Diabetogenic Action Research Articles

Individual and combined antagonism of aryl hydrocarbon receptor (AhR) and estrogen receptors (ERs) offers distinct level of protection against Bisphenol A (BPA)-induced pancreatic islet cell toxicity in mice.

Bisphenol A (BPA), a pervasive endocrine-disrupting chemical, is known to convey harmful impact on pancreatic islets through estrogen receptors (ERs). Conversely, BPA can activate aryl hydrocarbon receptor (AhR) in certain contexts and has raised concerns about potential toxicological effects. However, BPA-AhR interaction in the context of pancreatic islet toxicity is yet to be reported. We demonstrated the specific role of AhR and its interaction with ERs to mediate BPA toxicity in pancreatic islets. In vitro, isolated islet cells treated with BPA (1 nM), with or without CH22319 (10 mM) and ICI182780 (1 mM) and insulin release, glucose-stimulated insulin secretion (GSIS), cell viability, and pERK1/2 and pAkt expression were measured. In vivo, mice were treated with BPA (10 and 100 µg/kg body weight/day for 21 days) with or without intraperitonial co-treatment of CH22319 (AhR antagonist, 10mg/kg), and ICI182780 (ER antagonist, 500 µg/kg). Glucose homeostasis, insulin resistance, oxidative stress, and inflammatory markers were measured. In vitro data revealed the involvement of AhR in the BPA-mediated alteration in insulin secretion, GSIS, and pERK1/2 and pAkt expression which were counteracted by CH223191 (AhR antagonist) alone or with ICI182780 (ER antagonist). Further, CH223191 alone or with ICI182780 modulated BPA-induced oxidative stress and pro-inflammatory cytokines and alleviated islet cell dysfunction and impaired insulin secretion. In conclusion, therapeutic targeting of AhR and ER combined might be a promising target against diabetogenic action of BPA.

Exploring aryl hydrocarbon receptor (AhR) as a target for Bisphenol-A (BPA)-induced pancreatic islet toxicity and impaired glucose homeostasis: Protective efficacy of ethanol extract of Centella asiatica

The estrogenic impact of Bisphenol-A (BPA), a widely recognized endocrine disruptor, causes disruption of pancreatic β-cell function through estrogen receptors (ERs). While BPA's binding affinity for ERs is significantly lower than that of its natural counterpart, estrogen, recent observations of BPA's affinity for aryl hydrocarbon receptor (AhR) in specific cellular contexts have sparked a specific question: does AhR play a role in BPA's toxicological effects within the endocrine pancreas? To explore this question, we investigated BPA's (10 and 100 μg/ kg body weight/day for 21 days) potential to activate AhR within pancreatic islets and assessed the protective role of ethanol extract of Centella asiatica (CA) (200 and 400 mg/kg body weight/day for 21 days) against BPA-mediated toxicity in mouse model. Our results indicate that BPA effectively triggers the activation of AhR and modulates its target genes within pancreatic islets. In contrast, CA activates AhR but directs downstream pathways differentially and activates Nrf2. Additionally, CA was observed to counteract the disruption caused by BPA in glucose homeostasis and insulin sensitivity. Furthermore, BPA-induced oxidative stress and exaggerated production of proinflammatory cytokines were effectively counteracted by CA supplementation. In summary, our study suggests that CA influenced AhR signaling to mitigate the disrupted pancreatic endocrine function in BPA exposed mice. By shedding light on how BPA interacts with AhR, our research provides valuable insights into the mechanisms involved in the diabetogenic actions of BPA.

