Glucose-induced Insulin Secretion Research Articles

Selenomethionine modulates insulin secretion in the MIN6-K8 mouse insulinoma cell line.

Selenium is an essential trace element of interest for its potential role in glucose homeostasis. The present study investigated the impact of selenium supplementation as selenomethionine (SeMet) on insulin secretion in MIN6-K8 cells, a pancreatic β-cell model. We found that SeMet enhanced percent glucose-induced insulin secretion, while also increasing tolbutamide- and KCl-induced percent insulin secretion. RNA-sequencing showed that SeMet supplementation altered expression of several selenoproteins, including glutathione peroxidase 3 (Gpx3) and selenoprotein P (SelP). Targeted knockdown of Gpx3 increased both percent and total insulin release, while SelP knockdown increased insulin content and insulin release. Collectively, these studies support a putative role for selenium and selenoproteins in the regulation of insulin secretion, glucose homeostasis, and diabetes risk.

A20 controls expression of beta-cell regulatory genes and transcription factors

TNFAIP3 encodes a zinc finger protein called A20, which has potent anti-inflammatory and anti-apoptotic properties. A20 promotes beta-cell survival and protects against islet graft rejection in experimental models. The current study sought to investigate the mechanisms underlying the protective role of A20 in the pancreatic beta-cell. Two islet cell types were used for experiments: the insulin-secreting BRIN-BD11 cell line and human islet cells. A20 was silenced using siRNA against TNFAIP3, and knockdown was confirmed by qPCR and immunostaining of cells. Cell viability, cytotoxicity and apoptosis were assessed using the ApotoxGlo assay. Glucose-stimulated insulin secretion and production of inflammatory cytokines (TNFa, IL1b and IFNg) were measured by ELISA. Expression of beta-cell regulatory genes (Abcc8, Kcnj11, Kcnq1, Gck, Scl2a2) and transcription factors (Hnf1a, Pdx1, Nkx6.1, Ngn3) was determined by qPCR. A20 deficiency increased apoptosis, impaired glucose-induced insulin secretion, and reduced expression of beta-cell regulatory genes and transcription factors. Addition of recombinant A20 normalized gene expression profiles. TNFa, IL1b and IFNg were elevated in A20 deficient cells and found to independently elicit changes in gene expression. Analysis of PCR array data suggests that A20 action in the beta cell is largely, although not exclusively, driven by the P65 subunit of NF-kB. The current report demonstrates a role for A20 in controlling beta-cell integrity and survival, which likely results from the regulation of inflammatory signalling. Of particular note is the impact that A20 deficiency has on the expression of transcription factors regulating the maturation and normal function of beta cells.

Beta-Cell Ion Channels and Their Role in Regulating Insulin Secretion.

Beta cells of the pancreatic islet express many different types of ion channels. These channels reside in the β-cell plasma membrane as well as subcellular organelles and their coordinated activity and sensitivity to metabolism regulate glucose-dependent insulin secretion. Here, we review the molecular nature, expression patterns, and functional roles of many β-cell channels, with an eye toward explaining the ionic basis of glucose-induced insulin secretion. Our primary focus is on KATP and voltage-gated Ca2+ channels as these primarily regulate insulin secretion; other channels in our view primarily help to sculpt the electrical patterns generated by activated β-cells or indirectly regulate metabolism. Lastly, we discuss why understanding the physiological roles played by ion channels is important for understanding the secretory defects that occur in type 2 diabetes. © 2021 American Physiological Society. Compr Physiol 11:1-21, 2021.

Okamoto model for necrosis and its expansions, CD38-cyclic ADP-ribose signal system for intracellular Ca2+ mobilization and Reg (Regenerating gene protein)-Reg receptor system for cell regeneration.

In pancreatic islet cell culture models and animal models, we studied the molecular mechanisms involved in the development of insulin-dependent diabetes. The diabetogenic agents, alloxan and streptozotocin, caused DNA strand breaks, which in turn activated poly(ADP-ribose) polymerase/synthetase (PARP) to deplete NAD+, thereby inhibiting islet β-cell functions such as proinsulin synthesis and ultimately leading to β-cell necrosis. Radical scavengers protected against the formation of DNA strand breaks and inhibition of proinsulin synthesis. Inhibitors of PARP prevented the NAD+ depletion, inhibition of proinsulin synthesis and β-cell death. These findings led to the proposed unifying concept for β-cell damage and its prevention (the Okamoto model). The model met one proof with PARP knockout animals and was further extended by the discovery of cyclic ADP-ribose as the second messenger for Ca2+ mobilization in glucose-induced insulin secretion and by the identification of Reg (Regenerating gene) for β-cell regeneration. Physiological and pathological events found in pancreatic β-cells have been observed in other cells and tissues.

