Glucagon Stimulation Research Articles

PSUN369 Glucagonoma-Associated Dilated Cardiomyopathy in a Young Female: A Case Report

Abstract Background Dilated cardiomyopathy has been reported in patients with glucagonoma. Since glucagon increases myocardial cAMP levels independent of beta adrenoreceptor blockade, thereby increasing heart rate and cardiac output, chronic excessive glucagon stimulation of the heart may lead to cardiomyopathy (Chang-Chretien, 2004). Clinical Case A 26 year old female presented with a 2-year history of palpable epigastric mass, vomiting and weight loss. Abdominal CT showed a heterogeneously enhancing, lobulated pancreatic head-body mass measuring 6.7×6.1×9.9 cm and a hypo-enhancing nodule in hepatic segment IVb, worrisome for metastasis. Endoscopy-guided FNAB of the pancreatic mass revealed a well-differentiated pNET, Grade 3. Chromogranin and synaptophysin stains were positive, Ki-67 index was 33.6%. She was lost to follow-up. After 4 months, she was admitted due to 1 week history of increased vomiting episodes up to 10x daily and abdominal discomfort with 2 day history of incomprehensible speech and right-sided weakness. On examination, she was weak-looking, tachycardic (114 bpm), underweight (BMI 17.45 kg/m2) and with palpable, hard, non-tender epigastric mass measuring 10×7 cm. She also had hyperpigmented patches on both legs initially manifesting as intermittent oozing excoriations over the past 2 years. Cranial MRI revealed subacute CVD infarct. Anticoagulation was given. On the second day, she started having diarrheal episodes. Supportive management was given. Serum glucagon was markedly elevated (>25,000 pg/mL, normal <80). Serum PP (6562 pg/mL, normal <228) and gastrin (621 pg/mL, normal 13-115) were elevated. Serum VIP (<50 pg/mL, normal <75) was normal. Further investigations showed prediabetes (FBS 112 mg/dL, HbA1c 5.7%) and normocytic, normochromic anemia. Screening for MEN1 was unremarkable. On the third day, she had progression of slurred speech and right-sided weakness. Cranial MRI revealed acute lacunar infarcts. As part of hypercoagulability workup, 2D-Echocardiogram showed depressed ejection fraction (20.9%), dilated LV with normal relative wall thickness, and global hypokinesia of the LV wall, confirming dilated cardiomyopathy. Carotid and Venous Duplex scans were normal. Anti-heart failure regimen was initiated. Due to her current neurologic, cardiac and metabolic conditions, she cannot proceed with surgery and chemotherapy. She was given octreotide injection 30 mg every 4 weeks for 3 doses. Post-treatment, repeat abdominal CT and 2D-Echocardiogram showed no significant change. In the meantime, she had improved appetite and no recurrence of vomiting nor diarrhea. She denies palpitations and can better tolerate walking and climbing stairs. Conclusion We reported a rare case of glucagonoma in a young female with documented constellation of symptoms and complications associated with the syndrome, prominently including dilated cardiomyopathy. It is therefore recommended that cardiovascular evaluation should be initiated at the time of glucagonoma diagnosis for timely and appropriate management. Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.

Three-Year Observation of Glucose Metabolism After Pancreaticoduodenectomy: A Single-Center Prospective Study in Japan.