Pharmacological properties of Ensete glaucum seed extract: Novel insights for antidiabetic effects via modulation of oxidative stress, inflammation, apoptosis and MAPK signaling pathways

Ethnophamacological relevanceMedicinal plants are increasingly making important contributions to diabetic treatment. Ensete glaucum seeds have been widely used in folk medicine to treat diabetes. Aim of the studyThe study was aimed to investigate the protective effect and active mechanisms of E. glaucum seed extract (EGSE) against streptozotocin (STZ)-induced hyperglycemia. Materials and methodsHyperglycemic mice were treated with EGSE (25 and 50 mg/kg) or glibenclamide (5 mg/kg) once daily for 7 d. The effects of these treatments on changes in blood biochemical parameters, pancreatic, liver, and kidney histopathology, oxidative stress and inflammatory marker levels in pancreatic, hepatic, and renal tissues were assessed. Expression of several proteins in MAPK signaling pathway related to apoptosis in pancreatic tissue were investigated. Furthermore, ex vivo, in vitro, and in silico biological activities of EGSE and its compounds were also examined. ResultsEGSE and glibenclamide increased notably insulin, reduced significantly glucose, AST, ALT, BUN and creatinine levels in blood. Pancreatic islets, hepatic and renal tissue structure were restored by EGSE or glibenclamide. EGSE showed significant anti-oxidative stress and anti-inflammatory effects by enhancing GSH level and dropping MDA, NF-κB, TNF-α and IL-6 levels in these tissues. Particularly, EGSE exhibited pancreatic protective effect against STZ-induced apoptosis through the MAPK signaling pathway by down-regulation of p-p38 MAPK, ERK1/2, JNK1, p-AMPK, Bax, Bax/Bcl-2, cytochrome c, cleaved-caspase 3 and PARP expression, and slight up-regulation of Bcl-2 expression. Moreover, EGSE inhibited intestinal glucose absorption, PTP1B, α-amylase, and α-glucosidase activities. Its isolated compounds (Afzelechin and coniferaldehyde) showed PTP1B and α-glucosidase inhibitory activities, and potent structure-activity relationships. ConclusionThese findings indicated the hypoglycemic and protective effects of E. glaucum seed extract against the STZ diabetogenic action. E. glaucum seed is a potential candidate for further studies to confirm its activities as a therapeutic agent for diabetic patients.

Небіволол – бета-адреноблокатор з вазодилатаційними властивостями: досягнення і перспективи застосування

Огляд присвячений клінічному застосуванню β-адреноблокатора з вазодилатаційними властивостями – небівололу. Розглянуто основні фармакологічні властивості та характеристики препарату, його кардіоселективність та механізми вазодилатаційної дії. Показано особливості застосування небівололу в лікуванні есенціальної артеріальної гіпертензії, ішемічної хвороби серця та серцевої недостатності. Препарат не має діабетогенної дії при тривалому застосуванні, сприятливо впливає на показники ліпідного та вуглеводного обмінів. У хворих з ішемічною хворобою серця продемонстровано його антиангінальну й антиішемічну дію та зниження частоти рецидивів після виконання операцій на коронарних артеріях. Препарат добре толерується та має високу ефективність у зниженні показників смертності в пацієнтів віком понад 70 років з хронічною серцевою недостатністю, незалежно від фракції викиду лівого шлуночка. У лікуванні ішемічної хвороби серця при цукровому діабеті 2-го типу перевагу надають β-адреноблокаторам з вазодилатаційними властивостями. При необструктивних ураженнях коронарних артерій з-поміж β-адреноблокаторів перевагу надають небівололу для лікування мікросудинної стенокардії. У пацієнтів з артеріальною гіпертензією небіволол, крім антигіпертензивного ефекту, має сприятливий вплив на функцію ендотелію, метаболічний профіль, центральну гемодинаміку, якість життя пацієнтів, а також кращий профіль побічних ефектів.

Current achievements and prospects for the use of nebivolol in the treatment of patients with cardiovascular diseases

A literature review deals with the clinical use of nebivol as a beta-blocker (BB) with vasodilating properties. The principal pharmacological properties and characteristics of the drug, its cardioselectivity and mechanisms of vasodilation are presented. The special place of nebivolol in the treatment of essential arterial hypertension (AH), coronary heart disease (CHD) and heart failure (HF) is outlined. The drug does not possess a diabetogenic activity with a long-term use, and impacts favourably on the parameters of lipid and carbohydrate metabolism. In CHD patients, nebivolol demonstrates the anti-anginal and anti-ischemic activities, and reduces the frequency of angina recurrence after coronary artery interventions. The drug is well tolerated and characterized by a high effectiveness with respect to the reduction of mortality rates in patients with chronic HF over 70 years of age, regardless of the left ventricular ejection fraction. Vasodilating BB are preferred in the treatment of CHD patients with type 2 diabetes. In case of non-obstructive coronary lesions, nebivolol is chosen among existing BBs for the treatment of microvascular angina. The use of nebivolol in AH patients, in addition to the antihypertensive effect, is characterized by a favorable impact on the function of endothelium, the metabolic profile, central hemodynamics, health-related quality of life of patients, as well as more favorable profile of side effects.