Association of Serum Urotensin-II Levels with Insulin Resistance and Endothelin-I in Type-II Diabetes Mellitus Patients

Urotensin-II (UII), a pluripotent vasoactive cyclic peptide, exhibits the progression of cardiovascular diseases and the glucose metabolic disorder of insulin resistance. Type 2 Diabetes Mellitus (T2DM) is entirely associated with insulin resistance. This study aimed to demonstrate the association of UII with insulin resistance in diabetic and non-diabetic subjects. A total of 73 male and female subjects aged 40-60 years were recruited in this case-control study. They included 35 non- diabetic subjects with a body mass index of (BMI) ≤ 25 and 38 patients with Diabetes Mellitus and BMI ≥ 25. UII levels were assessed beside other vasoactive and clinical parameters. The results revealed that patients with T2DM had elevated UII and Endothelin-I (ET-I) levels, along with positive correlations with the insulin-resistance marker of Homeostatic Model Assessment for Insulin Resistance (HOMA-IR), blood pressure (BP), fasting blood glucose (FBG), hemoglobin A1c (HbA1C), and asymmetric dimethylarginine (ADMA). Results from stepwise multiple regressions indicated that UII correlated positively with the increases in the levels of serum cholesterol, ET-I, urea, ADMA, and FBG. This study concludes that the increase in UII level has a positive relation with insulin-resistance and the increase in ET-I level. However, UII could inhibit glucose-induced insulin secretion and, hence, can be utilized as a marker for T2DM and its complications through inflammatory microangiopathy.

Multiple Guanine Nucleotide Exchange Factors Mediate Glucose-Induced Rac1 Activation and Insulin Secretion: Is It Precise Regulatory Control or a Case of Two Peas from the Same Pod?

Glucose-stimulated insulin secretion involves G protein (Rac1)-mediated cytoskeletal remodeling and vesicular transport and fusion with the plasma membrane. Recent evidence implicates at least three guanine nucleotide exchange factors (GEFs), namely, Tiam1, Vav2, and P-Rex1, in glucose-induced activation of Rac1 and insulin secretion. This Viewpoint highlights potential mechanisms underlying Tiam1/Vav2/P-Rex1 sensitive Rac1-mediated insulin secretion in the glucose-stimulated β-cell.

The potential of the incorporated collagen microspheres in alginate hydrogel as an engineered three-dimensional microenvironment to attenuate apoptosis in human pancreatic islets

BackgroundTissue engineering is considered as a promising tool for remodeling the native cells microenvironment. In the present study, the effect of alginate hydrogel and collagen microspheres integrated with extracellular matrix components were evaluated in the decrement of apoptosis in human pancreatic islets. Materials/methods: For three-dimensional culture, the islets were encapsulated in collagen microspheres, containing laminin and collagen IV and embedded in alginate scaffold for one week. After that the islets were examined in terms of viability, apoptosis, genes and proteins expression including BAX, BCL2, active caspase-3, and insulin. Moreover, the islets function was evaluated through glucose-induced insulin and C-peptide secretion assay. In order to evaluate the structure of the scaffolds and the morphology of the pancreatic islets in three-dimensional microenvironments, we performed scanning electron microscopy. ResultsOur findings showed that the designed hydrogel scaffolds significantly improved the islets viability using the reduction of activated caspase-3 and TUNEL positive cells. ConclusionsThe reconstruction of the destructed matrix with alginate hydrogels and collagen microspheres might be an effective step to promote the culture of the islets.

