistic target of rapamycin complex 1 seems involved in the diet-induced beneficial effects, as also strengthened by in vitro experiments. Hence, our results suggest that brown and white fat may be targets of specific amino acids to control UCP1-dependent and -independent thermogenesis, thereby contributing to the improvement of metabolic health.

Sphingosine-1-Phosphate Metabolism in the Regulation of Obesity/Type 2 Diabetes.

Obesity is a pathophysiological condition where excess free fatty acids (FFA) target and promote the dysfunctioning of insulin sensitive tissues and of pancreatic β cells. This leads to the dysregulation of glucose homeostasis, which culminates in the onset of type 2 diabetes (T2D). FFA, which accumulate in these tissues, are metabolized as lipid derivatives such as ceramide, and the ectopic accumulation of the latter has been shown to lead to lipotoxicity. Ceramide is an active lipid that inhibits the insulin signaling pathway as well as inducing pancreatic β cell death. In mammals, ceramide is a key lipid intermediate for sphingolipid metabolism as is sphingosine-1-phosphate (S1P). S1P levels have also been associated with the development of obesity and T2D. In this review, the current knowledge on S1P metabolism in regulating insulin signaling in pancreatic β cell fate and in the regulation of feeding by the hypothalamus in the context of obesity and T2D is summarized. It demonstrates that S1P can display opposite effects on insulin sensitive tissues and pancreatic β cells, which depends on its origin or its degradation pathway.

Role of nutraceutical starch and proanthocyanidins of pigmented rice in regulating hyperglycemia: Enzyme inhibition, enhanced glucose uptake and hepatic glucose homeostasis using in vitro model

Dysregulation of glucose homeostasis result in hyperglycemia and pigmented rice, unique combination of high quality starch and phenolics has the potential in regulating it. In this study, pigmented rice was characterized in terms of nutraceutical starch (NS) and phenolic content. Further the effect of rice phenolics on carbolytic enzyme inhibition, glucose uptake, hepatic glucose homeostasis and anti-glycation ability was analyzed in vitro. The most relevant effect on enzyme inhibition (α-amylase: IC50-42.34 µg/mL; α-glucosidase: IC50:63.89 µg/mL), basal uptake of glucose (>39.5%) and anti-glycation ability (92%) was found in red rice (RR), than black rice (BR). The role of RR phenolics in regulating glucose homeostasis was deciphered using hepatic cell line system, which found up-regulation of glucose transporter 2 (GLUT2) and glycogen synthase 2 (GYS2); while expression of gluconeogenic genes were found down regulated. To our knowledge this study is the first report validating the role of starch-phenolic quality towards anti-hyperglycemic effect of RR.

Comparison of glucose degradation product and receptor levels in dıabetic and normal pregnancy

The aim of this study was to assess the diagnostic values of new biochemical markers that may be an alternative to the oral glucose tolerance test (OGTT) and determine the differences in these markers among three groups of women with varying degrees of glucose homeostasis dysregulation. This was a prospective study. All women were screened with 50 gram (g) oral glucose and a 100 g OGTT for gestational diabetes mellitus (GDM). The patients were divided into three groups depending on the result of the tests: no evidence of glucose metabolism abnormality (controls); impaired glucose tolerance (IGT); and GDM. All three groups were evaluated for serum human advanced glycation end-products (AGEs) concentrations, carboxymethyl lysine (CML) concentration and receptor for advanced glycation end-product concentrations (RAGE/AGER), body mass index (BMI), age, fasting glucose levels, obstetrical parameters and gestational age. The study included 180 women divided into 59 (32.8%) GDM, 50 (27.8%) IGT and 71 (39.4%) controls. Age was similar among the three groups. Whereas fasting glucose levels and BMI in the three groups was significantly different, AGEs, CML, RAGE/AGER levels were found as significantly different between the groups (p<0.001). In this study the use of AGEs, CML, and RAGE/AGER concentrations for the diagnosis and screening of gestational diabetes was investigated. It was found that advanced glycation products were significantly elevated in pregnancies with both IGT and GDM. These biochemical markers of glucose homeostasis dysregulation may have potential for GDM screening in the future.