Oral mometasone furoate administration preserves anti-inflammatory action with fewer metabolic adverse effects in rats

BackgroundExogenous glucocorticoids (CGs) possess relevant therapeutic effects but exert diabetogenic actions when in excess. Thus, ligands with potential therapeutic applications and fewer adverse effects are needed. To this, we analyzed whether mometasone furoate (MF), a CG expected to cause fewer side effects, given through systemic routes, could maintain the anti-inflammatory actions without relevant repercussions on metabolism. MethodsThe anti-inflammatory effect of MF was evaluated with both peritonitis and colitis models in rodents. Glucose and lipid metabolism were investigated in male and female rats treated daily with MF with different doses and routes of administration for seven days. The involvement of glucocorticoid receptor (GR) on MF actions was assessed in animals pretreated with mifepristone. Also, the potential reversibility of the adverse effects was assessed. Dexamethasone was used as a positive control. ResultsMF treatment resulted in glucose intolerance in male rats treated through intraperitoneal (ip) but not oral gavage route (og). In female rats, none of the routes led to glucose intolerance. MF treatment attenuated insulin sensitivity and increased pancreatic β-cell mass, regardless of the sex and route of administration. MF treatment through og route did not result in dyslipidemia, as observed in rats treated through the ip route (both sexes). The anti-inflammatory and metabolic adverse effects of MF were GR-dependent, and metabolic outcomes altered by MF administration were reversible. ConclusionMF maintains anti-inflammatory activity when administered by systemic routes and exerts less impact on metabolism when administered orally in male and female rats, effects that are GR-dependent and reversible.Category: Metabolic Disorders and Endocrinology.

Screening of Metabolism-Disrupting Chemicals on Pancreatic α-Cells Using In Vitro Methods.

Metabolism-disrupting chemicals (MDCs) are endocrine disruptors with obesogenic and/or diabetogenic action. There is mounting evidence linking exposure to MDCs to increased susceptibility to diabetes. Despite the important role of glucagon in glucose homeostasis, there is little information on the effects of MDCs on α-cells. Furthermore, there are no methods to identify and test MDCs with the potential to alter α-cell viability and function. Here, we used the mouse α-cell line αTC1-9 to evaluate the effects of MDCs on cell viability and glucagon secretion. We tested six chemicals at concentrations within human exposure (from 0.1 pM to 1 µM): bisphenol-A (BPA), tributyltin (TBT), perfluorooctanoic acid (PFOA), triphenylphosphate (TPP), triclosan (TCS), and dichlorodiphenyldichloroethylene (DDE). Using two different approaches, MTT assay and DNA-binding dyes, we observed that BPA and TBT decreased α-cell viability via a mechanism that depends on the activation of estrogen receptors and PPARγ, respectively. These two chemicals induced ROS production, but barely altered the expression of endoplasmic reticulum (ER) stress markers. Although PFOA, TPP, TCS, and DDE did not alter cell viability nor induced ROS generation or ER stress, all four compounds negatively affected glucagon secretion. Our findings suggest that αTC1-9 cells seem to be an appropriate model to test chemicals with metabolism-disrupting activity and that the improvement of the test methods proposed herein could be incorporated into protocols for the screening of diabetogenic MDCs.

