Increased Glucagon Secretion Research Articles

Intra-islet α-cell Gs signaling promotes glucagon release

Glucagon, a hormone released from pancreatic α-cells, is critical for maintaining euglycemia and plays a key role in the pathophysiology of diabetes. To stimulate the development of new classes of therapeutic agents targeting glucagon release, key α-cell signaling pathways that regulate glucagon secretion need to be identified. Here, we focused on the potential importance of α-cell Gs signaling on modulating α-cell function. Studies with α-cell-specific mouse models showed that activation of α-cell Gs signaling causes a marked increase in glucagon secretion. We also found that intra-islet adenosine plays an unexpected autocrine/paracrine role in promoting glucagon release via activation of α−cell Gs-coupled A2A adenosine receptors. Studies with α-cell-specific Gαs knockout mice showed that α-cell Gs also plays an essential role in stimulating the activity of the Gcg gene, thus ensuring proper islet glucagon content. Our data suggest that α-cell enriched Gs-coupled receptors represent potential targets for modulating α-cell function for therapeutic purposes.

Novel Therapeutic Agents for Management of Diabetes Mellitus: A Hope for Drug Designing against Diabetes Mellitus.

Diabetes mellitus (DM) is characterized by an absolute decline in insulin secretion and peripheral resistance and is the most prevalent metabolic and endocrine disorder. However, the pathogenesis of DM also includes adipocyte insulin resistance, increased glucagon secretion, increased renal glomerular glucose absorption, and neurotransmitter dysfunction. Although there is a wide spectrum of therapeutics available for glycemic control, owing to the identification of various pathogenic determinants of DM, management of DM remains challenging and complex. Current therapeutic interventions against DM focus mostly on glycemic control without considering the other pathological determinants that eventually lead to treatment failure and the progression of DM. Furthermore, long-term use of these conventionally available anti-diabetic drugs leads to various side effects, henceforth development of novel drugs against DM remains an unending search strategy for researchers. Various studies conducted in various parts of the world have proposed that these novel therapeutic interventions target multiple and alternate pathogenic hotspots involved in DM. The current review article discusses novel therapeutic options that hold particular promise to support their safety and discuss the side effects resulting from their use so that these novel candidate drugs can be effectively fabricated into potential drugs for the treatment of DM.

Conflicting Views About Interactions Between Pancreatic α-Cells and β-Cells.

In type 1 diabetes, the reduced glucagon response to insulin-induced hypoglycemia has been used to argue that β-cell secretion of insulin is required for the full glucagon counterregulatory response. For years, the concept has been that insulin from the β-cell core flows downstream to suppress glucagon secretion from the α-cells in the islet mantle. This core-mantle relationship has been supported by perfused pancreas studies that show marked increases in glucagon secretion when insulin was neutralized with antisera. Additional support comes from a growing number of studies focused on vascular anatomy and blood flow. However, in recent years this core-mantle view has generated less interest than the argument that optimal insulin secretion is due to paracrine release of glucagon from α-cells stimulating adjacent β-cells. This mechanism has been evaluated by knockout of β-cell receptors and impairment of α-cell function by inhibition of Gi designer receptors exclusively activated by designer drugs. Other studies that support this mechanism have been obtained by pharmacological blocking of glucagon-like peptide 1 receptor in humans. While glucagon has potent effects on β-cells, there are concerns with the suggested paracrine mechanism, since some of the supporting data are from isolated islets. The study of islets in static incubation or perifusion systems can be informative, but the normal paracrine relationships are disrupted by the isolation process. While this complicates interpretation of data, arguments supporting paracrine interactions between α-cells and β-cells have growing appeal. We discuss these conflicting views of the relationship between pancreatic α-cells and β-cells and seek to understand how communication depends on blood flow and/or paracrine mechanisms.

Secondary diabetes mellitus in pheochromocytomas and paragangliomas.

