Effect Of Glucagon Research Articles

Follistatin-controlled activin-HNF4α-coagulation factor axis in liver progenitor cells determines outcome of acute liver failure.

In patients with acute liver failure (ALF) who suffer from massive hepatocyte loss, liver progenitor cells (LPCs) take over key hepatocyte functions, which ultimately determines survival. This study investigated how the expression of hepatocyte nuclear factor 4α (HNF4α), its regulators, and targets in LPCs determines clinical outcome of patients with ALF. Clinicopathological associations were scrutinized in 19 patients with ALF (9 recovered and 10 receiving liver transplantation). Regulatory mechanisms between follistatin, activin, HNF4α, and coagulation factor expression in LPC were investigated in vitro and in metronidazole-treated zebrafish. A prospective clinical study followed up 186 patients with cirrhosis for 80months to observe the relevance of follistatin levels in prevalence and mortality of acute-on-chronic liver failure. Recovered patients with ALF robustly express HNF4α in either LPCs or remaining hepatocytes. As in hepatocytes, HNF4α controls the expression of coagulation factors by binding to their promoters in LPC. HNF4α expression in LPCs requires the forkhead box protein H1-Sma and Mad homolog 2/3/4 transcription factor complex, which is promoted by the TGF-β superfamily member activin. Activin signaling in LPCs is negatively regulated by follistatin, a hepatocyte-derived hormone controlled by insulin and glucagon. In contrast to patients requiring liver transplantation, recovered patients demonstrate a normal activin/follistatin ratio, robust abundance of the activin effectors phosphorylated Sma and Mad homolog 2 and HNF4α in LPCs, leading to significantly improved coagulation function. A follow-up study indicated that serum follistatin levels could predict the incidence and mortality of acute-on-chronic liver failure. These results highlight a crucial role of the follistatin-controlled activin-HNF4α-coagulation axis in determining the clinical outcome of massive hepatocyte loss-induced ALF. The effects of insulin and glucagon on follistatin suggest a key role of the systemic metabolic state in ALF.

The Effects of Glucagon and Insulin Combination toward on Neurodegeneration Following Traumatic Brain Injury in Rat Model

BACKGROUND: Traumatic brain injury (TBI) is a major cause of death and disability in the productive age. Glutamate excitotoxicity and hyperglycemia those occur following TBI are among the factors those influence secondary brain injury. AIM: This study aimed to determine the effect of glucagon and insulin combination on neuronal necrosis following TBI. METHODS: A total of 28 male wistar rats were randomized into four experimental groups: placebo, insulin, glucagon, and combination of glucagon and insulin. Each animal underwent controlled cortical impact model of TBI. The blood glucose and glutamate levels were measured before and 4 h following TBI. The brain tissues were collected to evaluate neuronal necrosis. RESULTS: Glucagon or glucagon and insulin combination were able to prevent the increased of blood glutamate levels following TBI (p < 0.05). Glucagon administration was associated high blood glucose level (198.10 ± 32.58 mg/dL); a combination with insulin was able to minimize the increased of blood glucose level (166.53 ± 18.48 mg/dL). Combination of glucagon and insulin had a lower number of neuronal necrosis compare to the other groups (p < 0.005). CONCLUSION: The combination of glucagon and insulin potentially exhibit neuroprotection effect on rats following TBI as being demonstrated by lower number of neuronal necrosis. This finding further indicates the role of glucose homeostasis in neuroprotection.

The stimulatory effects of glucagon on cortisol and GH secretion occur independently from FGF-21.

