Fasting Plasma Glucagon Levels Research Articles

Carotid body denervation improves hyperglycemia in obese mice.

The carotid bodies (CBs) have been implicated in glucose abnormalities in obesity via elevation of activity of the sympathetic nervous system. Obesity-induced hypertension is mediated by insulin receptor (INSR) signaling and by leptin, which binds to the leptin receptor (LEPRb) in CB and activates transient receptor potential channel subfamily M member 7 (TRPM7). We hypothesize that in mice with diet-induced obesity, hyperglycemia, glucose intolerance, and insulin resistance will be attenuated by the CB denervation (carotid sinus nerve dissection, CSND) and by knockdown of Leprb, Trpm7, and Insr gene expression in CB. In series of experiments in 75 male diet-induced obese (DIO) mice, we performed either CSND (vs. sham) surgeries or shRNA-induced suppression of Leprb, Trpm7, or Insr gene expression in CB, followed by blood pressure telemetry, intraperitoneal glucose tolerance and insulin tolerance tests, and measurements of fasting plasma insulin, leptin, corticosterone, glucagon and free fatty acids (FFAs) levels, hepatic expression of gluconeogenesis enzymes phosphoenolpyruvate carboxykinase (PEPCK) and glucose 6-phosphatase (G-6-Pase) mRNA and liver glycogen levels. CSND decreased blood pressure, fasting blood glucose levels and improved glucose tolerance without any effect on insulin resistance. CSND did not affect any hormone levels and gluconeogenesis enzymes, but increased liver glycogen level. Genetic knockdown of CB Leprb, Trpm7, and Insr had no effect on glucose metabolism. We conclude that CB contributes to hyperglycemia of obesity, probably by modulation of the glycogen-glucose equilibrium. Diabetogenic effects of obesity on CB in mice do not occur via activation of CB Leprb, Trpm7, and Insr.NEW & NOTEWORTHY This paper provides first evidence that carotid body denervation abolishes hypertension and improves fasting blood glucose levels and glucose tolerance in mice with diet-induced obesity. Furthermore, we have shown that this phenomenon is associated with increased liver glycogen content, whereas insulin sensitivity and enzymes of gluconeogenesis were not affected.

Different post-pancreatectomy glucagon responses to a meal test between surgical approaches

Residual pancreatic endocrine function is important for maintaining metabolic status after pancreatectomy and is closely related to patient nutritional status and prognosis. In contrast to insulin secretion, the significance of glucagon secretion following pancreatectomy remains unclear. In this study, we assessed the changes in pancreatic glucagon secretion during pancreatectomy to determine their pathophysiological significance. We evaluated glucagon and insulin secretion using a liquid meal tolerance test before and after pancreatectomy in patients scheduled to undergo pancreaticoduodenectomy (PD) or distal pancreatectomy (DP). After pancreatectomy, fasting plasma glucagon levels were significantly decreased in both the PD (n = 10) and DP (n = 5) groups (PD: from 18.4 to 10.5 pg/mL, p = 0.037; DP: from 21.0 to 12.1 pg/mL, p = 0.043), whereas postprandial plasma glucagon levels were not changed. In the liquid meal tolerance test after pancreatectomy, 60-min plasma glucagon levels and the area under the curve (AUC) for 0-120 min of PD were significantly higher than those for DP (60-min plasma glucagon: PD 49.0 vs. DP 21.7 pg/mL, p = 0.040; AUC0-120min: PD 4,749 vs. DP 3,564 μg min/mL, p = 0.028). Postoperative plasma glucose, serum insulin, and serum C-peptide levels during the liquid meal tolerance test were not significantly different between the two groups. Although fasting plasma glucagon levels decreased, postprandial glucagon responses were maintained after both PD and DP. The difference in residual meal-stimulated glucagon response between PD and DP suggests that a relative excess of postprandial glucagon is involved in the postoperative nutritional status after PD through its impact on systemic metabolic status.