Secondary diabetes mellitus (DM) in secretory pheochromocytomas and paragangliomas (PPGLs) is encountered in up to 50% of cases, with its presentation ranging from mild, insulin resistant forms to profound insulin deficiency states, such as diabetic ketoacidosis and hyperglycemic hyperosmolar state. PPGLs represent hypermetabolic states, in which adrenaline and noradrenaline induce insulin resistance in target tissues characterized by aerobic glycolysis, excessive lipolysis, altered adipokine expression, subclinical inflammation, as well as enhanced gluconeogenesis and glucogenolysis. These effects are mediated both directly, upon adrenergic receptor stimulation, and indirectly, via increased glucagon secretion. Impaired insulin secretion is the principal pathogenetic mechanism of secondary DM in this setting; yet, this is relevant for tumors with adrenergic phenotype, arising from direct inhibitory actions in beta pancreatic cells and incretin effect impairment. In contrast, insulin secretion might be enhanced in tumors with noradrenergic phenotype. This dimorphic effect might correspond to two distinct glycemic phenotypes, with predominant insulin resistance and insulin deficiency respectively. Secondary DM improves substantially post-surgery, with up to 80% remission rate. The fact that surgical treatment of PPGLs restores insulin sensitivity and secretion at greater extent compared to alpha and beta blockade, implies the existence of further, non-adrenergic mechanisms, possibly involving other hormonal co-secretion by these tumors. DM management in PPGLs is scarcely studied. The efficacy and safety of newer anti-diabetic medications, such as glucagon-like peptide 1 receptor agonists and sodium glucose cotransporter 2 inhibitors (SGLT2is), as well as potential disease-modifying roles of metformin and SGLT2is warrant further investigation in future studies.

Blocking IL-6 signaling improves glucose tolerance via SLC39A5-mediated suppression of glucagon secretion.

Hyperinsulinemia, hyperglucagonemia, and low-grade inflammation are frequently presented in obesity and type 2 diabetes (T2D). The pathogenic regulation between hyperinsulinemia/insulin resistance (IR) and low-grade inflammation is well documented in the development of diabetes. However, the cross-talk of hyperglucagonemia with low-grade inflammation during diabetes progression is poorly understood. In this study, we investigated the regulatory role of proinflammatory cytokine interleukin-6 (IL-6) on glucagon secretion. The correlations between inflammatory cytokines and glucagon or insulin were analyzed in rhesus monkeys and humans. IL-6 signaling was blocked by IL-6 receptor-neutralizing antibody tocilizumab in obese or T2D rhesus monkeys, glucose tolerance was evaluated by intravenous glucose tolerance test (IVGTT). Glucagon and insulin secretion were measured in isolated islets from wild-type mouse, primary pancreatic α-cells and non-α-cells sorted from GluCre-ROSA26EYFP (GYY) mice, in which the enhanced yellow fluorescent protein (EYFP) was expressed under the proglucagon promoter, by fluorescence-activated cell sorting (FACS). Particularly, glucagon secretion in α-TC1 cells treated with IL-6 was measured, and RNA sequencing was used to screen the mediator underlying IL-6-induced glucagon secretion. SLC39A5 was knocking-down or overexpressed in α-TC1 cells to determine its impact in glucagon secretion and cytosolic zinc density. Dual luciferase and chromatin Immunoprecipitation were applied to analyze the signal transducer and activator of transcription 3 (STAT3) in the regulation of SLC39A5 transcription. Plasma IL-6 correlate positively with plasma glucagon levels, but not insulin, in rhesus monkeys and humans. Tocilizumab treatment reduced plasma glucagon, blood glucose and HbA1c in spontaneously obese or T2D rhesus monkeys. Tocilizumab treatment also decreased glucagon levels during IVGTT, and improved glucose tolerance. Moreover, IL-6 significantly increased glucagon secretion in isolated islets, primary pancreatic α-cells and α-TC1 cells. Mechanistically, we found that IL-6-activated STAT3 downregulated the zinc transporter SLC39A5, which in turn reduced cytosolic zinc concentration and ATP-sensitive potassium channel activity and augmented glucagon secretion. This study demonstrates that IL-6 increases glucagon secretion via the downregulation of zinc transporter SLC39A5. This result revealed the molecular mechanism underlying the pathogenesis of hyperglucagonemia and a previously unidentified function of IL-6 in the pathophysiology of T2D, providing a potential new therapeutic strategy of targeting IL-6/glucagon to preventing or treating T2D.

Hyperglucagonaemia in diabetes: altered amino acid metabolism triggers mTORC1 activation, which drives glucagon production.

