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Temporal Patterns of Glucagon and Its Relationships with Glucose and Insulin following Ingestion of Different Classes of Macronutrients.
Göbl, C, Morettini, M, Salvatori, B, Alsalim, W, Kahleova, H, Ahrén, B, Tura, A
Nutrients. 2022;(2)
Abstract
BACKGROUND glucagon secretion and inhibition should be mainly determined by glucose and insulin levels, but the relative relevance of each factor is not clarified, especially following ingestion of different macronutrients. We aimed to investigate the associations between plasma glucagon, glucose, and insulin after ingestion of single macronutrients or mixed-meal. METHODS thirty-six participants underwent four metabolic tests, based on administration of glucose, protein, fat, or mixed-meal. Glucagon, glucose, insulin, and C-peptide were measured at fasting and for 300 min following food ingestion. We analyzed relationships between time samples of glucagon, glucose, and insulin in each individual, as well as between suprabasal area-under-the-curve of the same variables (ΔAUCGLUCA, ΔAUCGLU, ΔAUCINS) over the whole participants' cohort. RESULTS in individuals, time samples of glucagon and glucose were related in only 26 cases (18 direct, 8 inverse relationships), whereas relationship with insulin was more frequent (60 and 5, p < 0.0001). The frequency of significant relationships was different among tests, especially for direct relationships (p ≤ 0.006). In the whole cohort, ΔAUCGLUCA was weakly related to ΔAUCGLU (p ≤ 0.02), but not to ΔAUCINS, though basal insulin secretion emerged as possible covariate. CONCLUSIONS glucose and insulin are not general and exclusive determinants of glucagon secretion/inhibition after mixed-meal or macronutrients ingestion.
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SGLT2 Inhibition Increases Fasting Glucagon but Does Not Restore the Counterregulatory Hormone Response to Hypoglycemia in Participants With Type 1 Diabetes.
Boeder, SC, Gregory, JM, Giovannetti, ER, Pettus, JH
Diabetes. 2022;(3):511-519
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Abstract
Individuals with type 1 diabetes have an impaired glucagon counterregulatory response to hypoglycemia. Sodium-glucose cotransporter (SGLT) inhibitors increase glucagon concentrations. We evaluated whether SGLT inhibition restores the glucagon counterregulatory hormone response to hypoglycemia. Adults with type 1 diabetes (n = 22) were treated with the SGLT2 inhibitor dapagliflozin (5 mg daily) or placebo for 4 weeks in a randomized, double-blind, crossover study. After each treatment phase, participants underwent a hyperinsulinemic-hypoglycemic clamp. Basal glucagon concentrations were 32% higher following dapagliflozin versus placebo, with a median within-participant difference of 2.75 pg/mL (95% CI 1.38-12.6). However, increased basal glucagon levels did not correlate with decreased rates of hypoglycemia and thus do not appear to be protective in avoiding hypoglycemia. During hypoglycemic clamp, SGLT2 inhibition did not change counterregulatory hormone concentrations, time to recovery from hypoglycemia, hypoglycemia symptoms, or cognitive function. Thus, despite raising basal glucagon concentrations, SGLT inhibitor treatment did not restore the impaired glucagon response to hypoglycemia. We propose that clinical reduction in hypoglycemia associated with these agents is a result of changes in diabetes care (e.g., lower insulin doses or improved glycemic variability) as opposed to a direct, physiologic effect of these medications on α-cell function.
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Changes in Ghrelin and Glucagon following a Low Glycemic Load Diet in Women with PCOS.