An Overview of Prospective Drugs for Type 1 and Type 2 Diabetes.

The aim of this study is to provide an overview of several emerging anti-diabetic molecules. Diabetes is a complex metabolic disorder involving the dysregulation of glucose homeostasis at various levels. Insulin, which is produced by β-pancreatic cells, is a chief regulator of glucose metabolism, regulating its consumption within cells, which leads to energy generation or storage as glycogen. Abnormally low insulin secretion from β-cells, insulin insensitivity, and insulin tolerance lead to higher plasma glucose levels, resulting in metabolic complications. The last century has witnessed extraordinary efforts by the scientific community to develop anti-diabetic drugs, and these efforts have resulted in the discovery of exogenous insulin and various classes of oral anti-diabetic drugs. Despite these exhaustive anti-diabetic pharmaceutical and therapeutic efforts, long-term glycemic control, hypoglycemic crisis, safety issues, large-scale economic burden and side effects remain the core problems. The last decade has witnessed the development of various new classes of anti-diabetic drugs with different pharmacokinetic and pharmacodynamic profiles. Details of their FDA approvals and advantages/disadvantages are summarized in this review. The salient features of insulin degludec, sodium-glucose co-transporter 2 inhibitors, glucokinase activators, fibroblast growth factor 21 receptor agonists, and GLP-1 agonists are discussed. In the future, these new anti-diabetic drugs may have broad clinical applicability. Additional multicenter clinical studies on these new drugs should be conducted.

Modulation of Glucose Metabolism by Leaf Tea Constituents: A Systematic Review of Recent Clinical and Pre-clinical Findings.

Leaf teas are widely used as a purported treatment for dysregulated glucose homeostasis. The objective of this study was to systematically evaluate the clinical and cellular-metabolic evidence, published between January 2013 and May 2019, and indexed on PubMed, ScienceDirect, and Web of Science, supporting the use of leaf teas for this purpose. Fourteen randomized controlled trials (RCTs) (13 on Camellia sinensis teas) were included, with mixed results, and providing scant mechanistic information. In contrast, 74 animal and cell culture studies focusing on the pancreas, liver, muscle, and adipose tissue yielded mostly positive results and highlighted enhanced insulin signaling as a recurring target associated with the effects of teas on glucose metabolism. We conclude that more studies, including RCTs and pre-clinical studies examining teas from a wider variety of species beyond C. sinensis, are required to establish a stronger evidence base on the use of leaf teas to normalize glucose metabolism.

Antioxidant therapy in the management of fluoroquinolone-associated disability.

Fluoroquinolones (FQs) have been found to induce delayed mitochondrial toxicity and cytotoxicity. The most common adverse reactions associated with FQs involve the gastrointestinal tract, peripheral and central nervous system (including psychiatric disorders), cardiovascular system, musculoskeletal system and glucose homeostasis dysregulation. We present the case of a patient diagnosed with fluoroquinolone-associated disability (FQAD). Unfortunately there are no standard treatment options for FQAD. In this presented case intravenous antioxidant therapy combined with hyperbaric oxygen therapy as well as an application of platelet-rich plasma and mesenchymal stem cells for tendon repair appear promising. Identifying genetic predisposition for an increased risk of FQAD it seems to be necessary in the future.