Glucagon stimulation test (GST) is used to assess the hypothalamo-pituitary-adrenal (HPA) and growth hormone (GH) axes with an incompletely defined mechanism. We aimed to assess if glucagon acted through fibroblast growth factor-21 (FGF-21) to stimulate cortisol and GH secretion. The secondary outcome was to determine the relationship of FGF-21 with variable GH responses to GST in obesity. A total of 26 healthy participants; 11 obese (body mass index (BMI) > 30 kg/m2) and 15 leans (BMI < 25 kg/m2) were included. Basal pituitary and target hormone levels were measured and GST was performed. During GST, glucose, insulin, cortisol, GH, and FGF-21 responses were measured. The mean age of the participants was 26.3±3.6 years. Glucagon resulted in significant increases in FGF-21, glucose, insulin, cortisol, and GH levels. The levels of basal cortisol, GH, FGF-21, and IGF-1 were similar in the two groups. The peak GH and area under the curve (AUC)(GH) responses to GST in the obese group were lower than those of the normal-weight group with a different pattern of response. There were no differences between the groups in terms of peak cortisol, AUC(cortisol), peak insulin, AUC(insulin), peak FGF-21, and AUC(FGF21). Obesity was associated with significantly increased glucose and insulin responses and slightly decreased FGF-21 response to glucagon. Obesity was associated with blunted and delayed GH, but preserved cortisol responses to GST. This is the first study showing that glucagon stimulates the HPA and GH axis independently from FGF-21. The delayed GH response to GST in obesity does not seem to be related to FGF-21.

Antiobesity therapeutics with complementary dual-agonist activities at glucagon and glucagon-like peptide 1 receptors.

To develop more effective and long-lasting antiobesity and antidiabetic therapeutics by employing novel chemical modifications of glucagon-like peptide-1 receptor (GLP-1R) agonists. We constructed novel unimolecular dual agonists of GLP-1R and glucagon receptor prepared by linking sEx-4 and native glucagon (GCG) via lysine or triazole [sEx4-GCG(K) and sEx4-GCG(T), respectively] and evaluated their antiobesity and antidiabetic efficacy in the diabetic and obese mouse model. Both sEx4-GCG(K) and sEx4-GCG(T) showed the beneficial metabolic effects of GLP-1 and glucagon: they promoted weight loss and ameliorated insulin resistance and hepatic steatosis. They also increased thermogenesis in brown adipose tissue, and lipolysis and β-oxidation in white adipose tissue, with concomitant suppression of lipogenesis. Furthermore, both dual agonists activated the 5'-AMP-activated protein kinase signalling pathway and prevented palmitate-induced oxidative stress in skeletal muscle cells. Through their complementary dual agonism, sEx4-GCG(T) and sEx4-GCG(K) induce more marked weight loss and metabolic improvements than conventional agonists, and could be developed as novel therapeutic agents for the treatment of obesity and associated metabolic disorders in humans.

Reply to Rodgers: The hepatic glucose-mobilizing effect of glucagon is not mediated by cyclic AMP most of the time.

see main document.

Reply to Wewer Albrechtsen: The glucose-mobilizing effect of glucagon at fasting is mediated by cyclic AMP.

None

The glucose-mobilizing effect of glucagon at fasting is mediated by cyclic AMP

See main document

The effects of glucagon and the target of rapamycin (TOR) on skeletal muscle protein synthesis and age-dependent sarcopenia in humans.

Human target of rapamycin (TOR) is a kinase that stimulates protein synthesis in the skeletal muscle in response to amino acids and physical activity. A comprehensive literature search was conducted on the PubMed database from its inception up to May 2021 to retrieve information on the effects of TOR and glucagon on muscle function. Articles written in English regarding human subjects were included. l-leucine activates TOR to initiate protein synthesis in the skeletal muscle. Glucagon has a crucial role suppressing skeletal muscle protein synthesis by increasing l-leucine oxidation and the irreversible loss of this amino acid. Glucagon-induced l-leucine oxidation suppresses TOR and attenuates the ability of skeletal muscle to synthesize proteins. Conditions associated with increased glucagon secretion typically feature reduced ability to synthesize proteins in the skeletal muscle that may evolve into sarcopenia. Animal protein ingestion, unlike vegetable protein, stimulates glucagon secretion. High intake of animal protein increases l-leucine oxidation and promotes the use of amino acids as fuel. Sarcopenia and arterial stiffness characteristically occur together in conditions featuring insulin resistance, such as aging. Insulin resistance mediates the relationship between aging and sarcopenia and arterial stiffness. The loss of skeletal muscle fibers that characterizes sarcopenia is followed by collagen and lipid accumulation. Likewise, insulin resistance is associated with arterial stiffness and intima-media thickening due to adaptive accretion of collagen and lipids in the arterial wall. Human TOR participates in the pathogenesis of sarcopenia and arterial stiffness, although its effects remain to be fully elucidated.

