Inhibition Of Insulin Release Research Articles

Epinephrine also acts on beta cells and insulin secretion.

In a recent review examining neurotransmitter modulation of insulin secretion, the significant impact of epinephrine was not addressed. Its primary action involves inhibiting insulin release via alpha-adrenergic receptors, thereby reducing the response to insulin secretion stimulators, through the activation of K+ channels and resulting in membrane hyperpolarization in beta cells.

Insulin Resistance Develops Due to an Imbalance in the Synthesis of Cyclic AMP and the Natural Cyclic AMP Antagonist Prostaglandylinositol Cyclic Phosphate (Cyclic PIP)

The reasons initiating insulin resistance are not identified. Various metabolic derailments have been characterized. These are the outcome and not the initiation of insulin resistance. In animal models of type 2 diabetes and hypertension, a decreased hormonal stimulation of the synthesis of the cyclic AMP antagonist prostaglandylinositol cyclic phosphate (cyclic PIP) was determined. The resultant imbalance of the action of cyclic AMP and cyclic PIP shifts metabolic regulation to the dominance of catabolism and a decrease in imperative anabolism. This dominance develops gradually since the more cyclic AMP dominates, the more the synthesis of cyclic PIP will be inhibited. Vanishing actions of cyclic PIP are its 10-fold activation of glucose uptake in adipocytes, its inhibition of insulin release from pancreatic β-cells, its inhibition of PKA and its 7-fold activation of protein ser/thr phosphatase. Reduced synthesis of cyclic PIP results from (a) decreased substrate availability, (b) long-time elevated cyclic AMP levels resulting from stress overloads and (c) aging and the gradual decrease in the synthesis of hormones which likely maintain mechanisms that stimulate cyclic PIP synthesis. The need is to discover which hormones, such as growth hormone, insulin-like growth factor-1, dehydroepiandrosterone, and testosterone, are involved in maintaining the stimulation of cyclic PIP synthesis.

A metabolic role for CD47 in pancreatic β cell insulin secretion and islet transplant outcomes.

Diabetes is a global public health burden and is characterized clinically by relative or absolute insulin deficiency. Therapeutic agents that stimulate insulin secretion and improve insulin sensitivity are in high demand as treatment options. CD47 is a cell surface glycoprotein implicated in multiple cellular functions including recognition of self, angiogenesis, and nitric oxide signaling; however, its role in the regulation of insulin secretion remains unknown. Here, we demonstrate that CD47 receptor signaling inhibits insulin release from human as well as mouse pancreatic β cells and that it can be pharmacologically exploited to boost insulin secretion in both models. CD47 depletion stimulated insulin granule exocytosis via activation of the Rho GTPase Cdc42 in β cells and improved glucose clearance and insulin sensitivity in vivo. CD47 blockade enhanced syngeneic islet transplantation efficiency and expedited the return to euglycemia in streptozotocin-induced diabetic mice. Further, anti-CD47 antibody treatment delayed the onset of diabetes in nonobese diabetic (NOD) mice and protected them from overt diabetes. Our findings identify CD47 as a regulator of insulin secretion, and its manipulation in β cells offers a therapeutic opportunity for diabetes and islet transplantation by correcting insulin deficiency.

Oral Delivery of Insulin from Trimethyl Chitosan/Tragacanth: In Vitro, MTT, and In Vivo Bioactivity Tests

: Insulin-loaded Trimethyl Chitosan (TMC)/tragacanth microspheres were prepared by microemulsion dispersion and triggered in situ gelation. Microspheres were characterized by their mean size and distribution by laser diffraction spectroscopy and Brunauer-Emmet-Teller theory. Insulin encapsulation efficiency and in vitro release were determined by Bradford protein assay, and bioactivity was assessed in vitro using an enzyme-linked immunoassay diagnostic kit and in vivo using Wistar diabetic rats. TMC/tragacanth particles suppressed insulin release in acidic media and promoted a sustained release at near-neutral conditions. Micro-capsulated insulin was bioactive, demonstrated by both in vivo and in vitro bioassays.

Research Advancements on Fluorinated and Non-Fluorinated 4- Phenyl(thio)ureido-Substituted 2,2-Dimethylchromans Acting as Inhibitors of Insulin Release and Smooth Muscle Relaxants.

