Plasma Glucagon Concentrations Research Articles

Effects of Moderate Cycling Exercise on Blood Glucose Regulation Following Successful Clinical Islet Transplantation.

Islet transplantation is effective in preventing hypoglycemia in patients with type 1 diabetes (T1D). However, it is unknown whether transplanted islets regulate plasma glucose concentrations appropriately during and after exercise in human islet transplant recipient (ITxs). To determine the effect of exercise on plasma glucose, insulin, and glucagon concentrations in ITxs compared with control subjects (CONs) without diabetes. Participants completed two conditions in random order: 45 minutes of aerobic exercise (60% VO2peak) and 45 minutes of seated rest. Blood samples were drawn at baseline, immediately after exercise or rest, and every 15 minutes throughout a 60-minute recovery period. Postexercise (24 hours) interstitial glucose was monitored with continuous glucose monitoring (CGM). Twenty-four participants (12 ITxs, 12 CONs) completed the protocol. Plasma glucose decreased more over time with exercise in ITxs compared with CONs [main effects of treatment (P = 0.019), time (P = 0.001), and group (P = 0.012)]. Plasma glucose was lower during exercise vs rest in ITxs but not CONs [treatment by group interaction (P = 0.028)]. Plasma glucose decreased more during exercise than during rest [treatment by time interaction (P = 0.001)]. One ITx and one CON experienced plasma glucose concentrations <3.5 mmol/L at the end of exercise, both of whom returned above that threshold within 15 minutes. Nocturnal CGM glucose <3.5 mmol/L was detected in two CONs but no ITxs. Despite a greater plasma glucose decline during exercise in ITxs, hypoglycemia risk was similar during and after exercise in ITxs compared with CONs.

Copeptin, a surrogate marker for arginine vasopressin secretion, is positively associated with glucagon

To explore the association of plasma copeptin, the C-terminal portion of provasopressin and a stable surrogate marker for arginine vasopressin secretion, with plasma glucagon in obese men and men of normal weight. We measured fasting blood concentrations ofcopeptin and glucagon in 102 healthy obese men (mean ± sd age 49.4 ± 10.2 years) and a control group 27 healthy men of normal weight (mean ± sd age 51.5 ± 8.4 years). Differences between groups were evaluated using t-tests, and multiple linear regression analysis, adjusting for age and weight status (normal weight vs obese), was used to calculate unstandardized regression coefficients (β) with 95% CIs between copeptin and glucagon. Copeptin was (natural) log-transformed. The obese men had higher [median (interquartile range)] plasma copeptinconcentrations [6.6 (4.6-9.5) vs 4.9 (3.5-6.8) pmol/l; P = 0.040] and higher mean ± sd plasma glucagon concentrations (8.5 ± 3.8 vs 5.3 ± 1.4 pmol/l; P < 0.001) than the normal-weight men. Adjusted for age and weight status, copeptin was significantly associated with glucagon (β = 1.35, 95% CI 0.13-2.57; P = 0.031). No significant interaction effect between copeptin and weight status on glucagon was found (P = 0.81). Obese men had higher concentrations of copeptin and glucagon than men of normal weight. Copeptin was positively associated with glucagon. Our data suggest that increased arginine vasopressin-stimulated glucagon secretion might contribute to higher glucagon concentrations; therefore, increased arginine vasopressin secretion, in addition to other factors, could further aggravate the hyperglucagonaemic state found in obese individuals.

Determinants of Fasting Hyperglucagonemia in Patients with Type 2 Diabetes and Nondiabetic Control Subjects.

Fasting hyperglucagonemia can be detrimental to glucose metabolism in patients with type 2 diabetes (T2D) and may contribute to metabolic disturbances in obese and/or prediabetic subjects. However, the mechanisms underlying fasting hyperglucagonemia remain elusive. We evaluated the interrelationship between fasting hyperglucagonemia and demographic and biochemical parameters in 106 patients with T2D (31% female, age: 57 ± 9 years [mean ± standard deviation; body mass index (BMI): 30.1 ± 4.4 kg/m2; fasting plasma glucose (FPG): 9.61 ± 2.39 mM; hemoglobin A1c (HbA1c): 57.1 ± 13.1 mmol/mol] and 163 nondiabetic control subjects (29% female; age: 45 ± 17 years; BMI: 25.8 ± 4.1 kg/m2; FPG: 5.2 ± 0.4 mM; and HbA1c: 35.4 ± 3.8 mmol/mol). Multiple linear regression analysis was applied using a stepwise approach with fasting plasma glucagon as dependent parameter and BMI, waist-to-hip ratio (WHR), blood pressure, hemoglobin A1c, FPG, and insulin concentrations as independent parameters. Fasting plasma glucagon concentrations were significantly higher among patients with T2D (13.5 ± 6.3 vs. 8.5 ± 3.8 mM, P < 0.001) together with HbA1c (P < 0.001), FPG (P < 0.001), and insulin (84.9 ± 56.4 vs. 57.7 ± 35.3 mM, P < 0.001). When adjusted for T2D, HbA1c and insulin were significantly positive determinants for fasting plasma glucagon concentrations. Furthermore, WHR comprised a significant positive determinant. We confirm that fasting plasma glucagon concentrations are abnormally high in patients with T2D, and show that fasting plasma glucagon concentrations are influenced by WHR (in addition to glycemic control and fasting plasma insulin concentrations), which may point to visceral fat deposition as an important determinant of increased fasting plasma glucagon concentrations.

