RESUMO
It is not completely clear which organs are responsible for glucagon elimination in humans, and disturbances in the elimination of glucagon could contribute to the hyperglucagonemia observed in chronic liver disease and chronic kidney disease (CKD). Here, we evaluated kinetics and metabolic effects of exogenous glucagon in individuals with stage 4 CKD (n =16), individuals with Child-Pugh A-C cirrhosis (n = 16) and matched control individuals (n = 16), before, during and after a 60-minute glucagon infusion (4 ng/kg/min). Individuals with CKD exhibited a significantly lower mean metabolic clearance rate of glucagon (14.0 [95% CI 12.2;15.7] mL/kg/min) both compared to individuals with cirrhosis (19.7 [18.1;21.3] mL/kg/min, P < 0.001) and to control individuals (20.4 [18.1;22.7] mL/kg/min, P < 0.001). Glucagon half-life was significantly prolonged in the CKD group (7.5 [6.9;8.2] minutes) compared to individuals with cirrhosis (5.7 [5.2;6.3] minutes, P = 0.002) and control individuals (5.7 [5.2;6.3] minutes, P < 0.001). No difference in the effects of exogenous glucagon on plasma glucose, amino acids, or triglycerides was observed between groups. In conclusion, chronic kidney disease, but not liver cirrhosis leads to a significant reduction in glucagon clearance, supporting the kidneys as a primary site for human glucagon elimination.
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Oxytocin has been proposed to possess glucose-stabilizing effects through the release of insulin and glucagon from the pancreas. Also, exogenous oxytocin has been shown to stimulate extrapancreatic glucagon secretion in depancreatized dogs. Here, we investigated the effect of exogenous oxytocin on circulating levels of pancreatic and gut-derived glucose-stabilizing hormones (insulin [measured as C-peptide], glucagon, glucagon-like peptide 1 [GLP-1], and glucose-dependent insulinotropic polypeptide). We studied nine pancreatectomized (PX) patients and nine healthy controls (CTRLs) (matched on age and body mass index) before, during, and after an intravenous infusion of 10 IU of oxytocin administered over 12â¯min. Oxytocin did not increase plasma glucagon levels, nor induce any changes in plasma glucose, C-peptide, or GIP in any of the groups. Oxytocin decreased plasma glucagon levels by 19 ± 10â¯% in CTRLs (from 2.0 ± 0.5 [mean ± SEM] to 1.3 ± 0.2 pmol/l, P = 0.0025) and increased GLP-1 by 42 ± 22â¯% in PX patients (from 9.0 ± 1.0-12.7 ± 1.0 pmol/l, P = 0.0003). Fasting plasma glucose levels were higher in PX patients compared with CTRLs (13.1 ± 1.1 vs. 5.1 ± 0.1â¯mmol/l, P < 0.0001). In conclusion, the present findings do not support pancreas-mediated glucose-stabilizing effects of acute oxytocin administration in humans and warrant further investigation of oxytocin's gluco-metabolic effects.