The present study aimed at characterizing the impact of the presence or absence of fluorine atoms on the phenyl and benzopyran rings of 4-phenyl(thio)ureido-substituted 2,2- dimethylchromans on their ability to inhibit insulin release from pancreatic β-cells or to relax vascular smooth muscle cells. Most compounds were found to inhibit insulin secretion and to provoke a marked myorelaxant activity. The lack of a fluorine or chlorine atom at the 6-position of the 2,2-dimethylchroman core structure reduced the inhibitory activity on the pancreatic endocrine tissue. One of the most active compounds on both tissues, compound 11h (BPDZ 678), was selected for further pharmacological investigations. The biological data suggested that 11h mainly expressed the profile of a KATP channel opener on pancreatic β-cells, although a calcium entry blockade effect was also observed. On vascular smooth muscle cells, 11h behaved as a calcium entry blocker.

A pancreatic pause in breast cancer.

Breast cancer-derived extracellular vesicles suppress insulin release to increase systemic glucose availability.

Meeting abstracts from the 15th international conference on neonatal and childhood pulmonary vascular disease

Meeting abstracts from the 15th international conference on neonatal and childhood pulmonary vascular disease

Identification SNP rs5219 KCNJ11 gene and blood glucose levels in type 2 diabetes mellitus patients at Moewardi Hospital Surakarta

Diabetes Mellitus (DM) is a metabolic disease that developed due to the pancreas does not sufficient to produce insulin or the body cannot effectively use the insulin it produces. Genetic factors have an essential role in the development of Type 2 Diabetes Mellitus (DMT2), which impaired insulin production by pancreatic β cells, insulin resistance, and action. The single nucleotide polymorphisms (SNP) in the KCNJ11 rs5219 affected the pancreatic β cell activity that can inhibit insulin release, thus causing a decrease in therapeutic effectiveness. The purpose of this study is to identify the SNP rs5219 of the KCNJ11 gene and measure patient blood sugar levels as the outcome of therapy. A cross-sectional study was conducted prospectively at Moewardi Hospital, Surakarta, involving 10 patients with DMT2 who received sulfonylureas therapy. DNA was isolated from the whole blood sample of DMT2 patients. PCR amplification was performed to amplify the KCNJ11 gene, and followed by PCR sequencing. The 2-H PP, FPG , and HbA1c parameters were measured as therapeutic outcomes. The results showed that the genotype frequencies (AA-AG-GG) were 10%, 50% , and 40%, while the allele frequency (A-G) in the sample was 35% and 65%. The uncontrolled values for 2H-PP on genotype (AA and AG + GG) were 10% and 20%; uncontrolled FPG on genotypes AA and AG + GG were 10% and 40%; and uncontrolled HbA1c on genotype AA and AG + GG were 10% and 80%. This study conclusion is the presence of the SNP rs5219 KCNJ11 gene with A>G base change in DMT2 patients who received sulfonylurea therapy.

Ghrelin cell-expressed insulin receptors mediate meal- and obesity-induced declines in plasma ghrelin.

Mechanisms underlying postprandial and obesity-associated plasma ghrelin reductions are incompletely understood. Here, using ghrelin cell–selective insulin receptor–KO (GhIRKO) mice, we tested the impact of insulin, acting via ghrelin cell–expressed insulin receptors (IRs), to suppress ghrelin secretion. Insulin reduced ghrelin secretion from cultured gastric mucosal cells of control mice but not from those of GhIRKO mice. Acute insulin challenge and insulin infusion during both hyperinsulinemic-hypoglycemic clamps and hyperinsulinemic-euglycemic clamps lowered plasma ghrelin in control mice but not GhIRKO mice. Thus, ghrelin cell–expressed IRs are required for insulin-mediated reductions in plasma ghrelin. Furthermore, interventions that naturally raise insulin (glucose gavage, refeeding following fasting, and chronic high-fat diet) also lowered plasma ghrelin only in control mice — not GhIRKO mice. Thus, meal- and obesity-associated increases in insulin, acting via ghrelin cell–expressed IRs, represent a major, direct negative modulator of ghrelin secretion in vivo, as opposed to ingested or metabolized macronutrients. Refed GhIRKO mice exhibited reduced plasma insulin, highlighting ghrelin’s actions to inhibit insulin release via a feedback loop. Moreover, GhIRKO mice required reduced glucose infusion rates during hyperinsulinemic-hypoglycemic clamps, suggesting that suppressed ghrelin release resulting from direct insulin action on ghrelin cells usually limits ghrelin’s full potential to protect against insulin-induced hypoglycemia.

