Diabetogenic Factor Research Articles

Changes in insul resistance, glucose effectiveness, and first and second phase of insulin secretion in women aged 45-60 years old in Taiwan.

In women after menopause, the incidence of diabetes mellitus increases. Increased insulin resistance (IR), decreased glucose effectiveness (GE), and the first and second phases of insulin secretion (FPIS and SPIS), are the four most important factors that trigger glucose intolerance and diabetes (diabetogenic factor [DF]). In the cross-sectional study, we enrolled non-diabetic women between the ages of 45 and 60 years to observe the changes in DFs during the perimenopausal period and to elucidate the underlying mechanisms of diabetes in menopausal women. We randomly enrolled 4,194 women who underwent health checkups. Using demographic and biochemical data, IR, FPIS, SPIS, and GE were calculated using previously published equations. The relationship between the DFs and age was evaluated using a simple correlation. Body mass index, blood pressure, fasting plasma glucose, low-density lipoprotein-cholesterol, triglyceride, and SPIS were higher, and GE was lower in older women (≥ 52 years old). A significant decrease in GE and increased SPIS were observed with age. However, no changes were observed in IR or FPIS. The IR and FPIS did not change during perimenopause. Increased SPIS may compensate for the decrease in GE, which is probably one of the reasons for the higher incidence of diabetes in menopausal women.

1612-P: Energetic Contributions of GLP1 and GCGR Activity in GLP1/GIP/GCGR Triagonism

Glucagon has been implicated as a key diabetogenic factor. However, agonists that couple the lipolytic and thermogenic properties of Glucagon Receptor (GCGR) activity with the antidiabetic actions of incretins (GLP1, GIP), lack hyperglycemic side effects associated with GCGR activity. GCGR agonism stimulates energy expenditure (EE) that contributes to weight loss. Interestingly, we also identified that the anti-obesity effects of GCGR agonism persisted for 50d after treatment cessation. Thus, we hypothesized that GCGR activity paired with incretin action (GGG) will result in increased EE during treatment and prolonged weight loss after cessation. Diet-induced obese mice were treated for 14d with vehicle, GGG, or single receptor agonism via IUB288 (GCGR), Semagutide (Sema;GLP1R), or GIP-FA 085 (GIPR). Indirect calorimetry was conducted for d 2-4 of treatment and d 16-18 after cessation. Congruent with our prior studies, IUB288 increased EE compared to vehicle controls. Conversely, Sema-treated mice displayed decreased EE (d 2 and 3) while EE following GIP treatment was similar to vehicle controls. Intriguingly, GGG reduced EE on d 2, had similar EE to vehicle controls on d 3, with a trend towards increased EE on d 4, suggesting GGG treatment stimulates characteristics of both GLP1 and GCGR activity. Nutrient utilization, measured via Respiratory Quotient (RQ), was reduced during the light period with IUB288 treatment. GIP, Sema, and GGG reduced RQ, regardless of time of day. Interestingly, GGG regulation of RQ appeared most like Sema. After treatment cessation, Sema mice gained significantly more weight than IUB288 or GGG mice, despite similar food intake during rebound. Surprisingly, EE was not elevated in mice that formerly received IUB288 or GGG, suggesting another mechanism may be driving this effect. RQ was similar in all groups, except IUB288 mice, which exhibited increased RQ across the day. These data suggest that GGG exhibits effects of both GLP1R and GCGR agonism with respect to EE and RQ. Disclosure S.Nason: None. J.Antipenko: None. K.M.Habegger: Consultant; Glyscend Inc., Research Support; Eli Lilly and Company, Novo Nordisk, Glyscend Inc., Stock/Shareholder; Glyscend Inc. Funding Eli Lilly and Company

1343-P: The Acute Effects of Glucagon on Glucose Dynamics Are Not Impaired in Individuals with Nonalcoholic Fatty Liver Disease