The hepatic glucose-mobilizing effect of glucagon is not mediated by cyclic AMP most of the time.

The hepatic glucose-mobilizing effect of glucagon is not mediated by cyclic AMP most of the time.

Glucagon Reduces Neutrophil Migration and Increases Susceptibility to Sepsis in Diabetic Mice.

Sepsis is one of the most common comorbidities observed in diabetic patients, associated with a deficient innate immune response. Recently, we have shown that glucagon possesses anti-inflammatory properties. In this study, we investigated if hyperglucagonemia triggered by diabetes might reduce the migration of neutrophils, increasing sepsis susceptibility. 21 days after diabetes induction by intravenous injection of alloxan, we induced moderate sepsis in Swiss-Webster mice through cecum ligation and puncture (CLP). The glucagon receptor (GcgR) antagonist des-his1-[Glu9]-glucagon amide was injected intraperitoneally 24h and 1h before CLP. We also tested the effect of glucagon on CXCL1/KC-induced neutrophil migration to the peritoneal cavity in mice. Neutrophil chemotaxis in vitro was tested using transwell plates, and the expression of total PKA and phospho-PKA was evaluated by western blot. GcgR antagonist restored neutrophil migration, reduced CFU numbers in the peritoneal cavity and improved survival rate of diabetic mice after CLP procedure, however, the treatment did no alter hyperglycemia, CXCL1/KC plasma levels and blood neutrophilia. In addition, glucagon inhibited CXCL1/KC-induced neutrophil migration to the peritoneal cavity of non-diabetic mice. Glucagon also decreased the chemotaxis of neutrophils triggered by CXCL1/KC, PAF, or fMLP in vitro. The inhibitory action of glucagon occurred in parallel with the reduction of CXCL1/KC-induced actin polymerization in neutrophils in vitro, but not CD11a and CD11b translocation to cell surface. The suppressor effect of glucagon on CXCL1/KC-induced neutrophil chemotaxis in vitro was reversed by pre-treatment with GcgR antagonist and adenylyl cyclase or PKA inhibitors. Glucagon also increased PKA phosphorylation directly in neutrophils in vitro. Furthermore, glucagon impaired zymosan-A-induced ROS production by neutrophils in vitro. Human neutrophil chemotaxis and adherence to endothelial cells in vitro were inhibited by glucagon treatment. According to our results, this inhibition was independent of CD11a and CD11b translocation to neutrophil surface or neutrophil release of CXCL8/IL-8. Altogether, our results suggest that glucagon may be involved in the reduction of neutrophil migration and increased susceptibility to sepsis in diabetic mice. This work collaborates with better understanding of the increased susceptibility and worsening of sepsis in diabetics, which can contribute to the development of new effective therapeutic strategies for diabetic septic patients.