Tacrolimus inhibits insulin release and promotes apoptosis of Min6 cells through the inhibition of the PI3K/Akt/mTOR pathway.

As a calcineurin inhibitor, tacrolimus is commonly used as a first‑line immunosuppressant in organ transplant recipients. Post‑transplantation diabetes mellitus (PTDM) is a common complication following kidney transplantation and is associated with immunosuppressant drugs, such as tacrolimus. PTDM caused by tacrolimus may be related to its influence on insulin secretion and insulin resistance. However, the specific mechanism has not been fully elucidated. The aim of the present study was to investigate whether the PI3K/Akt/mTOR signaling pathway served an important role in the pathogenesis of PTDM induced by tacrolimus. In the present study, the Cell Counting Kit‑8 assay was used to measure the effect of tacrolimus on the viability of Min6 mouse insulinoma cells. The effects of tacrolimus on the insulin secretion and the activity of caspase‑3 of Min6 cells stimulated by glucose exposure were measured by ELISA. Superoxide dismutase (SOD) and malondialdehyde(MDA) levels were measured using WST‑8 and thiobarbituric acid assays, respectively. The effects of tacrolimus on the mRNA expression levels of PI3K, Akt and mTOR were detected by reverse transcription‑quantitative PCR (RT‑qPCR), whereas the protein expression levels of PI3K, Akt, mTOR, phosphorylated (p)‑AKT and p‑mTOR in Min6 cells were assessed using western blotting. The present data indicated that, compared with the control group, 5, 25and50ng/ml tacrolimus treatment could inhibit the insulin secretion of Min6 cells stimulated by glucose solution, and 50ng/ml tacrolimus could notably decrease the stimulation index (P<0.05). Moreover, 50ng/ml tacrolimus markedly increased the activity of caspase‑3 by 175.1% (P<0.05), it also decreased the SOD activity (P<0.01) and increased MDA levels (P<0.05). The RT‑qPCR results demonstrated that the mRNA expression levels of PI3K, Akt and mTOR were downregulated by 25and50ng/ml tacrolimus (P<0.01). Furthermore, the western blotting results suggested that tacrolimus had no significant effects on the expression levels of total PI3K, Akt and mTOR proteins (P>0.05), but 25and50ng/ml tacrolimus could significantly inhibit the expression levels of p‑Akt and p‑mTOR (P<0.01). In conclusion, tacrolimus decreased the activity and insulin secretion of pancreatic β cells and induced the apoptosis of islet β cells by inhibiting the mRNA expression levels of PI3K, Akt and mTOR and reducing the phosphorylation of Akt and mTOR proteins in the PI3K/Akt/mTOR signaling pathway, which may ultimately lead to the occurrence of diabetes mellitus, and may be considered as one of the specific mechanisms of PTDM caused by tacrolimus.

Diabetic Ketoacidosis and Dysregulation of Proglucagon Family of Molecules

ObjectivesAn increasing body of evidence supports a significant contributory role for pancreatic α-cell dysfunction in the pathophysiology of diabetic ketoacidosis (DKA). In normal physiology, high glucose levels stimulate insulin and inhibit glucagon secretion, while low glucose stimulates glucagon but inhibits insulin release. This regulatory mechanism is progressively lost in diabetes mellitus (DM), where diminished insulin levels are accompanied by hyperglucagonemia leading to the further aggravation of hyperglycemia caused by insulin deficiency. Glucagon is produced via the posttranslational modification of proglucagon in a process that also produces other proglucagon molecules including major proglucagon fragment (MPGF) and glucagon like peptide-1 (GLP-1). Here we hypothesized that DKA is associated with α-cell dysfunction leading to elevated levels of proglucagon molecules. MethodsWe measured levels of glucagon, GLP-1 and MPGF as indices of glucagon synthesis/α-cell function in the plasma of patients with DKA and in healthy controls. The inclusion criteria for DKA patients were glucose > 250 mg/dL, pH < 7.2, bicarbonate < 15mEq/L, presence of ketones and patients were part of a larger randomized trial. Samples were obtained at baseline prior to trial interventions. An independent sample t-test was used to compare differences. ResultsWe analyzed samples of 25 healthy controls and 59 individuals with DKA (47 T1DM and 12 T2DM) and found significant increase in glucagon levels in all of the DKA groups (controls 47 pg/mL (36, 67), T1DM 63 (40,135), T2DM 84 (61,105), p = 0.013). The differences were significant in MPGF too (controls 0.5 ng/mL (0.4, 0.8), T1DM 1.1 (0.7, 1.9), T2DM 1.3 (0.9, 2.0), p < 0.001), while differences in GLP-1 between groups did not reach statistical significance. C-peptide levels were significantly diminished in DKA and the levels of glucagon and C-peptide were strongly associated in healthy controls but not in DKA. ConclusionsOur data indicate that proglucagon family molecules may be actively contributing to the pathogenesis of DKA and may represent a potential site for future therapeutic interventions. Funding SourcesThe parental study of “Thiamine as adjunctive therapy for diabetic ketoacidosis” was supported through a grant from the National Institute of Health.