Glucagon is essential for glucose control and increased levels of glucagon (hyperglucagonemia) observed in patients with type 2 diabetes contribute to their hyperglycemia. Recently, hyperglucagonemia has also been found in individuals with non-alcoholic fatty liver disease (NAFLD) as well as impaired actions of glucagon on amino acid catabolism. Whether glucagon actions on hepatic glucose production are impaired is unknown. We investigated the acute effects of a single bolus of glucagon (0.2mg) on glucose dynamics in 18 normoglycemic individuals (age: 51±3 years, BMI; 31± 0.8kg/m2, hepatic fat content: 20±2%, fasting glucose: 5.5±0.1mM) with magnetic resonance imaging verified NAFLD and 22 controls (age: 38±3 years, BMI; 24± 0.8kg/m2, hepatic fat content: 4±0.1%, fasting glucose: 5.0±0.1mM) . On a separate day, a mixture of amino acids (14 g/L; 331 mg/min/kg body weight) was infused intravenously for 45min to evaluate the actions of endogenous glucagon on glucose dynamics. Glucose levels (see figure) were significantly increased in individuals with NAFLD 60min after the glucagon bolus and during the amino acid infusion with a maximal difference of 0.5mM 30min into the infusion. These data suggest that the actions of glucagon on hepatic glucose production are not impaired by NAFLD. Therefore, the hyperglucagonemia in patients with NAFLD may constitute a diabetogenic risk factor. Disclosure S.Kjeldsen: None. H.Vilstrup: None. F.V.Schiødt: Advisory Panel; Novo Nordisk. A.Møller: None. E.B.Rashu: None. L.Gluud: Advisory Panel; Novo Nordisk, Consultant; Pfizer Inc., Research Support; Alexion Pharmaceuticals, Inc., Gilead Sciences, Inc., Novo Nordisk, Sobi. S.B.Haugaard: None. J.J.Holst: Advisory Panel; Novo Nordisk, Board Member; Antag Therapeutics, Bainan Biotech. J.Rungby: Advisory Panel; Abbott, Boehringer Ingelheim International GmbH, Speaker’s Bureau; AstraZeneca, Bayer AG, Novo Nordisk, Pfizer Inc. N.J.Wewer albrechtsen: Research Support; Mercodia AB, Novo Nordisk, Regeneron Pharmaceuticals Inc., Speaker’s Bureau; Merck & Co., Inc., Mercodia AB. N.J.Jensen: None. M.Nilsson: None. N.Heinz: None. J.D.Nybing: None. F.H.Linden: None. E.Høgh-schmidt: n/a. M.P.Boesen: None. S.Madsbad: None. Funding NNF Excellence Emerging Investigator Grant – Endocrinology and Metabolism (Application No. NNF19OC0055001) , EFSD Future Leader Award (NNF21SA0072746) and DFF Sapere Aude.

Utilization of Mind-Body Intervention for Integrative Health Care of COVID-19 Patients and Survivors.

Recent findings suggest a correlation between COVID-19 and diabetes, although the underlying causes are still little understood. COVID-19 infection tends to induce severe symptoms in patients with underlying diabetes, increasing their mortality rate. Moreover, COVID-19 itself appears to be a diabetogenic factor. In addition, mental health conditions, such as depression due to lockdown and anxiety about infection, were found to affect glycemic control and immunity, highlighting the importance of mental health care during the pandemic. Mind–Body Intervention (MBI), which includes meditation, yoga, and qigong, has emerged as a tool for mental health management due to its effects on stress reduction and the promotion of mental and physical well-being. Here, we review the latest randomized controlled trials to determine the effects of MBI on glycemic control and the immune system and discuss the underlying mechanisms by which MBI facilitates the virtuous cycle of stress management, glycemic control, and immune modulation. Furthermore, we examine the actual utilization of MBI during the COVID-19 pandemic era through recent studies. With proper online education, non-pharmacological MBI may be more widely used as an important tool for self-health care that complements the usual treatment of COVID-19 patients and survivors.

Messages from the Small Intestine Carried by Extracellular Vesicles in Prediabetes: A Proteomic Portrait.