Cavβ3 Regulates Ca2+ Signaling and Insulin Expression in Pancreatic β-Cells in a Cell-Autonomous Manner

Voltage-gated Ca2+ (Cav) channels consist of a pore-forming Cavα1 subunit and auxiliary Cavα2-δ and Cavβ subunits. In fibroblasts, Cavβ3, independent of its role as a Cav subunit, reduces the sensitivity to low concentrations of inositol-1,4,5-trisphosphate (IP3). Similarly, Cavβ3 could affect cytosolic calcium concentration ([Ca2+]) in pancreatic β-cells. In this study, we deleted the Cavβ3-encoding gene Cacnb3 in insulin-secreting rat β-(Ins-1) cells using CRISPR/Cas9. These cells were used as controls to investigate the role of Cavβ3 on Ca2+ signaling, glucose-induced insulin secretion (GIIS), Cav channel activity, and gene expression in wild-type cells in which Cavβ3 and the IP3 receptor were coimmunoprecipitated. Transcript and protein profiling revealed significantly increased levels of insulin transcription factor Mafa, CaMKIV, proprotein convertase subtilisin/kexin type-1, and nitric oxide synthase-1 in Cavβ3-knockout cells. In the absence of Cavβ3, Cav currents were not altered. In contrast, CREB activity, the amount of MAFA protein and GIIS, the extent of IP3-dependent Ca2+ release and the frequency of Ca2+ oscillations were increased. These processes were decreased by the Cavβ3 protein in a concentration-dependent manner. Our study shows that Cavβ3 interacts with the IP3 receptor in isolated β-cells, controls IP3-dependent Ca2+-signaling independently of Cav channel functions, and thereby regulates insulin expression and its glucose-dependent release in a cell-autonomous manner.

Dietary citrate acutely induces insulin resistance and markers of liver inflammation in mice

Citrate is widely used as a food additive being part of virtually all processed foods. Although considered inert by most of the regulatory agencies in the world, plasma citrate has been proposed to play immunometabolic functions in multiple tissues through altering a plethora of cellular pathways. Here, we used a short-term alimentary intervention (24 hours) with standard chow supplemented with citrate in amount corresponding to that found in processed foods to evaluate its effects on glucose homeostasis and liver physiology in C57BL/6J mice. Animals supplemented with dietary citrate showed glucose intolerance and insulin resistance as revealed by glucose and insulin tolerance tests. Moreover, animals supplemented with citrate in their food displayed fed and fasted hyperinsulinemia and enhanced insulin secretion during an oral glucose tolerance test. Citrate treatment also amplified glucose-induced insulin secretion in vitro in INS1-E cells. Citrate supplemented animals had increased liver PKCα activity and altered phosphorylation at serine or threonine residues of components of insulin signaling including IRS-1, Akt, GSK-3 and FoxO1. Furthermore, citrate supplementation enhanced the hepatic expression of lipogenic genes suggesting increased de novo lipogenesis, a finding that was reproduced after citrate treatment of hepatic FAO cells. Finally, liver inflammation markers were higher in citrate supplemented animals. Overall, the results demonstrate that dietary citrate supplementation in mice causes hyperinsulinemia and insulin resistance both in vivo and in vitro, and therefore call for a note of caution on the use of citrate as a food additive given its potential role in metabolic dysregulation.

Effects of different statins on glucose-induced CA2+ oscillations and oxygen consumption from pancreatic β-cells: Mechanisms and clinical implications

Background and Aims: Statins are effective for lipid lowering, but some studies have shown that statins increase risk for onset of type 2 diabetes (T2D). Previously we showed that simvastatin (25-200 nM) but not pitavastatin inhibited glucose-induced insulin secretion by decreasing b-cell insulin content while metabolic coupling to exocytosis remained intact. Simvastatin also increased intracellular Calcium oscillations at low glucose (1-4 mM) compared to pitavastatin-treated and control cells. Here we extend our previous studies to investigate whether simvastatin induces b-cell glucose hypersensitivity leading to increased Ca2+ activity.

Olive Oil Lipophenols Induce Insulin Secretion in 832/13 β-Cell Models.