Be aware of critical drugs in emergency departments: An extreme iatrogenic insulin overdose via subcutaneous and intramuscular routes

Introduction: Insulin is a highly used parenteral medication in emergency departments. Although most severe insulin overdoses occur as suicide attempts, medication errors can be the reason. We aimed to highlight the potential medication errors in emergency departments due to the poor control of critical drugs like insulin and the similarities between the brand names of drugs, as we experienced during this case. &#x0D; Case Report: We present a 75-year-old diabetic woman with an extreme insulin overdose. A total of 3000 UI of insulin was administered by subcutaneous and intramuscular routes. She developed typical and atypical episodes of hypoglycemia requiring intravenous dextrose, a high-calorie diet, and glucagon administration. Almost all of the classic side effects of glucagon occurred during her intensive care unit follow-up. She recovered without any sequela or recurrence of hypoglycemia at the end of 5 days of admission.&#x0D; Conclusion: Insulin overdose can be a life-threatening condition by causing hypoglycemia. Albeit rare, insulin overdose can occur as a medication error in hospitals. To prevent such incidents for emergency departments, the medication errors should be objectively laid out, and proactive strategies should be integrated without adversely affecting acute care.

282-OR: The Effect of Glucagon on Rates of Hepatic Mitochondrial Oxidation and Pyruvate Carboxylase Flux in Man Assessed by Positional Isotopomer NMR Tracer Analysis (PINTA)

Dual GLP-1/glucagon agonists are now in clinical trials for the treatment of T2D and NASH. In addition to promoting further reduction in food intake on top of GLP-1, the glucagon component of these dual agonists may also promote increased rates of hepatic mitochondrial fat oxidation. In order to investigate this possibility we assessed the glucagon-specific effects of a dual agonist on rates of hepatic mitochondrial oxidation (VCS) and pyruvate carboxylase flux (VPC) in humans by infusing glucagon to achieve a physiological increase in plasma glucagon concentrations in combination with a novel 13C PINTA method to assess rates of hepatic VCS and VPC in 15 healthy volunteers using a paired study design. Following an overnight fast a 3-h IV infusion of [3-13C]lactate (4.3 μmol/Kg-min) and [1,2,3,4,5,6,6-2H7]glucose (0.22 μmol/Kg-min) was begun and during the last 2 hours glucagon (GLG) was co-infused [6 ng/(Kg-min)] or no GLG (CON). The GLG infusion resulted in a ~2.4 fold increase in plasma GLG conc. (from 75±11 to 183±20 pg/mL; P&amp;lt;0.0001), which was associated with an ~20% increase in both plasma C-peptide (from 1.89±0.17 to 2.30±0.26 ng/mL; P=0.02) and plasma insulin conc. (from 9.9±2.0 to 12.0±2.4 μU/mL; P=0.06). Plasma glucose conc. increased from 4.90±0.16 to 5.64±0.19 mmol/L (P=0.0001) which was associated with a tendency for increased rates of glucose production (CON:1042±123 vs. GLG:1148±122 μmol/min; p=0.086) despite no change in rates of VPC flux (CON: 403±69 vs. GLG: 373±55 μmol/min; p=NS). In contrast, this physiological increase in plasma GLG concentrations caused an 85% increase in rates of hepatic VCS (P&amp;lt;0.05). Conclusion: Taken together these studies demonstrate that a physiological increase in plasma glucagon promotes increased rates of hepatic mitochondrial oxidation in humans, which may provide additional benefits to the anorexic effects of dual GLP-1/glucagon agonists to reduce hepatic steatosis. Disclosure K. Petersen: Advisory Panel; Spouse/Partner; AstraZeneca, iMetabolic Biopharma Corporation, Janssen Research &amp; Development, LLC, Merck &amp; Co., Inc., Consultant; Spouse/Partner; Aegerion Pharmaceuticals Inc., Novo Nordisk, Research Support; Self; Gilead Sciences, Inc., Merck &amp; Co., Inc. G. I. Shulman: Consultant; Self; 89bio, Inc., BridgeBio, Ionis Pharmaceuticals, Maze Therapeutics, Novo Nordisk, Other Relationship; Self; AstraZeneca, Esperion Therapeutics, Inc, Generian Pharmaceuticals, Inc., Gilead Sciences, Inc., iMetabolic Biopharma Corporation, Janssen Research &amp; Development, LLC, Merck &amp; Co., Inc., The Liver Company. Funding Merck &amp; Co., Inc. (MISP583402); National Institutes of Health (R01DK113984)