The glucose tolerance of patients changes considerably from before to after pancreaticoduodenectomy wherein approximately half of the pancreas is resected. The aim of this prospective study was to investigate the incidence of and risk factors for diabetes after pancreaticoduodenectomy. This study is a part of an ongoing prospective study, the Kindai Prospective Study on Metabolism and Endocrinology after Pancreatectomy (KIP-MEP) study. Of the 457 patients enrolled to date, 96 patients without diabetes who underwent pancreaticoduodenectomy were investigated in this study. Preoperatively, 1 month post-pancreaticoduodenectomy, and every 6 months thereafter, the glucose metabolism and endocrine function were evaluated using the 75 g oral glucose tolerance test. Various other metabolic, endocrine, and exocrine indices were also examined over a period of up to 36 months. Of the 96 patients analyzed in this study, 33 were newly diagnosed with diabetes. The cumulative diabetes incidence at 36 months following pancreaticoduodenectomy was 53.8%. The preoperative insulinogenic index and ΔC-peptide in the glucagon stimulation test were significantly lower in the progressors to diabetes than in the nonprogressors. Multivariate Cox regression analysis demonstrated that the insulinogenic index was the only significant risk factor for new-onset diabetes. The majority of patients developed new-onset diabetes after pancreaticoduodenectomy, and a low value of the insulinogenic index was suggested to be a risk factor for diabetes. Preoperative assessment for the prediction of the onset of diabetes serves as useful information for patients and is important for postoperative glycemic control and diabetes management in patients who require pancreaticoduodenectomy.

Performance of glucagon stimulation test in diagnosing central adrenal insufficiency in children when utilising the Roche Elecsys® cortisol II assay: a pilot study.

The glucagon stimulation test (GST) is used for the simultaneous assessment of central adrenal insufficiency (CAI) and growth hormone deficiency. The new Roche cortisol II (C II) assay was recently introduced, confounding interpretation of the GST. The performance of the GST in diagnosing central adrenal insufficiency (CAI), utilising the C II assay, was therefore compared with that of the overnight metyrapone test (ONMTPT). A diagnostic accuracy study was performed by retrospectively analysing folders and laboratory records of 25 children and adolescents investigated for hypopituitarism with the GST and the ONMTPT between September 2016 and December 2019. The peak serum cortisol (C)of the GST, the post-metyrapone serum 11-deoxycortisol and adrenocorticotropin levels of the ONMTPT were recorded. Diagnostic performance of the GST at a previously suggested cut-off of 374nmol/L was evaluated. Seventeen boys and 8 girls, aged 1.7-16.3years (median 7.3years) were identified. The sensitivity of the post-GST C-level at 374nmol/L was 0.40 (95% confidence interval [CI] 0.17-0.69), specificity 0.64 (95% CI 0.39-0.84), positive predictive value 0.44 (95% CI 0.19-0.73), negative predictive value 0.60 (95% CI 0.36-0.80), accuracy 0.54 (95% CI 0.35-0.72), positive likelihood ratio (+LR) 0.93 (95% CI 0.49-1.77) and negative LR 1.12 (95% CI 0.40-3.15). The area under the receiver of operating characteristics(ROC) curve was 0.379 (95% CI 0.142-0.615). This study suggests that the GST at any C II cut-off cannot replace the ONMTPT as a diagnostic test for CAI in children. Findings should be confirmed in a larger study.

An Examination of Donor Factors That Impact the Results of the Glucagon Stimulation Test as an Assessment of the Pancreatic Graft Endocrine Function.

Delta C-peptide derived by the glucagon stimulation test is a reliable value for the evaluation of the pancreatic endocrine function after pancreas transplantation. We examined the associations between delta C-peptide as pancreatic graft endocrine function and donor background factors. Sixty-five cases of pancreatic transplantation from brain-dead donors, which were performed in our facility, were enrolled in this study. Enrolled recipients underwent a glucagon stimulation test within 1 to 3 months after transplantation to evaluate the pancreatic graft endocrine function with delta C-peptide to compare donor background factors. The following factors were associated with significant deterioration of the delta C-peptide: age of 50 years or greater, death from cerebrovascular accident, hemoglobin A1c level of 5.6% or greater, creatinine level of 1.0 mg/dL or greater, C-reactive protein level of 25 mg/dL or greater, and sodium level of 150 mmol/L or greater. In addition, increased numbers of these donor factors indicated significantly greater deterioration of the posttransplant pancreatic endocrine function ( P < 0.001). To secure insulin independence after pancreas transplantation, which means maintaining a delta C-peptide level of 1.0 ng/mL or greater on a glucagon stimulation test, the utilization of donors, who possesses more than equal to 3 of the donor factors identified in this study, should be carefully considered.