SIRT1 activation attenuates \u03b1 cell hyperplasia, hyperglucagonaemia and hyperglycaemia in STZ-diabetic mice

The NAD+-dependent lysine deacetylase, Sirtuin 1 (SIRT1), plays a central role in metabolic regulation. With type 1 diabetes a disease that is characterised by metabolic dysregulation, we sought to assess the impact of SIRT1 activation in experimental, streptozotocin (STZ)-induced diabetes. CD1 mice with and without STZ-induced diabetes were randomized to receive the SIRT1 activating compound, SRT3025, or vehicle over 20 weeks. Vehicle treated STZ-CD1 mice developed severe hyperglycaemia with near-absent circulating insulin and widespread beta cell loss in association with hyperglucagonaemia and expanded islet alpha cell mass. Without affecting ß-cell mass or circulating insulin, diabetic mice that received SRT3025 had substantially improved glycaemic control with greatly reduced islet α cell mass and lower plasma glucagon concentrations. Consistent with reduced glucagon abundance, the diabetes-associated overexpression of key gluconeogenic enzymes, glucose-6-phosphatase and PEPCK were also lowered by SRT3025. Incubating cultured α cells with SRT3025 diminished their glucagon secretion and proliferative activity in association with a reduction in the α cell associated transcription factor, Aristaless Related Homeobox (Arx). By reducing the paradoxical increase in glucagon, SIRT1 activation may offer a new, α-cell centric approach to the treatment of type 1 diabetes.

Glucose lowering and vascular protective effects of cycloset added to GLP-1 receptor agonists in patients with type 2 diabetes.

SummaryObjectiveTo determine the glucose‐lowering mechanism of action and the effects of a quick‐release bromocriptine‐QR, a D2‐dopamine agonist (Cycloset) on vascular function in patients with type 2 diabetes (T2D).Study design and methodsFifteen poorly controlled T2D treated with metformin plus glucagon‐like peptide‐1 receptor agonists (GLP‐1RA) were studied after 4 months of Cycloset, 3.2 mg/d. Subjects received a 5‐hour double‐tracer (iv 3‐3H‐glucose and oral 14C‐glucose) mixed meal test (MMT) to quantitate rates of endogenous glucose production (EGP), oral glucose appearance (RaO) and disappearance (Rd) pre‐ and post‐Cycloset. Vascular assessments included 2‐day continuous BP monitoring, reactive hyperaemia index (RHI) and arterial stiffness (AS).ResultsHbA1c decreased from 8.3 ± 0.3% to 7.7 ± 0.2% (P < 0.05), fasting plasma glucose did not change (143 ± 4 vs 147 ± 5) and mean plasma glucose during MTT decreased from 223 ± 3 to 210 ± 4 mg/dL (P < 0.05) after Cycloset. Basal EGP (2.2 ± 0.2 vs 2.1 ± 0.2 mg/kg min) was unchanged, but there was greater MMT suppression (1.1 ± 0.1 vs 0.7 ± 0.1, P < 0.05). After Cycloset, RaO declined from 2.0 ± 0.1 to 1.7 ± 0.2 mg/kg min and peripheral oral glucose appearance from 53.1 ± 3.2 to 44.4 ± 3.1 g (P < 0.01). There were no changes in plasma insulin or glucagon concentration. Systolic (134 ± 4 vs 126 ± 6), diastolic (78 ± 3 vs 73 ± 4), mean BP (97 ± 5 vs 90 ± 4) and pulse pressure (54 ± 2 vs 51 ± 2 mm Hg) were reduced; RHI increased from 1.4 ± 0.1 to 1.9 ± 0.3 au and AS decreased modestly (19.8 ± 4.1 to 16.2 ± 3.7 au, P = NS).ConclusionsAddition of Cycloset to GLP‐1 RA improved vascular indices and postprandial hyperglycaemia in T2DM primarily by lowering oral glucose appearance, suggesting that hepatic glucose uptake was enhanced. Improved vascular indices may explain the reduction in cardiovascular events observed with Cycloset therapy in patients with T2DM.

Paradigm Shifts in Nocturnal Glucose Control in Type 2 Diabetes.

A better understanding of nocturnal regulation of glucose homeostasis will provide the framework for designing rational therapeutic strategies to improve the management of overnight glucose in patients with type 2 diabetes (T2D). To establish the nocturnal pattern and regulation of glucose production (EGP) in humans and to determine whether the pattern is dysregulated in people with T2D. Subjects were infused with [3-3H] glucose overnight. Arterial blood samples were drawn for hormones and analytes to estimate EGP throughout the night. Deuterium-labeled water was provided to measure gluconeogenesis (GNG) using the hexamethylenetetramine method of Landau. Mayo Clinic Clinical Research Trials Unit, Rochester, MN, USA. A total of 43 subjects [23 subjects with T2D and 20 nondiabetic (ND) subjects comparable for age and body mass index] were included in this study. Glucose and EGP. Plasma glucose, C-peptide, and glucagon concentrations were higher throughout the night, whereas insulin concentrations were higher in subjects with T2D vs ND subjects at 1:00 and 4:00 am but similar at 7:00 am. EGP was higher in the subjects with T2D than in the ND subjects throughout the night (P < 0.001). Glycogenolysis (GGL) fell and GNG rose, resulting in significantly higher (P < 0.001) rates of GNG at 4:00 and 7:00 am and significantly (P < 0.001) higher rates of GGL at 1:00, 4:00, and 7:00 am in T2D as compared with ND. These data imply that optimal therapies for T2D for nocturnal/fasting glucose control should target not only the absolute rates of EGP but also the contributing pathways of GGL and GNG sequentially.