257-OR: Short-Term Hyperglucagonemia Induces Adipose Tissue Insulin Resistance and Inflammation In Vivo

Although the effect of glucagon on glucose metabolism has been well characterized, its effect on adipose tissue and lipid metabolism in humans in vivo has been poorly studied with controversial results. We examined the effect of short-term hyperglucagonemia on adipocyte metabolism in 8 healthy normal glucose tolerant subjects (5M/3F, age=35±5, BMI = 24±1) who received a 12-hour (6PM to 6AM) glucagon infusion (6ng/kg/min) with 14C-glycerol infusion; subcutaneous abdominal adipose tissue biopsy was obtained at 6AM. 8 weeks later subjects returned for a repeat study with 12-hour infusion of normal saline. Plasma glucagon increased from 57±3 to 219±21 pg/ml within one hour and remained elevated throughout the study. Glycerol turnover rate (5.1±0.6 vs. 3.8±0.6 µmol/kg•min, p&amp;lt;0.05) increased by 34%, and the adipose tissue insulin resistance index (fasting plasma FFA x Insulin) more than doubled (5.8±0.8 vs. 2.8±0.7 mM•mU/L, p&amp;lt;0.05) after 12-hour glucagon infusion compared to saline. mRNA expression of genes involved in lipolysis in adipose tissue were upregulated after glucagon infusion (ATGL, 1.14±0.07 vs. 0.77±0.03; HSL, 1.17±0.03 vs. 0.9±0.13; MGL, 1.2±0.04 vs. 0.82±0.2, all p&amp;lt;0.05). Plasma concentration of proinflammatory markers (IL-1β, 0.65±0.05 vs. 0.49±0.05 pg/mL; TNF-α, 2.03±0.23 vs. 1.75±0.17 pg/mL, both p&amp;lt;0.05) and lipidomes involved in inflammatory pathways (lysophosphatidylcholine, 126±11 vs. 51±7 nmol/ml, p&amp;lt;0.005; phosphatidylcholine, 385±24 vs. 306±25 nmol/ml, p&amp;lt;0.01; ceramide, 1.7±0.2 vs. 1.2±0.2 nmol/ml, p&amp;lt;0.01) also increased after 12-hour glucagon infusion. H&amp;E and CD68 immunofluorescence staining in adipose tissue displayed the crown-like structures (CLS) and increased infiltration of macrophages following glucagon infusion. Conclusion: Short-term (12-hour) physiologic hyperglucagonemia stimulates adipose tissue lipolysis, induces adipocyte insulin resistance, and promotes adipose tissue and systemic inflammation. Disclosure X. Chen: None. M. Fourcaudot: None. L. Norton: None. R. A. Defronzo: Other Relationship; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Intarcia Therapeutics, Inc., Janssen Pharmaceuticals, Inc., Novo Nordisk, Research Support; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Janssen Pharmaceuticals, Inc., Merck &amp; Co., Inc., Speaker’s Bureau; Self; AstraZeneca, Novo Nordisk. D. Tripathy: None. Funding Foundation for Advancing Veterans’ Health Research

