Glucagon Injection Research Articles

Glucagon Resistance in Individuals With Obesity and Hepatic Steatosis Can Be Measured Using the GLUSENTIC Test and Index.

Increased plasma levels of glucagon (hyperglucagonaemia) promote diabetes development but is also observed in patients with metabolic dysfunction-associated steatotic liver disease (MASLD). This may reflect hepatic glucagon resistance towards amino acid catabolism. A clinical test for measuring glucagon resistance has not been validated. We evaluated our glucagon sensitivity (GLUSENTIC) test, consisting of two study days: a glucagon injection and measurements of plasma amino acids, and an infusion of mixed amino acids and subsequent calculation of the GLUSENTIC index (primary outcome measure) from measurements of glucagon and amino acids. To distinguish glucagon-dependent from insulin-dependent actions on amino acid metabolism, we also studied patients with type 1 diabetes (T1D). The delta-decline in total amino acids was 49% lower in MASLD following exogenous glucagon (p=0.01), and the calculated GLUSENTIC index was 34% lower in MASLD (p<0.0001), but not T1D (p>0.99). In contrast, glucagon-induced glucose increments were similar in controls and MASLD (p=0.41). The GLUSENTIC test and index may be used to measure glucagon resistance in individuals with obesity and MASLD.

Persistent hypoglycemia in patients with liver cancer.

Hypoglycemia is one of the paraneoplastic syndrome manifestations that arise from primary and secondary liver cancer. Hypoglycemia usually presents in the late stage of the disease and indicates a poor prognosis. This case series displays the characteristics profile of patients with primary and secondary liver cancer who are presented with hypoglycemia in a tertiary referral hospital in Indonesia. The study included 41 liver cancer patients who were presented with hypoglycemia. Hepatocellular carcinoma was diagnosed in 51.2% of patients, metastatic liver disease in 14.6% of patients, and undiagnosed liver cancer in 34.1% of patients. The mean age was 47.7 years with male predominance (65.9%). Jaundice was found in 58.5% and hepatomegaly in 70.7% of patients. The mean (± S.D.) initial blood glucose was 42.15 ± 17.11 mg/dL and the Child-Pugh score was 9.93 ± 2.11. Based on imaging, tumor diameter was 12.6 ± 6.9 cm, multiple (61%), and involving both lobes (61%). Treatments for hypoglycemia included oral/enteral feeding, intravenous dextrose, and steroids. No treatment was given for the cancer because all patients were in an advanced stage. The treatment resulted in 41.5% blood glucose being controlled, 56.1% refractory, and 2.4% persistent. Mortality was 70.7% and in average occurred 5.76 ± 4.99 days after hypoglycemia. The mainstay of treatment in these cases is treating the tumor with cytoreduction. However, it was difficult to do cytoreduction because the tumor was already in an advanced stage. Beneficial supportive treatments for maintaining normal blood glucose are frequent meals, dextrose infusion, steroids, and glucagon. Hypoglycemia in liver cancer occurs due to the failure of the liver to fulfill body glucose demand because the liver parenchyma has been largely replaced by the tumor, in addition to the high production of insulin growth factor (IGF). Hypoglycemia is often caused by islet cell and non-islet cell tumors, with a higher occurrence in non-islet cell tumors due to paraneoplastic syndrome and the high metabolic requirements of the tumor. The mainstay of NICTH treatment is treating the tumor with cytoreduction. However, in an advanced stage, cytoreduction therapy is often challenging to conduct. Beneficial supportive treatments for controlling blood glucose are frequent meals, dextrose infusion, and the injection of steroids and glucagon. Steroids play a beneficial role in the treatment of persistent hypoglycemia in hepatocellular carcinoma by stimulating gluconeogenesis and increasing lipolysis. Steroids also have roles in the inhibition of peripheral glucose intake, suppression of big IGF-2 production, and modulation of the GH-IGF axis.

Plasma oxytocin levels in response to glucagon in patients with arginine vasopressin deficiency (central diabetes insipidus) and healthy controls

