Suppression Of Glucagon Levels Research Articles

Predicting GPR40 Agonists with A Deep Learning-Based Ensemble Model.

Recent studies have identified G protein-coupled receptor 40 (GPR40) as a promising target for treating type 2 diabetes mellitus, and GPR40 agonists have several superior effects over other hypoglycemic drugs, including cardiovascular protection and suppression of glucagon levels. In this study, we constructed an up-to-date GPR40 ligand dataset for training models and performed a systematic optimization of the ensemble model, resulting in a powerful ensemble model (ROC AUC: 0.9496) for distinguishing GPR40 agonists and non-agonists. The ensemble model is divided into three layers, and the optimization process is carried out in each layer. We believe that these results will prove helpful for both the development of GPR40 agonists and ensemble models. All the data and models are available on GitHub. (https://github.com/Jiamin-Yang/ensemble_model).

Momordica charantia (bitter melon) efficacy and safety on glucose metabolism in Korean prediabetes participants: a 12-week, randomized clinical study

This study was performed to investigate the effects of bitter melon extract (BME) on glucose metabolism, insulin resistance, and various metabolic parameters of participants with prediabetes. A 12-week randomized placebo-controlled clinical study was conducted with prediabetic patients. A total of 76 participants were randomly assigned to initiate the study. In the final analysis, 33 and 32 subjects were included in the BME and placebo groups, respectively. Results showed that 75 g oral glucose tolerance test (OGTT) blood glucose level decreased in BME group after 12 weeks. The glucose level after 30 min of glucose ingestion decreased significantly. The glucagon level in the BME group after 12 weeks significantly decreased 120 min after 75 g OGTT. These results suggested that bitter melon exhibits glucose-lowering effects through suppression of glucagon levels in people with prediabetes.

Altered hormonal and autonomic nerve responses to hypo- and hyperglycaemia are found in overweight and insulin-resistant individuals and may contribute to the development of type 2 diabetes

Aims/hypothesisResults from animal models and some clinical work suggest a role for the central nervous system (CNS) in glucose regulation and type 2 diabetes pathogenesis by modulation of glucoregulatory hormones and the autonomic nervous system (ANS). The aim of this study was to characterise the neuroendocrine response to various glucose concentrations in overweight and insulin-resistant individuals compared with lean individuals.MethodsOverweight/obese (HI, n = 15, BMI ≥27.0 kg/m2) and lean (LO, n = 15, BMI <27.0 kg/m2) individuals without diabetes underwent hyperinsulinaemic euglycaemic–hypoglycaemic clamps and hyperglycaemic clamps on two separate occasions with measurements of hormones, Edinburgh Hypoglycaemic Symptom Scale (ESS) score and heart rate variability (HRV). Statistical methods included groupwise comparisons with Mann–Whitney U tests, multilinear regressions and linear mixed models between neuroendocrine responses and continuous metabolic variables.ResultsDuring hypoglycaemic clamps, there was an elevated cortisol response in HI vs LO (median ΔAUC 12,383 vs 4793 nmol/l × min; p = 0.050) and a significantly elevated adrenocorticotropic hormone (ACTH) response in HI vs LO (median ΔAUC 437.3 vs 162.0 nmol/l × min; p = 0.021). When adjusting for clamp glucose levels, obesity (p = 0.033) and insulin resistance (p = 0.009) were associated with elevated glucagon levels. By contrast, parasympathetic activity was less suppressed in overweight individuals at the last stage of hypoglycaemia compared with euglycaemia (high-frequency power of HRV, p = 0.024). M value was the strongest predictor for the ACTH and PHF responses, independent of BMI and other variables. There was a BMI-independent association between the cortisol response and ESS score response (p = 0.024). During hyperglycaemic clamps, overweight individuals displayed less suppression of glucagon levels (median ΔAUC −63.4% vs −73.0%; p = 0.010) and more suppression of sympathetic relative to parasympathetic activity (low-frequency/high-frequency power, p = 0.011).Conclusions/interpretationThis study supports the hypothesis that altered responses of insulin-antagonistic hormones and the ANS to glucose fluctuations occur in overweight and insulin-resistant individuals, and that these responses are probably partly mediated by the CNS. Their potential role in development of type 2 diabetes needs to be addressed in future research.Graphical abstract