Diabetogenic action of statins — mechanisms and consequences. Review

Over the past 20 years, the data according to the primary and secondary prevention of cardiovascular disease (CVD) in patients with type 2 diabetes mellitus (DM 2), usually using predefined subgroup analyses, has consistently shown conclusive evidence of reduced relative and absolute risk of CVD. However, enthusiasm for using 3-hydroxyl-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors has been significantly reduced by the results of follow up of patients in whom DM developed against the background of statins’ administration.The mechanisms by which statins may contribute to the DM 2 development have not been fully understood, but both targeted and non-targeted effects may be involved. These effects include: the effects on the mevalonate pathway, accompanied by inhibition of several pathways of cellular biosynthesis; activation of gluconeogenesis processes by increasing the expression of key enzyme genes; disruption of insulin signalling pathways; changes in circulating free fatty acids; hormones; functional and structural state of β-cells; maturation/differentiation of adipocytes. Additional mechanisms, particularly epigenetic regulation mediated by specific miRNAs (a class of short non-coding RNA molecules involved in the regulation of RNA translation and degradation), are also involved in the reduction of insulin secretion.Currently investigations are being conducted to elucidate the statin-induced mechanisms of DM 2 development. It has been established that therapy with HMG-CoA reductase inhibitors, although it affects the accession of DM 2, but helps to reduce the accession and/or progression of CVD. Therefore, statins should be continued in patients at high or very high risk of CVD to achieve the target levels of low-density lipoprotein cholesterol. Therefore, before starting treatment, it is necessary to assess the degree of risk. HbA1c and blood glucose levels should be monitored regularly in people at high risk for developing DM 2 who receive statins.

In Vitro Assays to Identify Metabolism-Disrupting Chemicals with Diabetogenic Activity in a Human Pancreatic β-Cell Model.

There is a need to develop identification tests for Metabolism Disrupting Chemicals (MDCs) with diabetogenic activity. Here we used the human EndoC-βH1 β-cell line, the rat β-cell line INS-1E and dispersed mouse islet cells to assess the effects of endocrine disruptors on cell viability and glucose-stimulated insulin secretion (GSIS). We tested six chemicals at concentrations within human exposure (from 0.1 pM to 1 µM). Bisphenol-A (BPA) and tributyltin (TBT) were used as controls while four other chemicals, namely perfluorooctanoic acid (PFOA), triphenylphosphate (TPP), triclosan (TCS) and dichlorodiphenyldichloroethylene (DDE), were used as “unknowns”. Regarding cell viability, BPA and TBT increased cell death as previously observed. Their mode of action involved the activation of estrogen receptors and PPARγ, respectively. ROS production was a consistent key event in BPA-and TBT-treated cells. None of the other MDCs tested modified viability or ROS production. Concerning GSIS, TBT increased insulin secretion while BPA produced no effects. PFOA decreased GSIS, suggesting that this chemical could be a “new” diabetogenic agent. Our results indicate that the EndoC-βH1 cell line is a suitable human β-cell model for testing diabetogenic MDCs. Optimization of the test methods proposed here could be incorporated into a set of protocols for the identification of MDCs.

Type 1 Diabetes: A Promising Dialogue between Promiscuous T Cell Receptor and H‐2Db Peptide Complex

Obliteration of the beta cells mediated by CD8 T cells in the islets of Langerhans leads to the development of autoimmune disease, type 1 diabetes (T1D). During the kickoff of T1D, CD8 T cells play a pivotal role in the destruction of these pancreatic beta cells. The CD8 T cell clone AI4, previously isolated from the islets of a young diabetes‐prone NOD mouse, is found to be the most pathogenic among the population of CD8 T cell clones. Multiple natural and synthetic ligands for AI4 have been identified. These ligands include an unusually short seven‐residue peptide derived from the insulin A chain (InsA14‐20) that is recognized by AI4 in the context of H‐2Db but lacks a C‐terminal anchor residue. High diabetogenic activity of AI4 is accredited to the promiscuity, or cross reactivity, of its T cell receptor (TCR). We adopted the structural biology studies for understanding the mechanism of cross‐reactivity of the AI4 TCR with its multiple ligands. Unraveling the three‐dimensional structure of H‐2Db with AI4 ligands will help us to unveil the distinct mechanisms involved in the recognition and the cross‐reactivity of the AI4 TCR. In previous studies, our group has already reported two structures of the H‐2Db peptide complexes recognized by AI4. In our present work we have solved two additional structures of H‐2Db with AI4 ligands and several others are in progress. In addition to these studies, we have cloned, expressed and purified the AI4 TCR in a soluble form, which should allow us to obtain its structure alone and in complex with its multiple ligands. Our approach to study the interaction of promiscuous TCRs with their multiple ligands will allow us to uncover the likely multiple mechanisms that underlie TCR cross‐reactivity in autoimmunity.