Effect of Combination Therapy with Liraglutide plus Canagliflozin on HGP and HbA1c vs. Each Therapy Alone in T2DM

Background: We previously have shown that SGLT2 inhibitors cause an increase in HGP accompanied with an increase in plasma glucagon concentration. We hypothesized that the increase in plasma glucagon concentration is, at least in part, responsible for the increase in HGP. The aim of the present study was to examine whether inhibition of glucagon secretion by liraglutide can prevent the increase in HGP. Research Design and Methods: 51 T2DM patients (age=51±1 yr; 40% female; BMI=34.6±0.7; diabetes duration=6.8±0.8 yr; FPG=175±7; HbA1c=8.3±0.1%) were randomized to receive for 16 weeks: (i) canagliflozin 300 mg; (ii) liraglutide 1.8 mg; or (iii) canagliflozin 300 mg plus liraglutide 1.8 mg. HGP (measured with 3-3H-glucose infusion) and plasma glucagon concentration were measured before and after 16 weeks of treatment. Results: Canagliflozin monotherapy caused a significant reduction in HbA1c (-1.1±0.2%, p&amp;lt;0.01) accompanied with an increase in plasma glucagon concentration (by 28%, p&amp;lt;0.05) and HGP (by 15%, p&amp;lt;0.05) which lasted for 16 weeks. Conversely, liraglutide monotherapy caused a 1.6±0.5% (p&amp;lt;0.01) reduction in HbA1c accompanied by a small (6%) reduction in HGP (P=NS) without significant change in fasting plasma glucagon concentration. The combination of canagliflozin plus liraglutide caused a greater reduction in HbA1c (1.9±0.5%, p&amp;lt;0.vs. canagliflozin and p=NS vs. liraglutide) and attenuated the increase in fasting plasma glucagon and basal HGP at 16 weeks. Conclusion: These results: (1) support a possible role for increased plasma glucagon levels in the long term maintenance of increase in HGP caused by SGLT2i, and (2) suggest that factors other than/in addition to glucagon contribute to the initiation of the increase in HGP. Disclosure M. Abdul-Ghani: None. A.M. Ali: None. R.A. Martinez: None. J.M. Adams: None. E. Cersosimo: Research Support; Self; AstraZeneca, VeroScience, LLC.. Speaker's Bureau; Self; AstraZeneca, Sanofi, Janssen Pharmaceuticals, Inc., Eli Lilly and Company. C.L. Triplitt: Speaker's Bureau; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Janssen Pharmaceuticals, Inc., Eli Lilly and Company. Consultant; Self; Sanofi, Novo Nordisk Inc. R.A. DeFronzo: Speaker's Bureau; Self; AstraZeneca, Novo Nordisk Inc.. Advisory Panel; Self; AstraZeneca, Novo Nordisk Inc., Janssen Pharmaceuticals, Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Elcelyx Therapeutics, Inc., Intarcia Therapeutics, Inc.. Research Support; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Janssen Pharmaceuticals, Inc., Takeda Pharmaceuticals U.S.A., Inc..

Mild Physiologic Hyperglycemia Induces Hepatic Insulin Resistance in Healthy Normal Glucose Tolerant Subjects–Role of Glucagon and Gluconeogenic Substrates