PurposeWe recently demonstrated an additional oxytocin (OT) deficiency in patients with arginine vasopressin (AVP) deficiency (central diabetes insipidus) by using 3,4-methylenedioxy-methamphetamine (MDMA) as a novel provocation test. However, the implication of the MDMA provocation test in clinical practice might be challenging. Glucagon effectively stimulates vasopressinergic neurons with a strong increase in plasma copeptin. We therefore hypothesized that this provocation test might also stimulate OT.MethodsThis is a predefined secondary analysis of a prospective double-blind, randomised, placebo-controlled cross-over trial involving ten patients with AVP deficiency and ten sex- and body-mass index-matched healthy participants at the University Hospital Basel, Switzerland. Each participant underwent the glucagon test (s.c. injection of 1 mg glucagon) and placebo test (s.c. injection of 0.9% normal saline). Plasma OT levels were measured at baseline, 60, 120 and 180 min after injection. The primary objective was to determine whether glucagon stimulates OT and whether OT levels differ between patients with AVP deficiency and healthy participants. The primary outcome (maximum change in OT within 180 min) was compared between groups and conditions using a linear mixed effects model.ResultsIn healthy participants, the median OT at baseline was 82.7 pg/ml [62.3–94.3] and slightly increased to a maximum of 93.3 pg/ml [87.2–121.1] after injection of glucagon, resulting in a change increase of 24.9 pg/ml [5.1–27.8]. Similarly, in patients with AVP deficiency, the median OT at baseline was 73.9 pg/ml [65.3–81.6] and slightly increased after glucagon injection to 114.9 pg/ml [70.9–140.9], resulting in a change increase of 36.8 pg/ml [–2.2 to 51.2]. The results from the mixed model showed no effect between glucagon compared to placebo on OT (difference: –0.5 pg/ml; 95%-CI [–25, 24]; p = 0.97) and no significant treatment-by-group interaction effect between patients compared to healthy participants (interaction: 28 pg/ml; 95%-CI [–7, 62]; p = 0.13).ConclusionWe found no effect of glucagon on plasma OT levels and no difference between patients with AVP deficiency and healthy participants.

Efficiency of Gastric Decontamination and Activated Charcoal in Beta Blocker (Metoprolol) Poisoning; A Case Report

Beta blockers are negative inotrop and cronotrop in miyocardial activity. They are prescribed widely for multipl clinical conditions. Beta blocker overdose may ocur in patients who used it by accidently or for suicidal purposes. These drugs can effect cardiovascular functions as well as mental conditions. Many patients with overdose have fatal clinical conditions and require intensive treatment due to the drug effect. &#x0D; Our case is a 33 year-old-woman, took 100 miligrams of metoprolol (2 blister of a pocket) 1 hour ago with the intention of committing suicide. She had nausea and vomiting, dizziness. Vital signs; her blood pressure was 120/70, heart rate was 85, respiratory rate and saturation were normal. Electrocardiogram was in sinus rtym and there was no change in the ST segment. She was placed under observation and closely monitored. We administered gastric decontamination to throw out the medications she took 1 hour ago. We administered her 1 liter salin and antiemetic medication to manage the nausea. After a while she had bradicardia and vomiting. We applied her a glucagon and atropin injection and she was admitted to the intensive care unit. After 2 hours, she was completely recover and had no clinical symptoms. She got monitorized for a day and was discharged from the hospital after full recovery. Since we know that the use of high doses of beta blockers is mortal and has poor clinical outcome, we think that the patient in this case underwent gastric decontamination and active charcoal early and succesfully, so she was discharged from the hospital with good clinical outcome. &#x0D; As a result, it is thought that gastric decontamination and also active charcoal may be useful and lifesaving in case of drug overdose in early presentations.

Phosphofructokinase family genes in grass carp: Molecular identification and tissue-specific expression in response to glucose, insulin and glucagon.

It is widely acknowledged that glucose serves as the primary energy source for organisms. However, fish exhibit persistent postprandial hyperglycemia and are thought to have low glucose tolerance. Glycolysis serves as the ubiquitous pathway for glucose catabolism, with phosphofructokinase (PFK) acting as a crucial rate-limiting enzyme in this process and playing an indispensable role. PFK is classified into three isoforms based on their major expression sites, i.e., PFKM (skeletal muscle type), PFKL (liver type) and PFKP (platelet type). In this study, grass carp (Ctenopharyngodon idella) was used as animal model and the open reading frame (ORF) sequences of six PFK genetic isoforms of grass carp were cloned. Real-time PCR was used to detect its tissue distribution, and expression changes in oral glucose tolerance test (OGTT), insulin and glucagon injection experiments. The results showed that the ORF of pfkla, pfklb, pfkma, pfkmb, pfkpa and pfkpb genes was 2343, 2340, 2355, 2331, 2364 and 2349bp in length, respectively. The results of tissue distribution showed that pfkla and pfklb, homologous to mammalian pfkl, exhibited low expression levels in the liver of grass carp, but were expressed at the highest level in the brain. Muscle-type pfkma and pfkmb mRNA were found to be highly expressed in both red and white muscle, with pfkmb also exhibiting high expression levels in the heart, while platelet type pfkpa and pfkpb showed high mRNA abundances in the brain and heart. Oral glucose administration stimulated pfkma and pfkmb mRNA expression in the red muscle, and up-regulated pfklb mRNA levels in the liver at 3h post treatment, but it suppressed liver-type and platelet-type PFK genes expression in the brain. The expression of pfkmb in white muscle and pfkmb and pfkpb in heart were promoted by insulin, whereas the expression of pfkla and pfkpb in the brain, pfkma and pfkmb in the red muscle, pfkma in the white muscle, and pfklb in the liver was suppressed by insulin. As for glucagon, it inhibited pfkma and pfkmb mRNA expression in the red muscle, as well as pfklb in the liver, but it up-regulated PFK genes expression in most tissues detected, such as brain (pfklb, pfkpa and pfkpb), white muscle (pfkma and pfkmb), liver (pfkla) and heart (pfkmb and pfkpb). Our results suggest that PFK family genes have different or even opposite expression patterns in response to glucose, insulin and glucagon stimulation in various tissues of grass carp, which may contribute to glucose intolerance in fish.