Glycemic control is a mainstay of type 2 diabetes mellitus (T2DM) clinical management. Despite the continuous improvement in knowledge and progress in terms of treatment, the achievement of the physiologic metabolic profile is still an ongoing challenge in diabetic patients. Pancreatic β-cell line INS-1 832/13 was used to assess the insulin secretagogue activity of hydroxytyrosyl oleate (HtyOle) and tyrosyl oleate (TyOle), two naturally occurring lipophenols deriving from the conjugation of oleic acid (OA) and hydroxytyrosol (Hty) or tyrosol (Ty), respectively. The insulin secretion was determined under a glucose-induced insulin secretion (GSIS) condition by the ELISA method. The potential involvement of G-protein-coupled receptor 40 (GPR40), also known as free fatty acid receptor 1 (FFAR1), was investigated by both molecular docking and functional pharmacological approaches. Herein, we demonstrated that HtyOle and TyOle exerted a facilitatory activity on insulin secretion under the GSIS condition. Moreover, we provided evidence that both lipophenols are natural modulators of FFAR1 receptor. From our results, the anti-diabetes properties associated with olive oil consumption can be partly explained by the HtyOle and TyOle effects.

Novel insights into the genetically obese (ob/ob) and diabetic (db/db) mice: two sides of the same coin

BackgroundLeptin-deficient ob/ob mice and leptin receptor-deficient db/db mice are commonly used mice models mimicking the conditions of obesity and type 2 diabetes development. However, although ob/ob and db/db mice are similarly gaining weight and developing massive obesity, db/db mice are more diabetic than ob/ob mice. It remains still unclear why targeting the same pathway—leptin signaling—leads to the development of two different phenotypes. Given that gut microbes dialogue with the host via different metabolites (e.g., short-chain fatty acids) but also contribute to the regulation of bile acids metabolism, we investigated whether inflammatory markers, bacterial components, bile acids, short-chain fatty acids, and gut microbes could contribute to explain the specific phenotype discriminating the onset of an obese and/or a diabetic state in ob/ob and db/db mice.ResultsSix-week-old ob/ob and db/db mice were followed for 7 weeks; they had comparable body weight, fat mass, and lean mass gain, confirming their severely obese status. However, as expected, the glucose metabolism and the glucose-induced insulin secretion were significantly different between ob/ob and db/db mice. Strikingly, the fat distribution was different, with db/db mice having more subcutaneous and ob/ob mice having more epididymal fat. In addition, liver steatosis was more pronounced in the ob/ob mice than in db/db mice. We also found very distinct inflammatory profiles between ob/ob and db/db mice, with a more pronounced inflammatory tone in the liver for ob/ob mice as compared to a higher inflammatory tone in the (subcutaneous) adipose tissue for db/db mice. When analyzing the gut microbiota composition, we found that the quantity of 19 microbial taxa was in some way affected by the genotype. Furthermore, we also show that serum LPS concentration, hepatic bile acid content, and cecal short-chain fatty acid profiles were differently affected by the two genotypes.ConclusionTaken together, our results elucidate potential mechanisms implicated in the development of an obese or a diabetic state in two genetic models characterized by an altered leptin signaling. We propose that these differences could be linked to specific inflammatory tones, serum LPS concentration, bile acid metabolism, short-chain fatty acid profile, and gut microbiota composition.DUGQcxDcUnuc9Bgg7Th-A2Video abstract.

Gsα-dependent signaling is required for postnatal establishment of a functional β-cell mass

ObjectiveEarly postnatal life is a critical period for the establishment of the functional β-cell mass that will sustain whole-body glucose homeostasis during the lifetime. β cells are formed from progenitors during embryonic development but undergo significant expansion in quantity and attain functional maturity after birth. The signals and pathways involved in these processes are not fully elucidated. Cyclic adenosine monophosphate (cAMP) is an intracellular signaling molecule that is known to regulate insulin secretion, gene expression, proliferation, and survival of adult β cells. The heterotrimeric G protein Gs stimulates the cAMP-dependent pathway by activating adenylyl cyclase. In this study, we sought to explore the role of Gs-dependent signaling in postnatal β-cell development. MethodsTo study Gs-dependent signaling, we generated conditional knockout mice in which the α subunit of the Gs protein (Gsα) was ablated from β-cells using the Cre deleter line Ins1Cre. Mice were characterized in terms of glucose homeostasis, including in vivo glucose tolerance, glucose-induced insulin secretion, and insulin sensitivity. β-cell mass was studied using histomorphometric analysis and optical projection tomography. β-cell proliferation was studied by ki67 and phospho-histone H3 immunostatining, and apoptosis was assessed by TUNEL assay. Gene expression was determined in isolated islets and sorted β cells by qPCR. Intracellular cAMP was studied in isolated islets using HTRF-based technology. The activation status of the cAMP and insulin-signaling pathways was determined by immunoblot analysis of the relevant components of these pathways in isolated islets. In vitro proliferation of dissociated islet cells was assessed by BrdU incorporation. ResultsElimination of Gsα in β cells led to reduced β-cell mass, deficient insulin secretion, and severe glucose intolerance. These defects were evident by weaning and were associated with decreased proliferation and inadequate expression of key β-cell identity and maturation genes in postnatal β-cells. Additionally, loss of Gsα caused a broad multilevel disruption of the insulin transduction pathway that resulted in the specific abrogation of the islet proliferative response to insulin. ConclusionWe conclude that Gsα is required for β-cell growth and maturation in the early postnatal stage and propose that this is partly mediated via its crosstalk with insulin signaling. Our findings disclose a tight connection between these two pathways in postnatal β cells, which may have implications for using cAMP-raising agents to promote β-cell regeneration and maturation in diabetes.