The Difference in Glucagon Response to Breakfast Between Non-Obese Patients With Long-Duration Type 1 and Type 2 Diabetes

Background: A balanced action of insulin and glucagon is essential for treating diabetes. This study aimed to assess the change in blood glucagon levels from fasting to a postprandial state and to compare them between patients with type 1 diabetes (T1DM) and type 2 diabetes (T2DM). Methods: This study enrolled patients with T1DM (n = 13) who had undetectable serum C-peptide levels (< 0.02 ng/mL) and patients with T2DM (n = 13) whose age, gender, and body mass index were matched to cases (1:1) as controls. Plasma glucose, serum C-peptide, and plasma glucagon in fasting and 2 h after consuming a standard breakfast for diabetic patients were measured and compared between groups. Results: There were no significant differences in plasma glucose and hemoglobin A1c levels between patients with T1DM and T2DM. However, fasting plasma glucagon levels were significantly lower in patients with T1DM than those in patients with T2DM (19.2 ± 13.0 pg/mL vs. 31.6 ± 18.3 pg/mL, P = 0.029). Furthermore, the glucagon’s response to a standardized meal for diabetic patients differed between patients with T1DM and T2DM. Conclusions: The significant difference in glucagon response to the meal may be caused by the abnormal postprandial secretion of glucagon in patients with T1DM. The nutrient ratio of the meal may also influence glucagon secretion. J Endocrinol Metab. 2022;12(4-5):134-139 doi: https://doi.org/10.14740/jem834

Assessment of Two Different Glucagon Assays in Healthy Individuals and Type 1 and Type 2 Diabetes Patients.

Methods for glucagon analysis suffered in the past from lack of specificity and a narrow sensitivity range, which has led to inaccurate results and to the suggestion that type 1 diabetes (T1D) and type 2 diabetes (T2D) patients have elevated fasting glucagon levels. However, the availability of more specific and more sensitive methods to detect intact glucagon has shown that actual glucagon levels are lower than previously assumed. This study aimed to characterize fasting plasma glucagon levels in healthy individuals and T1D and T2D patients with two different glucagon assays. The study included 20 healthy individuals, 20 T1D and 20 T2D patients. Blood was collected under fasting conditions. A double-antibody sandwich enzyme-linked immunosorbent assay (ELISA) and a conventional radioimmunoassay (RIA) were used. A significant difference in fasting glucagon levels between healthy individuals and T2D was observed by ELISA, but not by RIA. ELISA also yielded lower glucagon levels in healthy individuals than in T1D and T2D patients which RIA did not. RIA produced significantly (p = 0.0001) higher overall median glucagon values than ELISA in a pooled analysis. These results underline the notion that the choice of selective laboratory methods is highly relevant for mechanistic endocrine research.

776-P: SGLT2i Increased the Fasting Glucagon Level in Patients with Diabetes: A Meta-analysis

Aims: Although it has long been assumed that increased glucagon level participants in the ketosis during sodium-glucose cotransporter 2 inhibitors (SGLT2i) treatment, the effect of SGLT2i on glucagon in diabetic patients remains controversial. Hence, we conducted this metanalysis to assess the overall effect of SGLT2i treatment on plasma glucagon level. Methods: PubMed/MEDLINE, Embase, and Cochrane databases were searched for studies published before August 2020. Clinical trials in type 1 diabetes (T1DM) and type 2 diabetes (T2DM) patients with the report of glucagon variation before and after SGLT2i treatment was included. Result: In total, 10 trials were included. Overall, SGLT2i treatment was associated with significantly increased fasting plasma glucagon level (WMD, 35.00 pg/ml; 95% CI, 24.48 to 45.52 pg/ml, P Conclusions: The increase in fasting glucagon level may be associated with the reduction of insulin, which may decrease the level of insulin-glucagon ratio and make patients susceptible to ketosis. Disclosure X. Zhu: None. C. Lin: None. L. Li: None. S. Hu: None. X. Cai: None. L. Ji: None. Funding National Natural Science Foundation of China (81970698, 81970708); Beijing Natural Science Foundation (7202216)

Impaired Suppression of Glucagon in Obese Subjects Parallels Decline in Insulin Sensitivity and Beta-Cell Function.