Evaluation of the DigiBete App, a Self-Management App for Type 1 Diabetes: Experiences of Young People, Families, and Healthcare Professionals.

Type 1 diabetes (T1DM) is a public health issue for children, young people, and families (CYPF) and requires innovative interventions. The DigiBete app is a self-management and educational app to help CYPF and healthcare professionals (HCPs) manage T1DM, featuring educational advice and resources such as guidance, quizzes, and educational and instructional videos on how to manage T1DM. To assess the impact and implementation of the app, the service-level evaluation deployed a mixed-methods design. App data were captured via the DigiBete platform and an online survey with a non-probability sample of HCPs (N = 178) and CYPF (N = 1165) = 1343. Overall, 55.7% (n = 512/919) of app users were female, and 4855 videos were viewed across the participating areas, with an average of 1213 videos per site (range 776-1679) and 4.4 videos per app user. The most popular videos were how to give a glucagon injection and "My Sick Day Rules", which showed what to do when CYPF were unwell due to T1DM. Interviews (n = 63) were undertaken with 38 CYPF and 25 HCPs. The findings indicate that CYPF and HCPs found the app an essential tool in the management of T1DM. CYPF and HCPs felt the app provided a valuable educational resource in a central location that was invaluable in an emergency or unknown situation. The app was a trusted and bona-fide source of information that could be accessed at any time. HCPs validated DigiBete in helping CYPF to manage their T1DM. At the same time, the app saved HCPs' service time and money and helped CYPF take back some of the control in managing their diabetes.

A Cross-sectional Study to Assess Beta-Cell Function in Individuals with Recently Diagnosed Young-Onset Type 2 Diabetes Mellitus and Its' Complications.

The primary objective was to assess beta-cell function of recently-diagnosed young-onset type 2 diabetes mellitus (T2DM) individuals using basal and stimulated C-peptide levels. The secondary objective was to examine the association between C-peptide with metabolic factors and diabetes complications. A cross-sectional study was conducted for young-onset T2DM individuals aged 18-35 years with a disease duration of not more than 5 years. Plasma C-peptide was measured before and after intravenous glucagon injection. Demographic data, medical history and complications were obtained from medical records and clinical assessment. Continuous data were expressed as median and interquartile range (IQR). Categorical variables were described as frequency or percentage. Multivariable linear regression analysis was used to determine factors associated with C-peptide levels. 113 participants with young-onset T2DM with a median (IQR) age of 29.0 (9.5) years and 24 (36) months were included in this study. The median (IQR) basal and stimulated C-peptide was 619 (655) pmol/L and 1231 (1024) pmol/L. Adequate beta-cell function was present in 78-86% of the participants based on the basal and stimulated C-peptide levels. We found hypertension, obesity and diabetic kidney disease (DKD) to be independently associated with higher C-peptide levels. In contrast, females, smokers, those on insulin therapy and with longer duration of disease had lower C-peptide levels. Most recently diagnosed young-onset T2DM have adequate beta-cell function. Elevated C-peptide levels associated with obesity, hypertension and diabetic kidney disease suggest insulin resistance as the key driving factor for complications.

FRI362 A Rare Case Of Coexisting Pancreatic Neuroendocrine Tumor And Nesidioblastosis