Continuous Glucose Monitoring Facilitates Diazoxide Use in the Management of Glut1 Deficiency Syndrome

Abstract Background: Glut1 deficiency syndrome (Glut1DS) is caused by mutations in SLC2A1 on chromosome 1p34.2, which impairs transmembrane glucose transport across the blood brain barrier resulting in hypoglycorrhachia and decreased glucose availability for brain metabolism. This causes a drug-resistant, metabolic epilepsy due to energy deficiency. Standard treatment for Glut1DS is the ketogenic diet (KD) but treatment options are limited if patients fail the KD. Diazoxide, which inhibits insulin release, was used sparingly in the past for a few Glut1DS patients to increase blood glucose levels and thus intracerebral glucose levels. Unfortunately, their treatment was complicated by unacceptable persistent hyperglycemia with blood glucoses in the 300s to 500s. We investigated the use of a continuous glucose monitor (CGM) to enable titration of diazoxide therapy in a patient with KD-resistant Glut1DS. Clinical Case: A 14-year-old girl with Glut1DS (c.398_399delGCinsTT:p.Lys133Phe) failed the KD due to severe nausea, vomiting, abdominal pain, and hypertriglyceridemia. Laboratory tests revealed CSF glucose of 36 mg/dL when blood glucose was 93 mg/dL. Over the course of 3 hospitalizations targeting blood glucose levels in the range of 120-180 mg/dL with diazoxide, EEG seizure activity decreased from 3 to 0 absence seizures per hour. CGM placement during the third hospitalization showed an average interstitial glucose of 157 mg/dL with glucose variability of 20.8% on diazoxide dose of 7.3 mg/kg/day. After discharge, CGM has been used to adjust diazoxide doses 2-4 times a week to achieve target interstitial glucoses of 140-180 mg/dL. Repeat laboratory tests revealed CSF glucose of 55 mg/dL when interstitial glucose was 158 mg/dL. Current diazoxide dose is 7.9 mg/kg/day and most recent hemoglobin A1c was 5.4%. Conclusions: This is the first report demonstrating CGM as a tool facilitating the safe initiation and real-time titration of diazoxide in Glut1DS patients who have failed the KD. Diazoxide addresses neuroglycopenia more physiologically by raising blood glucose levels and subsequently intracerebral glucose levels. CGM allows for more accurate titration of blood glucose with diazoxide while avoiding complications of hyperglycemia and thus introduces the possibility of diazoxide becoming a standard of care for Glut1DS. More broadly, CGM provides a valuable tool for the management of other disorders of glucose transport and carbohydrate metabolism.