The adiponectin receptor agonist AdipoRon normalizes glucose metabolism and prevents obesity but not growth retardation induced by glucocorticoids in young mice

ObjectiveGlucocorticoids (GCs) are highly effective anti-inflammatory and immunosuppressive drugs. However, prolonged GC therapy may cause numerous adverse effects leading to diabetes and obesity, as well as bone disorders such as osteoporosis in adults and growth retardation in children and adolescents. Prevention and care of the GC-induced adverse effects remain challenging. We have previously demonstrated the efficacy of a treatment with a non-peptidic agonist of adiponectin receptors, AdipoRon, to reverse behaviour disorders and fat mass gain induced by long-term GC treatment. In this work, we have established a relevant model of GC-induced growth and metabolic disorders and determined that AdipoRon is a potential therapeutic tool to reverse these metabolic disturbances. Methods5-Week-old mice were treated continuously with or without corticosterone (35 mg/L) in drinking water for seven consecutive weeks. Taking advantage of this mouse model displaying various growth and metabolic disorders, we assayed whether AdipoRon (daily intraperitoneal injection of 1 mg/kg/day for the last 20 days) might prevent the GC-induced adverse effects. The control group was treated with vehicle only. Nutritional behaviors and metabolic parameters were followed-up throughout the treatment. Serum insulin and leptin levels were measured by ELISA. Computed tomography and histological analysis of adipose tissue were assessed at the end of the experimental procedure. ResultsWe found that GC treatment in young mice resulted in continuously increased body weight gain associated with a food intake increase. Compared to vehicle-, GC-treated mice displayed early major hyperleptinemia (up to 6-fold more) and hyperinsulinemia (up to 20-fold more) maintained throughout the treatment. At the end of the experimental procedure, GC-treated mice displayed bone growth retardation (e.g. femur length 15.1 versus 14.0 mm, P < 0.01), higher abdominal adipose tissue volume (4.1 versus 2.3, P < 0.01) and altered glucose metabolism compared to control mice. Interestingly, AdipoRon prevented GC-induced effects on energy metabolism such as abdominal adiposity, insulinemia and leptinemia. However, AdipoRon failed to counteract bone growth retardation. ConclusionWe characterized the very early pathological steps induced by long-term GC in young mice in a relevant model, including growth retardation, fat mass gain and glucose homeostasis dysregulation. The adiponectin system stimulation enabled normalization of the adipose tissue and metabolic features of GC-treated mice. Adiponectin receptor agonists such as AdipoRon might constitute a novel way to counteract some GC-induced adverse effects.

Metabolic and vascular risk factors are associated with reduced cerebral blood flow and poorer midlife memory performance.

Midlife metabolic and vascular risk factors (MVRFs) predict cognitive decline and dementia; however, these risk factors tend to overlap, and the mechanisms underlying their effects on cognitive performance are not well understood. This cross‐sectional study investigates the contributions of MVRFs to regional cerebral blood flow (CBF) and verbal learning & memory among middle‐aged adults. We used partial least squares (PLS) analysis to create latent risk factor profiles and examine their associations to CBF in 93 regions of interest among 451 participants (age 50.3 ± 3.5 years) of the Coronary Artery Risk Development in Young Adults. This multivariate analysis revealed regional CBF was lower in relation to obesity (higher body mass index and waist circumference), dysregulated glucose homeostasis (higher fasting glucose, oral glucose tolerance, and higher fasting insulin), and adverse fasting lipid profile (lower high‐density lipoprotein cholesterol and higher triglycerides). In a sensitivity analysis, we found that significant associations between MVRFs and CBF were prominent in the hypertension‐medicated subgroup. In a mediation model, the PLS‐based MVRFs profile was associated with memory performance (rey auditory verbal learning test); however, CBF was not a significant mediator of this association. The results describe an adverse midlife metabolic profile that might set the stage for incipient dementia and contribute to widespread changes in CBF.