Abstract Disclosure: N. Mon: None. L.K. Tanwani: None. B. Martin: None. C. Scoggins: None. S.L. Mokshagundam: None. Introduction: Nesidioblastosis is a rare cause of endogenous hyperinsulinemic hypoglycemia in adult population. Pancreatic neuroendocrine tumors (NET) are also uncommon among pancreatic tumors. We report a case of a young man who presented with documented Whipple triad and was initially found to have pancreatic cyst. Further evaluation revealed concomitant pancreatic NET and adult nesidioblastosis. Case Report: A 36-year-old Caucasian male with history of anxiety, bipolar, and seizure disorder presented with witnessed seizures and was found to have blood glucose (BG) &amp;lt; 20 mg/dl. He reported recurrent hypoglycemia for 3 years with recent 4-5 ER visits for hypoglycemic seizures. Only medications he was taking were keppra and clonazepam. Physical exam was unremarkable. He was evaluated in Endocrine Clinic and a 72 Hour fast was performed. During the 72 hours fast his BG dropped to 48 mg/dl after 12 hrs. Insulin 16.1 uIU/mL, C peptide 3.02 ng/mL, Proinsulin 60.1 pmol/L, beta-hydroxybutyrate 0.08 mmol/l. BG increased to 116 mg/dl in 30 minutes after 1 mg glucagon injection. Other labs results were: 3PM cortisol 6.6 (7.0-25.0ug/dl), albumin 4.4 mg/dl, HbA1c 5.2%, Alcohol &amp;lt; 5ng/dl, negative urine toxicology screen. CT abdomen without contrast showed a 1.3 cm cyst in the tail of pancreas. Endoscopic ultrasonography revealed a round mixed solid and cystic mass (18x17 mm) with well-defined borders identified in the pancreas tail. The remainder of the pancreas was unremarkable. FNA of the cyst reported findings consistent with a well-differentiated neuroendocrine tumor. He underwent robotic enucleation of distal pancreatic lesion. Postoperative period was uneventful until 2 weeks after procedure when he again started having neuroglycopenic symptoms with lowest BG of 50 mg/dl in the fasting state. He was initiated on diazoxide 50 mg 3 times daily and then 100mg 3 times daily. He continued to have hypoglycemic episodes. Prednisone 10 mg was added at bedtime while waiting for surgery. He underwent distal 80 % pancreatectomy and splenectomy. Hypoglycemia resolved after the surgery. The final pathology was a well-differentiated NET WHO grade I with background neuroendocrine cell hyperplasia/nesidioblastosis. Conclusion: Endogenous hyperinsulinemic hypoglycemia is a rare disorder with nesidioblastosis being the important cause in children and insulinoma in adults, representing a spectrum of pathologic beta cell proliferation. There are very few reports of coexistence of both conditions in adults. Our patient also had an unusual type of insulinoma as it was cystic. The simultaneous occurrence of the two lesions offers significant challenges in diagnosis and management. The mainstay of treatment is surgical resection of insulinoma with localization of insulin hypersecretion; however, how much to remove in nesidioblastosis is still unclear. Presentation: Friday, June 16, 2023

Systematic Literature Review and Indirect Treatment Comparison of Three Ready-to-Use Glucagon Treatments for Severe Hypoglycemia.

Ready-to-use glucagon represents a significant advancement in the management of severe hypoglycemia for people with diabetes and their caregivers. This indirect treatment comparison (ITC) evaluated the efficacy and safety differences among the three ready-to-use glucagon treatments, Baqsimi® (nasal glucagon), Gvoke® (glucagon injection) and Zegalogue® (dasiglucagon injection), in adults and children with type 1 diabetes (T1D) or type 2 diabetes (T2D). A systematic literature review was conducted to identify randomized clinical trials assessing the efficacy and safety of Baqsimi, Gvoke or Zegalogue versus reconstituted, injectable glucagon (IG) in reversing insulin-induced hypoglycemia. Bayesian fixed-effect network meta-analysis was used to perform the ITC. Study endpoints included proportion of participants achieving treatment success, maximum blood glucose achieved, time to achieve treatment success and maximum blood glucose and treatment-emergent adverse events (TEAE). Ten clinical trials were included in the ITC (four for Baqsimi, three for Gvoke, and three for Zegalogue). All three treatments achieved high proportions of treatment success (> 98%). In adults, the efficacy results from combined T1D and T2D analysis were consistent with the T1D analysis, except statistically significantly faster in achieving treatment success for Baqsimi vs Gvoke in the combined analysis (13.96 vs 14.66min). The mean maximum blood glucose values were also statistically significantly lower for Baqsimi (168mg/dl) vs Gvoke (220mg/dl) and Zegalogue (190mg/dl). There was a trend towards a lower number of adults experiencing ≥ 1 TEAE with Baqsimi compared to Gvoke or Zegalogue, but no statistical significance was reached. Baqsimi, Gvoke and Zegalogue had comparable high proportions of treatment success in reversing insulin-induced hypoglycemia. Baqsimi achieved a lower mean maximum blood glucose value, which may have implications for the re-establishment of euglycemia. These findings may help support patients, caregivers and health care providers in their decision-making process when discussing various ready-to-use glucagon treatment options.

Two-Way Crossover Phase 1 Bioequivalence and Safety Studies in Healthy Adults for a Ready-to-Use, Room-Temperature, Liquid-Stable Glucagon Administered by Autoinjector, Prefilled Syringe, or Vial and Syringe.

