Hepatic-directed vesicle insulin (HDV-I), a novel investigational vesicle (<150 nm diameter) insulin delivery system that carries insulin and a specific hepatocyte-targeting molecule (HTM) in its phospholipid bilayer and has the ability to mimic a portal vein insulin infusion remotely [subcutaneous (SC) HDV-I] and noninvasively (oral HDV-I), has been developed. This review summarizes formulation development, subsequent refinements, and results of preclinical evaluation studies, including biodistribution, mechanistic, and toxicology studies of predominantly SC HDV-I, in various animal models. Studies conducted to date have confirmed the hepatocyte specificity of HDV and HDV-I and revealed that HDV-I can stimulate the conversion of hepatic glucose output to uptake at a dose that is <1% of the dose of regular insulin (RI) required for liver stimulation; suggest that the enhanced antihyperglycemic effect of HDV-I is due to hepatic glucose uptake; and in pancreatectomized dogs during an oral glucose tolerance test, HDV-I normalized blood glucose curves when compared to control curves in intact dogs and prevented secondary hypoglycemia in contrast to the same dose of RI. A 28-day SC HDV toxicity study in rats revealed no clinical, clinical laboratory, or histopathological findings, and the battery of three genetic toxicology studies was negative. Results support the hypothesis that HDV-I works by stimulating hepatic glucose uptake and/or glycogen storage in insulin-deficient animals. The ability to target the delivery of HDV-I to the liver reestablishes the liver as a major metabolic modulator of glucose metabolism. The future of HDV-I depends on the results of ongoing development and longer term clinical trials.

P oor control of postprandial glycemia in type 2 diabetes is associated with elevated rates of all-cause mortality (1), making postprandial hyperglycemia an attractive pharmaceutical target. Individuals who have type 2 diabetes and receive monoamine oxidase inhibitors demonstrate more frequent episodes of hypoglycemia (2), and those who take selective serotonin reuptake inhibitors have improved glucose tolerance (3) compared with similar individuals who do not take these drugs. Moreover, intraperitoneal administration of serotonin (5-hydroxytryptamine [5-HT]) or its precursor 5-hydroxytryptophan has a hypoglycemic effect in mice (4). 5-HT accumulated in both the liver and the brain of the mice, leaving a question of which tissue was responsible for the hypoglycemia. However, in subsequent studies, the mice were also treated with carbidopa, an inhibitor of peripheral but not central aromatic amino acid decarboxylase. Neither hypoglycemia nor hepatic accumulation of 5-HT was observed in carbidopa-treated mice, although brain levels of 5-HT were even higher than in the absence of carbidopa. Thus, it seemed that hypoglycemia was related to the elevation of hepatic 5-HT (5). We hypothesized that 5-HT can reduce postprandial glycemia by enhancing NHGU and examined this hypothesis in conscious dogs in which the pancreatic hormones and hepatic glucose load (HGL) could be fixed. RESEARCH DESIGN AND METHODSAnimals and surgical procedures. Studies were carried out on 16 conscious 42-h-fasted mongrel dogs of either sex with a mean weight of 24 Ϯ 1 kg. Diet and housing were as previously described (6), and the protocol was approved by the Vanderbilt University Medical Center Animal Care Committee.Approximately 16 days before study, each dog underwent a laparotomy for placement of ultrasonic flow probes around the portal vein and the hepatic artery, as well as for insertion of silicone rubber catheters for sampling in a hepatic vein, the portal vein, and a femoral artery and for infusion into a splenic and a jejunal vein as described in detail elsewhere (6,7). Criteria for study were as previously described (6,7).On the morning of the study, catheters and flow probe leads were exteriorized from their subcutaneous pockets (6,7). The splenic and jejunal catheters were used for intraportal infusion of insulin (Eli Lilly & Co., Indianapolis, IN), glucagon (GlucaGen; Bedford Laboratories, Bedford, OH), and 5-HT (5-HT creatinine sulfate complex; Sigma, St. Louis, MO). Angiocaths (Deseret Medical, Sandy, UT) were inserted into three peripheral veins. Experimental design. Each experiment consisted of a 90-min equilibration period (Ϫ120 to Ϫ30 min), a 30-min basal period (Ϫ30 to 0 min), and a 270-min experimental period (0 to 270 min) divided into four subperiods (P1, 0 -90 min; P2, 90 -150 min; P3, 150 -210 min, and P4, 210 -270 min). At Ϫ120 min, a primed, continuous infusion of [3-3 H]glucose and a continuous infusion of indocyanine green dye (5 g ⅐ kg Ϫ1 ⅐ min Ϫ1 ) were begun in all dogs, with the exception of two that did not re...