Hyperglycaemia is associated with alpha cell dysfunction, leading to dysregulated glucagon secretion in type 1 and type 2 diabetes; however, the mechanisms involved are still elusive. The nutrient sensor mammalian target of rapamycin complex 1 (mTORC1) plays a major role in the maintenance of alpha cell mass and function. We studied the regulation of alpha cell mTORC1 by nutrients and its role in the development of hyperglucagonaemia in diabetes. Alpha cell mTORC1 activity was assessed by immunostaining for phosphorylation of its downstream target, the ribosomal protein S6, and glucagon, followed by confocal microscopy on pancreatic sections and flow cytometry on dispersed human and mouse islets and the alpha cell line, αTC1-6. Metabolomics and metabolic flux were studied by 13C glucose labelling in 2.8 or 16.7 mmol/l glucose followed by LC-MS analysis. To study the role of mTORC1 in mediating hyperglucagonaemia in diabetes, we generated an inducible alpha cell-specific Rptor knockout in the Akita mouse model of diabetes and tested the effects on glucose tolerance by IPGTT and on glucagon secretion. mTORC1 activity was increased in alpha cells from diabetic Akita mice in parallel to the development of hyperglycaemia and hyperglucagonaemia (two- to eightfold increase). Acute exposure of mouse and human islets to amino acids stimulated alpha cell mTORC1 (3.5-fold increase), whereas high glucose concentrations inhibited mTORC1 (1.4-fold decrease). The mTORC1 response to glucose was abolished in human and mouse diabetic alpha cells following prolonged islet exposure to high glucose levels, resulting in sustained activation of mTORC1, along with increased glucagon secretion. Metabolomics and metabolic flux analysis showed that exposure to high glucose levels enhanced glycolysis, glucose oxidation and the synthesis of glucose-derived amino acids. In addition, chronic exposure to high glucose levels increased the expression of Slc7a2 and Slc38a4, which encode amino acid transporters, as well as the levels of branched-chain amino acids and methionine cycle metabolites (~1.3-fold increase for both). Finally, conditional Rptor knockout in alpha cells from adult diabetic mice inhibited mTORC1, thereby inhibiting glucagon secretion (~sixfold decrease) and improving diabetes, despite persistent insulin deficiency. Alpha cell exposure to hyperglycaemia enhances amino acid synthesis and transport, resulting in sustained activation of mTORC1, thereby increasing glucagon secretion. mTORC1 therefore plays a major role in mediating alpha cell dysfunction in diabetes. All sequencing data are available from the Gene Expression Omnibus (GEO) repository (accession no. GSE154126; https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE154126 ).

Robust increase in glucagon secretion after oral protein intake, but not after glucose or lipid intake in Japanese people without diabetes.

Few studies in Asian populations have analyzed how glucagon secretion is affected by ingested glucose, proteins or lipids, individually. To investigate the fluctuations of glucagon secretion after the intake of each of these nutrients, 10 healthy volunteers underwent oral loading tests using each of glucose, proteins and lipids, and blood levels of glucose, insulin and glucagon were measured every 30 min for 120 min. Whereas glucagon secretion was suppressed and minimally affected by oral glucose intake and lipid intake, respectively, oral protein intake robustly increased glucagon secretion, as well as insulin secretion. Further studies are needed to elucidate the mechanism by which protein loading increases glucagon secretion.

1224-P: Glucagon Secretion Increases with Age in People with Type 2 Diabetes

It has been shown that the decline in the number of pancreatic beta cells and the insulin-secreting capacity of individual pancreatic beta cells progressively decreases with age, and this functional decline is accelerated by the addition of hyperglycemia. While, glucagon (GCG) is elevated in diabetes, and elevated GCG not only increases blood glucose levels (GLUs), but also decreases muscle mass due to protein metabolism leading to decrease in muscle glucose uptake, making blood glucose control more difficult. However, there are no reports yet regarding to age-related changes in GCG secretion. In this study, we analyze the age-related changes in GCG secretion in people with type 2 diabetes (T2D) after insulin treatment to remove glucose toxicity. A retrospective analysis was performed on people with T2D hospitalized for a period of 5 years from December 2017 in whom a test meal load (carbohydrate 75.5-70g, protein 8.5g, fat 28.5g) was performed before and after insulin treatment, and GLUs and GCG were measured. Insulin (IRI) and/or C-peptide (CPR) were also measured. A total of 121 patients (70 males, age 64.2 ± 11.6 years) were included in the analysis. After insulin treatment, GCG secretion was almost all lower than before treatment. GCG secretion increased with age (P=0.014). Insulinogenic Index decreased with age (R=-0.286 P=0.004), and IRI/GLU and CPR/GLU at 120 minutes after the test meal load also decreased with age (R=-0.314 P=0.001, R=-0.324 P=0.001). We confirmed that there is an increase in GCG secretion with aging in people with T2D. This might be one of the reasons for the decrease in muscle mass and physical activity in elderly people with T2D. Further studies are needed to expand the number including people with normal glucose and impaired glucose tolerance. Acknowledgments:The Cookie Testing Study Group provided support. Disclosure S.Kaneko: Advisory Panel; Lilly Diabetes, Speaker's Bureau; AstraZeneca, Novo Nordisk, Sumitomo Dainippon Pharma Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Lilly Diabetes, Bayer Inc., Kowa Company, Ltd., Kyowa Kirin Co., Ltd. K.Motohashi: None. Y.Ueba: None. S.Tokumoto: None. Funding Cookie Testing Study Group