Using low-dose octreotide with diazoxide-resistant congenital hyperinsulinism resulting from compound heterozygous mutations in the ABCC8 gene.

Congenital hyperinsulinism (CHI) is an over-secretion of insulin by pancreatic ß-cells, causing hypoglycemia which can inhibit brain development in infants. CHI is primarily associated with mutations in the ABCC8 or KCNJ11 genes, which encode the SUR1 and KIR 6.2 subunits of the ATP-sensitive potassium (KATP) channel. Here, we report a case of hyperinsulinemic hypoglycemia with ABCC8 gene mutation in a full term, female, Korean infant who developed early onset hypoglycemia but was not subject to either genetic or metabolic workup. This infant was later admitted to the ER because of a hypoglycemic seizure, but her metabolic work up revealed that both her fasting insulin and C-peptide levels were within the normal range. Despite this glucagon stimulation produced positive results and the genetic workup revealed c.[298G>T(;)4252C>T] mutations in the ABCC8 gene. This indicated diazoxide treatment, but following an unsuccessful course of treatment we switched to octreotide which helped stabilize her glucose. Over 5 years of follow-up, the patient treated with a low dose of octreotide has had no hypoglycemic event, and her growth and psychomotor development remained within normal ranges. However, she is severely obese (BMI over 97 %) despite using octreotide. Thus, we report a mild case of CHI with octreotide treatment, wherein the patient has normal insulin and C-peptide levels and normal development, but is severe obese.

The effect of glucose dynamics on plasma copeptin levels upon glucagon, arginine, and macimorelin stimulation in healthy adults

PurposeNon-osmotic stimulation tests using glucagon, arginine, or macimorelin were recently evaluated for their ability to assess posterior pituitary function. Glucagon and arginine, but not macimorelin, stimulated copeptin secretion (a surrogate marker of vasopressin) and, therefore, provide novel tests to assess the posterior pituitary. The exact underlying mechanism behind their stimulatory effect remains elusive.MethodsThis analysis combined data from three diagnostic studies conducted at the University Hospital Basel, Switzerland. In total, 80 healthy adults underwent the glucagon (n = 22), arginine (n = 30), or macimorelin (n = 28) stimulation tests. The primary objective was to investigate glucose course upon glucagon, arginine, and macimorelin stimulation tests and its effect on plasma copeptin release.ResultsUpon glucagon stimulation, the median [IQR] glucose level at baseline was 5.0 [4.6, 5.2] mmol/l, peaked at 8.1 [7.2, 9.4] mmol/l after 30 min and decreased to a minimum of 3.8 [3.5, 4.5] mmol/l after 120 min. The median copeptin increase upon glucagon stimulation was 7.7 [2.6, 28.0] pmol/l. Upon arginine, the glucose level at baseline was 4.9 [4.8, 5.5] mmol/l, peaked at 6.0 [5.2, 6.4] mmol/l after 30 min and decreased to a minimum of 4.3 [3.8, 4.8] mmol/l after 60 min. The median copeptin increase upon arginine stimulation was 4.5 [2.9, 7.5] pmol/l. Upon macimorelin, glucose levels showed no notable dynamics over the 120 min, and no major change in copeptin was observed.In the pooled dataset, a decrease in glucose levels was significantly correlated with copeptin increase (ρ = 0.53, p < 0.01).ConclusionA similar course in plasma glucose was observed in the copeptin-stimulating test, i.e., after glucagon and arginine, while macimorelin had no effect on glucose and copeptin levels. We hypothesize that a drop in glucose levels observed upon glucagon and arginine might stimulate copeptin.

Evaluation of copeptin levels during glucagon stimulation test in children with suspected growth hormone deficiency

Evaluation of copeptin levels during glucagon stimulation test in children with suspected growth hormone deficiency

Evaluation of the Efficacy and Effects of Common Hepatic Artery Reconstruction in Pancreas Transplantation: A Randomized Controlled Trial.