Extracellular vesicles (EVs) mediate communication in physiological and pathological conditions. In the pathogenesis of type 2 diabetes, inter-organ communication plays an important role in its progress and metabolic surgery leads to its remission. Moreover, gut dysbiosis is emerging as a diabetogenic factor. However, it remains unclear how the gut senses metabolic alterations and whether this is transmitted to other tissues via EVs. Using a diet-induced prediabetic mouse model, we observed that protein packaging in gut-derived EVs (GDE), specifically the small intestine, is altered in prediabetes. Proteins related to lipid metabolism and to oxidative stress management were more abundant in prediabetic GDE compared to healthy controls. On the other hand, proteins related to glycolytic activity, as well as those responsible for the degradation of polyubiquitinated composites, were depleted in prediabetic GDE. Together, our findings show that protein packaging in GDE is markedly modified during prediabetes pathogenesis, thus suggesting that prediabetic alterations in the small intestine are translated into modified GDE proteomes, which are dispersed into the circulation where they can interact with and influence the metabolic status of other tissues. This study highlights the importance of the small intestine as a tissue that propagates prediabetic metabolic dysfunction throughout the body and the importance of GDE as the messengers. Data are available via ProteomeXchange with identifier PXD028338.

CAN PROLACTIN BE A MARKER FOR DEVELOPMENT AND PROGRESSION OF PCOS?

Background: Polycystic ovarian syndrome has been one of a major public health problem. It causes multifactorial in etiology such as menstrual dysfunction, hyperandrogenism, hirsutism, insulin resistance, dyslipidemia and obesity which increased risk of diabetes mellitus and cardiovascular disease. Prolactin has been reported as a potent lipogenic and diabetogenic factor, that affecting energy balance and fuel metabolism. The present study was designed to assess serum prolactin and insulin resistance in PCOS women and to compare them with healthy women as controls. Material And Methods: A comparative study including 50 women newly diagnosed as PCOS and 50 healthy women as controls was conducted. The age group for the study was 18-35 years. Fasting blood samples were drawn to assess serum prolactin, serum insulin and fasting blood sugar. Insulin resistance was calculated by homeostasis model assessment. Results: A signicant increase in fasting serum insulin (p<0.001) and HOMA – IR (p<0.001) were found in patients with PCOS in comparison with controls. Prolactin and FPG were found elevated in the PCOS women and were statistically signicant. Conclusions: The current study provides further evidence that signicantly higher fasting insulin and HOMA in PCOS group indicates presence of IR. IR in PCOS group may have a potential role in the prediction of dysglycemic disease in women with PCOS. This study found signicant correlation between serum prolactin and serum insulin

Exposure to novel and legacy per- and polyfluoroalkyl substances (PFASs) and associations with type 2 diabetes: A case-control study in East China.

Associations between per- and polyfluoroalkyl substances (PFASs) and the incidence of type 2 diabetes are controversial in epidemiological studies. In addition, limited data are available for assessing the health effects of novel PFAS alternatives. Our study evaluated the effects of PFAS exposure on type 2 diabetes by estimating the associations of PFASs in human serum with the risk of type 2 diabetes and levels of glycemic biomarkers and lipid fractions. The case-control study consisted of 304 participants from Shandong Province, East China, half of which were diagnosed with type 2 diabetes. Logistic regression showed that most PFASs were inversely associated with the risk of type 2 diabetes after adjusting for age, sex, and body mass index. However, concentrations of perfluorooctanoic acid (PFOA) in the control group were positively associated with fasting plasma glucose levels (β=0.04, 95% confidence interval (CI): 0.0003, 0.08), which may promote the development of type 2 diabetes. Furthermore, each log-unit increase in the concentrations of perfluorononanoic acid (PFNA), perfluoroundecanoic acid (PFUnDA), and 6:2 chlorinated polyfluoroalkyl ether sulfonic acid (Cl-PFESA) were associated with a total cholesterol increase (i.e., 17.49% (95% CI: 0.93%, 34.90%), 17.49% (95% CI: 4.71%, 31.83%), and 17.49% (95% CI: 4.71%, 31.83%), respectively). Positive associations were also observed between PFNA, PFUnDA, perfluorooctane sulfonate (PFOS), and 6:2 Cl-PFESA and low-density lipoprotein cholesterol. However, no associations between PFASs and hemoglobin A1c, triglycerides, or high-density lipoprotein cholesterol reached statistical significance, nor associations between PFAS mixtures and outcomes of interest. In conclusion, the significant correlations between serum PFASs and glycemic biomarkers and lipid fractions indicated that PFAS exposure may be a potential diabetogenic factor. To the best of our knowledge, this is the first study to assess the associations between novel Cl-PFESAs and type 2 diabetes, although the inverse associations observed require clarification in future studies.