The aim of the present study was to evaluate the effect of a physiologic increase in plasma glucose concentration on endogenous glucose production (EGP) in healthy NGT individuals. 16 NGT subjects [8 with and 8 without family history of T2DM (9M/7F, age = 44± 3 years, BMI = 26 ± 1 kg/m2)] participated in a 3-step hyperinsulinemic (10, 20, 40 mU/m2 min) euglycemic clamp before and after a 48 hour glucose infusion to increase plasma glucose conc by ∼45 mg/dl above baseline (89±4 to 136±4.9 mg/dl). EGP was measured with [3-3H] glucose and gluconeogenic rate was measured following administration of deuterated water. Plasma FFA, glucagon, lactate, glycerol and alanine concentrations also were measured. Following 48 hours of glucose infusion basal EGP increased from 2.05±0.09 to 3.06±0. mg/kg min (p=0.003) and hepatic insulin resistance index (EGP X Fasting Plasma Insulin) increased markedly and similarly (25.1±1.0 vs. 48.3± 3.2, p&amp;lt;0.005). The baseline plasma glucagon concentration tended to be higher following 48 hours of glucose infusion (64±3 vs. 77± 8 pg/ml, p=0.2) while the product of the plasma glucagon and insulin concentrations was markedly increased (540 ± 56 vs. 1336 ± 262, p=0.004). Although the baseline plasma FFA concentration was markedly reduced following 48 hours of glucose infusion (0.482 ±0.to 0.055± 0.01mM), there was no difference in plasma glycerol concentration (13.4±1.2 vs. 13.3 ± 2.2 mg/L p=ns). There were small increases in both the plasma lactate and alanine concentrations. Total body insulin sensitivity declined from 8.75±2.1 to 6.92± 6 mg.kg/min (p&amp;lt;0.05). Conclusion: Chronic (48 hr) physiologic hyperglycemia to levels seen in T2DM increases basal hepatic glucose production and induces hepatic and skeletal muscle insulin resistance in healthy NGT subjects. These results demonstrate, for the first time that glucotoxicity causes resistance to the suppressive effect of insulin on hepatic glucose production. Disclosure D. Tripathy: None. A. Merovci: None. E.R. Maldonado Corchado: None. R. Basu: Research Support; Self; AstraZeneca. R.A. DeFronzo: Speaker-s Bureau; Self; AstraZeneca, Novo Nordisk Inc.. Advisory Panel; Self; AstraZeneca, Novo Nordisk Inc., Janssen Pharmaceuticals, Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Elcelyx Therapeutics, Inc., Intarcia Therapeutics, Inc.. Research Support; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Janssen Pharmaceuticals, Inc., Takeda Pharmaceuticals U.S.A., Inc..

Mechanism by Which Dapagliflozin Induces Euglycemic Ketoacidosis in Rats

Sodium-glucose transport protein 2 inhibitors (SGLT2i) are the most recent class of antidiabetic agents; however concerns have been raised about their potential to induce euglycemic ketoacidosis by an unknown mechanism. Here we report that dapagliflozin increases rates of hepatic ketogenesis (35±4 vs. 136±8 μmol/[kg-min], p&amp;lt;0.0001) in normal Sprague-Dawley rats by increasing plasma catecholamine (epinephrine 0.5±0.1 vs. 7.3±0.5 nM, p&amp;lt;0.001, norepinephrine 2.5±0.5 vs. 19.8±5.2 nM, p&amp;lt;0.01) and corticosterone (115±15 vs. 233±28 ng/mL, p&amp;lt;0.01) concentrations secondary to volume depletion (weight change -1.9±0.4% vs. -7.1±0.4%), thereby increasing white adipose tissue lipolysis, hepatic acetyl-CoA content, hepatic glucose production and hepatic ketogenesis. Dapagliflozin-induced reductions in plasma insulin concentrations were shown to be necessary but not sufficient to induce these changes since the effects of dapagliflozin to increase hepatic ketogenesis were abrogated when extracellular volume depletion was prevented with saline infusion or free access to water. Furosemide treatment induced similar volume depletion and increases in plasma catecholamine and corticosterone concentrations without any associated changes in WAT lipolysis, hepatic glucose production or hepatic ketogenesis, likely due to its lack of an effect on plasma insulin levels. Furthermore the effects of dapagliflozin to promote increased rates of hepatic ketogenesis and hepatic glucose production were dissociated from changes in plasma glucagon concentrations, which increased (89.5±3.8 vs. 379.2±11.8 ng/mL, p&amp;lt;0.0001) through a central mechanism following ICV injection of dapagliflozin without any alterations in body weight or ketosis, and hepatic malonyl-CoA. Taken together these data identify SGLT2i-induced dehydration as a potential target to prevent SGLT2i-induced euglycemic ketoacidosis. Disclosure R.J. Perry: None.J.D. Song: None.Y. Wang: None. G.I. Shulman: Advisory Panel; Self; AstraZeneca, Janssen Research &amp; Development, Merck &amp; Co., Inc., Novo Nordisk Inc.. Research Support; Self; Gilead Sciences, Inc..

Mechanisms by Which Glucagon Acutely Stimulates Hepatic Mitochondrial Oxidation and Gluconeogenesis