Maintenance of postoperative graft flow is important in pancreas transplantation. In Japan, reconstruction of the common hepatic artery is performed primarily to increase perfusion in the pancreatic head. We investigated the effects of common hepatic artery reconstruction on patient and graft survival and endocrine functions. Twenty-nine cases of pancreas transplantation were registered in the clinical trial. Of the 29 cases, four were excluded because of the risk of ischemia without reconstruction or complicated reconstruction due to a narrow artery. A total of 25 cases were randomized into two groups: 13 in the non-reconstructed group and 12 in the reconstructed group. The 1-year patient survival and graft survival rates of the non-reconstructed and reconstructed groups were 92.3% and 83.3%, and 91.7% and 82.5%, respectively. The incidence of complications in the two groups was comparable, with 38.5% (5/13 cases) in the non-reconstructed group and 33.3% (4/12 cases) in the reconstructed group. The results of the glucagon stimulation test and oral glucose tolerance test at 1 month and 1 year post-transplantation were comparable. Common hepatic artery reconstruction is not essential unless there is risk of ischemia. This study was registered at the University Hospital Medical Information Network Clinical Trials Registry under UMIN000027213.

Improved Insulin Resistance and Glucose Variability by Super-Low Carbohydrate Diet

Background Diabetes mellitus (DM) has been more prevalent. American Diabetes Association (ADA) proposed the Standards of Medical Care in Diabetes-2022. For nutritional therapy, low carbohydrate diet (LCD) has been recognized for its benefits. Authors have continued diabetic research concerning LCD and meal tolerance test (MTT). Case Presentation The case is 61-year-old male with type 2 diabetes mellitus (T2DM) for years. His hemoglobin A1c (HbA1c) increased to 7.8% in autumn 2021, and further evaluation and treatment was conducted including LCD, daily check of meal and carbohydrate amount, 75 g OGTT, glucagon stimulation test (GST) and others. Results He was on super-LCD method including 12% of carbohydrate. His carbohydrate intake amount and 45-minutes post-prandial blood glucose showed significant correlation. The results of 75 g OGTT twice in May 2020 and December 2021 showed that similar pattern of glucose and insulin responses and insulinogenic index (IGI). In contrast, they showed decreased fasting immuno-reactive insulin (IRI) and Homeostasis model assessment insulin resistance (HOMA-R). For GST, C-peptide showed normal response. Discussion and Conclusion Judging from the results of MTT, OGTT, GST and IGI, he seems to show rather decreased insulin resistance by LCD associated with preserved insulin secretion ability to some degree. Further investigation would be required from pathophysiological point of view.

Quinine Effects on Gut and Pancreatic Hormones and Antropyloroduodenal Pressures in Humans-Role of Delivery Site and Sex.

ContextThe bitter substance quinine modulates the release of a number of gut and gluco-regulatory hormones and upper gut motility. As the density of bitter receptors may be higher in the duodenum than the stomach, direct delivery to the duodenum may be more potent in stimulating these functions. The gastrointestinal responses to bitter compounds may also be modified by sex.BackgroundWe have characterized the effects of intragastric (IG) versus intraduodenal (ID) administration of quinine hydrochloride (QHCl) on gut and pancreatic hormones and antropyloroduodenal pressures in healthy men and women.Methods14 men (26 ± 2 years, BMI: 22.2 ± 0.5 kg/m2) and 14 women (28 ± 2 years, BMI: 22.5 ± 0.5 kg/m2) received 600 mg QHCl on 2 separate occasions, IG or ID as a 10-mL bolus, in randomized, double-blind fashion. Plasma ghrelin, cholecystokinin, peptide YY, glucagon-like peptide-1 (GLP-1), insulin, glucagon, and glucose concentrations and antropyloroduodenal pressures were measured at baseline and for 120 minutes following QHCl.ResultsSuppression of ghrelin (P = 0.006), stimulation of cholecystokinin (P = 0.030), peptide YY (P = 0.017), GLP-1 (P = 0.034), insulin (P = 0.024), glucagon (P = 0.030), and pyloric pressures (P = 0.050), and lowering of glucose (P = 0.001) were greater after ID-QHCl than IG-QHCl. Insulin stimulation (P = 0.021) and glucose reduction (P = 0.001) were greater in females than males, while no sex-associated effects were found for cholecystokinin, peptide YY, GLP-1, glucagon, or pyloric pressures.ConclusionID quinine has greater effects on plasma gut and pancreatic hormones and pyloric pressures than IG quinine in healthy subjects, consistent with the concept that stimulation of small intestinal bitter receptors is critical to these responses. Both insulin stimulation and glucose lowering were sex-dependent.