104-OR: Glucoregulatory Effects of Hypothalamic Glucocorticoid Action In Vivo

Diabetes is characterized by dysregulated glucose homeostasis that leads to hyperglycemia, due in part to increased hepatic glucose production (GP) and insulin resistance. Excessive levels and/or action of glucocorticoids (GCs) are associated with obesity, insulin resistance, and hyperglycemia. We aim to delineate a mechanism of GC action in the mediobasal hypothalamus (MBH) that modulates GP in normal and pre-obese rodents. Male SD rats underwent stereotaxic MBH bilateral cannulation and intravenous (iv) and intraarterial catheterization to enable simultaneous direct infusions into the MBH, iv infusions, and blood sampling, respectively. Mildly hyperinsulinemic-euglycemic clamps with tracer dilution methodology combined with MBH GC infusion ± GC receptor (GR) inhibition enables measurement of GP and utilization while assessing MBH GC interaction with its MBH receptors independent of changes in plasma insulin, glucagon, and glucose levels. MBH GC infusion potently stimulates GP and lowers the requirement for exogenous glucose infusion without altering glucose utilization. This effect is mediated via GRs since co-infusion of GR antagonist mifepristone, or a HSP90 inhibitor, negates the ability of MBH GCs to increase GP. MBH GCs similarly increased glucose excursions during iv glucose tolerance tests, which was reversed with concomitant MBH mifepristone infusion. Rats fed with high fat diet (HFD) for 3 days had altered glucose kinetics and increased basal plasma corticosterone, insulin, and blood glucose levels without changes in body weight. Chronic MBH GR inhibition with MBH GR shRNA lowered GP compared to MBH mismatch control HFD rats with MBH vehicle infusions, suggesting that blocking excessive MBH GC action resulting from HFD-feeding attenuates GP to improve glucose homeostasis. We provide novel evidence that MBH GC action modulates GP in healthy and pre-obese rats. Importantly, targeted inhibition of MBH GC action may help improve glucose regulation in obesity-related metabolic disease. Disclosure E. Beaulieu-Bayne: None. M. Cardoso: None. H. Kim: None. S. Yang: None. J.T. Yue: None. Funding Diabetes Canada; Natural Sciences and Engineering Research Council of Canada; Alberta Diabetes Institute; Canadian Institutes of Health Research