1191-P: Increased Glucagon Sensitivity in Totally Pancreatectomized Patients

Glucagon secretion and signaling are affected in several metabolic disorders including different types of diabetes. To understand these mechanisms better, we investigated the effect of exogeneous glucagon in participants deprived of endogenous glucagon and/or insulin. We included nine middle-aged, normal-weight patients who had undergone total pancreatectomy (PX), eight patients with type 1 diabetes (T1D) and nine healthy controls in a randomized, double-blinded crossover study (groups were matched by age, gender and BMI). Participants received a 2.5-hour intravenous infusion of glucagon (4 ng/kg/min) and placebo (saline), respectively, under fasting conditions with usual basal insulin administration. Glucagon infusion increased plasma glucagon to similar supraphysiologic levels in all groups and increased glucose levels as assessed by baseline-subtracted area under the curve (bsAUC) by 2.2 and 3.5-fold, respectively, in the PX group compared to the T1D group (P=0.015) and control group (P In conclusion, well-known actions of glucagon are more pronounced in PX patients compared to matched T1D patients and healthy controls indicating an increased sensitivity to glucagon in response to the underlying loss of pancreatic glucagon secretion in PX patients. Disclosure I. Rix: Employee; Self; Zealand Pharma A/S. A. Lund: Speaker9s Bureau; Self; Novo Nordisk, Sanofi. L. F. Garvey: None. K. Owen: Employee; Self; Zealand Pharma A/S. C. Hansen: None. G. Van hall: n/a. J. J. Holst: Consultant; Self; Novo Nordisk, Other Relationship; Self; Antag Therapeutics, Bainan Biotech, MSD Corporation, Novo Nordisk, Other Relationship; Spouse/Partner; Antag Therapeutics, Bainan Biotech, Synklino ApS. T. Vilsboll: Consultant; Self; Amgen Inc., AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Bristol-Myers Squibb Company, Gilead Sciences, Inc., Lilly Diabetes, Merck Sharp & Dohme Corp., Mundipharma International, Novo Nordisk, Sanofi, Sun Pharmaceutical Industries Ltd. F. K. Knop: Advisory Panel; Self; MSD Corporation, Novo Nordisk A/S, Sanofi, Consultant; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Novo Nordisk A/S, Pharmacosmos, Zealand Pharma A/S, Research Support; Self; Novo Nordisk A/S, Zealand Pharma A/S, Speaker9s Bureau; Self; AstraZeneca, Bayer AG, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, MSD Corporation, Novo Nordisk A/S. Funding Innovation Fund Denmark; Novo Nordisk Foundation; A.P. Moller Foundation; Aase and Ejnar Danielsen Foundation; Inge & Per Refhall9s Research Grant; Augustinus Foundation

198-OR: The Stimulatory Effect of Glucagon on Insulin Secretion Is Glucose Dependent in Healthy Human Subjects

Glucagon is generally considered to be a counter-regulatory hormone with a primary role to raise blood glucose concentrations by increasing endogenous glucose production (EGP). However, recent preclinical findings support a paracrine action of glucagon to act directly on pancreatic beta cells to promote nutrient-stimulated insulin secretion. In mice, the divergent actions of glucagon are dependent on glycemic status: during fasting glucagon acts predominantly at the liver to raise blood glucose, whereas in the fed state when glycemia is elevated, the insulinotropic effects predominate to lower glucose. These mechanistic findings have not been extended to human physiology. Therefore, we designed a study to test the hypothesis that in healthy humans glucagon actions are also dependent on ambient glycemia. Subjects received glucagon (100 ng/kg) during fasting euglyemia or experimental hyperglycemia (~150 mg/dl) on separate days. On both days, glycemia was maintained for 60 min prior to a glucagon infusion for an additional 60 min. Blood glucose was monitored at bedside and plasma samples were analyzed for C-peptide and di-deuterated glucose enrichment to calculate HGP. During fasting euglycemia, blood glucose was 85 mg/dl and glucagon elicited an increase to a 60 minute average of 132 mg/dl with a peak at ~156 mg/dl at the end of the infusion. Concordant with increased glycemia was an immediate increase in HGP (1.8x) and a delayed increase in C-peptide AUC (1.5x). For the hyperglycemia studies, blood glucose was maintained at 150 mg/dl before and during glucagon administration. Here, glucagon caused a rapid and robust increase in C-peptide AUC (4x) and a more gradual increase in HGP (2x). This glycemic-dependent behavior of glucagon suggests a physiologic role to promote prandial insulin secretion in healthy subjects. This raises the possibility that this incretin function of glucagon plays a role in β-cell function in diabetic subjects. Disclosure S. M. Gray: None. G. Zhang: None. W. Bennett: None. J. Tong: None. J. Campbell: None. D. A. D’alessio: Advisory Panel; Self; Eli Lilly and Company, Sun Pharmaceutical Industries Ltd., Research Support; Self; Eli Lilly and Company, Merck &amp; Co., Inc. Funding National Institutes of Health (F32DK121420, R01DK101991)