Hyperglycemia Associated With Pasireotide: Results From a Mechanistic Study in Healthy Volunteers

Pasireotide (SOM230) is a somatostatin analog with affinity for somatostatin receptor subtypes sst₁₋₃ and sst₅. Clinical trials have demonstrated the efficacy of pasireotide in treating Cushing's disease and acromegaly but have also shown adverse effects on glucose metabolism. The aim of the study was to evaluate the mechanism of pasireotide-associated hyperglycemia. We conducted a randomized, single-center, open-label study. Forty-five healthy male volunteers were randomized to pasireotide 600 (n = 19), 900 (n = 19), or 1200 μg (n = 7) sc twice a day for 7 days. Randomization to 1200 μg was discontinued because of increased severity of gastrointestinal adverse events in this arm. An oral glucose tolerance test (OGTT), a hyperglycemic clamp test, and a hyperinsulinemic-euglycemic clamp test were performed on 3 consecutive days at baseline and treatment end. The effect of pasireotide on insulin secretion and hepatic/peripheral insulin sensitivity was measured. The secondary objective was to evaluate the effects of pasireotide on oral glucose absorption. Pasireotide treatment resulted in significant decreases in insulin AUC0-180 min during both the hyperglycemic clamp test (-77.5%; P < .001 in both dose groups) and the OGTT (-61.9%; P < .001 in both dose groups). Suppression of glucagon levels was less pronounced. No significant changes in hepatic or peripheral insulin sensitivity were found during the hyperinsulinemic-euglycemic clamp test. Additionally, significant increases in glucose AUC₀₋₁₈₀ min (+67.4%) and decreases in AUC₀₋₁₈₀ min glucagon-like peptide-1 (-46.7%) and glucose-dependent insulinotropic polypeptide levels (-69.8%) were observed during the OGTT. No dose dependency or unexpected adverse events were observed. Pasireotide-associated hyperglycemia is related to decreases in insulin secretion and incretin hormone responses, without changes in hepatic/peripheral insulin sensitivity.

Sitagliptin is effective and safe as add-on to insulin in patients with absolute insulin deficiency: a case series

IntroductionIt is generally believed that incretin-based therapies are effective in patients possessing certain levels of preserved β-cell function. So far, there are no reports that show the effectiveness of dipeptidyl peptidase-4 inhibitors in patients who absolutely lack the capacity for endogenous insulin secretion.Case presentationThis report describes the efficacy of sitagliptin in three Japanese patients (a 91-year-old Japanese woman with type 1 diabetes, a 54-year-old Japanese man with type 2 diabetes and a 30-year-old Japanese man with features of both type 1 and type 2 diabetes) who had no detectable post-meal C-peptide levels. Although they were receiving intensive insulin therapy together with some oral hypoglycemic agents, their glycemic control remained poor. Sitagliptin was added to the ongoing therapeutic regimen to provide better glycemic control. Although these patients had mild hypoglycemia, effective reductions of hemoglobin A1c levels were observed without any adverse events in the liver and kidney during the following 24 weeks. Two of the patients were able to reduce their insulin doses, and one of the patients could discontinue one of the oral hypoglycemic agents. There was no weight gain or gastrointestinal complaints among the three patients. Post-meal C-peptide levels remained undetectable after sitagliptin treatment.ConclusionThis report demonstrates that sitagliptin is effective and safe as an add-on therapy to insulin in reducing blood glucose levels in patients who absolutely lack the capacity for endogenous insulin secretion. The improvement seen in glycemic control could not be due to enhanced endogenous insulin secretion, since post-meal C-peptide levels remained undetectable after sitagliptin treatment, but it could be a result of other factors (for example, suppression of glucagon levels). However, the glucagon-suppressive effect of sitagliptin is known to be rather weak and short-lived. Given this background, a novel hypothesis that the glycemic effects of this drug may be caused by mechanisms that are independent of the glucagon-like peptide 1 axis (extra-pancreatic effect) will be discussed.