5-LB: Rescuing Alpha-Cell Function in Type 1 Diabetes

Increased glucagon secretion from the pancreatic alpha cell is the first and most important defense against hypoglycemia. In T1D this defense mechanism is lost. We propose that the loss of the neighboring beta cells causes, and in turn the loss of inhibitory signals they generated, is a key factor in the inability of alpha cells to respond appropriately to blood sugar levels. The sudden cessation of this inhibitory input during hypoglycemia is a necessary signal for the glucagon response. We hypothesize that reactivation of endogenous paracrine and autocrine signaling might restore the alpha cell’s ability to respond to hypoglycemia in T1D. We used isolated islets and tissue slices from non-diabetic organ donors and donors with T1D and measured dynamic hormone secretion and calcium recordings. We found that alpha cell responses are briefer than the sustained beta cell responses. If not reset by inhibitory input, the alpha cell is not able to respond again. Glucagon secretion can be recovered by activation of paracrine signals to inhibit the alpha cell. We found full glucagon recovery if reset for 15 min or longer using high glucose in healthy islets (no reset 0.51 +/- 0.09 vs. 5 min reset 0.99 +/- 0.12 vs. 15 min 1.63 +/- 0.31, fold change to baseline +/- SEM). In tissues from T1D donors, alpha cells failed to respond to decreases in glucose concentration despite normal glucagon content and responses to KCl depolarization. Baseline glucagon secretion was significantly elevated compared to healthy individuals (mean 25.93 +/- SEM 8.55 pM in T1D vs 7.49 +/- 2.21, p<0.05). Furthermore, we found severely diminished Ca2+ responses to both lowering glucose concentration and glutamate receptor stimulation. We demonstrate that alpha cells from T1D donors cannot mount an efficient glucagon response due to deficient glutamate receptor signaling and loss of paracrine inhibitory input. Our results suggest that restoring both signals rescues glucagon secretion. Disclosure J. Panzer: None. A. Pugliese: Consultant; Provention Bio, Inc. Funding American Diabetes Association (4-22-PDFPM-12 to J.P.); The Leona M. and Harry B. Helmsley Charitable Trust (2018PG-T1D053, G-2108-04793)

Time-dependent effects of endogenous hyperglucagonemia on glucose homeostasis and hepatic glucagon action.

Elevation of glucagon levels and increase in α cell proliferation is associated with states of hyperglycemia in diabetes. A better understanding of the molecular mechanisms governing glucagon secretion could have major implications for understanding abnormal responses to hypoglycemia in patients with diabetes and provide novel avenues for diabetes management. Using mice with inducible induction of Rheb1 in α cells (αRhebTg mice), we showed that short-term activation of mTORC1 signaling is sufficient to induce hyperglucagonemia through increased glucagon secretion. Hyperglucagonemia in αRhebTg mice was also associated with an increase in α cell size and mass expansion. This model allowed us to identify the effects of chronic and short-term hyperglucagonemia on glucose homeostasis by regulating glucagon signaling in the liver. Short-term hyperglucagonemia impaired glucose tolerance, which was reversible over time. Liver glucagon resistance in αRhebTg mice was associated with reduced expression of the glucagon receptor and genes involved in gluconeogenesis, amino acid metabolism, and urea production. However, only genes regulating gluconeogenesis returned to baseline upon improvement of glycemia. Overall, these studies demonstrate that hyperglucagonemia exerts a biphasic response on glucose metabolism: Short-term hyperglucagonemia lead to glucose intolerance, whereas chronic exposure to glucagon reduced hepatic glucagon action and improved glucose tolerance.