Hoover, SE, Gower, BA, Cedillo, YE, Chandler-Laney, PC, Deemer, SE, Goss, AM
The Journal of clinical endocrinology and metabolism. 2021;(5):e2151-e2161
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CONTEXT Altered satiety hormones in women with polycystic ovarian syndrome (PCOS) may contribute to obesity. Diets with a low glycemic load (GL) may influence appetite-regulating hormones including glucagon and ghrelin. OBJECTIVE To test the hypothesis that following a 4-week, eucaloric low vs high GL diet habituation, a low vs high GL meal will increase glucagon and decrease ghrelin to reflect greater satiety and improve self-reported fullness. METHODS Secondary analysis of a randomized crossover trial. PARTICIPANTS Thirty women diagnosed with PCOS. INTERVENTION Participants were provided low (41:19:40% energy from carbohydrate:protein:fat) and high (55:18:27) GL diets for 8 weeks each. At each diet midpoint, a solid meal test was administered to examine postprandial ghrelin, glucagon, glucose, insulin, and self-reported appetite scores. RESULTS After 4 weeks, fasting glucagon was greater with the low vs high GL diet (P = .035), and higher fasting glucagon was associated with lesser feelings of hunger (P = .009). Significant diet effects indicate 4-hour glucagon was higher (P < .001) and ghrelin was lower (P = .009) after the low vs high GL meal. A trending time × diet interaction (P = .077) indicates feelings of fullness were greater in the early postprandial phase after the high GL meal, but no differences were observed the late postprandial phase. CONCLUSION These findings suggest after low GL diet habituation, a low GL meal reduces ghrelin and increases glucagon in women with PCOS. Further research is needed to determine the influence of diet composition on ad libitum intake in women with PCOS.
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Effects of Duodenal Infusion of Lauric Acid and L-Tryptophan, Alone and Combined, on Fasting Glucose, Insulin and Glucagon in Healthy Men.
McVeay, C, Fitzgerald, PCE, Horowitz, M, Feinle-Bisset, C
Nutrients. 2019;(11)
Abstract
The fatty acid, lauric acid ('C12'), and the amino acid, tryptophan ('Trp'), when given intraduodenally at loads that individually do not affect energy intake, have recently been shown to stimulate plasma cholecystokinin, suppress ghrelin and reduce energy intake much more markedly when combined. Both fatty acids and amino acids stimulate insulin secretion by distinct mechanisms; fatty acids enhance glucose-stimulated insulin secretion, while amino acids may have a direct effect on pancreatic β cells. Therefore, it is possible that, by combining these nutrients, their effects to lower blood glucose may be enhanced. We have investigated the potential for the combination of C12 and Trp to have additive effects to reduce blood glucose. To address this question, plasma concentrations of glucose, insulin and glucagon were measured in 16 healthy, lean males during duodenal infusions of saline (control), C12 (0.3 kcal/min), Trp (0.1 kcal/min), or C12+Trp (0.4 kcal/min), for 90 min. Both C12 and C12+Trp moderately reduced plasma glucose compared with control (p < 0.05). C12+Trp, but not C12 or Trp, stimulated insulin and increased the insulin-to-glucose ratio (p < 0.05). There was no effect on plasma glucagon. In conclusion, combined intraduodenal administration of C12 and Trp reduced fasting glucose in healthy men, and this decrease was driven primarily by C12. The effects of these nutrients on postprandial blood glucose and elevated fasting blood glucose in type 2 diabetes warrant evaluation.
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Subjects with high fasting insulin also have higher postprandial GLP-1 and glucagon levels than controls with lower insulin.