Coadministration of sitagliptin or metformin has no major impact on the adverse metabolic outcomes induced by dexamethasone treatment in rats

AimsGlucocorticoids (GC) in excess cause glucose intolerance and dyslipidemia due to their diabetogenic actions. Conceptually, antidiabetic drugs should attenuate these side effects. Thus, we evaluated whether the coadministration of metformin or sitagliptin (or both) with dexamethasone could attenuate GC-induced adverse effects on metabolism. Materials and methodsAdult male rats were treated for 5 consecutive days with dexamethasone (1 mg/kg, body mass (bm), intraperitoneally). Additional groups were coadministered with metformin (300 mg/kg, bm, by oral gavage (og)) or sitagliptin (20 mg/kg, bm, og) or with both compounds in combination. The day after the last treatments, rats were submitted to glucose tolerance tests, pyruvate tolerance test, and euthanized for biometric, biochemical, morphologic, and molecular analyses. Key findingsDexamethasone treatment resulted in reduced body mass and food intake, increased blood glucose and plasma insulin, dyslipidemia, glucose intolerance, pyruvate intolerance, and increased hepatic content of glycogen and fat. Sitagliptin coadministration improved glucose tolerance compared with the control group, an effect paralleled with higher levels of active GLP-1 during an oral GTT. Overall, sitagliptin or metformin coadministration did not prevent any of the dexamethasone-induced metabolic disturbances. SignificanceCoadministration of sitagliptin or metformin result in no major improvement of glucose and lipid metabolism altered by dexamethasone treatment in male adult rats.

Syzygium jambos extract mitigates pancreatic oxidative stress, inflammation and apoptosis and modulates hepatic IRS-2/AKT/GLUT4 signaling pathway in streptozotocin-induced diabetic rats

The protective effect of Syzygium jambos (SJ) bark extract against streptozotocin-induced diabetes was tested in rats. Animals were treated with 100 or 200 mg/kg of the extract or glibenclamide, 0.5 mg/kg per os, once daily: started 2 days before streptozotocin (STZ) injection and lasted for 14 days after STZ injection. The effect of the extract was also evaluated on normal rats in comparison with glibenclamide. Diabetic animals showed an elevated blood glucose level, positive glycosuria, elevated fructosamine, pancreatic malondialdehyde, pancreatic TNF-a, and pancreatic caspase-3 levels and decreased serum insulin, pancreatic IL-10, pancreatic BCL-2, reduced glutathione (GSH), liver insulin substrate-2, liver phosphorylated protein kinase B (p-AKT) and liver glucose transporter 4 (GLUT4) levels. Histopathological examination of diabetic rats revealed islets destruction and vacuolation and collagen fibers deposition. All these changes were mitigated dose dependently by the extract. The high dose of the extract exerted comparable effects with glibenclamide in most studied parameters. These results indicated the protective role of SJ against the STZ diabetogenic action. In the pancreatic and hepatic tissue of diabetic rats, SJ effectively recovered pancreatic cells by reducing hyperglycemia through activating endogenous antioxidants, dynamic insulin production, and suppressing inflammation and apoptosis. The observed results might be attributed to the existence of 10 secondary metabolites as annotated by LC-MS. Taken together, S. jambos is a potential candidate for further studies to confirm its activities as a therapeutic agent for diabetic patients.