NBCe1 is a novel regulator of pancreatic β‐cell function in diabetes

Dysregulation of glucose homeostasis in Type 2 diabetes mellitus (T2DM) is attributed to pancreatic β‐cell failure in maintaining adequate glucose‐stimulated insulin secretion (GSIS) to compensate for diminished insulin action. Recent single cell transcriptomics studies of human pancreatic islets have identified Slc4a4 (encoding an electrogenic Na+‐nHCO3− cotransporter, NBCe1) as a gene repressed in healthy non‐diabetic β‐cells, but expressed in human T2DM β‐cells. However the role of Slc4a4/NBCe1 in pancreatic β‐cell function remains unknown. Thus, in the current study we set out to test the hypothesis that mis‐expression of Slc4a4 in β‐cells contributes to loss of GSIS and impaired glucose homeostasis in T2DM. Subsequently, we first assessed Slc4a4 mRNA expression in isolated human islets (Control vs. T2DM) by qPCR and quantified NBCe1 protein expression by immunofluorescence in autopsy‐derived human pancreas tissue (Control vs. T2DM). We observed a 4‐fold induction in Slc4a4 mRNA expression in T2DM islets compared to non‐diabetic controls (p=0.004 vs. Control) and significantly increased NBCe1 co‐localization with insulin‐positive β‐cells of T2DM patients compared to controls (p&lt;0.001 vs. Control). In addition, we also demonstrated that chronic inhibition of NBCe1 activity using the channel specific inhibitor (S0859) significantly enhanced GSIS in islets isolated from T2DM patients (~1.5‐fold increase vs. untreated, p=0.006). To delineate the role NBCe1 plays on β‐cell function in vivo, we generated β‐cell specific knockout (β‐Slc4a4−/−) mice by crossing Slc4a4fl/fl (G. Shull, UC) and Ins2‐Cre mouse models. We confirmed &gt;50% reduction in Slc4a4 mRNA expression in β‐Slc4a4−/− islets and complete ablation of NBCe1 protein expression. In order to model the environmental stress that leads to metabolic defects common to T2DM, we exposed β‐Slc4a4−/− mice and control littermates to either standard chow diet or 60% high fat diet (HFD) for 8 weeks ad libitum. Under chow‐fed conditions, β‐Slc4a4−/− mice displayed normal glucose tolerance (p&gt;0.05 vs. β‐Slc4a4+/+ Chow). Interestingly, β‐Slc4a4−/− mice exposed to HFD exhibited enhanced glucose tolerance and GSIS (p&lt;0.05 vs. β‐Slc4a4+/+ HFD) and thus were protected from development of T2DM phenotype characteristics of HFD treatment. Finally, to understand the mechanism by which Slc4a4 deletion enhanced β‐cell function, we performed RNA‐sequencing on islets isolated from β‐Slc4a4−/− and β‐Slc4a4+/+ mice exposed to chow diet or HFD. Notably, gene‐set enrichment analysis of Kyoto Encyclopedia of Genes and Genomes (KEGG) defined biological pathways revealed that Slc4a4 deletion enriched genes associated with the cell cycle (p&lt;0.001 vs. β‐Slc4a4+/+ Chow; p&lt;0.001 vs. β‐Slc4a4+/+ HFD), while suppressing genes associated with apoptosis (p=0.002 vs. β‐Slc4a4+/+ Chow; p=0.004 vs. β‐Slc4a4+/+ HFD) in the presence of both chow diet and HFD. These result suggest that mis‐expression of Slc4a4 plays a novel role in the induction of β‐cell failure in T2DM. Future studies will delineate exact molecular mechanisms underlying NBCe1‐mediated regulation of β‐cell function in health and under conditions of metabolic stress.Support or Funding InformationMayo Clinic Center of Biomedical DiscoveryThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Indirect Effects of Body Mass Index Growth on Glucose Dysregulation via Inflammation: Causal Moderated Mediation Analysis

Objective: No existing studies have examined the mediating role of chronic inflammation between obesity and dysregulated glucose homeostasis in adolescent samples. This study evaluated whether C-reactive protein (CRP), an inflammation biomarker, mediated the effects of growth (annual increase) in body mass index (BMI) on glycated hemoglobin (HbA_1c). Methods: BMI and biomarker data were used from wave I to wave IV of the National Longitudinal Study of Adolescent to Adult Health (Add Health study; 4,545 adolescents; mean age = 14.9 years; 55.7% female) with valid CRP data. A causal moderated mediation analysis evaluated the direct and indirect effects of BMI slope on HbA_1c via CRP across gender, with demographic and clinical characteristics as model covariates. Results: The participants displayed a linear BMI growth of 0.53–0.58 kg/m²/year throughout adolescence, with substantial interindividual variation. The BMI slope showed positive direct and indirect effects on HbA_1c via CRP across gender, and there was a significant exposure-mediator interaction effect. A standardized increase in the BMI slope raised the probability of an abnormal HbA_1c value by 6.0–8.5% in participants with various profiles. The total natural indirect effect accounted for 13.3–15.9% of the total effect in males and 21.2–22.7% in females. Conclusions: The findings provide support for the inflammation mechanism in the effects of adiposity on glucose homeostasis. In adolescents, excess BMI growth was linked with a higher risk of glucose dysregulation either directly or indirectly via chronic inflammation.

Large-scale genome-wide meta-analysis of polycystic ovary syndrome suggests shared genetic architecture for different diagnosis criteria.