Albinsson-Stenholm, E, Bergsén, J, Ingves, S, Vilhelmsson, N, Guldbrand, H, Nystrom, FH
Nutrition research (New York, N.Y.). 2019;:111-120
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Little is known about postprandial release of serum ghrelin, glucagon, and glucagon-like peptide-1 (GLP-1) in relation with differing fasting insulin levels. We hypothesized that these hormones are affected by insulin resistance, and hence, we compared different postprandial responses of GLP-1, glucagon, and ghrelin in subjects with relatively high (RHI) or relatively low (RLI) fasting insulin levels. The trial was a randomized crossover study with 4 different meal conditions. Fourteen nonobese or obese, healthy, men and 14 women were randomly assigned to the order of supervised intake of a 750 kcal drink with the same protein contents but with 20 energy-percent (E%) or 55 E% from carbohydrates, and the remaining energy from fat. Participants were also randomized to consume the drinks as 1 large beverage or as five 150-kcal portions every 30 minutes. The 28 subjects were divided into 2 equally sized groups based on fasting insulin levels. Statistics were done with general linear mixed model. Fasting insulin levels were 3-fold higher in the group with RHI compared with the RLI group (RHI: 1004 ± 510 pg/mL, RLI: 324 ± 123 pg/mL, P < .0005). Serum GLP-1 was highest in the RHI group after both single meals and after 5 drinks and following high- and low-carbohydrate meals (both P ≤ .002), and this was the case also for glucagon levels (both P ≤ .018), whereas ghrelin levels did not differ between groups. Thus, subjects with RHI displayed both higher postprandial serum GLP-1 and glucagon than the participants with RLI, suggesting that glucagon could play a role in the advent of dysglycemia by insulin resistance.
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Effects of Nicotinamide Riboside on Endocrine Pancreatic Function and Incretin Hormones in Nondiabetic Men With Obesity.
Dollerup, OL, Trammell, SAJ, Hartmann, B, Holst, JJ, Christensen, B, Møller, N, Gillum, MP, Treebak, JT, Jessen, N
The Journal of clinical endocrinology and metabolism. 2019;(11):5703-5714
Abstract
OBJECTIVE Augmenting nicotinamide adenine dinucleotide (NAD+) metabolism through dietary provision of NAD+ precursor vitamins translates to improved glucose handling in rodent models of obesity and diabetes. Preclinical evidence suggests that the NAD+/SIRT1 axis may be implicated in modulating important gut-related aspects of glucose regulation. We sought to test whether NAD+ precursor supplementation with nicotinamide riboside (NR) affects β-cell function, α-cell function, and incretin hormone secretion as well as circulating bile acid levels in humans. DESIGN A 12-week randomized, double-blind, placebo-controlled, parallel-group trial in 40 males with obesity and insulin resistance allocated to NR at 1000 mg twice daily (n = 20) or placebo (n = 20). Two-hour 75-g oral glucose tolerance tests were performed before and after the intervention, and plasma concentrations of glucose, insulin, C-peptide, glucagon, glucagon-like peptide 1 (GLP-1), and glucose-dependent insulinotropic polypeptide (GIP) were determined. β-Cell function indices were calculated based on glucose, insulin, and C-peptide measurements. Fasting plasma concentrations of bile acids were determined. RESULTS NR supplementation during 12 weeks did not affect fasting or postglucose challenge concentrations of glucose, insulin, C-peptide, glucagon, GLP-1, or GIP, and β-cell function did not respond to the intervention. Additionally, no changes in circulating adipsin or bile acids were observed following NR supplementation. CONCLUSION The current study does not provide evidence to support that dietary supplementation with the NAD+ precursor NR serves to impact glucose tolerance, β-cell secretory capacity, α-cell function, and incretin hormone secretion in nondiabetic males with obesity. Moreover, bile acid levels in plasma did not change in response to NR supplementation.
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Preserved glucose response to low-dose glucagon after exercise in insulin-pump-treated individuals with type 1 diabetes: a randomised crossover study.
