Incretin Hormone Release Does Not Involve Hepatic Portal Vein Glucose Sensors

Abstract

The incretin effect, which is defective in individuals with T2D, involves the secretion of GLP-1 and GIP when glucose is given orally, but not when it is infused via a peripheral vein. Glucose ingestion results in a hepatic portal vein/arterial glucose gradient. This activates portal vein glucose sensors which play an important role in the regulation of glucose metabolism during feeding. It is unknown whether these sensors contribute to GLP-1 or GIP secretion during glucose ingestion. To test the hypothesis that portal but not peripheral vein glucose infusion would stimulate incretin hormone secretion, intraportal (infusion) and femoral artery (sampling) catheters were placed in 6 dogs. Two weeks later the animals were administered an oral glucose tolerance test (OGTT; 0.9 g/kg) and one and two weeks after that the arterial plasma glucose profile which occurred during each OGTT was matched by infusing glucose either into the portal (Po) or a peripheral (Pe) vein. The AUCs for glucose (0-180 min; total) were nearly identical: 8251±325, 8219±334 and 8200±341 mg/dl (180 min) in the OGTT, Po and Pe treatments, respectively. The total glucose administered was reduced in the Pe (562±76 mg/kg) compared to the OGTT and Po treatments (900±0 and 856±92 mg/kg, respectively). During the 1st hour the arterial insulin and c-peptide responses were ∼25% greater in the OGTT compared to the other treatments, whereas there was <5% difference in their levels in Po vs. Pe. Arterial glucagon fell modestly in all treatments. Oral glucose administration increased arterial GLP-1 and GIP levels by >6-fold over basal, but their levels did not change in Po or Pe. The 0-180 min AUCs for GLP-1 were 669±218, 315±128 and 323±81 pg/ml, and for GIP were 14725±1506, 2556±529 and 2658±316 pg/ml in the OGTT, Po and Pe treatments, respectively. Thus, activation of portal vein glucose sensors did not stimulate the release of, or insulinotropic response to, incretin hormones in the overnight fasted dog, but portal vein glucose entry enhanced glucose clearance. Disclosure D.S. Edgerton: Speaker's Bureau; Self; Novo Nordisk A/S. G. Kraft: None. M.S. Smith: None. L. Moore: None. B. Farmer: None. H. Sara: None. M. Scott: None. M. Moore: None. M.A. Nauck: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim GmbH, Eli Lilly and Company, Fractyl Laboratories, Inc., GlaxoSmithKline plc., Berlin-Chemie AG, Merck Sharp & Dohme Corp., Novo Nordisk A/S. Speaker's Bureau; Self; AstraZeneca, Boehringer Ingelheim GmbH, Eli Lilly and Company, Berlin-Chemie AG, Merck Sharp & Dohme Corp., Medscape, Novo Nordisk A/S. Research Support; Self; AstraZeneca, Berlin-Chemie AG, Eli Lilly and Company, Merck Sharp & Dohme Corp., Novartis AG, GlaxoSmithKline plc., Novo Nordisk A/S. Consultant; Self; Nordic Bioscience, Empros. A.D. Cherrington: Advisory Panel; Self; Biocon. Consultant; Self; Boston Scientific Corporation. Research Support; Self; Boston Scientific Corporation. Consultant; Self; Eli Lilly and Company. Advisory Panel; Self; Fractyl Laboratories, Inc.. Stock/Shareholder; Self; Fractyl Laboratories, Inc.. Consultant; Self; Galvani Bioelectronics Limited. Research Support; Self; Galvani Bioelectronics Limited. Consultant; Self; MedImmune. Advisory Panel; Self; Metavention. Stock/Shareholder; Self; Metavention. Consultant; Self; Novo Nordisk Inc.. Research Support; Self; Novo Nordisk Inc.. Advisory Panel; Self; NuSirt Biopharma, Inc., Sensulin Labs, LLC.. Other Relationship; Self; Sensulin Labs, LLC.. Consultant; Self; Silver Lake. Research Support; Self; Silver Lake. Consultant; Self; Thermalin Diabetes, LLC., Thetis Pharmaceuticals LLC.. Stock/Shareholder; Self; Thetis Pharmaceuticals LLC.. Advisory Panel; Self; VTV Therapeutics. Consultant; Self; VTV Therapeutics. Advisory Panel; Self; Zafgen. Research Support; Self; Zafgen. Stock/Shareholder; Self; Zafgen. Consultant; Self; Abvance. Other Relationship; Self; Abvance. Consultant; Self; California Institute for Biomedical Research (Calibr). Advisory Panel; Self; These Three Medical, Inc (T3M).