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The dose response of postprandial plasma glucose (PPG) to add-on, premeal oral hepatic-directed vesicle-insulin (HDV-I), an investigational lipid bio-nanoparticle hepatocyte-targeted insulin delivery system, was evaluated in a 3-test-meal/day model in type 2 diabetes patients. The single-blind, placebo-controlled, dose-escalating trial enrolled 6 patients with HbA(1c) 8.6 ± 2.0% (70.0 ± 21.9 mmol/mol) and on stable metformin therapy. Patients received oral HDV-I capsules daily 30 minutes before breakfast, lunch, and dinner as follows: placebo capsules, 0.05, 0.1, 0.2, and 0.4 U/kg on days 1, 2, 3, 4, and 5, respectively. Outcome measures were PPG and incremental PPG area under the concentration-time curve (AUC). All 4 doses of oral HDV-I statistically significantly lowered mean PPG (P ≤ .0110 each) and incremental PPG (P ≤ .0352 each) AUC compared to placebo. A linear dose response was not observed. The 0.05 U/kg dose was the minimum effective dose in the dosage range studied. Three adverse events unrelated to treatment were observed. Add-on oral HDV-I 0.05-0.4 U/kg significantly lowered PPG excursions and the dose response curve was flat. These results are consistent with the lack of a linear dose response between portal and systemic plasma insulin concentrations in previous animal and human studies. Oral HDV-I was safe and well tolerated.

Hepatic-directed vesicle insulin (HDV) uses a hepatocyte-targeting moiety passively attaching free insulin, improving subcutaneous insulin's hepatic biodistribution. We assessed HDV-insulin lispro (HDV-L) versus insulin lispro (LIS) in type 1 diabetes (T1D). RESEARCH DESIGN AND METHODSInsulin Liver Effect (ISLE-1) was a 26-week, phase 2b, multicenter, randomized, double-blind, noninferiority trial. RESULTSAmong 176 randomized participants (HDV-L n 5 118, LIS n 5 58), the difference in change from baseline A1C was 0.09% (95% CI 20.18% to 0.35%), confirming noninferiority (prespecified margin £0.4%). Overall, there were no statistically significant differences between treatments for hypoglycemia or insulin dosing. However, baseline A1C modified the treatment group effect (interaction P < 0.001) on clinically apparent hypoglycemia designated by treatment-blinded investigators as severe. Thus, at higher baseline A1C, there was less hypoglycemia and lower insulin dosing with similar A1C outcomes during HDV-L versus LIS, whereas greater risk of hypoglycemia despite similar A1C outcomes and insulin doses was observed with lower baseline A1C. Among poorly controlled participants (A1C ‡8.5%), incidence rates of severe hypoglycemia in the HDV-L and LIS arms were 69 and 97 events/100 person-years, respectively (P 5 0.03), whereas with A1C <8.5%, respective rates were 191 and 21 events/100 person-years (P 5 0.001). Similar A1Cdependent trends in hypoglycemia were seen with continuous glucose monitoring. Among poorly controlled participants, bolus insulin doses at end point were ∼25% lower with HDV-L (P 5 0.02), despite similar A1C outcomes; in bettercontrolled participants, insulin doses and A1Cs were stable over time in both subgroups. No safety signals were identified.