1150-P: A Hyperhomocysteinemia-Inducing Diet Alters Gut Microbiome and Glucose Homeostasis

Hyperhomocysteinemia (HHcy) is a risk factor for higher mortality in type 2 diabetic patients. A high methionine low folate (HMLF) diet chronically induces HHcy by causing homocysteine (Hcy) accumulation in systemic circulation. A higher systemic Hcy level is clinically associated with the incidence of diabetes mellitus. However, whether HHcy negatively impacts on glucose metabolism and insulin sensitivity remains inconclusive and contradictory. Meanwhile, very few studies have focused on the direct impact of HMLF diet on glucose homeostasis, and that on the gut flora. To understand the impact of HMLF diet, C57BL/6 mice were fed a HMLF diet for 8 consecutive weeks. HMLF diet feeding successfully induced HHcy, caused progressive body weight loss, and slightly impaired glucose homeostasis, as revealed by slight glucose intolerance and insulin resistance, in C57BL/6 mice. Of noted, HMLF diet feeding altered the gut microbiome profile that the relative abundance of porphyromonadaceae family of bacteria was enriched in diet-induced HHcy mice. Interestingly, a previous study correlated the higher frequency of porphyromonadaceae with the development of GLP-1 resistance, implying that HMLF diet might prompt the development of GLP-1 resistance. GLP-1 resistance results in the impairment on glucose-induced insulin secretion. These results provide novel insights into the roles of impaired glucose homeostasis and gut microbiome in the pathogenesis of HHcy-related complications. In short, an improper dietary pattern might impair glucose homeostasis by altering the gut microbiome profile. Disclosure C. Cheng: None. C. Wang: None. Y. Huang: None. Funding Chinese University of Hong Kong (4930709); Hong Kong Research Grants Council Senior Research Fellow Scheme 2020/21 (SRFS2021-4S04)

A radioligand receptor binding assay for measuring of insulin secreted by MIN6 cells after stimulation with glucose, arginine, ornithine, dopamine, and serotonin.

We adapted a radioligand receptor binding assay for measuring insulin levels in unknown samples. The assay enables rapid and accurate determination of insulin concentrations in experimental samples, such as from insulin-secreting cells. The principle of the method is based on the binding competition of insulin in a measured sample with a radiolabeled insulin for insulin receptor (IR) in IM-9 cells. Both key components, radiolabeled insulin and IM-9 cells, are commercially available. The IR binding assay was used to determine unknown amounts of insulin secreted by MIN6 β cell line after stimulation with glucose, arginine, ornithine, dopamine, and serotonin. The experimental data obtained by the IR binding assay were compared to the results determined by RIA kits and both methods showed a very good agreement of results. We observed the stimulation of glucose-induced insulin secretion from MIN6 cells by arginine, weaker stimulation by ornithine, but inhibitory effects of dopamine. Serotonin effects were either stimulatory or inhibitory, depending on the concentration of serotonin used. The results will require further investigation. The study also clearly revealed advantages of the IR binding assay that allows the measuring of a higher throughput of measured samples, with a broader range of concentrations than in the case of RIA kits. The IR binding assay can provide an alternative to standard RIA and ELISA assays for the determination of insulin levels in experimental samples and can be especially useful in scientific laboratories studying insulin production and secretion by β cells and searching for new modulators of insulin secretion.

