Current artificial pancreas systems (AP) operate via subcutaneous (SC) glucose sensing and SC insulin delivery. Due to slow diffusion and transport dynamics across the interstitial space, even the most sophisticated control algorithms in on-body AP systems cannot react fast enough to maintain tight glycemic control under the effect of exogenous glucose disturbances caused by ingesting meals or performing physical activity. Recent efforts made towards the development of an implantable AP have explored the utility of insulin infusion in the intraperitoneal (IP) space: a region within the abdominal cavity where the insulin-glucose kinetics are observed to be much more rapid than the SC space. In this paper, a series of canine experiments are used to determine the dynamic association between IP insulin boluses and plasma glucose levels. Data from these experiments are employed to construct a new mathematical model and to formulate a closed-loop control strategy to be deployed on an implantable AP. The potential of the proposed controller is demonstrated via in-silico experiments on an FDA-accepted benchmark cohort: the proposed design significantly outperforms a previous controller designed using artificial data (time in

Enterically delivered tregopil is rapidly absorbed and restores a portal-to-peripheral vascular distribution. These characteristics should improve postprandial hyperglycaemia in types 1 and 2 diabetes.

It is unknown whether activation of hepato-portal vein (PV) glucose sensors plays a role in incretin hormone amplification of oral glucose-stimulated insulin secretion (GSIS). In previous studies, PV glucose infusion increased GSIS through unknown mechanisms, perhaps neural stimulation of pancreatic β-cells and/or stimulation of gut incretin hormone release. Thus, there could be a difference in the incretin effect when comparing GSIS with portal rather than leg vein (LV) glucose infusion. Plasma insulin and incretin hormones were studied in six overnight-fasted dogs. An oral glucose tolerance test (OGTT) was administered, and then 1 and 2 wk later the arterial plasma glucose profile from the OGTT was mimicked by infusing glucose into either the PV or a LV. The arterial glucose levels were nearly identical between groups (AUCs within 1% of each other). Oral glucose administration increased arterial GLP-1 and GIP levels by more than sixfold, whereas they were not elevated by PV or LV glucose infusion. Oral glucose delivery was associated with only a small incretin effect (arterial insulin and C-peptide were 21 ± 23 and 24 ± 17% greater, respectively, during the 1st hour with oral compared with PV glucose and 14 ± 37 and 13 ± 35% greater, respectively, in oral versus LV; PV versus LV responses were not significantly different from each other). Thus, following an OGTT incretin hormone release did not depend on activation of PV glucose sensors, and the insulin response was not greater with PV compared with LV glucose infusion in the dog. The small incretin effect points to species peculiarities, which is perhaps related to diet.

Glucagon’s effect on hepatic glucose production (HGP), under hyperglycemic conditions, is time dependent such that after an initial burst of HGP, it slowly wanes. It is not known whether this is also the case under hypoglycemic conditions, where an increase in HGP is essential. This question was addressed using adrenalectomized dogs to avoid the confounding effects of other counterregulatory hormones. During the study, infusions of epinephrine and cortisol were given to maintain basal levels. Somatostatin and insulin (800 µU·kg−1·min−1) were infused to induce hypoglycemia. After 30 min, glucagon was infused at a basal rate (1 ng·kg−1·min−1, baGGN group, n = 5 dogs) or a rate eightfold basal (8 ng·kg−1·min−1, hiGGN group, n = 5 dogs) for 4 h. Glucose was infused to match the arterial glucose levels between groups (≈50 mg/dL). Our data showed that glucagon has a biphasic effect on the liver despite hypoglycemia. Hyperglucagonemia stimulated a rapid, transient peak in HGP (4-fold basal production) over ~60 min, which was followed by a slow reduction in HGP to a rate 1.5-fold basal. During the last 2 h of the experiment, hiGGN stimulated glucose production at a rate fivefold greater than baGGN (2.5 vs. 0.5 mg·kg−1·min−1, respectively), indicating a sustained effect of the hormone. Of note, the hypoglycemia-induced rises in norepinephrine and glycerol were smaller in hiGGN compared with the baGGN group despite identical hypoglycemia. This finding suggests that there is reciprocity between glucagon and the sympathetic nervous system such that when glucagon is increased, the sympathetic nervous response to hypoglycemia is downregulated.

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).