657-P: Potential Effect of a Novel Combination of GLP-1RA (efpeglenatide) and Long-Acting Glucagon Analog (HM15136) in Animal Models of Metabolic Disorders

In addition to glycemic control, GLP-1RA efficacy is established in obesity. However, more efforts are still required to close efficacy gap with bariatric surgery. Recent studies demonstrate the favorable effect of glucagon (GCG) receptor activation on energy expenditure and hepatic lipid metabolism. So, combination of GCG with GLP-1RA not only enhances body weight loss (BWL) barely achieved by current therapy, but also expands its therapeutic utility to various metabolic disorders. Previously, we confirmed the long-acting GCG properties of HM15136 from animal to human. In addition, GLP-1 class effect of efpeglenatide (Efpe), once-weekly GLP-1RA, was confirmed in clinical studies. Thus, to develop a novel combination therapy, we investigated potential effects of Efpe and HM15136 combination in animal models of metabolic disorders. In DIO mice, 4 weeks treatment of Efpe and HM15136 combination (COMBO) showed more BWL than Efpe mono treatment. Of note, greater BWL was also confirmed for COMBO treatment compared to acylated GLP-1/GIP co-agonist (-18.5, -55.9, -44.9% vs. vehicle for Efpe, COMBO, GLP-1/GIP). Similar results were observed when measuring fat mass (-19.5%, -83.8%, -77.2% vs. vehicle for Efpe, COMBO, GLP-1/GIP) and blood lipid profiles (total cholesterol: -41.8%, -82.0%, -63.2% vs. vehicle for Efpe, COMBO, GLP-1/GIP) in DIO mice. To further demonstrate benefits of this novel COMBO, additional study was performed in DIO/STZ rats, and COMBO treatment consistently showed more BWL than Efpe (-5.1, -12.1% vs. vehicle for Efpe, COMBO) along with numerically more HbA1c reduction (-1.0, -1.5% vs. vehicle for Efpe, COMBO). Therefore, HM15136 might be a novel COMBO partner for Efpe, providing enhanced BWL and favorable metabolic profiles. These results warrants further evaluation for therapeutic potential of this novel COMBO in various metabolic disorders including dyslipidemia and NASH. Disclosure J. Lee: Employee; Self; Hanmi Pharmaceutical. J. Kim: Employee; Self; Hanmi Pharmaceutical. S. Lee: Employee; Self; Hanmi Pharmaceutical. J. Choi: Employee; Self; Hanmi Pharmaceutical. E. Park: Employee; Self; Hanmi Pharmaceutical. D. Kim: Employee; Self; Hanmi Pharmaceutical. S. Bae: Employee; Self; Hanmi Pharmaceutical. S. Lee: Employee; Self; Hanmi Pharmaceutical. I. Choi: Employee; Self; Hanmi Pharmaceutical.