To examine the relationship between plasma glucagon levels and insulin sensitivity and insulin secretion in obese subjects. Suppression of plasma glucagon was examined in 275 obese Hispanic Americans with varying glucose tolerance. All subjects received a 2-hour oral glucose tolerance test (OGTT) and a subset (n = 90) had euglycemic hyperinsulinemic clamp. During OGTT, we quantitated suppression of plasma glucagon concentration, Matsuda index of insulin sensitivity, and insulin secretion/insulin resistance (disposition) index. Plasma glucagon suppression was compared between quartiles of insulin sensitivity and beta-cell function. Fasting plasma glucagon levels were similar in obese subjects with normal glucose tolerance (NGT), prediabetes, and type 2 diabetes (T2D), but the fasting glucagon/insulin ratio decreased progressively from NGT to prediabetes to T2D (9.28 ± 0.66 vs 6.84 ± 0.44 vs 5.84 ± 0.43; P < 0.001). Fasting and 2-hour plasma glucagon levels during OGTT progressively increased and correlated positively with severity of insulin resistance (both Matsuda index and euglycemic hyperinsulinemic clamp). The fasting glucagon/insulin ratio declined with worsening insulin sensitivity and beta-cell function, and correlated with whole-body insulin sensitivity (Matsuda index, r = 0.81; P < 0.001) and beta-cell function (r = 0.35; P < 0.001). The glucagon/insulin ratio also correlated and with beta-cell function during OGTT at 60 and 120 minutes (r = -0.47; P < 0.001 and r = -0.32; P < 0.001). Insulin-mediated suppression of glucagon secretion in obese subjects is impaired with increasing severity of glucose intolerance and parallels the severity of insulin resistance and beta-cell dysfunction.

Variation in plasma glucagon levels according to obesity status in Japanese Americans with normal glucose tolerance.

Japanese Americans living in the United States are genetically identical to Japanese people, but have undergone a rapid and intense westernization of their lifestyle. This study investigated variability in glucagon secretion after glucose loading among Japanese Americans with normal glucose tolerance (NGT) according to obesity status. The 75-g oral glucose tolerance test (OGTT) was performed for 138 Japanese Americans (aged 40-75 years) living in Los Angeles. Plasma glucagon levels measured using the sandwich enzyme-linked immunosorbent assay were compared according to body mass index (BMI) categories among 119 individuals with NGT. The individuals were classified into three categories according to their BMI values: <22 kg/m2 (n = 37), 22-24.9 kg/m2 (n = 46), and ≥25 kg/m2 (n = 36). Fasting plasma glucagon levels and glucagon-area under the curve levels during the OGTT were the highest in the BMI ≥25 kg/m2 group. Fasting glucagon levels were correlated with BMI (r = 0.399, p < 0.001), fasting insulin levels (r = 0.275, p = 0.003) and the homeostasis model assessment-insulin resistance (r = 0.262, p = 0.004). In conclusion, our findings suggest that fasting hyperglucagonemia is associated with obesity and insulin resistance even during the NGT stage in the Japanese American population.

Hyperglucagonemia in youth is associated with high plasma free fatty acids, visceral adiposity, and impaired glucose tolerance.

To delineate potential mechanisms for fasting hyperglucagonemia in childhood obesity by studying the associations between fasting plasma glucagon concentrations and plasma lipid parameters and fat compartments. Cross-sectional study of children and adolescents with obesity (n = 147) and lean controls (n = 43). Differences in free fatty acids (FFAs), triglycerides, insulin, and fat compartments (quantified by magnetic resonance imaging) across quartiles of fasting plasma glucagon concentration were analyzed. Differences in oral glucose tolerance test (OGTT) glucagon response was tested in high vs low FFAs, triglycerides, and insulin. Human islets of Langerhans were cultured at 5.5 mmol/L glucose and in the absence or presence of a FFA mixture with total FFA concentration of 0.5 mmol/L and glucagon secretion quantified. In children with obesity, the quartile with the highest fasting glucagon had higher insulin (201 ± 174 vs 83 ± 39 pmol/L, P < .01), FFAs (383 ± 52 vs 338 ± 109 μmol/L, P = .02), triglycerides (1.5 ± 0.9 vs 1.0 ± 0.7 mmol/L, P < .01), visceral adipose tissue volume (1.9 ± 0.8 vs 1.2 ± 0.3 dm3 , P < .001), and a higher prevalence of impaired glucose tolerance (IGT; 41% vs 8%, P = .01) than the lowest quartile. During OGTT, children with obesity and high insulin had a worse suppression of glucagon during the first 10 minutes after glucose intake. Glucagon secretion was 2.6-fold higher in islets treated with FFAs than in those not treated with FFAs. Hyperglucagonemia in childhood obesity is associated with hyperinsulinemia, high plasma FFAs, high plasma triglycerides, visceral adiposity, and IGT. The glucagonotropic effect of FFAs on isolated human islets provides a potential mechanism linking high fasting plasma FFAs and glucagon levels.