A Systemic Review: Clinical Manifestation of Diabetes Mellitus and Role of Pharmacist in Management of Type-II Diabetes

Diabetes Mellitus is a condition in which the metabolism of carbohydrates, proteins, and lipids is disrupted owing to reduced insulin production, increased Glucagon secretion, and the development of insulin resistance in body cells. Type II DM differs from type I DM in that beta cells are not destroyed. The prevalence of diabetes in Pakistan varies based on age, gender, and geography. Genetic, behavioral, and environmental factors contribute to the development of type II diabetes. Insulin resistance by the cells and a decreased or inadequate quantity of insulin produced by the beta cells of the pancreas result in Type II diabetes, which is characterized by high amounts of proinflammatory cytokines and free fatty acids in plasma. In diabetic individuals, the imbalance between insulin and glucagon production results in an increased amount of glucagon in the blood and hyperglycemia. Insulin resistance develops in response to physical inactivity, steroid use, and a high-calorie diet, and glucagon and glucose-dependent insulinotropic polypeptide (GIP) levels also rise. Major consequences of diabetes include diabetic retinopathy, neuropathy and vasculopathy, end-stage renal disease, cardiovascular disease, and stroke. In this review we discuss the medication therapy as well as insulin role in the management. And also focus on the role of pharmacist in the management of DM-11 since tailored patient education is more effective than group sessions in maintaining poorly managed diabetes. Among the nonpharmacologic parts of diabetes treatment is teaching patients about the advantages of a healthy diet, physical activity, and medicine for decreasing hyperglycemia. In treating type 2 diabetes, bariatric surgery is more effective than medication. Depending on the patient's state, anti-diabetic drugs may either lower insulin resistance or boost insulin secretion.

Ketone Bodies and Brain Metabolism: New Insights and Perspectives for Neurological Diseases.

Ketone Bodies and Brain Metabolism: New Insights and Perspectives for Neurological Diseases.

Role of Glucagon in The Metabolic Response

Historically, glucagon is the counter-regulatory hormone of insulin. Glucagon secretion is induced by fasting conditions or hypoglycaemia to increase glucose levels. Glucagon is the dominant product of alpha cells in the islet and was first identified in 1923 during an attempt to purify insulin, where it was identified as a contaminant hyperglycaemia factor. Further research determined that the hyperglycaemic action of glucagon is mediated by increased hepatic glycogenolysis and gluconeogenesis to increase endogenous glucose production. Insulin and glucagon as opposing hormones work together for glycaemic control. Diabetic hyperglycaemia is caused by increased impaired insulin action and inappropriately elevated glucagon levels. This review summarizes an important function of glucagon is its role as a regulator of glucose homeostasis. Increased plasma glucagon levels lead to increased hepatic glucose production. The balance between insulin and glucagon is responsible for maintaining euglycaemia conditions. In conditions of hypoglycaemia, increased glucagon secretion leads to increased hepatic glucose production through a number of cellular mechanisms including suppression of glycogenesis and glycolysis and stimulation of glycogenolysis and gluconeogenesis

Serpentine Enhances Insulin Regulation of Blood Glucose through Insulin Receptor Signaling Pathway

Insulin sensitizers targeting insulin receptors (IR) are a potential drug for the treatment of diabetes. Serpentine is an alkaloid component in the root of Catharanthus roseus (L.) G. Don. Serpentine screened by surface plasmon resonance (SPR) technology has the ability to target IR. The objective of this study was to investigate whether serpentine could modulate the role of insulin in regulating blood glucose through insulin receptors in cells and in animal models of diabetes. SPR technology was used to detect the affinity of different concentrations of serpentine with insulin receptors. The Western blotting method was used to detect the expression levels of key proteins of the insulin signaling pathway in C2C12 cells and 3T3-L1 cells as well as in muscle and subcutaneous adipose tissue of diabetic mice after serpentine and insulin treatment. Diabetic mice were divided into four groups and simultaneously injected with insulin or serpentine, and the blood glucose concentration and serum levels of insulin, glucagon, and C-peptide were measured 150 min later. mRNA levels of genes related to lipid metabolism and glucose metabolism in liver, muscle, and subcutaneous adipose tissue were detected by RT-PCR. Serpentine was able to bind to the extracellular domain of IR with an affinity of 2.883 × 10-6 M. Serpentine combined with insulin significantly enhanced the ability of insulin to activate the insulin signaling pathway and significantly enhanced the glucose uptake capacity of C2C12 cells. Serpentine enhanced the ability of low-dose insulin (1 nM) and normal-dose insulin (100 nM) to activate the insulin signaling pathway. Serpentine also independently activated AMPK phosphorylation, thus stimulating glucose uptake by C2C12 cells. In high-fat-diet/streptozotocin (HFD/STZ)-induced diabetic mice, serpentine significantly prolonged the hypoglycemic time of insulin, significantly reduced the use of exogenous insulin, and inhibited endogenous insulin secretion. In addition, serpentine alone significantly increased the expression of GSK-3β mRNA in muscle tissue, thus enhancing glucose uptake, and at the same time, serpentine significantly increased glucagon secretion and liver gluconeogenesis. Serpentine enhances the ability of insulin to regulate blood glucose through the insulin receptor, and can also regulate blood glucose alone, but it has a negative regulation mechanism and cannot produce a hypoglycemic effect. Therefore, serpentine may be useful as an insulin sensitizer to assist insulin to lower blood glucose.