Safety Assessment and Potential Risks of the Glucagon Stimulation Test in the Diagnosis of Secondary Adrenal Insufficiency.

Although it takes more time, the Glucagon Stimulation Test (GST) is a reliable measure for assessing growth hormone (GH) and Adrenocorticotropic Hormone (ACTH) secretion. The GST is considered to be a safe test; however, it still has mild side effects and potential risks. The objective of this study was to analyze the side effects of the GST while testing adrenal-insufficient patients. This was a prospective study in which GST was performed in eighty-one patients (44 men, 37 women, mean age: 35.83A9.62 years) with the pituitary disorder. The GST consisted of an intramuscular injection of 1 mg of glucagon. Blood samples were collected at baseline, and 30, 60, 90, 120, 150, 180, and 210 min after glucagon injection for cortisol measurements. All patients were asked to report side effects associated with this test. The mean peak blood glucose level under GST was 9.01A.03 mmol/L, and the mean glycemic nadir was 4.34A.75 mmol/L most frequently found during the 30th minute (p <10-3). During the test, 35 subjects (43.2%) had side effects with a mean age of 42.89 A19.75 years. Frequent side effects included: nausea (29.62%), vomiting (27.16%), abdominal cramps (18.51%) and hunger (13.58%). All patients tolerated the test until the end. Adverse effects were significantly more prevalent in patients older than 50 years (p=0.012). The GST is a reliable alternative to assess the hypothalamic pituitary adrenal axis but should be cautiously used especially in the elderly, despite minor side effects.

Investigation of pituitary functions after acute coronavirus disease 2019.

Although coronavirus disease 2019 (COVID-19) mainly involves the lungs, it also affects many systems. The hypothalamic/pituitary axis is vulnerable to hypoxia, hypercoagulation, endothelial dysfunction and autoimmune changes induced by COVID-19 infection. Given that there is no extensive investigation on this issue, we investigated the pituitary functions three to seven months after acute COVID-19 infection. Forty-three patients after diagnosis of COVID-19 infection and 11 healthy volunteers were included in the study. In addition to the basal pituitary hormone levels, growth hormone (GH) and hypothalamo-pituitary adrenal (HPA) axes were evaluated by glucagon stimulation test (GST) and low-dose adrenocorticotropic hormone (ACTH) stimulation test, respectively. The peak cortisol responses to low-dose ACTH test were insufficient in seven (16.2%) patients. Twenty (46.5%) and four (9.3%) patients had inadequate GH and cortisol responses to GST, respectively. Serum insulin-like growth factor-1 (IGF-1) values were also lower than age and sex-matched references in four (9.3%) patients. The peak GH responses to GST were lower in the patient group when compared to the control group. Other abnormalities were mild thyroid-stimulating hormone elevation in four (9.3%) patients, mild prolactin elevation in two (4.6%) patients and central hypogonadism in four (9.3%) patients. Mean total testosterone values were lower in male patients when compared to male controls; however, the difference was not significant. These findings suggest that COVID-19 infection may affect pituitary functions, particularly the HPA and GH axes. These insufficiencies should be kept in mind in post-COVID follow-up. Long-term data are needed to determine whether these deficiencies are permanent or not.