Selenium Deficiency-Induced Pancreatic Pathology Is Associated with Oxidative Stress and Energy Metabolism Disequilibrium.

Selenium (Se) is an essential micronutrient that plays a crucial role in development and physiological processes. The present study aimed to investigate the effects of Se deficiency on pancreatic pathology and the potential mechanism in pigs. Twenty-four castrated male Yorkshire pigs were divided into two groups and fed a Se-deficient diet (0.007mgSe/kg) or a Se-adequate diet (0.3mgSe/kg) for 16weeks. The serum concentrations of insulin and glucagon, Se concentration, histologic characteristics, apoptotic status, antioxidant activity, free radical content, and major metabolite concentrations were analyzed. The results showed that Se deficiency reduced the concentrations of insulin and glucagon in the serum and of Se in pancreas, decreased the number of islets and cells in the local islets, and induced pancreatic apoptosis. Se deficiency caused a redox imbalance, which led to an increase in the content of free radicals and decreased the activity of antioxidant enzymes. Of 147 targeted metabolites judged to be present in pancreas, only hypotaurine and D-glucuronic acid had differential concentrations with the false discovery rate < 0.05. Pathway analysis using metabolites with differential expression (unadjusted P < 0.05, fold change > 1.4 or < 0.67) found that 8 glycolytic metabolites were significantly increased by Se-deficient, whereas most of the tricarboxylic acid cycle and pentose phosphate pathway metabolites were not significantly changed. Our studies indicated that Se deficiency-induced pancreatic pathology was associated with oxidative stress and enhanced activity of glycolysis, which may provide gaining insight into the actions of Se as a diabetogenic factor.

Exposure to organochlorine pesticides and the risk of type 2 diabetes in the population of East China

Organochlorine pesticides (OCPs) have been reported to be associated with an elevated risk of type 2 diabetes, although no study has focused on such associations in Chinese populations. In this case-control study, we aimed to explore the associations between OCPs and type 2 diabetes and their potential mechanisms in a population from East China. Participants diagnosed with type 2 diabetes and nondiabetic participants from Shandong Province, East China, were enrolled in this case-control study. Six OCPs (β-HCH, trans-chlordane, trans-nonachlor, p,p'-DDE, p,p'-DDT and mirex/kepone) were detected in more than 75% of serum samples. Logistic regression analysis and multiple linear regression analysis were used to assess the associations between OCP exposure and the outcomes. After adjusting for potential confounding factors such as age, sex and body mass index, all six OCPs showed positive associations with type 2 diabetes in a linear dose-response manner. Serum concentrations of β-HCH and p,p'-DDE were associated with higher levels of fasting plasma glucose in participants without diabetes, although no OCPs showed significant associations with hemoglobin A1c. In addition, certain OCPs showed significantly positive associations with triglycerides, total cholesterol, and low-density lipoprotein cholesterol and negative relationships with high-density lipoprotein cholesterol in nondiabetics, indicating that OCP exposure may disrupt lipid metabolism. Findings in the current study indicated that OCPs may be a diabetogenic factor in the population of this study. To our knowledge, this is the first study to investigate the associations between OCP exposure and type 2 diabetes in a Chinese population.