Glucagon has been suggested to be both pathogenic and protective against type 2 diabetes (T2D) reflecting our poor understanding of the molecular mechanisms by which glucagon alters hepatic metabolism. Using Positional Isotopomer NMR Tracer Analysis (PINTA) we found that acute glucagon infusion stimulates rates of hepatic gluconeogenesisin glycogen-depleted mice by promoting increases in intrahepatic lipolysis and hepatic acetyl-CoA content (75±6 vs. 101±6 nmol/g, p=0.01), pyruvate carboxylase flux (VPC, 70.9±3.9 vs. 99.9±7.1 µmol/[kg-min], p=0.008) and mitochondrial oxidation (90.0±12.9 vs. 452.1±78.3 µmol/[kg-min], p=0.001) in vivo. Each of these effects was abrogated in liver-specific Inositol Trisphosphate Receptor-I (InsP3R-I) knockout mice demonstrating that intracellular calcium signaling is necessary for these processes. Liver specific knockdown of adipocyte triglyceride lipase abolished acute glucagon stimulation of gluconeogenesis (control 70.5±2.9 vs. 103.3±3.3 µmol/[kg-min], p&amp;lt;0.0001 and ATGL knockdown 69.7±1.7 vs. 69.6±2.0 µmol/[kg-min], p=0.9) and VPC (control 63.3±5.0 vs. 100.0±4.8 µmol/[kg-min], p=0.0003, ATGL knockdown 58.9±4.9 vs. 59.2±3.2 µmol/[kg-min], p=0.9) in WT mice demonstrating the necessity of hepatocellular lipolysis in mediating this process. Chronic increases in plasma glucagon concentrations reversed high fat diet-induced hepatic steatosis (liver triglyceride 50.1±8.5 vs. 28.3±5.1 mg/g, p=0.04; liver membrane diacylglycerol 801±142 vs. 448±47 nmol/g, p=0.03, PKCε membrane/cytosol 1.76±0.40 vs. 0.23±0.04, p=0.0009) and glucose intolerance (GTT glucose AUC 1.44±0.vs. 1.13±0.mM-min, p=0.003, insulin AUC 226.8±18.7 vs. 90.2±11.2 nM-min, p&amp;lt;0.0001). These results provide new insights into glucagon biology and suggest that glucagon and InsP3R-I may be therapeutic targets to reverse nonalcoholic fatty liver disease and T2D. Disclosure R.J. Perry: None. Y. Wang: None. A.L. Brill: None. L. Peng: None. D. Zhang: None. S. Dufour: None. Y. Zhang: None. X. Zhang: None. Y. Nozaki: None. G. Cline: None. B.E. Ehrlich: None. K. Petersen: Research Support; Spouse/Partner; Gilead Sciences, Inc.. Advisory Panel; Spouse/Partner; AstraZeneca, Merck &amp; Co., Inc., Novo Nordisk A/S. G.I. Shulman: Advisory Panel; Self; AstraZeneca, Janssen Research &amp; Development, Merck &amp; Co., Inc., Novo Nordisk Inc.. Research Support; Self; Gilead Sciences, Inc..

Impacts of pre- and postnatal nutrition on glucagon regulation and hepatic signalling in sheep.

To evaluate the long-term impacts of early-life nutritional manipulations on glucagon secretion and hepatic signalling, thirty-six twin-pregnant ewes during their last trimester were exposed to NORM (fulfilling 100% of daily energy/protein requirements), HIGH (fulfilling 150/110% of daily energy/protein requirements) or LOW (50% of NORM) diets. Twin lambs were assigned after birth to a moderate (CONV) or high-carbohydrate high-fat (HCHF) diet until 6 months. Then, responses in plasma glucagon concentrations and glucagon ratios relative to previously reported values for insulin, glucose and lactate were determined after intravenous bolus injections of glucose or propionate (fed and 2-day fasting state). Hepatic mRNA expressions of glucagon receptor (GCGR), glucose-6-phosphatase (G6PC), phosphoenolpyruvate carboxykinase (PEPCK) and fructose 1,6-biphosphatase (FBP) were also determined in a sub group of autopsied lambs. Expression of GCGR and all three enzymes were supressed by prenatal LOW compared to NORM (except PEPCK) and HIGH (except FBP) nutrition. The postnatal HCHF diet reduced plasma glucagon responses to propionate and hepatic mRNA expression of all genes. In response to propionate, insulin/glucagon ratio was decreased (fasted state), but lactate/glucagon and glucose/glucagon increased in HCHF compared to CONV lambs. In conclusion, prenatal undernutrition and postnatal overnutrition had similar long-term implications and reduced hepatic glucagon signalling. Glucagon secretory responses to propionate were, however, not related to the prenatal nutrition history, but negatively affected by the postnatal obesogenic diet. The pancreatic α-cell compared to β-cells may thus be less sensitive towards late gestation malnutrition, whereas hepatic glucagon signalling appears to be a target of prenatal programming.

Impact of gastric emptying and small intestinal transit on blood glucose, intestinal hormones, glucose absorption in the morbidly obese.

This study evaluated gastric emptying (GE) and small intestinal (SI) transit in people with morbid obesity and their relationships to glycaemia, incretin hormones, and glucose absorption METHODS: GE and caecal arrival time (CAT) of a mixed meal were assessed in 22 morbidly obese (50.2 ± 2.5 years; 13 F:9 M; BMI: 48.6 ± 1.8 kg/m2) and 10 lean (38.6 ± 8.4 years; 5 F:5 M; BMI: 23.9 ± 0.7 kg/m2) subjects, using scintigraphy. Blood glucose, plasma 3-O-methylglucose, insulin, glucagon, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) were measured. Insulin sensitivity and resistance were also quantified RESULTS: When compared with lean subjects, GE (t50: 60.7 ± 6.5 vs. 41.1 ± 7.3 min; P = 0.04) and CAT (221.5 ± 9.8 vs. 148.0 ± 7.1 min; P = 0.001) of solids were prolonged in morbid obesity. Postprandial rises in GIP (P = 0.001), insulin (P = 0.02), glucose (P = 0.03) and 3-O-methylglucose (P = 0.001) were less. Whereas GLP-1 increased at 45 mins post-prandially in lean subjects, there was no increase in the obese (P = 0.04). Both fasting (P = 0.045) and postprandial (P = 0.012) plasma glucagon concentrations were higher in the obese CONCLUSIONS: GE and SI transit are slower in the morbidly obese, and associated with reductions in postprandial glucose absorption, and glycaemic excursions, as well as plasma GIP and GLP-1.