ODP192 Empagliflozin associated Euglycemic Diabetic Ketoacidosis and the Terrible Triad

Abstract Background Among diabetic patients, newer drug classes such as SGLT2i have been reported to present with Euglycemic Diabetic Ketoacidosis (eDKA), wherein these patients are without signs of elevated glucose levels. However, this condition can coexist with acute pancreatitis (AP) and hypertriglyceridemia (HTG), which is also known as the terrible triad. Clinical Case We were presented with a 31-year old diabetic male maintained on empagliflozin 25mg OD and metformin 500mg OD, discontinued his medication four months ago, and recently started retaking empagliflozin one week ago. He presented with drowsiness, severe abdominal pain rated as 9/10, and vomiting. An NGT was inserted and on further workup, acidosis was present on ABG with an anion gap of 28 mEq/L. AP was noted on abdominal ultrasound with an amylase of 768 U/L. CBG was 167mg/dL, Hba1c of 7.4%, Creatinine of 1. 05mg/dL, with ketonuria on urinalysis. Hydration was started with referral to endocrinology service. Insulin drip was started, and CBGs ranged from 145-229mg/dL while on drip. Hydration was increased accordingly, considering the patient's intake and output. Further workup was done, and lipid profile revealed severe hypertriglyceridemia at 1724.78mg/dL and elevated VLDL at 342mg/dL. Statin was prescribed, and eventually, insulin drip was titrated down with resolution of acidosis. Insulin was then shifted to subcutaneous regimen. Diet was also transitioned to clear liquids and eventually into diabetic diet. The patient was sent home and was uneventful after. eDKA develops due to increased glucagon secretion and decreased insulin production, promoting glucose to fat metabolism and ultimately stimulating ketogenesis. These agents decrease the blood glucose level by increasing urinary glucose excretion leading to a reduction in insulin secretion from the pancreatic β-cells. The terrible or enigmatic triad consisting of AP, HTG, and DKA/eDKA has been well reported but has a complex process. HTG results as a product of the reduced lipoprotein lipase activity in peripheral tissues, which decreases the removal of VLDL from the plasma. In AP cases, HTG only accounts for a minority (2-7%) of cases, but the risk was increased with levels above 1000mg/dL, such as in our patient. In the study by Simons-Linares et al., having the said triad had higher odds of having SIRS, shock, sepsis, and parenteral nutrition when compared to AP patients alone. eDKA patients can present with non-specific signs and symptoms such as nausea, vomiting, and abdominal pain, which can delay the diagnosis in patients. Fortunately, it was recognized early on, and there was a quick response in managing the case. Conclusion To date, there is scarcity among reports of the terrible triad, especially with empagliflozin use. Therefore, we can stress the importance of keen assessments and history taking in detecting the triad for an early aggressive approach to prevent adverse outcomes. Presentation: No date and time listed

Urotensin II receptor knockout alleviates streptozotocin‐induced hyperglucagonemia and diabetic kidney disease