Steineck, IIK, Ranjan, A, Schmidt, S, Clausen, TR, Holst, JJ, Nørgaard, K
Diabetologia. 2019;(4):582-592
Abstract
AIMS/HYPOTHESIS This study aimed to compare the increase in plasma glucose after a subcutaneous injection of 200 μg glucagon given after 45 min of cycling with resting (study 1) and to investigate the effects of glucagon when injected before compared with after 45 min of cycling (study 2). We hypothesised that: (1) the glucose response to glucagon would be similar after cycling and resting; and (2) giving glucagon before the activity would prevent the exercise-induced fall in blood glucose during exercise and for 2 h afterwards. METHODS Fourteen insulin-pump-treated individuals with type 1 diabetes completed three visits in a randomised, placebo-controlled, participant-blinded crossover study. They were allocated by sealed envelopes. Baseline values were (mean and range): HbA1c 54 mmol/mol (43-65 mmol/mol) or 7.1% (6.1-8.1%); age 45 years (23-66 years); BMI 26 kg/m2 (21-30 kg/m2); and diabetes duration 26 years (8-51 years). At each visit, participants consumed a standardised breakfast 2 h prior to 45 min of cycling or resting. A subcutaneous injection of 200 μg glucagon was given before or after cycling or after resting. The glucose response to glucagon was compared after cycling vs resting (study 1) and before vs after cycling (study 2). RESULTS The glucose response to glucagon was higher after cycling compared with after resting (mean ± SD incremental peak: 2.6 ± 1.7 vs 1.8 ± 2.0 mmol/l, p = 0.02). As expected, plasma glucose decreased during cycling (-3.1 ± 2.8 mmol/l) but less so when glucagon was given before cycling (-0.9 ± 2.8 mmol/l, p = 0.002). The number of individuals reaching glucose values ≤3.9 mmol/l was the same on the 3 days. CONCLUSIONS/INTERPRETATION Moderate cycling for 45 min did not impair the glucose response to glucagon compared with the glucose response after resting. The glucose fall during cycling was diminished by a pre-exercise injection of 200 μg glucagon; however, no significant difference was seen in the number of events of hypoglycaemia. TRIAL REGISTRATION Clinicaltrials.gov NCT02882737 FUNDING The study was funded by the Danish Diabetes Academy founded by Novo Nordisk foundation and by an unrestricted grant from Zealand Pharma.
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Effects of anagliptin on plasma glucagon levels and gastric emptying in patients with type 2 diabetes: An exploratory randomized controlled trial versus metformin.
Nakagawa, T, Nagai, Y, Yamamoto, Y, Miyachi, A, Hamajima, H, Mieno, E, Takahashi, M, Inoue, E, Tanaka, Y
Diabetes research and clinical practice. 2019;:107892
Abstract
AIMS: Glucagon has an important role in glucose homeostasis. Recently, a new plasma glucagon assay based on liquid chromatography-high resolution mass spectrometry was developed. We evaluated the influence of a dipeptidyl peptidase-4 inhibitor (anagliptin) on plasma glucagon levels in Japanese patients with type 2 diabetes by using this new assay. METHODS Twenty-four patients with type 2 diabetes were enrolled in a prospective, single-center, randomized, open-label study and were randomly allocated to 4 weeks of treatment with metformin (1000 mg/day) or anagliptin (200 mg/day). A liquid test meal labeled with sodium [13C] acetate was ingested before and after the treatment period. Samples of blood and expired air were collected over 3 h. Plasma levels of glucose, glucagon, C-peptide, glucagon-like peptide-1 (GLP-1), and glucose-dependent insulinotropic polypeptide (GIP) were measured, and gastric emptying was also evaluated. RESULTS Twenty-two patients completed the study (metformin group: n = 10; anagliptin group: n = 12). Glycemic control showed similar improvement in both groups. In the anagliptin group, there was a slight decrease of the incremental area under the plasma concentration versus time curve for glucagon after the test meal (P = 0.048). In addition, the plasma level of active GLP-1 and GIP was increased, and plasma C-peptide was also increased versus baseline. Neither anagliptin nor metformin delayed gastric emptying. CONCLUSIONS In patients with type 2 diabetes maintained endogenous insulin secretion, anagliptin increased the plasma level of active GLP-1 and GIP in association with a slight stimulation of insulin secretion and slight inhibition of glucagon secretion, but did not delay gastric emptying. Clinical Trial Registry: University hospital Medical Information Network UMIN000028293.