Hyperglycemia With Use of Vagal Nerve Stimulator

Abstract Introduction: In patient with diabetes and refractory epilepsy requiring vagal nerve stimulator (VNS), glycemic management can be challenging. Clinical experience is limited in this scenario. Case Report: A 67-year-old male, BMI 30 kg/m2, with history of type 2 diabetes and hemispheric hemangioma complicated by seizure disorder is referred to our diabetes clinic for evaluation of persistent hyperglycemia. The patient reports 25-year history of seizures that have been difficult to control with antiepileptic drugs alone and eventually requiring VNS placement. Patient has normal kidney (eGFR &amp;gt; 60mL/min) and liver function. His antiepileptic drug regimen consisted of gabapentin and as needed lorazepam. He was never on glucocorticoids. Glycated hemoglobin (HgA1c) at our initial evaluation was 10.1%. His anti-glycemic regimen consisted of glipizide monotherapy. Fasting and pre-prandial blood glucose were in the 200-400mg/dL range with occasional values higher than 500mg/dL. This was confirmed with 14-day continuous glucose monitoring that showed average blood glucose of 287mg/dL with 100 percent above target (higher than 180 mg/dL). We optimized therapy by adding once daily glargine, pioglitazone and continued glipizide. At follow up visit, HgA1c still remained high at 10.5%, despite medication adherence. Patient emphasized that hyperglycemia was related to VNS use and given documented hyperglycemia with blood glucose range 500–600 mg/dL when on higher output current of 2 milliamps, his neurologist approved a trial off VNS for 4 weeks. His glucose improved to average less than 200 mg/dL and HgA1c decreased to 9.1% on the same anti-glycemic regimen. Device was re-started due to recurrence of seizures, however the output current and “on time” were reduced to minimal effective range for optimizing seizure therapy while avoiding hyperglycemia. Subsequent HgA1C improved to 8.7%. Discussion: VNS is a FDA approved device for epilepsy and depression. It works by intermittent stimulation or “on/off” periods. In animal studies, elevation of blood glucose was noted with afferent stimulation. Conversely, efferent activation lowers blood glucose. There are limited human studies on the effects of vagal nerve stimulation on glycemic control. The few available, showed variation in blood glucose based on output current and length of on/off period. This should be factored in during glycemic evaluation and management and close collaboration with neurology is essential. Reference: (1) Strauss H, et al. Cervical Vagal Nerve Stimulation Impairs Glucose Tolerance and Suppresses Insulin Release in Conscious Rats. Physiological Reports 2018; 6(24): 1–9 (2) Strauss H, et al. Effect of Vagus Nerve Stimulation on Blood Glucose Concentration in Epilepsy Patients - Importance of Stimulation Parameters. Physiological Reports 2019; 7(14): 1–10

Diabetes and sleep

Sleep has often been thought of as a “restorative” process for the mind and the body; however, it has been shown that it also directly affects many metabolic and hormonal processes. Sleep which is a key factor in physiological restitution also modulates the metabolic, endocrine, and cardiovascular systems and thus has medical implications which include decreased glucose tolerance and insulin sensitivity. Reduction in the time available for sleep is a hallmark of modern society which has developed during the past few decades with increase in the time available for work and leisure, often viewed as harmless and efficient. In normal, healthy individuals, glucose tolerance varies across the day, with total sleep loss or even a 2-h reduction of sleep/night for 1 week there is increased levels of proinflammatory cytokines and low grade inflammation, a condition known to predispose to insulin resistance and diabetes. Sleep deprivation is associated with disturbances in the secretion of the counter regulatory hormones such as growth hormone and cortisol. Elevated evening cortisol levels can lead to morning insulin resistance, while the sympathetic nervous system inhibits insulin release while the parasympathetic system stimulates it, thus leading to elevated glucose levels. Adults are sleeping less and less in our society. Yet sleep is no longer thought of as strictly a restorative process for the body. The importance of sleep for metabolic function and specifically glucose homeostasis is now widely accepted, as many studies have shown a correlation between sleep deprivation or poor sleep quality and an increased risk of diabetes.

Metabolic Acidosis and its Predisposing Factor: Euglycemic Ketoacidosis Caused by Empagliflozin and Low-Carbohydrate Ketogenic Diet in Type 2 Diabetes Mellitus. Case Report