207.3: Predictive Value of C-peptide Measures for Clinical Outcomes of Islet Transplantation in Type 1 Diabetes: A Report From the Collaborative Islet Transplant Registry (CITR)

CITR Investigators Introduction: Long-standing type 1 diabetes (T1D) can lead to impaired awareness of hypoglycemia and high-risk for severe hypoglycemic episodes (SHE). Islet transplantation (ITx) can restore endogenous insulin production, ameliorate glucose control, and abolish SHE. In the DCCT, a stimulated C-peptide >0.2 nmol/L was associated with lower HbA1c, reduced insulin requirements, and decreased prevalence of SHE. We set forth to determine what measures of C-peptide and levels are associated with achievement of ITx positive outcomes in T1D. Methods: Collaborative Islet Transplant Registry (CITR) Islet-Alone recipients with pre-transplant C-peptide <0.1 nmol/L and mean follow up of 4.6±1.1 years were included in the analyses (n=677). Post-transplant metabolic measures obtained from arginine stimulation test, IVGTT, OGTT, glucagon stimulation test and mixed meal stimulation test (MMTT) were evaluated. Predictive value of these measures for 7 primary outcomes of clinical ITx (i.e., absence of SHEs (ASHE); HbA1c<7.0%; HbA1c <7.0% & ASHE; HbA1c≤6.5; HbA1c≤6.5% & ASHE; insulin independence; and ASHE, HbA1c≤6.5%, and insulin independence) was assessed by area under the curve of receiver-operator characteristics curves (ROC-AUC). Measures with the highest ROC-AUC were then selected for determination of optimal cut points by ITx outcome. Results: Fasting C-peptide, MMTT stimulated C-peptide, fasting C-peptide to Glucose (Cpep/Glu) ratio, and MMTT stimulated Cpep/Glu ratio showed the highest ROC-AUCs among all measures evaluated (Table 1). Fasting C-peptide was highly predictive for ASHE (ROC-AUC = 0.9228; optimal cut point = 0.07 nmol/L), and the composite outcome of ASHE, HbA1c≤6.5%, and insulin independence (ROC-AUC = 0.8456; optimal cut point = 0.33 nmol/L) (Table 2). However, MMTT stimulated Cpep/Glu ratio outperformed both fasting and stimulated C-peptide for all outcomes except ASHE alone. Optimal cut point for the ideal composite outcome of ASHE, HbA1c≤6.5%, and insulin independence was 0.12 nmol/mmol for the MMTT stimulated Cpep/Glu ratio, and 0.97 nmol/L for MMTT stimulated C-peptide (Table 2). Discussion/Conclusion: Fasting C-peptide reliably predicts rates of ITx primary endpoints and is similar to other C-peptide measures at predicting ASHE. Although marginal endogenous fasting C-peptide is sufficient to eliminate SHEs, higher levels are required to achieve optimal ITx outcomes. The MMTT stimulated Cpep/Glu ratio provides better predictiveness for composite ITX outcomes, including insulin independence. In the absence of a MMTT, a fasting C-peptide ≥0.33 nmol/L is a reassuring measure of optimal metabolic control in ITx T1D recipients.The CITR has been funded continuously by grants from the National Institute of Diabetes and Digestive and Kidney Diseases since 2001 (Grants 1UCHDK098086-01, 1UC4DK114839-01) to collect data on the efficacy and safety of clinical islet transplantation from US and collaborating international institutions. The Juvenile Diabetes Research Foundation provided supplemental funding for reimbursement of efforts to report data from the European and Australian sites from 2006–2015. No other sponsors have provided support to the CITR. MRR is supported in part by Public Health Service Research Grant R01 DK 091331-8. We thank all the study participants and staff.