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Postprandial levels of GLP-1, GIP and glucagon after 2 years of weight loss with a Paleolithic diet: a randomised controlled trial in healthy obese women.
Otten, J, Ryberg, M, Mellberg, C, Andersson, T, Chorell, E, Lindahl, B, Larsson, C, Holst, JJ, Olsson, T
European journal of endocrinology. 2019;(6):417-427
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Objective To investigate how weight loss by different diets impacts postprandial levels of glucagon-like peptide 1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP) and glucagon. Methods In this single-centre, parallel group 2-year trial, 70 healthy postmenopausal obese women were randomised to the Paleolithic diet or a healthy control diet based on Nordic Nutrition Recommendations. Both diets were without calorie restriction. The primary outcome was the change in fat mass. Here, secondary analyses on GLP-1, GIP and glucagon measured during an OGTT are described. Results In the Paleolithic diet group, mean weight loss compared to baseline was 11% at 6 months and 10% at 24 months. In the control diet group, mean weight loss was 6% after 6 and 24 months (P = 0.0001 and P = 0.049 for the comparison between groups at 6 and 24 months respectively). Compared to baseline, the mean incremental area under the curve (iAUC) for GLP-1 increased by 34 and 45% after 6 and 24 months in the Paleolithic diet group and increased by 59% after 24 months in the control diet group. The mean iAUC for GIP increased only in the Paleolithic diet group. The area under the curve (AUC) for glucagon increased during the first 6 months in both groups. The fasting glucagon increase correlated with the β-hydroxybutyrate increase. Conclusions Weight loss caused an increase in postprandial GLP-1 levels and a further rise occurred during weight maintenance. Postprandial GIP levels increased only after the Paleolithic diet. Reduced postprandial glucagon suppression may be caused by a catabolic state.
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Glucagon Levels During Short-Term SGLT2 Inhibition Are Largely Regulated by Glucose Changes in Patients With Type 2 Diabetes.
Lundkvist, P, Pereira, MJ, Kamble, PG, Katsogiannos, P, Langkilde, AM, Esterline, R, Johnsson, E, Eriksson, JW
The Journal of clinical endocrinology and metabolism. 2019;(1):193-201
Abstract
CONTEXT The mechanism mediating sodium glucose cotransporter-2 (SGLT2) inhibitor-associated increase in glucagon levels is unknown. OBJECTIVE To assess short-term effects on glucagon, other hormones, and energy substrates after SGLT2 inhibition and whether such effects are secondary to glucose lowering. The impact of adding a dipeptidyl peptidase-4 inhibitor was addressed. DESIGN, SETTING, AND PATIENTS A phase 4, single-center, randomized, three-treatment crossover, open-label study including 15 patients with type 2 diabetes treated with metformin. INTERVENTIONS Patients received a single-dose of dapagliflozin 10 mg accompanied by the following in randomized order: isoglycemic clamp (experiment DG); saline infusion (experiment D); or saxagliptin 5 mg plus saline infusion (experiment DS). Directly after 5-hour infusions, a 2-hour oral glucose tolerance test (OGTT) was performed. RESULTS Glucose and insulin levels were stable in experiment DG and decreased in experiment D [P for difference (Pdiff) < 0.001]. Glucagon-to-insulin ratio (Pdiff < 0.001), and levels of glucagon (Pdiff < 0.01), nonesterified fatty acids (Pdiff < 0.01), glycerol (Pdiff < 0.01), and β-OH-butyrate (Pdiff < 0.05) were lower in DG vs D. In multivariate analysis, change in glucose level was the main predictor of change in glucagon level. In DS, glucagon and active GLP-1 levels were higher than in D, but glucose and insulin levels did not differ. During OGTT, glucose levels rose less and glucagon levels fell more in DS vs D. CONCLUSION The degree of glucose lowering markedly contributed to regulation of glucagon and insulin secretion and to lipid mobilization during short-term SGLT2 inhibition.