Basal Oral Insulin Analog I338 Enhances Meal-Related Hepatic Glucose Disposal

Abstract

Oral insulin avoids the need for injections, and insulin enters via the hepatic portal vein (Po), the normal route of secretion. We examined the effect of I338, an acylated analog designed for oral use, dosed either Po to match the oral absorption profile or IV to match the steady state basal subcutaneous (SC) plasma profile, on a Po glucose challenge. To achieve steady-state concentrations in normal dogs, I338 was infused IV 45 min daily for 4 days. On day 5 a primed, continuous infusion of 3-3H glucose was given. After 90 min of equilibration and 30 min of basal sampling, a clamp was conducted (0-300 min), with somatostatin to inhibit pancreatic secretion and basal glucagon replacement. In the LOW dogs (n=5) I338 (pmol/kg/min) was infused either Po at 40 (0-45 min to mimic oral absorption) or IV at 1 (0-300 min to mimic subcutaneous [SC] delivery), approximately an equivalent daily dose (1800 vs. 1440 pmol/kg, Po vs. IV). High dose dogs (HI; n=4) received I338 at 50 (Po) or 5 (IV) pmol/kg/min. A Po glucose infusion mimicking meal absorption was given via computer algorithm from 30-252 min. All dogs were studied twice, 2 weeks apart in random order, receiving both Po and IV I338. Po vs. IV, respectively, resulted in: 1) lower glycemic levels (peak glucose LOW 6.2±0.3 and 10.3±0.6,* HI 4.5±0.3, and 7.8±0.8* mM); 2) increased net hepatic glucose uptake (AUC30-240 min Low 218.4±151.8 and -852.0±371.4,* HI 732.6±338.5 and -58.5±578.4* µmol/kg); 3) enhanced glucose clearance (AUC30-240 min LOW 481.9±29.7 and 359.4±33.7,* HI 874.3±99.8 and 495.3±25.9* mL/kg) and 4) greater peak hepatic fractional glucose extraction (LOW 0.05±0.02 and -0.01±0.01,* HI 0.10±0.and 0.04±0.02*)(*P<0.vs. corresponding Po treatment). In short, Po basal I338 delivery produced superior glucose lowering and hepatic glucose disposal during a morning “meal” compared to SC-like delivery. Thus basal oral I338 can improve the glycemic response to the first meal after dosing, potentially improving glucose disposal at subsequent meals via the 2nd meal effect. Disclosure M.C. Moore: None. E. Nishimura: Stock/Shareholder; Self; Novo Nordisk A/S. Employee; Self; Novo Nordisk A/S. Stock/Shareholder; Spouse/Partner; Novo Nordisk A/S. C.L. Brand: Other Relationship; Self; Novo Nordisk A/S. T. Kjeldsen: Stock/Shareholder; Self; Novo Nordisk A/S. Employee; Self; Novo Nordisk A/S. Stock/Shareholder; Spouse/Partner; Novo Nordisk A/S. P. Madsen: Employee; Self; Novo Nordisk A/S. Stock/Shareholder; Self; Novo Nordisk A/S. Employee; Spouse/Partner; Novo Nordisk A/S. Stock/Shareholder; Spouse/Partner; Novo Nordisk A/S. H.H. Refsgaard: Employee; Self; Novo Nordisk A/S. Stock/Shareholder; Self; Novo Nordisk A/S. Employee; Spouse/Partner; Novo Nordisk A/S. Stock/Shareholder; Spouse/Partner; Novo Nordisk A/S. K. Wassermann: Employee; Self; Novo Nordisk A/S. Stock/Shareholder; Self; Novo Nordisk A/S. S. Gram-Nielsen: Employee; Self; Novo Nordisk A/S. M.S. Smith: None. L. Moore: None. B. Farmer: None. J.R. Hastings: None. P.E. Williams: None. 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).

MetAP2 inhibitor treatment of high-fat and -fructose-fed dogs: impact on the response to oral glucose ingestion and a hyperinsulinemic hyperglycemic clamp

“…This enhancement of liver glycogen storage is consistent with that reported in a high-fat-fed rat model treated with a similar compound, compared with pair-fed control animals not given drug treatment (1). With the exception of inhaled or orally administered insulin analogs (11,24), which remain uncommon in diabetes treatment or still under development (9), it is rare for diabetes medications to enhance NHGU. Subcutaneous delivery of the available insulin products is associated with increased peripheral (muscle and fat) glucose uptake but not with substantial stimulation of liver glucose uptake (10,27).…”