Assuntos
Glicemia , Polipeptídeo Inibidor Gástrico , Peptídeo 1 Semelhante ao Glucagon , Glucagon , Insulina , Ocitocina , Pancreatectomia , Humanos , Ocitocina/farmacologia , Ocitocina/administração & dosagem , Ocitocina/sangue , Ocitocina/metabolismo , Masculino , Glucagon/sangue , Glucagon/metabolismo , Feminino , Pessoa de Meia-Idade , Glicemia/metabolismo , Peptídeo 1 Semelhante ao Glucagon/sangue , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Insulina/sangue , Insulina/metabolismo , Polipeptídeo Inibidor Gástrico/sangue , Polipeptídeo Inibidor Gástrico/metabolismo , Idoso , Adulto , Peptídeo C/sangue , Peptídeo C/metabolismoRESUMO
OBJECTIVE: The metabolic phenotype of totally pancreatectomised patients includes hyperaminoacidaemia and predisposition to hypoglycaemia and hepatic lipid accumulation. We aimed to investigate whether the loss of pancreatic glucagon may be responsible for these changes. METHODS: Nine middle-aged, normal-weight totally pancreatectomised patients, nine patients with type 1 diabetes (C-peptide negative), and nine matched controls underwent two separate experimental days, each involving a 150-min intravenous infusion of glucagon (4â ng/kg/min) or placebo (saline) under fasting conditions while any basal insulin treatment was continued. RESULTS: Glucagon infusion increased plasma glucagon to similar high physiological levels in all groups. The infusion increased hepatic glucose production and decreased plasma concentration of most amino acids in all groups, with more pronounced effects in the totally pancreatectomised patients compared with the other groups. Glucagon infusion diminished fatty acid re-esterification and tended to decrease plasma concentrations of fatty acids in the totally pancreatectomised patients but not in the type 1 diabetes patients. CONCLUSION: Totally pancreatectomised patients were characterised by increased sensitivity to exogenous glucagon at the level of hepatic glucose, amino acid, and lipid metabolism, suggesting that the metabolic disturbances characterising these patients may be rooted in perturbed hepatic processes normally controlled by pancreatic glucagon.
Assuntos
Diabetes Mellitus Tipo 1 , Glucagon , Fígado , Pancreatectomia , Humanos , Glucagon/sangue , Glucagon/metabolismo , Masculino , Pessoa de Meia-Idade , Feminino , Fígado/metabolismo , Fígado/efeitos dos fármacos , Adulto , Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 1/tratamento farmacológico , Diabetes Mellitus Tipo 1/sangue , Metabolismo dos Lipídeos/efeitos dos fármacos , Glicemia/metabolismo , Glicemia/efeitos dos fármacos , Aminoácidos/metabolismo , Aminoácidos/administração & dosagem , Aminoácidos/sangue , Glucose/metabolismoRESUMO
Recent advancements in understanding glucagon-like peptide 2 (GLP-2) biology and pharmacology have sparked interest in targeting the GLP-2 receptor (GLP-2R) in the treatment of obesity. GLP-2 is a proglucagon-derived 33-amino acid peptide co-secreted from enteroendocrine L cells along with glucagon-like peptide 1 (GLP-1) and has a range of actions via the GLP-2R, which is particularly expressed in the gastrointestinal tract, the liver, adipose tissue, and the central nervous system (CNS). In humans, GLP-2 evidently induces intestinotrophic effects (i.e., induction of intestinal mucosal proliferation and improved gut barrier function) and promotes mesenteric blood flow. However, GLP-2 does not seem to have appetite or food intake-reducing effects in humans, but its gut barrier-promoting effect may be of interest in the context of obesity. Obesity is associated with reduced gut barrier function, increasing the translocation of proinflammatory gut content to the circulation. This phenomenon constitutes a strong driver of obesity-associated systemic low-grade inflammation, which in turn plays a major role in the development of most obesity-associated complications. Thus, the intestinotrophic and gut barrier-improving effect of GLP-2, which in obese rodent models shows strong anti-inflammatory potential, may, in combination with food intake-reducing strategies, e.g., GLP-1 receptor (GLP-1) agonism, be able to rectify core pathophysiological mechanism of obesity. Here, we provide an overview of GLP-2 physiology in the context of obesity pathophysiology and review the pharmacological potential of GLP-2R activation in the management of obesity and related comorbidities.