Sodium-glucose co-transporter-2 inhibitors (SGLT2i) are medications used in type 2 diabetes mellitus (T2DM) that control high blood sugar levels and promote normoglycemia by preventing glucose reabsorption and facilitating glucosuria. Three SGLT2i (canagliflozin, dapagliflozin, and empagliflozin) are approved in the United States. Euglycemic ketoacidosis or ketoacidosis with a lower than expected hyperglycemia is a rare adverse event associated with SGLT2i. Low-carbohydrate ketogenic diet (LCKD) may lower the threshold for the development of SGLT2i-induced ketoacidosis in T2DM. We report a rare case of diabetic ketoacidosis in a type 2 diabetic patient with a blood glucose level of 159 mg/dl in the presence of empagliflozin and LCKD. He had recently started eating a LCKD. He presented with the nonspecific complaints of fatigue, headache, nausea, abdominal pain, and chest discomfort. He had run out of his anti-diabetic medications and started retaking them a week ago. Labs showed metabolic acidosis with ketonuria and glucosuria. His presentation was attributed to the reintroduction of empagliflozin in the presence of a LCKD. SGLT2i put patients at risk of euglycemic ketoacidosis in T2DM due to glucosuria, euglycemia, and suppressed insulin release. Lifestyle changes, such as LCKD, may lower the threshold further due to excessive lipolysis, beta-oxidation, and hepatic ketogenesis. Practitioners should educate patients about this adverse effect. Patients should consult with their physicians before incorporating a LCKD in their lifestyle if they are using SGLT2i.

The Insulinostatic Effect of Ghrelin Requires MRAP2 Expression in δ Cells

SummaryGhrelin regulates both energy intake and glucose homeostasis. In the endocrine pancreas, ghrelin inhibits insulin release to prevent hypoglycemia during fasting. The mechanism through which this is accomplished is unclear, but recent studies suggest that ghrelin acts on δ cells to stimulate somatostatin release, which in turn inhibits insulin release from β cells. Recently, the Melanocortin Receptor Accessory Protein 2 (MRAP2) was identified as an essential partner of the ghrelin receptor (GHSR1a) in mediating the central orexigenic action of ghrelin. In this study we show that MRAP2 is expressed in islet δ cells and is required for ghrelin to elicit a calcium response in those cells. Additionally, we show that both global and δ cell targeted deletion of MRAP2 abrogates the insulinostatic effect of ghrelin. Together, these findings establish that ghrelin signaling within δ cells is essential for the inhibition of insulin release and identify MRAP2 as a regulator of insulin secretion.

Physiological Effect of Ghrelin on Body Systems.

Ghrelin is a relatively novel multifaceted hormone that has been found to exert a plethora of physiological effects. In this review, we found/confirmed that ghrelin has effect on all body systems. It induces appetite; promotes the use of carbohydrates as a source of fuel while sparing fat; inhibits lipid oxidation and promotes lipogenesis; stimulates the gastric acid secretion and motility; improves cardiac performance; decreases blood pressure; and protects the kidneys, heart, and brain. Ghrelin is important for learning, memory, cognition, reward, sleep, taste sensation, olfaction, and sniffing. It has sympatholytic, analgesic, antimicrobial, antifibrotic, and osteogenic effects. Moreover, ghrelin makes the skeletal muscle more excitable and stimulates its regeneration following injury; delays puberty; promotes fetal lung development; decreases thyroid hormone and testosterone; stimulates release of growth hormone, prolactin, glucagon, adrenocorticotropic hormone, cortisol, vasopressin, and oxytocin; inhibits insulin release; and promotes wound healing. Ghrelin protects the body by different mechanisms including inhibition of unwanted inflammation and induction of autophagy. Having a clear understanding of the ghrelin effect in each system has therapeutic implications. Future studies are necessary to elucidate the molecular mechanisms of ghrelin actions as well as its application as a GHSR agonist to treat most common diseases in each system without any paradoxical outcomes on the other systems.

Interleukin-1 Receptor-Induced Nitric Oxide Production in the Pancreas Controls Hyperglycemia Caused by Scorpion Envenomation

Tityus serrulatus causes numerous scorpion envenomation accidents and deaths worldwide. The symptoms vary from local to systemic manifestations, culminating in pulmonary edema and cardiogenic shock. Among these events, transitory hyperglycemia is a severe manifestation that influences pulmonary edema, hemodynamic alterations, and cardiac disturbances. However, the molecular mechanism that leads to increased glucose levels after T. serrulatus envenomation remains unknown. This study aimed to investigate our hypothesis that hyperglycemia due to scorpion envenomation involves inflammatory signaling in the pancreas. The present study showed that T. serrulatus venom induces the production of IL-1α and IL-1β in the pancreas, which signal via IL-1R and provoke nitric oxide (NO) production as well as edema in β-cells in islets. Il1r1−/− mice were protected from transitory hyperglycemia and did not present disturbances in insulin levels in the serum. These results suggest that the pathway driven by IL-1α/IL-1β-IL-1R-NO inhibits insulin release by β-cells, which increases systemic glucose concentration during severe scorpion envenomation. A supportive therapy that inhibits NO production, combined with antiserum, may help to prevent fatal outcomes of scorpion envenomation. Our findings provide novel insights into the design of supportive therapy with NO inhibitors combined with antiscorpion venom serum to overcome fatal outcomes of scorpion envenomation.