Evaluation of prolactin and insulin resistance in women with polycystic ovarian syndrome

Background: Polycystic ovarian syndrome has been one of a major public health problem in India that leads to medical consequences. It causes multifactorial in etiology such as menstrual dysfunction, hyperandrogenism, hirsutism, insulin resistance, dyslipidemia and obesity which increased risk of diabetes mellitus and cardiovascular disease. Prolactin has been reported as a potent lipogenic and diabetogenic factor, that affecting energy balance and fuel metabolism. The present study was designed to assess serum prolactin and insulin resistance in PCOS women and to compare them with healthy women as controls. Material and Methods: A comparative study including 50 women diagnosed as PCOS and 50 age and BMI matched healthy women as controls was conducted. The age group for the study was 18-35 years. Body Mass Index was calculated as a physical parameter. Fasting blood samples were drawn to assess serum prolactin, serum insulin, HbA1c and fasting blood sugar. Insulin resistance was calculated by homeostasis model assessment. Results: A significant increase in fasting serum insulin (p<0.001) and HOMA – IR (p<0.001) were found in patients with PCOS in comparison with controls. Mean BMI, prolactin, HbA1c and FBS were found elevated in the PCOS women but they were not statistically significant. No significant correlations were found between BMI, serum prolactin and serum insulin. Conclusions: The current study provides further evidence that significantly higher fasting insulin and HOMA in PCOS group indicates presence of IR. IR in PCOS group may have a potential role in the prediction of dysglycemic disease in women with PCOS. This study could not find any significant correlation between serum prolactin, serum insulin and BMI.

Salivary N1-Methyl-2-Pyridone-5-Carboxamide, a Biomarker for Uranium Uptake, in Kuwaiti Children Exhibiting Exceptional Weight Gain.

In a longitudinal study of 6,158 Kuwaiti children, we selected 94 for salivary metabolomic analysis who were neither obese (by waist circumference) nor metabolic syndrome (MetS) positive (<3 diagnostic features). Half (43) remained healthy for 2 years. The other half (51) were selected because they became obese and MetS positive 2 years later. In the half becoming obese, metabolomic analysis revealed that the level of salivary N1-Methyl-2-pyridone-5-carboxamide (2PY) had the highest positive association with obesity (p = 0.0003, AUC = 0.72) of 441 salivary biochemicals detected. 2PY is a recognized uremic toxin. Also, 2PY has been identified as a biomarker for uranium uptake. Considering that a relatively recent military conflict with documented uranium contamination of the area suggests that this weight gain could be a toxicological effect of long-time, low-level uranium ingestion. Comparison of salivary 2PY in samples from the USA and Kuwait found that only Kuwait samples were significantly related to obesity. Also, the geographic distribution of both reported soil radioactivity from 238U and measured salivary 2PY was highest in the area where military activity was highest. The prevalence pattern of adult diabetes in Kuwait suggests that a transient diabetogenic factor has been introduced into the Kuwaiti population. Although we did not measure uranium in our study, the presence of a salivary biomarker for uranium consumption suggests potential toxicity related to obesity in children.

Effects of diabetic pharmacotherapy on prolactin hormone in patients with type 2 diabetes mellitus: Bane or Boon.

Prolactin is a polypeptide hormone secreted from the anterior part of the pituitary gland which was implicated as a diabetogenic factor in the pathogenesis of type 2 diabetes mellitus (T2DM). Therefore, the aim of the present study was to evaluate prolactin serum levels in patients with T2DM regarding the effect of diabetic pharmacotherapy. Eighty patients with T2DM compared with 25 male healthy controls were recruited and divided into four groups: Group I – 29 patients with T2DM treated with metformin, Group II – 30 patients with T2DM treated with glyburide, Group III – 21 patients with T2DM treated with glyburide plus metformin, and Group IV – 25 control male healthy patients. Prolactin serum levels were high in patients with T2DM compared with controls (P < 0.01). Prolactin serum levels were higher in glyburide-treated patients compared with metformin-treated patients (P < 0.01). This study concludes that high prolactin levels in patients with T2DM are linked with diabetic complications and regarded as a beneficial phenomena to overcome IR and diabetic complications. Metformin but not glyburide reduced prolactin levels due to the improvement of insulin resistance.