274-OR: Beta-Cell Dysfunction Is Associated with Impaired Insulin-Mediated Suppression of Glucagon in Obese Hispanic Americans

Recent studies have demonstrated an increase in the glucagon:insulin ratio in lean versus obese subjects. We assessed insulin-mediated suppression of plasma glucagon levels in 260 obese Hispanic Americans (59 NGT, HbA1c= 5.1±0.1%, BMI= 32.6±0.7; 109 Prediabetes, HbA1c= 5.8±0.1%, BMI= 33.8±0.5; 92 T2D, HbA1c= 7.3±0.2%, BMI= 34±0.5) with varying glucose tolerance. Subjects participated in a 2-h OGTT with measurement of plasma glucose, insulin, glucagon concentrations. During the OGTT, we quantitated insulin-mediated suppression of plasma glucagon concentration, Matsuda Index of insulin sensitivity, and the insulin secretion/insulin sensitivity (disposition) index using plasma C-peptide concentration. There was no difference in fasting plasma glucagon level between obese subjects with normal glucose tolerance (NGT), prediabetes, and type 2 diabetes (T2D). However, there was a progressive decrease in fasting glucagon:insulin ratio from NGT to prediabetes to T2D (8.71±0.72 vs. 6.92±0.53 vs. 5.66±0.41, P&amp;lt;0.01). During OGTT at 60 min, glucagon:insulin ratio increased from NGT to T2D (0.93±0.09 vs. 0.89±0.07 vs. 2.33±0.20, P&amp;lt;0.001), and the suppression of plasma glucagon (compared to basal value) was markedly decreased (10.3±3.4% vs. 9.3±1.9% vs. 2.5±2.8%, P&amp;lt;0.05). At 120 min (OGTT), glucagon:insulin ratio was increased in T2D versus NGT (1.28±0.17 vs. 2.0±0.20, P&amp;lt;0.01). The glucagon:insulin ratio was closely correlated with whole body insulin sensitivity and β-cell function during the fasting state (Matsuda Index, r= 0.51, P&amp;lt;0.001; Disposition Index, r= 0.30, P&amp;lt;0.001) and with Disposition Index during the OGTT at 60 and 120 min (r= -0.41, P&amp;lt;0.001; r= -0.21, P&amp;lt;0.01), respectively. Collectively, these findings indicate that insulin-mediated suppression of glucagon secretion is impaired with increasing severity of glucose intolerance in obese Hispanic Americans and is closely associated with insulin resistance and β-cell dysfunction. Disclosure X. Chen: None. E.R. Maldonado Corchado: None. A. Merovci: None. E. Case: None. D. Tripathy: None. R.A. DeFronzo: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Elcelyx Therapeutics, Inc., Intarcia Therapeutics, Inc., Janssen Pharmaceuticals, Inc., Novo Nordisk Inc. Research Support; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Janssen Pharmaceuticals, Inc., Merck &amp; Co., Inc. Speaker's Bureau; Self; AstraZeneca, Novo Nordisk Inc.