Plasma and urinary levels of UII, a potent vasoactive peptide, are elevated in diabetes mellitus (DM) patients. UII receptor (UT) expression levels are also increased in the kidneys of humans and animals with DM. Palosuran, an orally active UT antagonist, increased insulin levels and improved renal function in uninephrectomized streptozotocin (STZ)‐treated rats. However, human studies on the potential use of palosuran for kidney protection in diabetes were inconclusive. In addition to UT antagonism, palosuran can activate somatostatin receptors. Also, the reduced affinity of palosuran for UT in intact cells and tissues suggests that it may not be an optimal UT antagonist. Thus, using non‐selective and less potent UT antagonists constitutes a weakness in the scientific rigor of the prior attempts to dissect UT as a potential therapeutic target in DKD. Hence, studies using genetic animal models and highly selective and potent pharmacological antagonists are needed to fill the gaps of understanding on the pathophysiological significance of the UII system in DM. In the present study, we examine the development of hyperglycemia and DKD in the wild‐type (WT) and UT knockout (KO) mouse model of type 1 DM.STZ‐treated mice showed increased blood glucose levels, glucosuria, decreased plasma insulin levels, and diabetic kidney disease (DKD), which UT KO attenuated. However, UT KO failed to reverse STZ‐induced insulin deficiency. To understand the underlying mechanism for alleviating hyperglycemia and DKD in UT KO despite the uncorrected insulin deficiency, we tested the role of the primary insulin counterregulatory hormone, glucagon. We found that STZ treatment increased plasma glucagon levels in WT mice but not in UT KO mice. This finding was supported by double immunohistochemistry of pancreatic islet sections, where STZ treatment reduced insulin and increased glucagon staining. UT KO reversed only the effect of STZ on glucagon staining. These findings suggest that UT KO protects the glucagon‐producing alpha cells but not the insulin‐producing beta cells.UII increased glucagon secretion in a cultured pancreatic alpha cell line, which UT inhibition reversed. Next, to determine how UII triggers glucagon secretion, we performed membrane potential recordings in alpha cells using the perforated‐patch clamp technique. UII produced depolarization of alpha cells. This effect was abolished by UT inhibition. Calcium (Ca2+) imaging demonstrated that UII stimulates intracellular Ca2+ ([Ca2+]i) elevation in alpha cells, which T‐ and L‐type Ca2+ channel blockers attenuated.Taken together, the results of this study suggest that: (1) STZ‐treatment causes insulin deficiency, hyperglycemia, glucosuria, DKD, and hyperglucagonemia. (2) UT KO reverses STZ effects, except insulin deficiency. (3) UII increases glucagon secretion by alpha cells, mediated by UII‐induced membrane depolarization and Ca2+ influx via T‐ and L‐type Ca2+ channels. Therefore, the reversal of hyperglycemia, glucosuria, and DKD in UT KO might be linked to the reversal of hyperglucagonemia.

2 ′ -O-Methylperlatolic Acid Enhances Insulin-Regulated Blood Glucose-Lowering Effect through Insulin Receptor Signaling Pathway

Purpose Insulin receptor (InsR) sensitizers represent a new type of therapeutic agent for the treatment of diabetes, with 2′-O-methylperlatolic acid (2-O-M) being a potential InsR targeting drug. The purpose of this study was to determine whether 2-O-M functions as an activator of the insulin signaling pathway, regulating glucose hemostasis through the InsR and exerting a glucose-lowering effect in an animal model of diabetes. Methods SPR-based analyses were used to detect the binding of different concentrations of 2-O-M to the InsR. The protein levels of IR-β, p-IR, AKT, and p-AKT in Hepa and C2C12 cell lines and liver and muscle tissues were determined by western blotting. Glucose uptake capacity was determined in C2C12 cells. Streptozotocin-induced diabetic mice were randomly divided into four groups: the control, insulin treated, 2-O-M treated, and combined insulin and 2-O-M treated. Mice were injected with 2-O-M or normal saline and the average blood glucose concentration after 120 min, and the serum levels of insulin, glucagon, and C-peptide were measured. Next, qRT-PCR was performed to detect the mRNA expression of genes involved in lipid and glucose metabolism in the liver and muscle tissues. Results 2-O-M binds to the extracellular domain of the InsR. Moreover, combination treatment with 2-O-M and insulin resulted in significant activation of the insulin signaling pathway in vitro and significant stimulation of the glucose uptake capacity of C2C12 myotubes. In mice with streptozotocin-induced diabetes, 2-O-M significantly prolonged the blood glucose-lowering effect of insulin, significantly reduced the secretion of exogenous insulin, and reduced the blood glucose concentration in vivo. In addition, treatment with 2-O-M alone significantly enhanced the phosphorylation of AKT in muscle tissue, which enhanced glucose uptake in C2C12 myotubes. Further, 2-O-M significantly increased glucagon secretion and enhanced liver gluconeogenesis to prevent hypoglycemia. Conclusion 2-O-M enhances the hypoglycemic effect of insulin through the insulin signaling pathway and can be used as a complement to insulin. This synergetic effect may lower the required dose of insulin and protect β cells.