Hyperglycemia and Glucagon Suppression: Possible Importance of the Vagus and Enteric Humoral Factors

Augmentation of insulin release after oral glucose by a gastrointestinal humoral mechanism is well accepted. The suggestion of a similar mechanism for suppression of glucagon release after oral glucose has not been previously tested. In this study, plasma glucagon levels have been estimated in five normal subjects after both oral and iv administration of glucose. A variable iv glucose infusion rate with frequent monitoring of blood glucose was used to match the hyperglycemia produced by the 50 g oral glucose and the iv glucose loads. Virtually complete suppression of plasma glucagon levels was seen in both cases (nadir of glucagon levels 16 +/- 6 pg/ml for oral glucose; 11.4 +/- 3 pg/ml for iv glucose). Thus, enteric humoral factors did not facilitate glucagon suppression after oral glucose ingestion in man. The vagus nerve is also involved in mediating the alpha-cell response to hypoglycemia and, thus, to examine whether hyperglycemia suppresses glucagon release through a vagal mechanism, iv atropine (15 microgram/kg) was given 20 min before administration of oral or iv glucose. Atropinization delayed the glucagon suppression after oral glucose, but this delay was probably related to delayed glucose absorption from the gut. With iv glucose, atropinization did not affect the degree of suppression of glucagon levels. It is concluded that alpha-cell suppression in response to hyperglycemia is not mediated via the vagus.

Evidence for an insulin-independent alpha-cell abnormality in human diabetes

E V I D E N C E for the occurrence of abnormalities of insulin and glucagon secretion has been established in both juvenile and adult onset diabetes. Questions remain, however, as to whether or not these defects are independent of each other. It has been suggested that glucagon secretion in the diabetic is entirely secondary to insulin deficiency, ~ but others have suggested that in addition to dysfunction partially correctable by insulin there is in human diabetes a defect independent of insulin lack. 2 Studies of the earliest stages of diabetes and prediabetes might help to resolve these questions. There are few studies relevant to the question of whether o~-cell dysfunction may occur in prediabetes. Day and Tattersall 3 determined the effect of a 50-g oral glucose load on glucagon levels in the nondiabetic monozygotic co-twins of diabetics, normal subjects, untreated juvenile-onset type and newly diagnosed maturity-onset diabetics. Glucagon levels among the twins were intermediate between those of the normals, whose levels suppressed significantly, and the diabetics, whose levels increased significantly following oral glucose, in spite of the similarities in serum insulin levels among all groups during the first 60 min of the test. The group of twins discordant for less than 10 yr did not show suppression ofglucagon levels, and differed significantly at 1 point from those discordant for > 10 yr in whom glucagon appeared to suppress normally. Statistically significant differences in insulin levels were not found. These data were interpreted as evidence suggesting the possibility of abnormal glucagon secretion in the prediabetic state. Kirk and co-workers 4 reported the insulin and glucagon levels following a 25-g glucose infusion given over a 2-min period among nondiabetic first-degree relatives of diabetics and controls without a family history of diabetes. Among 5 of 15 relatives in whom diminished early phase (5 rain) insulin release was found, glucagon levels did not change whereas among the other relatives and controls glucagon levels suppressed to a significant degree 5-20 min postinfusion. The authors concluded that their data provided evidence of the presence of an alpha cell abnormality at a very early stage of genetic diabetes, but recognized that the data did not elucidate whether or not the c~or /3-cell abnormali ty was primary or secondary. To determine if abnormalities in glucagon secretion could be found among the Pima Indians prior to the onset of diabetes the effect of a 40-min 5 m g /k g / rain arginine infusion on glucagon secretion was determined among 32 prediabetic and 27 normal Indians of similar age and weight. 5 Glucagon levels rose