1860-P: Liver Fat and Visceral Fat Are Associated with Different Metabolic and Pathophysiologic Profiles but with Similar Relationships with Whole Body Insulin Resistance

MRI-based examinations of hepatic steatosis and body fat are becoming more familiar and useful for metabolic studies including NAFLD. MRI-estimated proton density fat fraction (MRI-PDFF) can haptic fat exactly without biopsy, enabling us to evaluate the effect of liver fat more sophisticatedly than ever. Although hepatic fat and visceral fats are both important for metabolic and cardiovascular diseases, detailed evaluation of the effect of each fat depot on various metabolic profiles have not been performed, In the present study, we evaluated the differential effect between hepatic and visceral fats on various metabolic profiles including glucose and lipid metabolism, islet cell function, insulin resistance, and inflammation. A total of 82 subjects (25 healthy volunteers and 57 patients with suspected, or proven NAFLD) who underwent MRI examinations for MRI-PDFF and visceral fat measurement. Additionally, anthropometric and laboratory studies and total body fat measurement by DXA were also performed. Other causes of chronic liver diseases, such as alcoholic, autoimmune or viral hepatitis, and other diseases, were excluded from the study. The amounts of hepatic fat and visceral fats measured by MRI showed similar significant correlations with HOMA-IR (r=0.540 vs. r=0.538, p &amp;lt;0.01, respectively) as with A1C (r=0.448 vs. r=0.495, p &amp;lt;0.01 each). However, hepatic fat showed more close association with FBS, triacylglycerol, complement factor C3, and cytokeratin 18. Visceral fat correlated more with fasting plasma insulin, glucagon and angiotensinogen levels. Total body fat measured by DXA did not show such characteristic patterns of correlations and showed only a weak or no correlation with those parameters. Thus, our results showed that both hepatic fat and visceral fat depots are important determinants of whole-body insulin resistance and glucose metabolism. Disclosure I. Park: None. K. Lee: None. D. Lee: None.

Positive correlation between fasting plasma glucagon and serum C-peptide in Japanese patients with diabetes

AimsGlucagon plays pivotal roles in systemic glucose homeostasis mainly by promoting hepatic glucose output. Using a sandwich enzyme-linked immunosorbent assay (ELISA), we evaluated fasting plasma glucagon levels in hospitalized patients with type 1 or type 2 diabetes, and assessed the relationships between glucagon levels and various clinical parameters. MethodsWe enrolled adult Japanese diabetes patients admitted to Osaka University Medical Hospital for glycemic control between July 2017 and May 2018 in this study. After patients had fasted for 12 h, blood samples were obtained and plasma glucagon levels were measured using a sandwich ELISA. ResultsTotal 107 patients participated in the study. The mean fasting plasma glucagon level of patients with acute onset type 1 diabetes was significantly lower than that of patients with type 2 diabetes (p < 0.05). Plasma glucagon levels were not significantly correlated with plasma glucose levels in patients with type 1 diabetes or in patients with type 2 diabetes. Multiple regression analysis indicated that fasting glucagon levels were independently and significantly correlated with fasting serum C-peptide levels in patients with type 2 diabetes. ConclusionsOur results suggest that insulin and glucagon secretion are balanced in the fasting state in patients with type 2 diabetes.

Relationship Between Fasting Plasma Glucagon Level and Renal Function-A Cross-Sectional Study in Individuals With Type 2 Diabetes.

Background and AimThe kidney is the main site for glucagon clearance. However, a recent study showed that hyperglucagonemia in patients with end-stage renal disease might not be caused by full-length intact glucagon. Additionally, the relationship between glucagon and renal function in early-stage chronic kidney disease (CKD) has not yet been characterized. We studied the association of fasting glucagon with renal function across a wide range of glomerular filtration rates (GFRs) in participants with type 2 diabetes.Participants and Methods326 participants with type 2 diabetes and renal function spanning CKD stage 1 to 5 were included in the present cross-sectional study. Fasting full-length plasma glucagon was quantified using a newly developed ELISA (Mercodia AB, Uppsala, Sweden).ResultsThe fasting plasma glucagon level was elevated linearly from CKD stage 1 to 5 [from a median of 2.5 pM (interquartile range, 1.4 to 4.7) in CKD 1 to a median of 8.3 pM (interquartile range, 5.9 to 12.8) in CKD 5; P for trend < 0.0001], from as early as CKD stage 2 compared with that in stage 1 (Bonferroni-corrected P < 0.0001). The estimated GFR and homeostatic model of assessment–insulin resistance were the main determinants of the fasting glucagon level. These explained 14.3% and 10.3% of the glucagon variance, respectively. Albuminuria was not associated with fasting glucagon after adjustment for estimated GFR.ConclusionsFasting full-length glucagon was elevated linearly with the deterioration in renal function in individuals with type 2 diabetes, even in those with early CKD. In addition to renal function, insulin sensitivity was also a main determinant of glucagon variance.