Add-on value of tirzepatide versus semaglutide

Type 2 diabetes is a complex disease with several key defects, including impaired insulin secretion, increased glucagon secretion, and insulin resistance, which is exacerbated by obesity. Thus, besides lifestyle measures, pharmacological therapy should aim to target most, if not all, of these anomalies. To reach this goal, combining drugs with different complementary modes of action is commonly used in clinical practice. Receptor agonists of GLP-1, a well known incretin hormone, tackle several of these defects in type 2 diabetes.

MECHANISMS IN ENDOCRINOLOGY: The physiology of neuronostatin.

In 2008, the first evidence of a new hormone called neuronostatin was published. The hormone was discovered using a bioinformatic method and found to originate from the same preprohormone as somatostatin. This small peptide hormone of 13 amino acids and a C-terminal amidation was soon found to exert pleiotropic physiological effects. In animal studies, neuronostatin has been shown to reduce food intake and delay gastric emptying and gastrointestinal transit. Furthermore, neuronostatin has been shown to affect glucose metabolism by increasing glucagon secretion during situations when glucose concentrations are low. Additionally, neuronostatin has been shown to affect neural tissue and cardiomyocytes by suppressing cardiac contractility. The effects of neuronostatin have not yet been delineated in humans, but if the effects found in animal studies translate to humans it could position neuronostatin as a promising target in the treatment of obesity, hypertension and diabetes. In this review, we describe the discovery of neuronostatin and the current understanding of its physiological role and potential therapeutic applicability.

The evolving story of incretins (GIP and GLP-1) in metabolic and cardiovascular disease: A pathophysiological update.

The incretin hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) have their main physiological role in augmenting insulin secretion after their nutrient-induced secretion from the gut. A functioning entero-insular (gut-endocrine pancreas) axis is essential for the maintenance of a normal glucose tolerance. This is exemplified by the incretin effect (greater insulin secretory response to oral as compared to "isoglycaemic" intravenous glucose administration due to the secretion and action of incretin hormones). GIP and GLP-1 have additive effects on insulin secretion. Local production of GIP and/or GLP-1 in islet α-cells (instead of enteroendocrine K and L cells) has been observed, and its significance is still unclear. GLP-1 suppresses, and GIP increases glucagon secretion, both in a glucose-dependent manner. GIP plays a greater physiological role as an incretin. In type 2-diabetic patients, the incretin effect is reduced despite more or less normal secretion of GIP and GLP-1. While insulinotropic effects of GLP-1 are only slightly impaired in type 2 diabetes, GIP has lost much of its acute insulinotropic activity in type 2 diabetes, for largely unknown reasons. Besides their role in glucose homoeostasis, the incretin hormones GIP and GLP-1 have additional biological functions: GLP-1 at pharmacological concentrations reduces appetite, food intake, and-in the long run-body weight, and a similar role is evolving for GIP, at least in animal studies. Human studies, however, do not confirm these findings. GIP, but not GLP-1 increases triglyceride storage in white adipose tissue not only through stimulating insulin secretion, but also by interacting with regional blood vessels and GIP receptors. GIP, and to a lesser degree GLP-1, play a role in bone remodelling. GLP-1, but not GIP slows gastric emptying, which reduces post-meal glycaemic increments. For both GIP and GLP-1, beneficial effects on cardiovascular complications and neurodegenerative central nervous system (CNS) disorders have been observed, pointing to therapeutic potential over and above improving diabetes complications. The recent finding that GIP/GLP-1 receptor co-agonists like tirzepatide have superior efficacy compared to selective GLP-1 receptor agonists with respect to glycaemic control as well as body weight has renewed interest in GIP, which previously was thought to be without any therapeutic potential. One focus of this research is into the long-term interaction of GIP and GLP-1 receptor signalling. A GLP-1 receptor antagonist (exendin [9-39]) and, more recently, a GIP receptor agonist (GIP [3-30] NH2 ) and, hopefully, longer-acting GIP receptor agonists for human use will be helpful tools to shed light on the open questions. A detailed knowledge of incretin physiology and pathophysiology will be a prerequisite for designing more effective incretin-based diabetes drugs.