To demonstrate bioequivalence and safety for a ready-to-use room-temperature liquid-stable glucagon administered subcutaneously (SC) through a glucagon autoinjector (GAI) or a glucagon vial and syringe kit (GVS), versus a glucagon prefilled syringe (G-PFS). Healthy adults (N = 32) were randomly assigned to receive 1-mg glucagon as GAI or G-PFS, and then as the alternative three to seven days later. Other healthy adults (N = 40) were randomly assigned to receive 1-mg glucagon as GVS or G-PFS, and then as the alternative two days later. Samples for plasma glucagon were obtained through 240 minutes after glucagon injection. Bioequivalence was declared when the geometric mean estimate ratio of the area under-the-concentration-versus-time curve from 0 to 240 minutes (AUC0-240) and maximum concentration (Cmax) for plasma glucagon between treatment groups was contained within the bounds of 80% and 125%. Adverse events (AEs) were recorded. The 90% confidence intervals (CIs) for AUC0-240 and Cmax geometric mean ratios for G-PFS to GAI and GVS to G-PFS were contained within the bounds 80% to 125% (G-PFS:GAI AUC0-240 95.05%, 119.67% and Cmax 88.01%, 120.24%; GVS:G-PFS AUC0-240 87.39%, 100.66% and Cmax 89.08%, 106.08%). At least one AE occurred in 15.6% (5/32) participants with GAI, 25% (18/72) with G-PFS, and 32.5% (13/40) with GVS. Sixty-nine of 73 (94.5%) AEs were mild, and none were serious. Nausea was the most common (33/73 [45%]). Bioequivalence and safety were established after 1 mg of this ready-to-use room-temperature liquid-stable glucagon, administered SC to healthy adults, by autoinjector, prefilled syringe, or vial and syringe kit.

Impact of intravenous injection of glucagon on anastomotic leakage in esophagectomy

BackgroundAnastomotic leakage after esophagectomy affects the early postoperative state and prognosis. However, effective measures to prevent anastomotic leakage in esophagogastric anastomosis have not been established. MethodsThis single-center, retrospective, observational study included 147 patients who underwent esophagectomy for esophageal cancer between 2010 and 2020. Glucagon was administered to extend the gastric tube in patients who underwent esophagectomy from January 2016. The patients were divided into two groups: a glucagon-treated group (2016–2020) and a control group (2010–2015). The incidence of anastomotic leakage was compared between the two groups for evaluation of the preventive effects of glucagon administration on anastomotic leakage. ResultsThe length of the gastric tube from the pyloric ring to the final branch of the right gastroepiploic artery was extended by 2.8 cm after glucagon injection. The incidence of anastomotic leakage was significantly lower in the glucagon-treated group (19% vs. 38%; p = 0.014). Multivariate analysis showed that glucagon injection was the only independent factor associated with a reduction in anastomotic leakage (odds ratio, 0.26; 95% confidence interval, 0.07–0.87). Esophagogastric anastomosis was performed proximal to the final branch of the right gastroepiploic artery in 37% patients in the glucagon-treated group, and these cases showed a lower incidence of anastomotic leakage than did those with anastomosis distal to the final branch of the right gastroepiploic artery (10% vs. 25%, p = 0.087). ConclusionsExtension of the gastric tube by intravenous glucagon administration during gastric mobilization in esophagectomy for esophageal cancer may be effective in preventing anastomotic leakage.

Assessment of T2-weighted Image Quality at Prostate MRI in Patients with and Those without Intramuscular Injection of Glucagon.

Purpose To assess whether administration of intramuscular (IM) glucagon improves T2-weighted image quality at multiparametric MRI (mpMRI) of the prostate. Materials and Methods In this Health Insurance Portability and Accountability Act-compliant single-center study, the authors retrospectively analyzed radiology reports from 3960 mpMRI examinations (2495 after exclusions) performed between September 2013 and September 2019 and performed outcome comparisons and semiquantitative image assessment of axial T2-weighted images from 120 consecutive mpMRI examinations performed between May 2015 and February 2016. Three experienced radiologists blinded to administration of IM glucagon assessed images using a five-point Likert scale (5 = no motion or blur) for overall image quality, anatomic delineation (prostate capsule, rectum, and lymph nodes), and identification of benign prostatic hyperplasia nodules. Wilcoxon rank sum and χ2 tests were used to assess quantitative parameters. Results The number of mpMRI radiology reports (599 examinations performed with glucagon; 1896, without glucagon) mentioning blur or motion were similar between groups (P = .82). Regression analysis of semiquantitative image quality assessments of T2-weighted images from mpMRI examinations (60 performed with glucagon; 60, without glucagon) demonstrated that images with glucagon were more likely to receive higher scores (4 or 5 rating) than those without glucagon only when the rectum (P = .001) and lymph nodes (P = .01) were evaluated, not when the prostatic capsule, benign prostatic hyperplasia nodules, or overall image quality was evaluated. No evidence of differences was found in identified Prostate Imaging Reporting and Data System (PI-RADS) lesions or targeted-biopsy Gleason scores. Conclusion Administration of IM glucagon did not improve T2-weighted image quality in prostate MRI examinations and showed similar PI-RADS scores and biopsy yields compared with examinations without glucagon. Keywords: MRI, Genital/Reproductive, Urinary, Prostate, Oncology, Observer Performance © RSNA, 2023 Online supplemental material is available for this article. See also commentary by Eberhardt in this issue.