Targeting hepatic glutaminase activity to ameliorate hyperglycemia.

Glucagon levels increase under homeostatic, fasting conditions, promoting the release of glucose from the liver by accelerating the breakdown of glycogen (also known as glycogenolysis). Glucagon also enhances gluconeogenic flux, including from an increase in the hepatic consumption of amino acids. In type 2 diabetes, dysregulated glucagon signaling contributes to the elevated hepatic glucose output and fasting hyperglycemia that occur in this condition. Yet, the mechanism by which glucagon stimulates gluconeogenesis remains incompletely understood. Contrary to the prevailing belief that glucagon acts primarily on cytoplasmic and nuclear targets, we find glucagon-dependent stimulation of mitochondrial anaplerotic flux from glutamine that increases the contribution of this amino acid to the carbons of glucose generated during gluconeogenesis. This enhanced glucose production is dependent on protein kinase A (PKA) and is associated with glucagon-stimulated calcium release from the endoplasmic reticulum, activation of mitochondrial α-ketoglutarate dehydrogenase, and increased glutaminolysis. Mice with reduced levels of hepatic glutaminase 2 (GLS2), the enzyme that catalyzes the first step in glutamine metabolism, show lower glucagon-stimulated glutamine-to-glucose flux in vivo, and GLS2 knockout results in higher fasting plasma glucagon and glutamine levels with lower fasting blood glucose levels in insulin-resistant conditions. As found in genome-wide association studies (GWAS), human genetic variation in the region of GLS2 is associated with higher fasting plasma glucose; here we show in human cryopreserved primary hepatocytes in vitro that these natural gain-of-function missense mutations in GLS2 result in higher glutaminolysis and glucose production. These data emphasize the importance of gluconeogenesis from glutamine, particularly in pathological states of increased glucagon signaling, while suggesting a possible new therapeutic avenue to treat hyperglycemia.

Steroid-Induced Hyperglycemia Successfully Treated With Once-Weekly Dulaglutide in an Old Patient With Type 2 Diabetes

Glucocorticoids induce hyperglycemia in case of pancreatic alpha- and beta-cell dysfunction. Glucagon-like peptide-1 receptor agonists (GLP-1RA) may prevent steroid-induced hyperglycemia by improving hyperglucagonemia and insulin secretion. An 85-year-old man was treated with oral prednisolone for chronic hypersensitivity pneumonitis, and his glycemic control deteriorated after the initiation of steroid therapy. After the administration of dulaglutide injection, his glycemic control was improved and we could discontinue insulin therapy. Both fasting and postprandial plasma glucagon levels were significantly suppressed by a GLP-1RA, dulaglutide. GLP-1RAs therapy may be a useful strategy for the treatment of steroid-induced hyperglycemia. J Endocrinol Metab. 2018;8(1):10-12 doi: https://doi.org/10.14740/jem491w

Improved Glycemic Control due to Reduction in Glucagon Levels by the Administration of Once-Weekly Dulaglutide in a Non-Obese Patient With Type 2 Diabetes

Treatment with glucagon-like peptide-1 receptor agonists (GLP-1RAs) is a cornerstone for the management of obesity and type 2 diabetes. GLP-1RAs improve the glycemic control by suppressing glucagon secretion and stimulating insulin secretion in patients with type 2 diabetes. Here, we report the case of a patient with type 2 diabetes with postprandial hyperglucagonemia who was successfully treated by the administration of once-weekly dulaglutide. A 67-year-old, non-obese woman was admitted to our hospital for preoperative glycemic control. Her glycemic control significantly improved after the administration of dulaglutide. Both fasting and postprandial plasma glucagon levels were effectively suppressed by dulaglutide, which ameliorated hyperglycemia. Thus, to achieve an optimal glycemic control, clinicians should consider suppressing glucagon secretion in addition to improving insulin secretion and sensitivity. J Endocrinol Metab. 2018;8(1):6-9 doi: https://doi.org/10.14740/jem486w