Abnormalities of glucagon suppression and stimulation of insulin secretion in response to rising glucose concentrations interact in impaired fasting glucose and impaired glucose tolerance

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

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.

Glucose Tolerance after Pancreatectomy: A Prospective Observational Follow-Up Study of Pancreaticoduodenectomy and Distal Pancreatectomy

Effects of pancreatectomy on glucose tolerance have not been clarified, and evidence regarding the difference in postoperative glucose tolerance between pancreaticoduodenectomy (PD) and distal pancreatectomy (DP) is lacking. This prospective, single-center observational study analyzed 40 patients undergoing PD and 29 patients undergoing DP (Clinical trial registry number UMIN000008122). Glucose tolerance, including insulin secretion (Δ C-peptide immunoreactivity, ΔCPR) and insulin resistance (homeostasis model assessment of insulin resistance, HOMA-IR) were assessed before and 1 month after pancreatectomy using the oral glucose tolerance test (OGTT) and glucagon stimulation test. We assessed long-term hemoglobin A1c (HbA1c) levels in patients, with a follow-up time of 3 years. Percentages of patients diagnosed with abnormal OGTT decreased after PD (from 12 [30%] to 7 [17.5%] of 40 patients, p= 0.096); however, they increased after DP (from 4 [13.8%] to 8 [27.6%] of 29 patients, p= 0.103), although the changes were not statistically significant. ΔCPR decreased after both PD (from 3.2 to 1.0 ng/mL, p < 0.001) and DP (from 3.3 to 1.8 ng/mL, p < 0.001). HOMA-IR decreased after PD (from 1.10 to 0.68, p<0.001), but did not change after DP (1.10 and 1.07, p= 0.42). Median HbA1c level was higher after DP than after PD for up to 3 years, but the differences were not statistically significant. In comparisons of pre- and 1 month post-pancreatectomy data, glucose tolerance showed improvement after PD, whereas it worsened after DP. Insulin secretion decreased after both PD and DP. Insulin resistance improved after PD, but did not change after DP. Further studies are warranted to clarify mechanisms of improved insulin resistance after PD.

Renoprotective Effects of Incretin-Based Therapy in Diabetes Mellitus.

Glucagon-like peptide-1 (GLP-1) receptor agonists are recently discovered antidiabetic drugs with potent hypoglycemic effects. Among different mechanisms of activity, these compounds were shown to reduce blood glucose by suppression of glucagon secretion and stimulation of glucose-dependent insulin secretion. These antidiabetic agents have a minor risk of hypoglycemia and have been suggested as a second-line therapy to be added to metformin treatment to further optimize glycemic control in diabetes. More recently, scientific evidence suggests that GLP-1 receptor agonists may particularly afford protection from diabetic nephropathy through modulation of the molecular pathways involved in renal impairment and so improve renal function. This additional benefit adds further weight for these compounds to become promising drugs not only for glycemic control but also to prevent diabetic complications. In this review, we have updated evidence on the beneficial effects of GLP-1 receptor agonists on diabetic nephropathy and detailed the underlying pathophysiological mechanisms.

1253-P: Markers of Beta-Cell Death and Insulin Secretion in Ketosis-Prone Diabetes (KPDM)