Zinc Supplementation Does Not Affect Glucagon Response to Intravenous Glucose and Insulin Infusion in Patients with Well-Controlled Type 2 Diabetes.

Glucagon dysregulation is an essential component in the pathophysiology of type 2 diabetes. Studies in vitro and in animal models have shown that zinc co-secreted with insulin suppresses glucagon secretion. Zinc supplementation improves blood glucose control in patients with type 2 diabetes, although there is little information about how zinc supplementation may affect glucagon secretion. The objective of this study was to evaluate the effect of 1-year zinc supplementation on fasting plasma glucagon concentration and in response to intravenous glucose and insulin infusion in patients with type 2 diabetes. A cross-sectional study was performed after 1-year of intervention with 30mg/day zinc supplementation or a placebo on 28 patients with type 2 diabetes. Demographic, anthropometric, and biochemical parameters were determined. Fasting plasma glucagon and in response to intravenous glucose and insulin infusion were evaluated. Patients of both placebo and supplemented groups presented a well control of diabetes, with mean values of fasting blood glucose and glycated hemoglobin within the therapeutic goals established by ADA. No significant differences were observed in plasma glucagon concentration, glucagon/glucose ratio or glucagon/insulin ratio fasting, after glucose or after insulin infusions between placebo and supplemented groups. No significant effects of glucose or insulin infusions were observed on plasma glucagon concentration. One-year zinc supplementation did not affect fasting plasma glucagon nor response to intravenous glucose or insulin infusion in well-controlled type 2 diabetes patients with an adequate zinc status.

Evidence of a liver-alpha cell axis in humans: hepatic insulin resistance attenuates relationship between fasting plasma glucagon and glucagonotropic amino acids.

The secretion of glucagon is controlled by blood glucose and inappropriate secretion of glucagon contributes to hyperglycaemia in diabetes. Besides its role in glucose regulation, glucagon regulates amino acid metabolism in hepatocytes by increasing ureagenesis. Disruption of this mechanism causes hyperaminoacidaemia, which in turn increases glucagon secretion. We hypothesised that hepatic insulin resistance (secondary to hepatic steatosis) via defective glucagon signalling/glucagon resistance would lead to impaired ureagenesis and, hence, increased plasma concentrations of glucagonotropic amino acids and, subsequently, glucagon. To examine the association between glucagon and amino acids, and to explore whether this relationship was modified by hepatic insulin resistance, we studied a well-characterised cohort of 1408 individuals with normal and impaired glucose regulation. In this cohort, we have previously reported insulin resistance to be accompanied by increased plasma concentrations of glucagon. We now measure plasma levels of amino acids in the same cohort. HOMA-IR was calculated as a marker of hepatic insulin resistance. Fasting levels of glucagonotropic amino acids and glucagon were significantly and inversely associated in linear regression models (persisting after adjustment for age, sex and BMI). Increasing levels of hepatic, but not peripheral insulin resistance (p > 0.166) attenuated the association between glucagon and circulating levels of alanine, glutamine and tyrosine, and was significantly associated with hyperaminoacidaemia and hyperglucagonaemia. A doubling of the calculated glucagon-alanine index was significantly associated with a 30% increase in hepatic insulin resistance, a 7% increase in plasma alanine aminotransferase levels, and a 14% increase in plasma γ-glutamyltransferase levels. This cross-sectional study supports the existence of a liver-alpha cell axis in humans: glucagon regulates plasma levels of amino acids, which in turn feedback to regulate the secretion of glucagon. With hepatic insulin resistance, reflecting hepatic steatosis, the feedback cycle is disrupted, leading to hyperaminoacidaemia and hyperglucagonaemia. The glucagon-alanine index is suggested as a relevant marker for hepatic glucagon signalling.

Periodontal pathogenic bacteria, Aggregatibacter actinomycetemcomitans affect non-alcoholic fatty liver disease by altering gut microbiota and glucose metabolism

Increasing evidence indicates that periodontitis affects non-alcoholic fatty liver disease (NAFLD). We examined the relationship between periodontal bacterial infection and clinical/biochemical parameters in 52 NAFLD patients. Anti-Aggregatibacter actinomycetemcomitans (Aa) antibody titers correlated positively with visceral fat, fasting plasma insulin, and HOMA-IR; and negatively with the liver/spleen ratio. C57BL/6J mice (8-weeks-old) were given Aa or saline (control) for 6 weeks, and were fed either normal chow (NCAa, NCco) or high-fat diet (HFAa and HFco). NCAa and HFAa mice presented impaired glucose tolerance and insulin resistance compared to control mice. HFAa mice showed higher hepatic steatosis than HFco animals. Liver microarray analysis revealed that 266 genes were differentially expressed between NCAa and NCco mice. Upregulated genes in Aa-administrated mice were enriched for glucagon signaling pathway, adipocytokine signaling pathway and insulin resistance. Consistently, plasma glucagon concentration was higher in NCAa mice. In addition, Akt phosphorylation was lower in the liver of NCAa/HFAa than in NCco/HFco mice. Based on 16S rRNA sequencing, Aa administration changed composition of the gut microbiota. Metagenome prediction in gut microbiota showed upregulation of fatty acid biosynthesis and downregulation of fatty acid degradation in Aa-administered mice. Thus, infection with Aa affects NAFLD by altering the gut microbiota and glucose metabolism.