120-LB: The Metabolic Effects of Initiation Pitavastatin vs. Rosuvastatin: Twelve Months Real-World Data on Hyperlipidemic Patients with and without Diabetes (DM)

Introduction & Purpose: Statin treatment is an integral part of cardiovascular prevention. Recent studies have highlighted their potential diabetogenic action, mostly in a dose-dependent mode. Pitavastatin has studies showing that this statin may not follow the above rule. The present retrospective study highlights the metabolic effects of initiating pitavastatin vs. rosuvastatin therapy in diabetic and nondiabetic statin-naive patients. Materials & Methods: A total of 74 hyperlipidemic patients included: 41 with DM, mean age 62.4 years (23 on Pitavastatin + 18 on Rosuvastatin)33 non-DM, mean age 62.2 years (15 on Pitavastatin + 18 on Rosuvastatin)Biochemical data were extracted from the medical records of the participants after consent. Results: For the group of patients with DM, we found that those on Pitavastatin showed statistically significant difference in increasing HDL and decreasing total cholesterol, LDL, triglycerides and γGT. Those on Rosuvastatin showed decrease in total cholesterol, LDL, triglycerides without HDL increase. For the group of patients without DM, we found that mean fasting blood glucose was 97.2mg/dl before Rosuvastatin initiation and 104.1mg/dL after 1 year. A statistically significant difference was recorded also in reducing total cholesterol and LDL and increasing γGT. Accordingly, blood glucose was 102 before Pitavastatin initiation and 95.6mg/dL after 1 year. A statistically significant difference was recorded in HDL increase and total cholesterol, LDL, triglycerides, γGT and ALT decrease. Conclusion: In accordance to prospective studies, this retrospective short term “real world” study highlights the rosuvastatin-induced carbohydrate metabolism disorder and the favorable effects of pitavastatin in glucose metabolism and biochemical liver markers, as well as the beneficial effect on lipid profile, regardless the presence of DM. Disclosure D. Lygnos: None. A. Papazafiropoulou: None. S. Soteriades: None. N. D. Loxas: None. M. Xenou: None. I. Zoupas: None. E. Fousteris: None.

Comparative evaluation of feeding effects of A1 and A2 cow milk derived casein hydrolysates in diabetic model of rats

• The study was designed with Type-1 diabetes as the backdrop. During the trial period of 60 days, none of the rats became pre-diabetic due to respective hydrolysate feeding. • Anti-diabetic potential of indigenous cow milk (A2) derived casein hydrolysates was not indicated as it failed to offer resistance to diabetes induction using streptozotocin. • Feeding of A1 or A2 cow milk derived casein hydrolystaes did not cause any deteriorative effect on the blood biochemical profile and histopathology of major organs like heart, liver and kidney. The present study was designed to test diabetogenic activity of A1 and A2 casein hydrolysates and other related pathological conditions, in murine species. 6 weeks old adult male wistar rats were selected and first divided into 3 groups (n = 12) as Control, A1CH and A2CH were fed with respective A1 and A2 casein hydrolysate diets for 50 days. On 51st day, each group was divided into 2 sub groups (n = 6) and diabetes was induced in one subgroup of each group using Streptozotocin, which resulted in 6 sub groups. The fasting blood glucose level and other biochemical, diabetic specific parameters and histopathological findings post sacrifice, did not differ significantly (p > 0.05) among control, A1CH and A2CH groups. Whereas, the diabetic rats showed significant (p < 0.05) increase in the fasting blood glucose levels, blood biochemicals and significant (p < 0.05) decrease in body weight, HDL, insulin and C-peptide levels when compared to healthy rats. However, there was no significance (p < 0.05) difference in various biochemical, diabetic specific parameters and histopathological findings among the diabetic groups viz. , STZ, A1CH + STZ, A2CH + STZ except the significantly ( p < 0.05) higher levels of cholesterol and LDL noticed in A1CH + STZ as compared to STZ group. The results suggest that A1 and A2 casein hydrolysates did not have any marked effect on various health parameters when fed for 60 days to the healthy rats and the STZ induced rats for the last 10 days of the study.