Transcriptomic and methylomic analysis reveal the toxicological effect of 2,3,7,8-Tetrachlorodibenzodioxin on human embryonic stem cell

Cumulating epidemiological studies demonstrated that environmental exposure to endocrine disrupting chemicals (EDCs) during the early stages of fetal development is associated with the increase in disease susceptibility in later life. The fetal developmental plasticity is considered as a protective mechanism against an undesirable prenatal environment. Dioxin is one of the environmental contaminants and is considered a diabetogenic factor. Experimental animal and human epidemiological studies have revealed that dioxin exposure was associated with insulin resistance and altered beta cell function. But the effect of dioxin exposure in early stage of fetal development is still largely unknown. In this report, we used the human embryonic stem cell (hESC) line, VAL-3, as a model, together with Methyl-CpG Binding Domain (MBD) protein-enriched genome sequencing and transcriptome sequencing (RNA-seq), in order to determine the dynamic changes of the epigenetic landscape and transcriptional dysregulation in hESC upon dioxin exposure. The bioinformatics analyses including the Database for Annotation, Visualization and Integrated Discovery (DAVID) analysis and Ingenuity Pathway Analysis (IPA) highlighted the predisposed neural, hepatic, cardiac and metabolic toxicological effects of dioxin during the fetal development.

Precision Medicine in Obesity and Type 2 Diabetes: The Relevance of Early-Life Exposures.

Type 2 diabetes is highly prevalent and devastating. Obesity is a diabetogenic factor, driving insulin resistance and a compensatory demand for increased insulin secretion from the pancreatic β cells; a failure to address this demand results in diabetes. Accordingly, primary and secondary prevention of obesity are at the core of diabetes prevention programs. The development of obesity and declining β-cell function often span many years or decades before diabetes is clinically manifest. Thus, characterizing the early-life process and risk factors that set disease trajectories may yield novel targets for early intervention and help improve the accuracy of prediction algorithms, factors germane to the emerging field of precision medicine. Here, we overview the concepts of precision medicine and fetal programming. We discuss the barriers to preventing obesity and type 2 diabetes in adulthood and present the rationale for considering early-life events in this context. In so doing, we discuss proof-of-concept studies and cutting-edge technological developments that are likely to transform current thinking on the etiology and pathogenesis of obesity and type 2 diabetes. We also review the factors hampering progress, including the success and failures of pregnancy intervention trials. Obesity and type 2 diabetes are among the major health and economic burdens of our time. Defeating these diseases is likely to require life-course approaches, which may include aggressive interventions informed by biomarker profiling undertaken during early life.

Arsenic, diabetes-related genes and diabetes prevalence in a general population from Spain: The Hortega Study

Background Several studies suggest that inorganic arsenic exposure may be associated with diabetes, but the evidence is not sufficient, especially in populations exposed at low-moderate levels. Polymorphisms (SNPs) in diabetes-related genes have been clearly involved in diabetes risk. We evaluated the interaction of 256 polymorphisms in diabetes-related genes with inorganic arsenic exposure on diabetes risk in the Hortega Study, a representative sample of a general population from Valladolid, Spain. Methods Total urine arsenic was measured in 1451 men and women from Valladolid, Spain. Urine arsenic species (inorganic and methylated arsenic species and arsenobetaine (Asb)) were available in 295 randomly selected participants. To account for the confounding introduced by seafood arsenic (mostly Asb) in total arsenic, we designed a multiple imputation model to predict the missing Asb levels. Prevalent type 2 diabetes (T2D) was defined as fasting glucose levels ≥ 126 mg/dL, non-fasting glucose levels ≥ 200 mg/dL, by physician diagnosis or by diabetes treatment use. Results 108 (7.4%) participants had prevalent T2D. The overall geometric mean of total arsenic was 65.9 μg/g (99.1 and 64.4 μg/g in participants with and without T2D, respectively). The adjusted odds ratios (95% confidence intervals) for T2D comparing the highest with the lowest tertile of total arsenic were 1.71 (0.94 3.13) and 2.52 (1.68 3.80) before and after adjusting for Asb, respectively. Several genotypes were marginally associated with higher risk of diabetes. Top 3 SNPs were rs4135168 (p-value=0.003), rs4135225 (p-value=0.007) in gene TXN and rs9435739 (p-value=0.008) in gene SDHB. Conclusions The findings support the role of arsenic as a diabetogenic factor and the importance of controlling for seafood arsenic in populations with high seafood intake. These preliminary arsenic-gene interaction results require confirmation but provide support to evaluate gene-environment interactions in larger studies.

