glucagon-like-peptide-1 and Hypopituitarism

The gastrointestinal hormone ghrelin stimulates growth hormone secretion and appetite, but recent studies indicate that ghrelin also stimulates the secretion of the appetite-inhibiting and insulinotropic hormone glucagon-like peptide-1 (GLP-1).. To investigate the putative effect of ghrelin on GLP-1 secretion in vivo and in vitro.. A randomized placebo-controlled crossover study was performed in eight hypopituitary subjects. Ghrelin or saline was infused intravenously (1 pmol/min × kg) after collection of baseline sample (0 min), and blood was subsequently collected at time 30, 60, 90, and 120 minutes. Mouse small intestine was perfused (n = 6) and GLP-1 output from perfused mouse small intestine was investigated in response to vascular ghrelin administration in the presence and absence of a simultaneous luminal glucose stimulus. Ghrelin receptor expression was quantified in human (n = 11) and mouse L-cells (n = 3) by RNA sequencing and RT-qPCR, respectively.. Ghrelin did not affect GLP-1 secretion in humans (area under the curve [AUC; 0-120 min]: ghrelin infusion = 1.37 ± 0.05 min × nmol vs. saline infusion = 1.40 ± 0.06 min × nmol [P = 0.63]), but induced peripheral insulin resistance. Likewise, ghrelin did not stimulate GLP-1 secretion from the perfused mouse small intestine model (mean outputs during baseline/ghrelin infusion = 19.3 ± 1.6/25.5 ± 2.0 fmol/min, n = 6, P = 0.16), whereas glucose-dependent insulinotropic polypeptide administration, used as a positive control, doubled GLP-1 secretion (P < 0.001). Intraluminal glucose increased GLP-1 secretion by 4-fold (P < 0.001), which was not potentiated by ghrelin. Finally, gene expression of the ghrelin receptor was undetectable in mouse L-cells and marginal in human L-cells.. Ghrelin does not interact directly with the L-cell and does not directly affect GLP-1 secretion.

Topics: Administration, Intravenous; Adult; Aged; Animals; Cells, Cultured; Cross-Over Studies; Denmark; Double-Blind Method; Ghrelin; Glucagon-Like Peptide 1; Humans; Hypopituitarism; Intestinal Mucosa; Intestines; L Cells; Male; Mice; Mice, Inbred C57BL; Middle Aged; Placebos; Secretory Pathway; Up-Regulation

Glucagon-like peptide-1 (GLP-1) is an incretin hormone used therapeutically in type 2 diabetes and obesity. The interplay between ambient free fatty acids (FFAs) and GLP-1 remains unclear. Acipimox suppresses adipose tissue lipolysis via activation of the PUMA-G (also known as HCA2 and GPR109a) receptor.. To investigate whether lowering of serum FFA level with acipimox affects GLP-1 secretion.. Two randomized crossover studies were performed in human subjects. Rat intestine was perfused intra-arterially and intraluminally, and l-cells were incubated with acipimox.. The participants were healthy overweight subjects and hypopituitary adult patients.. The overweight participants received acipimox 250 mg 60 minutes before an oral glucose test. The hypopituitary patients received acipimox 250 mg 12, 9, and 2 hours before and during the metabolic study day, when they were studied in the basal state and during a hyperinsulinemic euglycemic clamp.. Acipimox suppressed FFA but did not affect insulin in the clinical trials. In overweight subjects, the GLP-1 increase after the oral glucose tolerance test (area under the curve) was more than doubled [4119 ± 607 pmol/L × min (Acipimox) vs 1973 ± 375 pmol/L × min (control), P = 0.004]. In hypopituitary patients, acipimox improved insulin sensitivity (4.7 ± 0.8 mg glucose/kg/min (Acipimox) vs 3.1 ± 0.5 mg glucose/kg/min (control), P = 0.005], and GLP-1 concentrations increased ~40%. An inverse correlation between FFA and GLP-1 concentrations existed in both trials. In rat intestine, acipimox did not affect GLP-1 secretion, and l-cells did not consistently express the putative receptor for acipimox.. Acipimox treatment increases systemic GLP-1 levels in both obese subjects and hypopituitary patients. Our in vitro data indicate that the underlying mechanisms are indirect.

Topics: Adult; Animals; Blood Glucose; Cells, Cultured; Cross-Over Studies; Enteroendocrine Cells; Fatty Acids, Nonesterified; Glucagon-Like Peptide 1; Glucose Tolerance Test; Humans; Hypolipidemic Agents; Hypopituitarism; Insulin Resistance; Intestinal Mucosa; Lipolysis; Male; Middle Aged; Overweight; Pilot Projects; Primary Cell Culture; Pyrazines; Rats

To identify possible abnormalities specific for obesity in hypopituitary patients.. Cross-sectional case-control study. MEASUREMENTS AND STUDY SUBJECTS: Body composition (DEXA) and measurements of fasting plasma levels of glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptides (GLPs), insulin, C-peptide, glucose, leptin and lipids were performed in 25 hypopituitary patients (15 obese, 10 normal weight) and 26 BMI and age-matched healthy controls (16 obese, 10 normal weight). All hypopituitary patients had GH deficiency and received adequate substitution therapy on this and other deficient axes (3 +/- 1).. Fasting GIP-levels were significantly higher in obese hypopituitary patients compared to lean hypopituitary patients (P < 0.01), while the fasting concentrations of GLP-1 and GLP-2 were comparable between obese and lean hypopituitary patients. The same trend was seen in obese healthy controls vs. lean controls. No differences were observed in glucose, insulin or C-peptide between the hypopituitary patients and the controls. Leptin levels were increased in obese hypopituitary patients compared to lean hypopituitary patients when adjusted for gender. At least a 2-fold higher level of leptin was observed in women compared to men in both patient groups and healthy controls. Lean female hypopituitary patients had higher leptin levels than matched controls.. Fasting levels of GIP were elevated in obese substituted hypopituitary patients, while fasting concentrations of GLPs were similar. Obese hypopituitary patients had the same degree of hyperinsulinaemia, affected glucose tolerance, dyslipoproteinaemia and central obesity as obese healthy controls. Further studies are required to identify the possible biochemical reasons for obesity in patients with apparently well-substituted hypopituitarism.

Topics: Adult; Anthropometry; Body Composition; Case-Control Studies; Cross-Sectional Studies; Fasting; Female; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptide 2; Glucagon-Like Peptides; Human Growth Hormone; Humans; Hypopituitarism; Leptin; Lipids; Male; Middle Aged; Obesity; Peptide Fragments; Peptides; Thinness