Isoprenoid Derivatives of Lysophosphatidylcholines Enhance Insulin and GLP-1 Secretion through Lipid-Binding GPCRs.

Insulin plays a significant role in carbohydrate homeostasis as the blood glucose lowering hormone. Glucose-induced insulin secretion (GSIS) is augmented by glucagon-like peptide (GLP-1), a gastrointestinal peptide released in response to ingesting nutriments. The secretion of insulin and GLP-1 is mediated by the binding of nutrients to G protein-coupled receptors (GPCRs) expressed by pancreatic β-cells and enteroendocrine cells, respectively. Therefore, insulin secretagogues and incretin mimetics currently serve as antidiabetic treatments. This study demonstrates the potency of synthetic isoprenoid derivatives of lysophosphatidylcholines (LPCs) to stimulate GSIS and GLP-1 release. Murine insulinoma cell line (MIN6) and enteroendocrinal L cells (GLUTag) were incubated with LPCs bearing geranic acid (1-GA-LPC), citronellic acid (1-CA-LPC), 3,7-dimethyl-3-vinyloct-6-enoic acid (GERA-LPC), and (E)-3,7,11-trimethyl- 3-vinyldodeca-6,10-dienoic acid (1-FARA-LPC). Respective free terpene acids were also tested for comparison. Besides their insulin- and GLP-1-secreting capabilities, we also investigated the cytotoxicity of tested compounds, the ability to intracellular calcium ion mobilization, and targeted GPCRs involved in maintaining lipid and carbohydrate homeostasis. We observed the high cytotoxicity of 1-GERA-LPC and 1-FARA-LPC in contrast 1-CA-LPC and 1-GA-LPC. Moreover, 1-CA-LPC and 1-GA-LPC demonstrated the stimulatory effect on GSIS and 1-CA-LPC augmented GLP-1 secretion. Insulin and GLP-1 release appeared to be GPR40-, GPR55-, GPR119- and GPR120-dependent.

Offspring of Obese Dams Exhibit Sex-Differences in Pancreatic Heparan Sulfate Glycosaminoglycans and Islet Insulin Secretion.

Offspring of obese mothers suffer higher risks of type 2 diabetes due to increased adiposity and decreased β cell function. To date, the sex-differences in offspring islet insulin secretion during early life has not been evaluated extensively, particularly prior to weaning at postnatal day 21 (P21). To determine the role of maternal obesity on offspring islet insulin secretion, C57BL/6J female dams were fed chow or western diet from 4 weeks prior to mating to induce maternal obesity. First, offspring of chow-fed and obese dams were evaluated on postnatal day 21 (P21) prior to weaning for body composition, glucose and insulin tolerance, and islet phasic insulin-secretion. Compared to same-sex controls, both male and female P21 offspring born to obese dams (MatOb) had higher body adiposity and exhibited sex-specific differences in glucose tolerance and insulin secretion. The male MatOb offspring developed the highest extent of glucose intolerance and lowest glucose-induced insulin secretion. In contrast, P21 female offspring of obese dams had unimpaired insulin secretion. Using SAX-HPLC, we found that male MatOb had a decrease in pancreatic heparan sulfate glycosaminoglycan, which is a macromolecule critical for islet health. Notably, 8-weeks-old offspring of obese dams continued to exhibit a similar pattern of sex-differences in glucose intolerance and decreased islet insulin secretion. Overall, our study suggests that maternal obesity induces sex-specific changes to pancreatic HSG in offspring and a lasting effect on offspring insulin secretion, leading to the sex-differences in glucose intolerance.

Deconstructing the origins of sexual dimorphism in sensory modulation of pancreatic β cells