Hyperglucagonemia correlates with plasma levels of non-branched-chain amino acids in patients with liver disease independent of type 2 diabetes

Patients with type 2 diabetes (T2D) and patients with nonalcoholic fatty liver disease (NAFLD) frequently exhibit elevated plasma concentrations of glucagon (hyperglucagonemia). Hyperglucagonemia and α-cell hyperplasia may result from elevated levels of plasma amino acids when glucagon's action on hepatic amino acid metabolism is disrupted. We therefore measured plasma levels of glucagon and individual amino acids in patients with and without biopsy-verified NAFLD and with and without type T2D. Fasting levels of amino acids and glucagon in plasma were measured, using validated ELISAs and high-performance liquid chromatography, in obese, middle-aged individuals with I) normal glucose tolerance (NGT) and NAFLD, II) T2D and NAFLD, III) T2D without liver disease, and IV) NGT and no liver disease. Elevated levels of total amino acids were observed in participants with NAFLD and NGT compared with NGT controls (1,310 ± 235 µM vs. 937 ± 281 µM, P = 0.03) and in T2D and NAFLD compared with T2D without liver disease (1,354 ± 329 µM vs. 511 ± 235 µM, P < 0.0001). Particularly amino acids with known glucagonotropic effects (e.g., glutamine) were increased. Plasma levels of total amino acids correlated to plasma levels of glucagon also when adjusting for body mass index (BMI), glycated hemoglobin (HbA1c), and cholesterol levels (β = 0.013 ± 0.007, P = 0.024). Elevated plasma levels of total amino acids associate with hyperglucagonemia in NAFLD patients independently of glycemic control, BMI or cholesterol - supporting the potential importance of a "liver-α-cell axis" in which glucagon regulates hepatic amino acid metabolism. Fasting hyperglucagonemia as seen in T2D may therefore represent impaired hepatic glucagon action with increasing amino acids levels. NEW & NOTEWORTHY Hypersecretion of glucagon (hyperglucagonemia) has been suggested to be linked to type 2 diabetes. Here, we show that levels of amino acids correlate with levels of glucagon. Hyperglucagonemia may depend on hepatic steatosis rather than type 2 diabetes.

Glycemic and Metabolic Effects of Two Long Bouts of Moderate-Intensity Exercise in Men with Normal Glucose Tolerance or Type 2 Diabetes.

The glycemic and insulinemic responses following 30-60 min of exercise have been extensively studied, and a dose-response has been proposed between exercise duration, or volume, and improvements in glucose tolerance or insulin sensitivity. However, few studies have examined the effects of longer bouts of exercise in type 2 diabetes (T2D). Longer bouts may have a greater potential to affect glucagon, interleukin-6 (IL-6) and incretin hormones [i.e., glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP)]. To examine the effect of two bouts of long-duration, moderate-intensity exercise on incretins, glucagon, and IL-6 responses before and after exercise, as well as in response to an oral glucose tolerance test (OGTT) conducted the following day. Twelve men, six with and six without T2D, participated in two separate conditions (i.e., exercise vs. rest) according to a randomized crossover design. On day 1, participants either rested or performed two 90 min bouts of treadmill exercise (separated by 3.5 h) at 80% of their ventilatory threshold. All participants received standardized meals on day 1. On day 2 of each condition, glucose and hormonal responses were measured during a 4-h OGTT. On day 1, exercise increased IL-6 at the end of the first bout of exercise (exercise by time interaction p = 0.03) and GIP overall (main effect of exercise p = 0.004). Glucose was reduced to a greater extent in T2D following exercise (exercise by T2D interaction p = 0.03). On day 2, GIP and active GLP-1 were increased in the fasting state (p = 0.05 and p = 0.03, respectively), while plasma insulin and glucagon concentrations were reduced during the OGTT (p = 0.01 and p = 0.02, respectively) in the exercise compared to the rest condition for both healthy controls and T2D. Postprandial glucose was elevated in T2D compared to healthy control (p < 0.05) but was not affected by exercise. Long-duration, moderate-intensity aerobic exercise can increase IL-6. On the day following exercise, fasting incretins remained increased but postprandial insulin and glucagon were decreased without affecting postprandial glucose. This long duration of exercise may not be appropriate for some people, and further research should investigate why next day glucose tolerance was unchanged.