Improved Glycemic Control due to Reduction in Glucagon Levels by the Administration of Once-Weekly Dulaglutide in a Non-Obese Patient With Type 2 Diabetes

Treatment with glucagon-like peptide-1 receptor agonists (GLP-1RAs) is a cornerstone for the management of obesity and type 2 diabetes. GLP-1RAs improve the glycemic control by suppressing glucagon secretion and stimulating insulin secretion in patients with type 2 diabetes. Here, we report the case of a patient with type 2 diabetes with postprandial hyperglucagonemia who was successfully treated by the administration of once-weekly dulaglutide. A 67-year-old, non-obese woman was admitted to our hospital for preoperative glycemic control. Her glycemic control significantly improved after the administration of dulaglutide. Both fasting and postprandial plasma glucagon levels were effectively suppressed by dulaglutide, which ameliorated hyperglycemia. Thus, to achieve an optimal glycemic control, clinicians should consider suppressing glucagon secretion in addition to improving insulin secretion and sensitivity. J Endocrinol Metab. 2018;8(1):6-9 doi: https://doi.org/10.14740/jem486w

Effects of dietary biotin supplementation on glucagon production, secretion, and action.

Despite increasing evidence that pharmacologic concentrations of biotin modify glucose metabolism, to our knowledge there have not been any studies addressing the effects of biotin supplementation on glucagon production and secretion, considering glucagon is one of the major hormones in maintaining glucose homeostasis. The aim of this study was to investigate the effects of dietary biotin supplementation on glucagon expression, secretion, and action. Male BALB/cAnN Hsd mice were fed a control or a biotin-supplemented diet (1.76 or 97.7mg biotin/kg diet) for 8wk postweaning. Glucagon gene mRNA expression was measured by the real-time polymerase chain reaction. Glucagon secretion was assessed in isolated islets and by glucagon concentration in plasma. Glucagon action was evaluated by glucagon tolerance tests, phosphoenolpyruvate carboxykinase (Pck1) mRNA expression, and glycogen degradation. Compared with the control group, glucagon mRNA and secretion were increased from the islets of the biotin-supplemented group. Fasting plasma glucagon levels were higher, but no differences between the groups were observed in nonfasting glucagon levels. Despite the elevated fasting glucagon levels, no differences were found in fasting blood glucose concentrations, fasting/fasting-refeeding glucagon tolerance tests, glycogen content and degradation, or mRNA expression of the hepatic gluconeogenic rate-limiting enzyme, Pck1. These results demonstrated that dietary biotin supplementation increased glucagonexpression and secretion without affecting fasting blood glucose concentrations or glucagon tolerance and provided new insights into the effect of biotin supplementation on glucagon production and action.

The Dual Amylin- and Calcitonin-Receptor Agonist KBP-042 Works as Adjunct to Metformin on Fasting Hyperglycemia and HbA1c in a Rat Model of Type 2 Diabetes

KBP-042 is a dual amylin and calcitonin receptor agonist that increases glucose tolerance and insulin action and reduces body weight in rat models of obesity and prediabetes. The objective of the present study was to 1) evaluate KBP-042 as a treatment of late-stage type 2 diabetes in a rat model and 2) assess the value of adding KBP-042 to the standard of care, metformin, to consider KBP-042 as a relevant drug for treating patients with type 2 diabetes. Two studies were included: an intervention study and a prevention study. In the intervention study, treatment with 5 µg/kg KBP-042 was initiated in 11-week-old Zucker diabetic fatty (ZDF) rats, in which glucose tolerance, fasting glycemia, and glycated hemoglobin were assessed after 4 weeks. In the prevention study, either metformin (400 mg/kg), KBP-042 (5 µg/kg), or a combination of both were administered to ZDF rats for a total of 9 weeks. Glycemia, glucose tolerance, and insulin tolerance were tested. Furthermore, fasting plasma insulin and glucagon levels were evaluated. Finally, pancreatic content of insulin was assessed as a surrogate marker of beta-cell mass. It was found that KBP-042 was efficient in lowering fasting plasma glucose as well as improving glucose tolerance, both as prevention and intervention of disease progression. Furthermore, KBP-042 was efficient in combination with metformin and had additional effects compared with either therapy alone. In conclusion, KBP-042 is a highly relevant therapeutic candidate against type 2 diabetes, effective both as an add-on therapy to metformin and as a stand-alone therapy.