Approximately 50% of obese Black individuals present with diabetic ketoacidosis (DKA) at new-onset of diabetes undergo remission from insulin (fasting blood glucose [FBG &amp;lt;130 mg/dl, random BG &amp;lt; 180 mg/dl and HbA1c &amp;lt; 7% and off insulin therapy &amp;gt; 1 week) with intensive insulin treatment due to improved pancreatic beta(β)-cell secretion. Controversy exists whether KPDM is type 1 or type 2 diabetes and whether β-cell death contributes to DKA and β-cell secretion. Circulating unmethylated to methylated insulin DNA ratio (unMeth/MethINS) levels were found to correlate with β-cell death and β-cell secretion in patients at high risk for type 1 diabetes. In this exploratory study, we hypothesized that increased circulating unMeth/MethINS ratio at presentation of DKA correlates with decreased β-cell secretion in KPDM. Obese Black individuals presenting with DKA without GAD-65 antibodies were recruited 3-4 days after discharge from the hospital (Visit 1, n=22) and at insulin remission (Visit 2, n=19). Serum circulating unMeth/MethINS levels were measured at Visit 1. β-cell secretion was measured with glucagon stimulation tests (GST) performed at Visit 1 and Visit 2 and calculated as 6-min (maximum[Max]) and Delta (Max-baseline) C-peptide levels. At Visit 1, mean age was 38 ± 12 years and 7 (32%) were female. Mean BMI was 39.4 ± 10.6 kg/m2 with mean baseline HbA1c of 12.4 ± 1.8%. C-peptide levels increased significantly from Visit 1 to Visit 2 and expressed as median with minimum and maximum: Max (Visit 1: 2.94 [0.65, 12.07] vs. Visit 2: 5.87 [1.83, 12.11] ng/ml, p=0.011) and Delta (Visit 1: 1.57 (0.24, 6.88) vs. Visit 2: 2.80 [0.46, 9.01], p=0.047). UnMeth/MethINS ratio at Visit 1 was not significantly correlated (Spearman) with C-peptide levels at Visit 1 (Max: r=0.02, p=0.93, Delta: r=0.04, p=0.84) or at Visit 2 (Max: r=-0.07, p=0.79, Delta: r=0.03, p=0.89). Our data shows that in patients with KPDM, markers of β-cell death are not correlated with insulin secretion indicating that KPDM is consistent with type 2 diabetes. Disclosure P. Vellanki: Consultant; Self; Boehringer Ingelheim Pharmaceuticals, Inc. O. Oladejo: None. M. Fayfman: None. G. Davis: None. A. Migdal: None. L. R. Staimez: None. A. K. Smith: None. G. E. Umpierrez: Research Support; Self; AstraZeneca, Dexcom, Inc., Novo Nordisk. Funding National Institute of Diabetes and Digestive and Kidney Diseases (P30DK111024, UL1TR002378, K23DK11324-01A1)

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.

Comparative Effects of the Branched-Chain Amino Acids, Leucine, Isoleucine and Valine, on Gastric Emptying, Plasma Glucose, C-Peptide and Glucagon in Healthy Men.

(1) Background: Whey protein lowers postprandial blood glucose in health and type 2 diabetes, by stimulating insulin and incretin hormone secretion and slowing gastric emptying. The branched-chain amino acids, leucine, isoleucine and valine, abundant in whey, may mediate the glucoregulatory effects of whey. We investigated the comparative effects of intragastric administration of leucine, isoleucine and valine on the plasma glucose, C-peptide and glucagon responses to and gastric emptying of a mixed-nutrient drink in healthy men. (2) Methods: 15 healthy men (27 ± 3 y) received, on four separate occasions, in double-blind, randomised fashion, either 10 g of leucine, 10 g of isoleucine, 10 g of valine or control, intragastrically, 30 min before a mixed-nutrient drink. Plasma glucose, C-peptide and glucagon concentrations were measured before, and for 2 h following, the drink. Gastric emptying of the drink was quantified using 13C-acetate breath-testing. (3) Results: Amino acids alone did not affect plasma glucose or C-peptide, while isoleucine and valine, but not leucine, stimulated glucagon (p < 0.05), compared with control. After the drink, isoleucine and leucine reduced peak plasma glucose compared with both control and valine (all p < 0.05). Neither amino acid affected early (t = 0–30 min) postprandial C-peptide or glucagon. While there was no effect on overall gastric emptying, plasma glucose at t = 30 min correlated with early gastric emptying (p < 0.05). (4) Conclusion: In healthy individuals, leucine and isoleucine lower postprandial blood glucose, at least in part by slowing gastric emptying, while valine does not appear to have an effect, possibly due to glucagon stimulation.