658-P: Sustained Glucagon Effect on Cardiovascular Renal and Metabolic Disorders Mediated by a Long-Acting Glucagon Analog, HM15136, in Animal Disease Models

Obesity is an increasing health problem worldwide, implicated with various metabolic disorders such as cardiovascular disease and chronic kidney disease (CKD). Previously, we showed that chronic treatment of HM15136, a long-acting GCG analog, led to robust body weight loss (BWL) in rodent obese models. Moreover, recent studies unveiled a novel role of GCG in vasodilation and inflammation. So, we hypothesized that HM15136 improve chronic metabolic disorders via direct action in addition to secondary effect to BWL. Here, we investigated potential therapeutic effect of HM15136 in animal models of cardiovascular renal and metabolic diseases. In DIO mice, BW, liver triglyceride (TG), and blood cholesterol (CHO) were measured, and all measurements were significantly reduced by HM15136 treatment (-37.5, -72.7, -78.4% vs. vehicle for BW, liver TG, blood CHO at day 17). Next, to explore therapeutic effect of HM15136 on cardiovascular renal diseases, spontaneously hypertensive rats, known model for hypertensive CKD, were used. Interestingly, abnormal elevation in blood pressure and renal function markers such as urine albumin/creatinine ratio (-23.6% vs. SHR vehicle at day 46) was meaningfully reduced by HM15136 treatment. In unilateral ureteral obstruction mice, known as acute kidney injury model, similar results were observed (-17.6%, -48.2% vs. vehicle for serum creatinine, kidney pro-collagen1α1 at day 12). Consistently, increase of vasodilation markers in rat aorta and inhibition of human primary podocyte apoptosis were confirmed, explaining underlying mechanism for these beneficial effects. Therefore, HM15136 could mitigate obesity and related complications especially hypertension and CKD. Hence, mechanistic study results highlight the essential role of direct GCG engagement in improvement of cardiovascular renal and metabolic diseases. Further studies are needed to assess a clinical relevance of these findings. Disclosure J. Lee: Employee; Self; Hanmi Pharmaceutical. S. Lee: Employee; Self; Hanmi Pharmaceutical. J. Kim: Employee; Self; Hanmi Pharmaceutical. E. Park: Employee; Self; Hanmi Pharmaceutical. J. Lee: Employee; Self; Hanmi Pharmaceutical. D. Kim: Employee; Self; Hanmi Pharmaceutical. Y. Kim: None. I. Choi: Employee; Self; Hanmi Pharmaceutical.

The stimulatory effects of glucagon on cortisol and GH secretion occur independently from FGF-21

The stimulatory effects of glucagon on cortisol and GH secretion occur independently from FGF-21

The stimulatory effects of glucagon on cortisol and GH secretion occur independently from FGF-21

Glucagon stimulation test (GST) is used to assess the hypothalamo-pituitary-adrenal (HPA) and growth hormone (GH) axes with an incompletely defined mechanism. We aimed to assess if glucagon acted through fibroblast growth factor-21 (FGF-21) to stimulate cortisol and GH secretion. The secondary outcome was to determine the relationship of FGF-21 with variable GH responses to GST in obesity. A total of 26 healthy participants; 11 obese (body mass index (BMI) > 30 kg/m2) and 15 leans (BMI < 25 kg/m2) were included. Basal pituitary and target hormone levels were measured and GST was performed. During GST, glucose, insulin, cortisol, GH, and FGF-21 responses were measured. The mean age of the participants was 26.3±3.6 years. Glucagon resulted in significant increases in FGF-21, glucose, insulin, cortisol, and GH levels. The levels of basal cortisol, GH, FGF-21, and IGF-1 were similar in the two groups. The peak GH and area under the curve (AUC)(GH) responses to GST in the obese group were lower than those of the normal-weight group with a different pattern of response. There were no differences between the groups in terms of peak cortisol, AUC(cortisol), peak insulin, AUC(insulin), peak FGF-21, and AUC(FGF21). Obesity was associated with significantly increased glucose and insulin responses and slightly decreased FGF-21 response to glucagon. Obesity was associated with blunted and delayed GH, but preserved cortisol responses to GST. This is the first study showing that glucagon stimulates the HPA and GH axis independently from FGF-21. The delayed GH response to GST in obesity does not seem to be related to FGF-21.

The stimulatory effects of glucagon on cortisol and GH secretion occur independently from FGF-21

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)