Maternal transfer of environmentally relevant polybrominated diphenyl ethers (PBDEs) produces a diabetic phenotype and disrupts glucoregulatory hormones and hepatic endocannabinoids in adult mouse female offspring

Polybrominated diphenyl ethers (PBDEs) are brominated flame retardant chemicals and environmental contaminants with endocrine-disrupting properties that are associated with diabetes and metabolic syndrome in humans. However, their diabetogenic actions are not completely characterized or understood. In this study, we investigated the effects of DE-71, a commercial penta-mixture of PBDEs, on glucoregulatory parameters in a perinatal exposure model using female C57Bl/6 mice. Results from in vivo glucose and insulin tolerance tests and ex vivo analyses revealed fasting hyperglycemia, glucose intolerance, reduced sensitivity and delayed glucose clearance after insulin challenge, decreased thermogenic brown adipose tissue mass, and exaggerated hepatic endocannabinoid tone in F1 offspring exposed to 0.1 mg/kg DE-71 relative to control. DE-71 effects on F0 dams were more limited indicating that indirect exposure to developing offspring is more detrimental. Other ex vivo glycemic correlates occurred more generally in exposed F0 and F1, i.e., reduced plasma insulin and altered glucoregulatory endocrines, exaggerated sympathoadrenal activity and reduced hepatic glutamate dehydrogenase enzymatic activity. Hepatic PBDE congener analysis indicated maternal transfer of BDE-28 and -153 to F1 at a collective level of 200 ng/g lipid, in range with maximum values detected in serum of human females. Given the persistent diabetogenic phenotype, especially pronounced in female offspring after developmental exposure to environmentally relevant levels of DE-71, additional animal studies should be conducted that further characterize PBDE-induced diabetic pathophysiology and identify critical developmental time windows of susceptibility. Longitudinal human studies should also be conducted to determine the risk of long-lasting metabolic consequences after maternal transfer of PBDEs during early-life development.

Mouse models of growth hormone deficiency.

Nearly one century of research using growth hormone deficient (GHD) mouse lines has contributed greatly toward our knowledge of growth hormone (GH), a pituitary-derived hormone that binds and signals through the GH receptor and affects many metabolic processes throughout life. Although delayed sexual maturation, decreased fertility, reduced muscle mass, increased adiposity, small body size, and glucose intolerance appear to be among the negative characteristics of these GHD mouse lines, these mice still consistently outlive their normal sized littermates. Furthermore, the absence of GH action in these mouse lines leads to enhanced insulin sensitivity (likely due to the lack of GH's diabetogenic actions), delayed onset for a number of age-associated physiological declines (including cognition, cancer, and neuromusculoskeletal frailty), reduced cellular senescence, and ultimately, extended lifespan. In this review, we provide details about history, availability, growth, physiology, and aging of five commonly used GHD mouse lines.

Statins and Higher Diabetes Mellitus Risk: Incidence, Proposed Mechanisms, and Clinical Implications.

3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors are ubiquitously prescribed for cardiovascular disease (CVD) prevention and treatment. However, the use of statins has been linked to the development of new-onset diabetes mellitus (NODM), which could possibly increase future CVD risk. This phenomenon necessitates a clear discussion of the possible etiologies of this relationship and its broader clinical consequences. We discuss the reported incidence of NODM in statin users through a rigorous review of data from metaanalyses of randomized control trials examining this association. We also highlight the various possible mechanisms responsible for the development of statin-induced diabetes mellitus. Finally, we examine the clinical implications of this effect on future CVD risk and identify specific patient factors that can be used for risk-stratification strategies. Data from 14 randomized control trials metaanalyses suggest a 9-33% higher risk of NODM with statin use. Several cellular, molecular, and genetic mechanisms, as well as lifestyle habits, have been identified as potential underlying factors responsible for this elevated risk. The principle mode of the diabetogenic action of statins is still unclear, though it is likely the result of a complex interplay of pancreatic and extrapancreatic effects. It is understood that patient populations with a greater predisposition to diabetes mellitus, and those with thicker epicardial adiposity are more at risk for the development of statin-induced NODM. Despite these observations, robust data from a variety of investigations suggest that the CVD preventative benefits of statin treatment significantly outweigh the risks associated with the development of NODM. Nevertheless, further study must better identify the causative mechanisms involved in this process, its natural history, and the unique factors that will help clinicians risk stratify and appropriately monitor patients on statin therapy.