Twice-daily injections and multiple daily injections of insulin in toddlers with type 1 diabetes: a retrospective cohort study.

Twice-daily injections and multiple daily injections of insulin in toddlers with type 1 diabetes: a retrospective cohort study.

Parasympathetic control of gastrointestinal motility and cross-branch actions of parasympathetic neuromodulation.

Parasympathetic control of gastrointestinal motility and cross-branch actions of parasympathetic neuromodulation.

ODP313 Glucagon-Stimulated Copeptin Measurements in the Differential Diagnosis of Diabetes Insipidus: A Double-Blind Randomized Placebo-Controlled Study

Abstract Background The differential diagnosis of diabetes insipidus and primary polydipsia is challenging. To date, the most reliable approaches are copeptin measurement after hypertonic saline infusion or arginine, which is a known growth hormone secretagogue but has recently also been shown to stimulate the neurohypophysis. Similar to arginine, glucagon is also known to stimulate growth hormone release, but its effect on the neurohypophysis unknown. Methods In this double-blind, randomized, placebo-controlled trial, we enrolled 22 healthy participants, 10 patients with central diabetes insipidus and 10 patients with primary polydipsia at the University Hospital Basel. Each participant underwent the glucagon test, i. e., subcutaneous injection of 1mg glucagon, and placebo test, i. e., subcutaneous injection of 1 ml 0.9% sodium. Plasma copeptin levels were measured at baseline and 30, 60, 90, 120, 150, 180 minutes after injection. The primary objective was to determine whether glucagon stimulates copeptin and to explore whether the copeptin response differentiates between diabetes insipidus and primary polydipsia. Findings: The median (IQR) age of all participants was 27 years (23; 32), 59% were female. In healthy participants, glucagon injection stimulated copeptin with a median (IQR) increase of 7.56 (2.38; 28. 03) pmol/l, while placebo had no effect (0.10pmol/l (-0.70; 0.68); difference: 7.67 (1.98, 27. 09) pmol/l, p &amp;lt; 0. 001). In patients with central diabetes insipidus, copeptin showed no relevant increase after glucagon injection, with an increase of 0.55pmol/l (0.21; 1.65), whereas copeptin was stimulated in patients with primary polydipsia with an increase of 15.70 (5.99; 24.39) pmol/l. Using a copeptin cutoff level of 4.6pmol/l had a sensitivity of 100% (95%CI 100-100) and a specificity of 90% (95%CI 70-100) to discriminate between diabetes insipidus and primary polydipsia. Interpretation: Glucagon stimulates the neurohypophysis, and glucagon-stimulated plasma copeptin has the potential to be used for a safe, novel, and precise test in the differential diagnosis of polyuria-polydipsia syndrome. Presentation: No date and time listed

Using endogenous glycogen as relaxation agent for imaging liver metabolism by MRI

Glycogen plays essential roles in glucose metabolism. Imaging glycogen in the liver, the major glycogen reservoir in the body, may shed new light on many metabolic disorders. 13C magnetic resonance spectroscopy (MRS) has become the mainstream method for monitoring glycogen in the body. However, the equipment of special hardware to standard clinical magnetic resonance imaging (MRI) scanners limits its clinical applications. Herein, we utilized endogenous glycogen as a T2-based relaxation contrast agent for imaging glycogen metabolism in the liver in vivo. The in vitro results demonstrated that the transverse relaxation rate of glycogen strongly correlates with the concentration, pH, and field strength. Based on the Swift-Connick theory, we characterized the exchange property of glycogen and measured the exchange rate of glycogen as 31,847 Hz at 37 °C. Besides, the viscosity and echo spacing showed no apparent effect on the transverse relaxation rate. This unique feature enables visualization of glycogen signaling in vivo through T2-weighted MRI. Two hours-post intraperitoneal injection of glucagon, a clinical drug to promote glycogenolysis and gluconeogenesis, the signal intensity of the mice's liver increased by 1.8 times from the T2-weighted imaging experiment due to the decomposition of glycogen. This study provides a convenient imaging strategy to non-invasively investigate glycogen metabolism in the liver, which may find clinical applications in metabolic diseases.