Polycystic ovary syndrome (PCOS) is a disorder characterized by hyperandrogenism, ovulatory dysfunction and polycystic ovarian morphology. Affected women frequently have metabolic disturbances including insulin resistance and dysregulation of glucose homeostasis. PCOS is diagnosed with two different sets of diagnostic criteria, resulting in a phenotypic spectrum of PCOS cases. The genetic similarities between cases diagnosed based on the two criteria have been largely unknown. Previous studies in Chinese and European subjects have identified 16 loci associated with risk of PCOS. We report a fixed-effect, inverse-weighted-variance meta-analysis from 10,074 PCOS cases and 103,164 controls of European ancestry and characterisation of PCOS related traits. We identified 3 novel loci (near PLGRKT, ZBTB16 and MAPRE1), and provide replication of 11 previously reported loci. Only one locus differed significantly in its association by diagnostic criteria; otherwise the genetic architecture was similar between PCOS diagnosed by self-report and PCOS diagnosed by NIH or non-NIH Rotterdam criteria across common variants at 13 loci. Identified variants were associated with hyperandrogenism, gonadotropin regulation and testosterone levels in affected women. Linkage disequilibrium score regression analysis revealed genetic correlations with obesity, fasting insulin, type 2 diabetes, lipid levels and coronary artery disease, indicating shared genetic architecture between metabolic traits and PCOS. Mendelian randomization analyses suggested variants associated with body mass index, fasting insulin, menopause timing, depression and male-pattern balding play a causal role in PCOS. The data thus demonstrate 3 novel loci associated with PCOS and similar genetic architecture for all diagnostic criteria. The data also provide the first genetic evidence for a male phenotype for PCOS and a causal link to depression, a previously hypothesized comorbid disease. Thus, the genetics provide a comprehensive view of PCOS that encompasses multiple diagnostic criteria, gender, reproductive potential and mental health.

A single extra copy of Down syndrome critical region 1–4 results in impaired hepatic glucose homeostasis

ObjectivesDuring fasting, hepatic gluconeogenesis is induced to maintain energy homeostasis. Moreover, abnormal dysregulation of hepatic glucose production is commonly observed in type 2 diabetes. However, the signaling components controlling hepatic glucose production to maintain normal glucose levels are not fully understood. Here, we examined the physiological role of Down syndrome critical region 1–4 (DSCR1-4), an endogenous calcineurin signaling inhibitor in the liver that mediates metabolic adaptation to fasting. MethodsWe assessed the effect of cyclosporine A, an inhibitor of calcineurin signaling on gluconeogenic gene expression in primary hepatocytes. DSCR1-4 expression was examined in diet- and genetically-induced mouse models of obesity. We also investigated the metabolic phenotype of a single extra copy of DSCR1-4 in transgenic mice and how DSCR1-4 regulates glucose homeostasis in the liver. ResultsTreatment with cyclosporin A increased hepatic glucose production and gluconeogenic gene expression. The expression of DSCR1-4 was induced by refeeding and overexpressed in obese mouse livers. Moreover, transgenic mice with a single extra copy of DSCR1-4 exhibited pyruvate intolerance and impaired glucose homeostasis. Mechanistically, DSCR1-4 overexpression increased phosphorylation of the cAMP response element-binding protein, which led to elevated expression levels of gluconeogenic genes and, thus, enhanced hepatic glucose production during fasting. ConclusionA single extra copy of DSCR1-4 results in dysregulated hepatic glucose homeostasis and pyruvate intolerance. Our findings suggest that nutrient-sensitive DSCR1-4 is a novel target for controlling hepatic gluconeogenesis in diabetes.

Dysregulated glucose homeostasis in congenital central hypoventilation syndrome.