Assuntos
Receptor do Peptídeo Semelhante ao Glucagon 2 , Obesidade , Animais , Humanos , Peptídeo 2 Semelhante ao Glucagon/metabolismo , Receptor do Peptídeo Semelhante ao Glucagon 2/agonistas , Receptor do Peptídeo Semelhante ao Glucagon 2/metabolismo , Obesidade/metabolismo , Obesidade/tratamento farmacológicoRESUMO
Objective: In obesity and type 2 diabetes, hyperglucagonaemia may be caused by elevated levels of glucagonotropic amino acids due to hepatic glucagon resistance at the level of amino acid turnover. Here, we investigated the effect of exogenous glucagon on circulating amino acids in obese and non-obese individuals with and without type 2 diabetes. Design: This was a post hoc analysis in a glucagon infusion study performed in individuals with type 2 diabetes (n = 16) and in age, sex, and body mass index-matched control individuals without diabetes (n = 16). Each group comprised two subgroups of eight individuals with and without obesity, respectively. Methods: All participants received a 1-h glucagon infusion (4 ng/kg/min) in the overnight fasted state. Plasma amino acid concentrations were measured with frequent intervals. Results: Compared to the control subgroup without obesity, baseline total amino acid levels were elevated in the control subgroup with obesity and in the type 2 diabetes subgroup without obesity. In all subgroups, amino acid levels decreased by up to 20% in response to glucagon infusion, which resulted in high physiological steady-state glucagon levels (mean concentration: 74 pmol/L, 95% CI [68;79] pmol/L). Following correction for multiple testing, no intergroup differences in changes in amino acid levels reached significance. Conclusion: Obesity and type 2 diabetes status was associated with elevated fasting levels of total amino acids. The glucagon infusion decreased circulating amino acid levels similarly in all subgroups, without significant differences in the response to exogenous glucagon between individuals with and without obesity and type 2 diabetes. Significance statement: The hormone glucagon stimulates glucose production from the liver, which may promote hyperglycaemia if glucagon levels are abnormally elevated, as is often seen in type 2 diabetes and obesity. Glucagon levels are closely linked to, and influenced by, the levels of circulating amino acids. To further investigate this link, we measured amino acid levels in individuals with and without obesity and type 2 diabetes before and during an infusion of glucagon. We found that circulating amino acid levels were higher in type 2 diabetes and obesity, and that glucagon infusion decreased amino acid levels in both individuals with and without type 2 diabetes and obesity. The study adds novel information to the link between circulating levels of glucagon and amino acids.
RESUMO
CONTEXT: In healthy individuals, glucose-dependent insulinotropic polypeptide (GIP) enhances insulin secretion and reduces bone resorption by up to 25% estimated by absolute placebo-corrected changes in carboxy-terminal type 1 collagen crosslinks (CTX) during GIP and glucose administration. In patients with type 2 diabetes (T2D), GIP's insulinotropic effect is impaired and effects on bone may be reduced. OBJECTIVE: To investigate GIP's effect on bone biomarkers in patients with T2D. DESIGN: Randomized, double-blinded, crossover study investigating 6 interventions. PATIENTS: Twelve male patients with T2D. INTERVENTIONS: A primed continuous 90-minute GIP infusion (2 pmol/kg/min) or matching placebo (saline) administered at 3 plasma glucose (PG) levels (i.e., paired days with "insulin-induced hypoglycemia" (PG lowered to 3 mmol/L), "fasting hyperglycemia" (mean PG ~8 mmol/L), or "aggravated hyperglycemia" (mean PG ~12 mmol/L). MAIN OUTCOME MEASURES: Bone biomarkers: CTX, procollagen type 1 N-terminal propeptide (P1NP) and PTH. RESULTS: On days with insulin-induced hypoglycemia, CTX was suppressed by up to 40â ±â 15% during GIP administration compared with 12â ±â 11% during placebo infusion (Pâ <â 0.0001). On days with fasting hyperglycemia, CTX was suppressed by up to 36â ±â 15% during GIP administration, compared with 0â ±â 9% during placebo infusion (Pâ <â 0.0001). On days with aggravated hyperglycemia, CTX was suppressed by up to 47â ±â 23% during GIP administration compared with 10â ±â 9% during placebo infusion (Pâ =â 0.0005). At all glycemic levels, P1NP and PTH concentrations were similar between paired days after 90 minutes. CONCLUSIONS: Short-term GIP infusions reduce bone resorption by more than one-third (estimated by absolute placebo-corrected CTX reductions) in patients with T2DM, suggesting preserved bone effects of GIP in these patients. PRÉCIS: Short-term GIP infusions reduce the bone resorption marker CTX by one-third in patients with type 2 diabetes independent of glycemic levels.