375-P: Indirect Treatment Comparison (ITC) of Three Ready-to-Use Glucagon Treatments for Severe Hypoglycemia: Baqsimi, Gvoke, and Zegalogue

Objective: To evaluate and compare the efficacy and safety of 3 ready-to-use glucagon treatments for severe hypoglycemia in adults and children with diabetes: Baqsimi (nasal glucagon) , Gvoke (glucagon injection) , and Zegalogue (dasiglucagon injection) . Methods: A systematic literature review was conducted to identify randomized clinical trials assessing the efficacy and safety of ready-to-use glucagon vs. reconstituted injectable glucagon. Bayesian fixed-effect network meta-analysis was used to perform the ITC of Gvoke and Zegalogue vs. Baqsimi. Endpoints included the proportion of participants achieving treatment success, maximum blood glucose, and treatment-emergent adverse events. Mean time to treatment success and to maximum blood glucose were also analyzed for Gvoke vs. Baqsimi, but not for Zegalogue due to reporting differences (mean vs. median) . Results and Conclusion: Ten trials were included in the ITC, including 4 for Baqsimi, 3 for Gvoke, and 3 for Zegalogue. Baqsimi had comparable efficacy with Gvoke and with Zegalogue (Table) , and all 3 treatments achieved high treatment success (&amp;gt;98%) in adults and children with diabetes. In adults, results from the combined T1D and T2D analysis were consistent with the T1D analysis, except a statistically significant faster time achieving treatment success observed for Baqsimi vs. Gvoke in the combined analysis. Disclosure M. Gimenez: Advisory Panel; Eli Lilly and Company, Medtronic, Novo Nordisk, Sanofi. Speaker's Bureau; AstraZeneca, Eli Lilly and Company, Novo Nordisk, Sanofi. K. Khunti: Consultant; Abbott, Amgen Inc., AstraZeneca, Bayer AG, Berlin-Chemie AG, Boehringer Ingelheim International GmbH, Lilly, Merck Sharp &amp; Dohme Corp., Napp Pharmaceuticals Limited, Novartis AG, Novo Nordisk, Roche Diabetes Care, Sanofi-Aventis Deutschland GmbH, Servier Laboratories. Research Support; AstraZeneca, Boehringer Ingelheim International GmbH, Lilly, Merck Sharp &amp; Dohme Corp., Novartis AG, Novo Nordisk, Sanofi-Aventis Deutschland GmbH. K. Syring: Employee; Eli Lilly and Company. L.A. Baker: None. R.J. Threlkeld: Employee; Lilly Diabetes. Y. Yan: Employee; Eli Lilly and Company. M. Matsuhisa: Research Support; Nissui, Sysmex Corp. Speaker's Bureau; Astellas Pharma Inc., Eli Lilly and Company, Merck Sharp &amp; Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Novo Nordisk, Sanofi, Sumitomo Dainippon Pharma Co., Ltd., Takeda Pharmaceutical Company Limited. Funding Funded by Eli Lilly and Company.

0592 Hybrid Closed Loop Insulin Delivery Systems Reduce Perceived Hypoglycemia During Sleep in Adults With Long-Standing Type 1 Diabetes and Hypoglycemia Unawareness

Abstract Introduction Sleep-associated hypoglycemia is a major concern for individuals with type 1 diabetes (T1D). Hybrid closed loop insulin delivery systems with continuous glucose monitoring (HCL-CGM) may reduce the perceived frequency, severity, and impact of sleep-associated hypoglycemia. This analysis assessed changes in perceived sleep-associated hypoglycemia in individuals with T1D at high risk for hypoglycemia after initiating HCL-CGM. Methods Seven adults (median age=53y) with long-standing T1D (median duration=41y) and hypoglycemia unawareness participated in an ongoing 18-month clinical trial assessing effectiveness of HCL-CGM. At baseline and every 6 months thereafter, participants completed the validated Hypoglycemia Awareness Questionnaire (HypoA-Q), a 33-item tool consisting of three subscales (impaired awareness, symptom level, and symptom frequency), and 16 conceptually distinct items, including six items that relate to the frequency, severity, and impact of sleep-associated hypoglycemia, each which is scored and assessed individually. Friedman Tests assessed changes in items over the 18-month interval and Kendall’s W determined effect sizes. Results HCL-CGM significantly reduced the reported frequency of the following questions: (a) “How often you have had a hypo during your sleep?” (χ2(3)=8.4, p&amp;lt;0.05; moderate effect size, W=0.40) and (b) “…and were unable treat yourself when you woke up?” (χ2(3)=12.1, p&amp;lt;0.05; large effect size, W=0.57). HCL-CGM also reduced the reported frequency to: (c) “…and someone else gave you sugar by mouth?” (χ2(3)=7.2, p&amp;lt;0.07; moderate effect size, W=0.34). By contrast, HCL-CGM did not affect reported frequency to the questions: (d) “…which led to a major problem?” (p&amp;gt;0.05; moderate effect size, W=0.26)”; (e) “…and someone else gave you a glucagon injection?” (p&amp;gt;0.05; small effect size, W=0.14); and (f) “…where you stayed asleep and only later realized that you had been hypo?” (p&amp;gt;0.05; small effect size, W=0.19). Conclusion HCL-CGM improved various critical aspects of perceived sleep-associated hypoglycemic events in individuals most at-risk for hypoglycemia. Our results have important implications for self-care and patient treatment in this population. Support (If Any) NIH R01DK117488 (NG), R01DK091331 (MRR), K99NR017416 (SKM), and UL1TR001878 (University of Pennsylvania Center for Human Phenomic Science); NASA NNX14AN49G and 80NSSC20K0243 (NG); Pennsylvania Department of Health SAP 4100079750 (IL).