Myt3 Mediates Laminin-V/Integrin-β1-Induced Islet-Cell Migration via Tgfbi.

Myt3 is a prosurvival factor in pancreatic islets; however, its role in islet-cell development is not known. Here, we demonstrate that myelin transcription factor 3 (Myt3) is expressed in migrating islet cells in the developing and neonatal pancreas and thus sought to determine whether Myt3 plays a role in this process. Using an ex vivo model of islet-cell migration, we demonstrate that Myt3 suppression significantly inhibits laminin-V/integrin-β1-dependent α- and β-cell migration onto 804G, and impaired 804G-induced F-actin and E-cadherin redistribution. Exposure of islets to proinflammatory cytokines, which suppress Myt3 expression, had a similar effect, whereas Myt3 overexpression partially rescued the migratory ability of the islet cells. We show that loss of islet-cell migration, due to Myt3 suppression or cytokine exposure, is independent of effects on islet-cell survival or proliferation. Myt3 suppression also had no effect on glucose-induced calcium influx, F-actin remodeling or insulin secretion by β-cells. RNA-sequencing (RNA-seq) analysis of transduced islets showed that Myt3 suppression results in the up-regulation of Tgfbi, a secreted diabetogenic factor thought to impair cellular adhesion. Exposure of islets to exogenous transforming growth factor β-induced (Tgfbi) impaired islet-cell migration similar to Myt3 suppression. Taken together, these data suggest a model by which cytokine-induced Myt3 suppression leads to Tgfbi de-repression and subsequently to impaired islet-cell migration, revealing a novel role for Myt3 in regulating islet-cell migration.

Apolipoprotein CIII links islet insulin resistance to β-cell failure in diabetes

Insulin resistance and β-cell failure are the major defects in type 2 diabetes mellitus. However, the molecular mechanisms linking these two defects remain unknown. Elevated levels of apolipoprotein CIII (apoCIII) are associated not only with insulin resistance but also with cardiovascular disorders and inflammation. We now demonstrate that local apoCIII production is connected to pancreatic islet insulin resistance and β-cell failure. An increase in islet apoCIII causes promotion of a local inflammatory milieu, increased mitochondrial metabolism, deranged regulation of β-cell cytoplasmic free Ca(2+) concentration ([Ca(2+)]i) and apoptosis. Decreasing apoCIII in vivo results in improved glucose tolerance, and pancreatic apoCIII knockout islets transplanted into diabetic mice, with high systemic levels of the apolipoprotein, demonstrate a normal [Ca(2+)]i response pattern and no hallmarks of inflammation. Hence, under conditions of islet insulin resistance, locally produced apoCIII is an important diabetogenic factor involved in impairment of β-cell function and may thus constitute a novel target for the treatment of type 2 diabetes mellitus.

β-Hydroxypyruvate: a new diabetogenic factor?