Background Congenital central hypoventilation syndrome (CCHS) is a rare disorder of autonomic control. A hypoglycaemic seizure in a 4-year-old girl with CCHS led to a more detailed examination of glycaemic control in a cohort of children with CCHS. Methods We conducted an observational cohort study of glucose homeostasis in seven children (3 months to 12 years) with genetically confirmed CCHS using a combination of continuous glucose monitoring (CGM), fasting studies and oral glucose tolerance test (OGTT). CGM was used to compare the effect of diazoxide and dietary intervention in the index patient. Results Hypoglycaemia was not elicited by fasting in any of the patients. Increased postprandial glycaemic variability was evident in all patients using CGM, with seven of seven patients demonstrating initial postprandial hyperglycaemia (plasma-glucose concentration >7.8 mmol/L), followed by asymptomatic hypoglycaemia (plasma-glucose concentration ≤2.8 mmol/L) in two of seven patients that was also demonstrated on OGTT. Both diazoxide and low Glycaemic Index (GI) dietary intervention reduced the proportion of CGM readings <4 mmol/L; however, diazoxide also increased the proportion of readings in the hyperglycaemic range. Conclusions Glucose variability associated with autonomic dysfunction may be unrecognised in CCHS, particularly in children with more severe phenotypes. This report highlights the occurrence of hyperglycaemia as well as hypoglycaemia in CCHS. Given the challenges of recognising hypoglycaemia based on clinical symptomatology, the use of CGM may facilitate its identification allowing appropriate management. The observed normoglycaemia during fasting combined with increased postprandial plasma blood glucose level (BGL) variability is more consistent with dumping syndrome than persistent hyperinsulinism. Dietary modifications therefore may be more effective than diazoxide in managing hypoglycaemia.

Overweight and obese patients with nickel allergy have a worse metabolic profile compared to weight matched non-allergic individuals.

BackgroundA lack of balance between energy intake and expenditure due to overeating or reduced physical activity does not seem to explain entirely the obesity epidemic we are facing, and further factors are therefore being evaluated. Nickel (Ni) is a ubiquitous heavy metal implied in several health conditions. Regarding this, the European Food Safety Authority has recently released an alert on the possible deleterious effects of dietary Ni on human health given the current levels of Ni dietary intake in some countries. Pre-clinical studies have also suggested its role as an endocrine disruptor and have linked its exposure to energy metabolism and glucose homeostasis dysregulation. Ni allergy is common in the general population, but preliminary data suggest it being even more widespread among overweight patients.ObjectivesThe aim of this study has been to evaluate the presence of Ni allergy and its association with the metabolic and endocrine profile in overweight and obese individuals.MethodsWe have evaluated 1128 consecutive overweight and obese outpatients. 784 were suspected of being allergic to Ni and 666 were assessed for it. Presence of Ni allergy and correlation with body mass index (BMI), body composition, metabolic parameters and hormonal levels were evaluated.ResultsWe report that Ni allergy is more frequent in presence of weight excess and is associated with worse metabolic parameters and impaired Growth Hormone secretion.ConclusionsWe confirm that Ni allergy is more common in obese patients, and we report for the first time its association with worse metabolic parameters and impaired function of the GH-IGF1 axis in human subjects.

Heparan Sulfate of ß Cells Regulates Insulin Secretion and Contributes to Normal Glucose Homeostasis

Heparan sulfate (HS) is a linear polysaccharide and abundantly distributes around cell surface. HS can interact with various bioactive molecules and enhance their signal transduction. Thus, HS is involved in diverse biological functions including development, maturation and proliferation of various tissues. Previous reports demonstrated the expression of HS in β-cells and suggested the possible involvement of HS in functions of β-cells. However, the importance of HS for β-cells remains largely unknown. In the present study, we generated mice with β-cell specific deletion of Ext1 (cKO), which encodes an essential enzyme for HS synthesis, to investigate the detailed roles of HS in β-cell development and function. cKO mice had decreased body weight despite increased food intake compared to control mice. cKO mice showed impaired glucose tolerance associated with decreased insulin secretion upon glucose challenge, without insulin resistance. Glucose-induced insulin secretion from isolated islets of cKO mice was also significantly reduced. These results indicate the contribution of HS in β-cells to insulin secretion and glucose homeostasis. The expression of several genes essential for glucose-induced insulin secretion was decreased in cKO islets. Pdx1 and MafA, which are important transcriptional factors for β-cell development and maturation, were reduced in cKO islets, indicating HS promotes development and maturation of β-cells. Immunohistochemical analysis of the cKO pancreas revealed reduced β-cell mass and islet number. The percentage of BrdU- or Ki67-positive β-cells was decreased in cKO islets, suggesting the involvement of HS in the proliferation of β-cells. Insufficient vascularization in cKO islets might contribute to the abnormal islet architecture. These data demonstrate that HS plays diverse roles in β-cell development and maturation, and that loss of HS leads to insufficient insulin secretion and dysregulation of glucose homeostasis. Disclosure T. Matsuzawa: None. T. Yoshikawa: None. A. Sugawara: None. K. Yanai: None.