High Plasma Glucagon Levels Correlate with Waist-to-Hip Ratio, Suprailiac Skinfold Thickness, and Deep Subcutaneous Abdominal and Intraperitoneal Adipose Tissue Depots in Nonobese Asian Indian Males with Type 2 Diabetes in North India.

We aimed to correlate plasma glucagon levels with anthropometric measures and abdominal adipose tissue depots. Nonobese males (n = 81; BMI < 25 kg/m2) with T2DM of less than one-year duration and nonobese males without diabetes (n = 30) were evaluated for the following: anthropometry (BMI, waist circumference, W-HR, and truncal skinfolds), whole-body DEXA (for body fat and fat-free mass), and MRI scan (for volumes of subcutaneous abdominal adipose tissue (SCAT) including superficial and deep, intra-abdominal visceral adipose tissue (including intraperitoneal adipose tissue (IPAT), retroperitoneal adipose tissue, liver span and fatty liver, and pancreatic volume)). Plasma glucose and glucagon, serum insulin, hepatic transaminases, and lipid profile were measured. Significantly higher levels of fasting and postprandial glucagon (p < 0.001) and fasting and postprandial insulin (p < 0.001) were seen in patients with T2DM. The mean values of fasting and postprandial plasma glucagon levels were higher in T2DM patients with NAFLD (n = 37) as compared to T2DM patients without NAFLD (n = 44). Four independent predictors were derived for fasting glucagon levels in patients with T2DM, namely, W-HR, suprailiac skinfold thickness, IPAT, and deep SCAT (p < 0.05; r2 = 0.84). These observations in Asian Indians may have significance for diabetes therapies which impact glucagon levels.

Effectiveness of the glucagon test in estimating islet function for liraglutide treatment in a lean diabetic patient with impaired insulin response to glucose

A 52-year-old lean woman was admitted to hospital for a medical examination in July 2010. A 75 g oral glucose test (75 g OGTT) revealed postprandial hyperglycemia (above 200 mg/dl at 120 min) and she was diagnosed with diabetes mellitus. She was negative for diabetes-related autoantibodies. The 75 g OGTT also revealed a very low insulinogenic index (I.I.) of 0.024 μU/ml/mg/dl; however, her plasma C-peptide immunoreactivity (CPR) response to glucagon was preserved (0.94 and 5.56 at 0 and 6 min, respectively). At the same time, she also suffered from Fe-deficiency anemia due to endometriosis, for which treatment with leuprorelin was initiated after hospitalization in August 2010. Meanwhile, her postprandial plasma glucose level continued to increase. Subsequently, on November 30, 2010, alogliptin therapy at a dose of 6.25 mg was initiated, which was increased to 25 mg on December 28, 2010. Leuprorelin therapy was discontinued on January 14, 2011; however, her plasma glucose level remained high despite the alogliptin therapy. Administration of 0.3 mg liraglutide was initiated on March 15, 2011, and the dose was increased to 0.6 mg on June 7, 2011. The plasma glucose level, glycosylated hemoglobin (HbA1c) level, and 1.5 anhydroglucitol level gradually improved, as did her I.I. Moreover, fasting plasma glucagon levels were suppressed by liraglutide. Her fasting serum CPR to plasma glucose ratio and homeostasis model assessment (HOMA-R) were low both before and after liraglutide administration. These results suggest that the fasting CPR to glucose ratio may underestimate residual islet function in lean patients with high insulin sensitivity. Thus, a glucagon test may be useful to estimate residual islet function when administering liraglutide treatment in lean diabetes patients.