The incidence of type 2 diabetes mellitus (T2DM) is increasing at an alarming rate. Insulin secretory dysfunction and insulin resistance are characteristic features of T2DM. However, their relative contributions to the progression from normal glucose tolerance to impaired glucose tolerance (IGT) to T2DM remain unknown. This limits the capacity of researchers to establish therapeutic interventions for T2DM. Glucose-dependent insulinotropic polypeptide (GIP) and GLP-1 are the two primary incretin hormones secreted by intestinal K and L cells, respectively. Secretion of these incretins increases postprandially and they potentiate glucose-stimulated insulin secretion (GSIS). Despite blunted incretin responses in patients with T2DM, insulinotropic responses to exogenously administered GLP-1 remain active in these patients (1). Although controversy exists, a recent study demonstrated that insulin secretory responses to GIP were retained in patients with T2DM (1,2). Additionally, incretin response to GIP is improved by reducing blood glucose levels in patients with T2DM (3). These findings support the rationale for use of incretin-based pharmacotherapies in the treatment and management of T2DM. However, identification of the mechanism by which the function of K cells contributes to the development of T2DM is still elusive and requires a good model of study. To determine the role of K cells in the regulation of metabolism, K cells were eliminated from mice by expressing the diphtheria toxin A-chain gene in GIP-producing cells (DT mice). Despite a severely impaired …

Assessment of Prolactin and Insulin resistance in women with Polycystic ovarian syndrome.

Background: Polycystic ovarian syndrome(PCOS), the most common cause of infertility, is a disorder characterized by chronic anovulation, hyperandrogenism, hyperinsulinemia, and often presence of obesity. Prolactin has been reported as a potent lipogenic and diabetogenic factor, that affecting energy balance and fuel metabolism. The present study was designed to assess serum prolactin and insulin resistance in PCOS women and to compare them with healthy women as controls. Material and Methods: A comparative study including 30 women diagnosed as PCOS and 30 age and BMI matched healthy women as controls was conducted. The age group for the study was 18-35 years. Fasting blood samples were drawn to assess serum prolactin, serum insulin, HbA1c and fasting blood sugar(FBS). Insulin resistance(IR) was calculated by homeostasis model assessment(HOMA). Body Mass Index(BMI) was also calculated. Results: A significant increase in fasting serum insulin (p<0.001) and HOMA IR (p<0.001) were found in patients with PCOS in comparison with controls. Mean BMI, prolactin, HbA1c and FBS were found elevated in the PCOS women but they were not statistically significant. No significant correlations were found between BMI, serum prolactin and serum insulin. Conclusions: The current study provides further evidence that significantly higher fasting insulin and HOMA in PCOS group indicates presence of IR. IR in PCOS group may have a potential role in the prediction of dysglycemic disease in women with PCOS. We could not find any significant correlation between serum prolactin, serum insulin and BMI because our study consisted of a limited number of PCOS subjects.

Ghrelin's second life: from appetite stimulator to glucose regulator.

Ghrelin, a 28 amino acid peptide hormone produced by the stomach, was the first orexigenic hormone to be discovered from the periphery. The octanoyl modification at Ser³, mediated by ghrelin O-acyltransferase (GOAT), is essential for ghrelin's biological activity. Ghrelin stimulates food intake through binding to its receptor (GRLN-R) on neurons in the arcuate nucleus of the hypothalamus. Ghrelin is widely expressed throughout the body; accordingly, it is implicated in several other physiological functions, which include growth hormone release, gastric emptying, and body weight regulation. Ghrelin and GRLN-R expression are also found in the pancreas, suggesting a local physiological role. Accordingly, several recent studies now point towards an important role for ghrelin and its receptor in the regulation of blood glucose homeostasis, which is the main focus of this review. Several mechanisms of this regulation by ghrelin have been proposed, and one possibility is through the regulation of insulin secretion. Despite some controversy, most studies suggest that ghrelin exerts an inhibitory effect on insulin secretion, resulting in increased circulating glucose levels. Ghrelin may thus be a diabetogenic factor. Obesity-related type 2 diabetes has become an increasingly important health problem, almost reaching epidemic proportions in the world; therefore, antagonists of the ghrelin-GOAT signaling pathway, which will tackle both energy- and glucose homeostasis, may be considered as promising new therapies for this disease.