Microglia Activation Regulates Systemic Glucose Tolerance

Obesity and high fat diet (HFD) consumption in rodents is associated with hypothalamic inflammation and activation of microglia, the resident CNS immune cells. Recently, we provided evidence that microglia are critical intermediary cells that transmit the inflammatory signal induced by HFD exposure. Mice with a conditional knockout of IKKb specifically in microglia (CX3CR1CreERT2 x IKKbeta fl/fl, MGKO) have reduced susceptibility to HFD-associated hyperphagia and DIO compared with IKKb fl/fl littermate controls (Ctl). Surprisingly, despite their reduced fat mass, HFD-fed MGKO mice have equal glucose intolerance to Ctls as well as no improvement in white adipose tissue inflammation or hepatic triglyceride content. Together these data suggest dissociation between microglial regulation of energy and glucose homeostasis. To address this possibility, we pair-fed MGKO mice to Ctl mice, resulting in matched body weights during HFD feeding. Pair-fed MGKO mice showed a greater degree of impairment in glucose tolerance and insulin sensitivity with preserved insulin secretion compared to controls. Similarly, chemical inactivation of microglia using centrally-administered minocycline worsens insulin sensitivity in HFD-fed rats. Finally, using several distinct genetic models, we show that microglial activation acutely improves glucose tolerance and insulin sensitivity. Together, these data reveal a novel aspect of CNS regulation of metabolism in which microglial inflammatory activation promotes HFD overconsumption and weight gain but offsets obesity-associated dysregulation of glucose homeostasis. These results indicate the need for pathway-specific targeting to develop glial-based therapeutics for obesity and diabetes. Disclosure J. Douglass: None. M. Valdearcos: None. S.K. Koliwad: None. J. Thaler: Research Support; Self; Novo Nordisk A/S.

Heparan sulfate in pancreatic β-cells contributes to normal glucose homeostasis by regulating insulin secretion

Heparan sulfate (HS), a linear polysaccharide, is involved in diverse biological functions of various tissues. HS is expressed in pancreatic β-cells and may be involved in β-cell functions. However, the importance of HS for β-cell function remains unknown. Here, we generated mice with β-cell-specific deletion of Ext1 (βExt1CKO), which encodes an enzyme essential for HS synthesis, to investigate the detailed roles of HS in β-cell function. βExt1CKO mice decreased body weights compared with control mice, despite increased food intake. Additionally, βExt1CKO mice showed impaired glucose tolerance associated with decreased insulin secretion upon glucose challenge. Glucose-induced insulin secretion (GIIS) from isolated βExt1CKO islets was also significantly reduced, highlighting the contribution of HS to insulin secretion and glucose homeostasis. The gene expression essential for GIIS was decreased in βExt1CKO islets. Pdx1 and MafA were downregulated in βExt1CKO islets, indicating that HS promoted β-cell development and maturation. BrdU- or Ki67-positive β-cells were reduced in βExt1CKO pancreatic sections, suggesting the involvement of HS in the proliferation of β-cells. Moreover, insufficient vascularization in βExt1CKO islets may contribute to central distribution of α-cells. These data demonstrate HS plays diverse roles in β-cells, and that loss of HS leads to insufficient insulin secretion and dysregulation of glucose homeostasis.