The effect of glucagon on local subcutaneous blood flow in non-diabetic volunteers; a proof-of-concept study

IntroductionGlucagon and insulin are the two most important hormones in glucose metabolism and have been incorporated in the dual-hormonal artificial pancreas, a device for automated glucose regulation for people with diabetes type 1. Currently the subcutis is the preferred site of hormone delivery for insulin-only as well as dual-hormonal artificial pancreas systems. The delay in glucose-lowering effect after subcutaneous injection of insulin is substantial, in contrast to the elevation of blood glucose values after subcutaneously injected glucagon which is occurs shortly after injection. We hypothesize that this is caused by properties of glucagon and have investigated the vasodilative effect of glucagon on subcutaneous blood flow in this proof-of-concept study. MethodsTwenty-two volunteers received subcutaneous injections of 0.1 mg and 0.01 mg glucagon, and saline on the abdomen. Blood flow was measured by a laser doppler blood flowmeter for 35 min after injections. ResultsInjection of 0.1 mg glucagon resulted in a significant increase in blood flow compared with baseline blood flow for all time intervals. Significant increase was also observed after the 0.01 mg glucagon injection, except between two- and five-min post injection. The inter-individual variance was large and a third of the subjects did not show an apparent increase in local subcutaneous blood flow after the 0.1 mg glucagon injection. ConclusionThis proof-of-concept study shows that micro-boluses of glucagon increases local subcutaneous blood flow on the abdomen of non-diabetic subjects. However, the vasodilative effect of glucagon is not observed in all subjects. The trial was not registered to protect intellectual property rights.

Antidiabetic Activity of Noni (Morinda citrifolia) Extract on Swiss Webster Male Glucagon-Induced Mice

The antidiabetic activity of noni (Morinda citrifolia) extract on the blood glucose level of Swiss Webster male mice (Mus musculus) has been examined. This research aims to study the antidiabetic activity of noni fruit extract on blood glucose level by either induced or not induced with glucagon. Twenty-eight Webster male mice were divided into two main treatment groups. The first treatment group was further divided into four treatment sub-groups. These are (i) blank control (without any treatment), (ii) given distilled water only, (iii) given the extract in a dosage of 1,5 g/kg body weight (bw), and (iv) given the extract in a dosage of 3 g/kg bw. The second treated group was divided into three other treatment group. These are: (i) glucagon+ distilled water, (ii) glucagon+the extract in a dosage of 1,5 g/kg bw, and (iii) glucagon+the extract in a dosage of 3 g/kg bw. The experiment was done with four replicates to each sub-group. The volume of distilled water and the extract were given by gavage in a dosage of 10 ml/kg bw, whereas the glucagon was given through intramuscular injection in a dosage of 20 µg/kg bw. The treated sub-groups without glucagon were injected with distilled water and the extract once every two weeks for eight weeks (1th,3th,5th,7th week) with per week interval for blood sampling (zero,2nd,4th,6th,8th week). The blood glucose levels (BGL) of this sub-group is fasting blood glucose level (BGLf) and two hours post-prandial (2-hrs pp) blood glucose level). The sub-groups with glucagon injection were given distilled water and the extract once a week for four weeks (1th-4th week) with three times per week blood sampling, namely before glucagon injection (BGLa), 10 minutes after the injection (BGLb) and 2 minutes after distilled water or the extract. The results of the statistic test showed (ANOVA p&lt;0,05) that BGL of noni fruit extract-treated mice (doses: 1,5 and 3 g/kg bw) without glucagon injection for eight weeks, tends to decrease. The distilled water feeding does not affect BGL. It can be seen that during 8 weeks of distilled water treatment, it appears that BGLf and BGLe of the distilled water group were not significantly different from the control group. Mice treated with noni fruit extract (doses: 1,5 and 3 g/kg bw) and glucagon injection for four weeks, showed constant BGL. The conclusion is that nony fruit extract helps to decrease blood glucose levels in both groups of mice either induced or not induced with glucagon. That can be seen from the result of statistical tests that shows BGLf and BGLe of the noni group, both at a dose of 1.5 g / kg bw and 3 g / kg bw, from week 2 to week 8 were significantly different from the control group. Meanwhile, in the mice treated with glucagon in the noni group with both doses, BGL decreased after administration of noni. That also shows the significant difference of BGLf and BGLe of the noni group with the control group