Interactions between Atorvastatin and the Farnesoid X Receptor Impair Insulinotropic Effects of Bile Acids and Modulate Diabetogenic Risk

Bile acids such as chenodeoxycholic acid (CDC) acutely enhance insulin secretion via the farnesoid X receptor (FXR). Statins, which are frequently prescribed for type 2 diabetic patients suffering from dyslipidemia, are known for their diabetogenic risk and are reported to interact with the FXR. Our study investigates whether this interaction is relevant for beta cell signaling and plays a role for negative effects of statins on glycemic control. Experiments were performed with islets and islet cells from C57BL/6N wildtype and FXR knock-out mice. Culturing islets with atorvastatin (15 µM) for 24 h decreased glucose-stimulated insulin secretion by approximately 30 % without affecting ATP synthesis. Prolonged exposure for 7 d lowered the concentration necessary for impairment of insulin release to 150 nM. After 24-h culture with atorvastatin, the ability of CDC (500 nM) to elevate [Ca2+]c was diminished and the potentiating effect on insulin secretion was completely lost. Mevalonate largely reduced the negative effect of atorvastatin. Nuclear activity of FXR was reduced by atorvastatin in a mouse FXR reporter assay. The atorvastatin-induced decrease in insulin release was also present in FXR-KO mice. Though not a prerequisite, FXR seems to influence the degree of damage caused by atorvastatin in dependence of its interaction with CDC: Preparations responding to CDC with an increase in insulin secretion under control conditions were less impaired by atorvastatin than preparations that were non-responsive to CDC. Extended stimulation of FXR by the synthetic agonist GW4064, which is suggested to induce translocation of FXR from the cytosol into the nucleus, increased the inhibitory effect of atorvastatin. In conclusion, atorvastatin inhibits insulin release and prevents positive effects of bile acids on beta cell function. Both interactions may contribute to progression of type 2 diabetes mellitus. SIGNIFICANCE STATEMENT: This study shows that the diabetogenic risk of statins is coupled to the activity of FXR-dependent signaling pathways in beta cells. On the one hand, statins abolish the insulinotropic effects of bile acids and on the other hand, FXR determines the level of impairment of islet function by the statin.

Pancreatic β-cell-specific deletion of insulin-degrading enzyme leads to dysregulated insulin secretion and β-cell functional immaturity.

Inhibition of insulin-degrading enzyme (IDE) has been proposed as a possible therapeutic target for type 2 diabetes treatment. However, many aspects of IDE's role in glucose homeostasis need to be clarified. In light of this, new preclinical models are required to elucidate the specific role of this protease in the main tissues related to insulin handling. To address this, here we generated a novel line of mice with selective deletion of the Ide gene within pancreatic beta-cells, B-IDE-KO mice, which have been characterized in terms of multiple metabolic end points, including blood glucose, plasma C-peptide, and intraperitoneal glucose tolerance tests. In addition, glucose-stimulated insulin secretion was quantified in isolated pancreatic islets and beta-cell differentiation markers and insulin secretion machinery were characterized by RT-PCR. Additionally, IDE was genetically and pharmacologically inhibited in INS-1E cells and rodent and human islets, and insulin secretion was assessed. Our results show that, in vivo, life-long deletion of IDE from beta-cells results in increased plasma C-peptide levels. Corroborating these findings, isolated islets from B-IDE-KO mice showed constitutive insulin secretion, a hallmark of beta-cell functional immaturity. Unexpectedly, we found 60% increase in Glut1 (a high-affinity/low-Km glucose transporter), suggesting increased glucose transport into the beta-cell at low glucose levels, which may be related to constitutive insulin secretion. In parallel, IDE inhibition in INS-1E and islet cells resulted in impaired insulin secretion after glucose challenge. We conclude that IDE is required for glucose-stimulated insulin secretion. When IDE is inhibited, insulin secretion machinery is perturbed, causing either inhibition of insulin release at high glucose concentrations or constitutive secretion.