The CD137 Ligand Is Important for Type 1 Diabetes Development but Dispensable for the Homeostasis of Disease-Suppressive CD137+ FOXP3+ Regulatory CD4 T Cells.

CD137 modulates type 1 diabetes (T1D) progression in NOD mice. We previously showed that CD137 expression in CD4 T cells inhibits T1D, but its expression in CD8 T cells promotes disease development by intrinsically enhancing the accumulation of β-cell-autoreactive CD8 T cells. CD137 is expressed on a subset of FOXP3+ regulatory CD4 T cells (Tregs), and CD137+ Tregs are the main source of soluble CD137. Soluble CD137 suppresses T cells in vitro by binding to the CD137 ligand (CD137L) upregulated on activated T cells. To further study how the opposing functions of CD137 are regulated, we successfully targeted Tnfsf9 (encoding CD137L) in NOD mice using the CRISPR/Cas9 system (designated NOD.Tnfsf9 -/-). Relative to wild-type NOD mice, T1D development in the NOD.Tnfsf9 -/- strain was significantly delayed, and mice developed less insulitis and had reduced frequencies of β-cell-autoreactive CD8 T cells. Bone marrow chimera experiments showed that CD137L-deficient hematopoietic cells were able to confer T1D resistance. Adoptive T cell transfer experiments showed that CD137L deficiency on myeloid APCs was associated with T1D suppression. Conversely, lack of CD137L on T cells enhanced their diabetogenic activity. Furthermore, neither CD137 nor CD137L was required for the development and homeostasis of FOXP3+ Tregs. However, CD137 was critical for the in vivo T1D-suppressive activity of FOXP3+ Tregs, suggesting that the interaction between CD137 and CD137L regulates their function. Collectively, our results provide new insights into the complex roles of CD137-CD137L interaction in T1D.

Interleukin-27 Is Essential for Type 1 Diabetes Development and Sjögren Syndrome-like Inflammation

SUMMARYHuman genetic studies implicate interleukin-27 (IL-27) in the pathogenesis of type 1 diabetes (T1D), but the underlying mechanisms remain largely unexplored. To further define the role of IL-27 in T1D, we generated non-obese diabetic (NOD) mice deficient in IL-27 or IL-27Rα. In contrast to wild-type NOD mice, both NOD.Il27−/− and NOD.Il27ra−/− strains are completely resistant to T1D. IL-27 from myeloid cells and IL-27 signaling in T cells are critical for T1D development. IL-27 directly alters the balance of regulatory T cells (Tregs) and T helper 1 (Th1) cells in pancreatic islets, which in turn modulates the diabetogenic activity of CD8 T cells. IL-27 also directly enhances the effector function of CD8 T cells within pancreatic islets. In addition to T1D, IL-27 signaling in T cells is also required for lacrimal and salivary gland inflammation in NOD mice. Our study reveals that IL-27 contributes to autoimmunity in NOD mice through multiple mechanisms and provides substantial evidence to support its pathogenic role in human T1D.

Statins and the potential for higher diabetes mellitus risk

ABSTRACTIntroduction: 3-Hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins) are widely used for cardiovascular disease (CVD) prevention. Long-term use of statins has been linked to the development of diabetes mellitus (DM) which increases CVD risk.Areas covered: We discussed the reported incidence of DM in statin users, various possible mechanisms responsible for the development of DM and the clinical implications of this association on CVD risk. Relevant supporting literature was identified using MEDLINE/EMBASE search.Expert opinion: Data from available RCTs and observational studies suggest a 10–45% higher risk of new-onset DM with statin use compared to nonusers. Several cellular, molecular, and genetic mechanisms, and lifestyle changes have been studied and discussed as potential underlying mechanisms responsible for this elevated DM risk with statin therapy. The mode of the diabetogenic action of statins is still unclear and an interplay of pancreatic and peripheral effects in the pathogenesis of DM is a possibility. Despite these observations, the CVD preventative benefit of statin treatment outweighs the CVD risk associated with of development of new DM. There is a need for further research to identify the exact mechanisms involved so as to specifically target causative factors and individualize treatment.