Effect of conjugated linoleic acid and acetate on milk fat synthesis and adipose lipogenesis in lactating dairy cows

During biohydrogenation-induced milk fat depression (MFD), nutrients are spared from milk fat synthesis and are available for other metabolic uses. Acetate is the major carbon source spared and it may increase lipid synthesis in adipose tissue during MFD. The objective of this study was to compare the effect of trans-10,cis-12 conjugated linoleic acid (CLA) and the amount of acetate spared during CLA-induced MFD on adipose tissue lipogenesis. Nine multiparous, lactating, ruminally cannulated Holstein cows (244 ± 107 d in milk; 25 ± 8.4 kg of milk/d; mean ± standard deviation) were randomly assigned to treatments in a 3 × 3 Latin square design. Experimental periods were 4 d followed by a 10-d washout. Treatments were control (CON), ruminal infusion of acetate (AC; continuous infusion of 7 mol/d adjusted to pH 6.1 with sodium hydroxide), or abomasal infusion of CLA (10 g/d of both trans-10,cis-12 CLA and cis-9,trans-11 CLA). Dry matter intake, milk yield, and milk protein yield and percentage were not affected by treatments. Compared with CON, milk fat yield decreased 23% and fat percent decreased 28% in CLA, and milk fat yield increased 20% in AC. Concentration and yield of milk de novo synthesized fatty acids (<C16) were reduced and concentration of preformed fatty acids (>C16) was increased by CLA, compared with CON. Yield of de novo synthesized fatty acids and palmitic acid was increased by AC, compared with CON. Lipogenesis capacity of adipose tissue explants was decreased 72% by CLA, but was not affected by AC. Acetate oxidation by adipose explants was not affected by treatments. Treatments had no effect on expression of key lipogenic factors, lipogenic enzymes, and leptin; however, expression of fatty acid binding protein 4 was reduced in CLA compared with CON. Additionally, hormone-sensitive lipase and perilipin 1 were decreased by CLA and acetate. Plasma glucose and glucagon concentrations were not affected by treatments; however, CLA increased nonesterified fatty acids 17.7%, β-hydroxybutyrate 16.1%, and insulin 27.8% compared with CON, and AC increased plasma β-hydroxybutyrate 18%. In conclusion, during CLA-induced MFD in low-producing cow adipose tissue was sensitive to the anti-lipogenic effects of CLA, while spared acetate did not stimulate adipose lipogenesis. However, acetate may play an important role in stimulating lipogenesis and improving energy status in the mammary gland under normal conditions.

Common variation in the sodium/glucose cotransporter 2 gene SLC5A2 does neither affect fasting nor glucose-suppressed plasma glucagon concentrations.

AimInhibition of sodium/glucose cotransporter 2 (SGLT2), the key transport protein in renal glucose reabsorption, promotes glucose excretion and represents a new concept in the therapy of type-2 diabetes. In addition, SGLT2 inhibition elevates circulating glucagon concentrations and enhances hepatic glucose production. Since SGLT2 is expressed in human pancreatic α-cells and regulates glucagon release, we tested whether common variants of the SGLT2 gene SLC5A2 associate with altered plasma glucagon concentrations in the fasting state and upon glucose challenge.MethodsA study population of 375 healthy subjects at increased risk for type-2 diabetes, phenotyped by a 5-point oral glucose tolerance test (OGTT) and genotyped for recently described SLC5A2 tagging single nucleotide polymorphisms (SNPs), was selected for plasma glucagon measurements.ResultsAfter adjustment for gender, age, body mass index, and insulin sensitivity, the four tagging SNPs (rs9924771, rs3116150, rs3813008, rs9934336), tested separately or as genetic score, were neither significantly nor nominally associated with plasma glucagon concentrations at any time during the OGTT, with the inverse AUC of glucagon or the glucagon fold-change during the OGTT (p ≥ 0.2, all). Testing for genotype-related differences in the time course of the glucagon response using MANOVA did also not reveal any significant or nominal associations (p ≥ 0.5, all).ConclusionWe could not obtain statistically significant evidence for a role of common SLC5A2 variants in the regulation of glucagon release in the fasting state or upon glucose challenge. Moreover, the reported nominal effects of individual SLC5A2 variants on fasting and post-challenge glucose levels may probably not be mediated by altered glucagon release.

Differential circulating concentrations of adipokines, glucagon and adropin in a clinical population of lean, overweight and diabetic cats

BackgroundDyslipidemia, dysregulated adipokine secretion and alteration in glucagon and adropin concentrations are important obesity-related factors in the pathophysiology of human Type 2 diabetes; however, their roles in the pathophysiology of feline diabetes mellitus are relatively unknown. Here, we determined the concentrations of circulating leptin, adiponectin, pro-inflammatory cytokines, glucagon, adropin, triglycerides, and cholesterol, in non-diabetic lean and overweight cats and newly diagnosed diabetic cats. Client-owned cats were recruited and assigned into 3 study groups: lean, overweight and diabetic. Fasting blood samples were analyzed in lean, overweight and diabetic cats at baseline and 4 weeks after consumption of high protein/low carbohydrate standardized diet.ResultsSerum concentrations of triglycerides were greater in diabetics at baseline and were increased in both diabetic and overweight cats at 4 weeks. Plasma leptin concentrations were greater in diabetic and overweight at baseline and 4 weeks, whereas adiponectin was lower in diabetics compared to lean and overweight cats at baseline and 4 weeks. Diabetics had greater baseline plasma glucagon concentrations compared to lean, lower adropin than overweight at 4 weeks, and lower IL-12 concentrations at 4 weeks than baseline.ConclusionsOur results suggest that feline obesity and diabetes mellitus are characterized by hypertriglyceridemia and hyperleptinemia; however, diabetic cats have significantly lower adiponectin and adropin compared to overweight cats. Thus, despite having similar body condition, overweight and diabetic cats have differential circulating concentrations of adiponectin and adropin.