The regulation of glucose-stimulated insulin secretion and glucose excursion has a sensory component that operates in a sex-dependent manner. ObjectiveHere, we aim to dissect the basis of the sexually dimorphic interaction between sensory neurons and pancreatic β cells and its overall impact on insulin release and glucose homeostasis. MethodsWe used viral retrograde tracing techniques, surgical and chemodenervation models, and primary cell-based co-culture systems to uncover the biology underlying sex differences in sensory modulation of pancreatic β-cell activity. ResultsRetrograde transsynaptic labeling revealed a sex difference in the density of sensory innervation in the pancreas. The number of sensory neurons emanating from the dorsal root and nodose ganglia that project in the pancreas is higher in male than in female mice. Immunostaining and confocal laser scanning microscopy confirmed the higher abundance of peri-islet sensory axonal tracts in the male pancreas. Capsaicin-induced sensory chemodenervation concomitantly enhanced glucose-stimulated insulin secretion and glucose clearance in male mice. These metabolic benefits were blunted when mice were orchidectomized prior to the ablation of sensory nerves. Interestingly, orchidectomy also lowered the density of peri-islet sensory neurons. In female mice, capsaicin treatment did not affect glucose-induced insulin secretion nor glucose excursion and ovariectomy did not modify these outcomes. Interestingly, same- and opposite-sex sensory-islet co-culture paradigms unmasked the existence of potential gonadal hormone-independent mechanisms mediating the male-female difference in sensory modulation of islet β-cell activity. ConclusionTaken together, these data suggest that the sex-biased nature of the sensory control of islet β-cell activity is a result of a combination of neurodevelopmental inputs, sex hormone-dependent mechanisms and the potential action of somatic molecules encoded by the sex chromosome complement.

Paternal High-Protein Diet Programs Offspring Insulin Sensitivity in a Sex-Specific Manner

The impact of maternal nutrition on offspring is well documented. However, the implication of pre-conceptional paternal nutrition on the metabolic health of the progeny remains underexplored. Here, we investigated the impact of paternal high-protein diet (HPD, 43.2% protein) consumption on the endocrine pancreas and the metabolic phenotype of offspring. Male Wistar rats were given HPD or standard diet (SD, 18.9% protein) for two months. The progenies (F1) were studied at fetal stage and in adulthood. Body weight, glycemia, glucose tolerance (GT), glucose-induced insulin secretion in vivo (GIIS) and whole-body insulin sensitivity were assessed in male and female F1 offspring. Insulin sensitivity, GT and GIIS were similar between F1 females from HPD (HPD/F1) and SD fathers (SD/F1). Conversely, male HPD/F1 exhibited increased insulin sensitivity (p < 0.05) and decreased GIIS (p < 0.05) compared to male SD/F1. The improvement of insulin sensitivity in HPD/F1 was sustained even after 2 months of high-fat feeding. In male HPD/F1, the β cell mass was preserved and the β cell plasticity, following metabolic challenge, was enhanced compared to SD/F1. In conclusion, we provide the first evidence of a sex-specific impact of paternal HPD on the insulin sensitivity and GIIS of their descendants, demonstrating that changes in paternal nutrition alter the metabolic status of their progeny in adulthood.

Effects of xenin-25 on insulin and glucagon secretions in healthy conscious sheep

The aim of present study was to determine effect of an intravenous injection of xenin-25 on insulin and glucagon secretion in healthy conscious sheep. After feeding once at 17:00, the experiment was started from 9:00 on the next day. Xenin-25 was intravenously (i.v.) injected at a dose of 100 to 1000 pmol/kg with and without the simultaneous injection of glucose at a dose of 200 μmol/kg, and blood was withdrawn before and after the injections. A single xenin-25 injection at 100 and 300 pmol/kg significantly increased the plasma insulin concentration, whereas the 1000 pmol/kg dose did not elicit significantly enhanced insulin response. Plasma glucose and glucagon concentrations did not significantly change after a single xenin-25 injection. Xenin-25 injection significantly and dose-dependently augmented the glucose-induced insulin secretion. However, the changes in the plasma glucose and glucagon level after the glucose injection were not altered by xenin injection. A prior intravenous injection of the neurotensin receptor subtype-1 (NTR-1) antagonist SR 48692 at 100 nmol/kg did not modify the glucose-induced change in plasma insulin caused by xenin-25 at 300 pmol/kg, and intravenous injection of the NTR-2 agonist levocabastine at 1000 pmol/kg did not augment the insulin response to the glucose injection. On the other hand, no xenin-25 immunopositive cells were detected in the ovine pancreas. The mRNAs of the three NTR subtypes were highly expressed in the ovine pancreas in comparison with the expression in the abomasum. These results suggest that xenin-25 released from the upper gastrointestinal tract plays a role of an insulinotropic factor in sheep, possibly through NTRs in the pancreatic islets, but not via NTR-2.