Insulin Delivery Into the Peripheral Circulation: A Key Contributor to Hypoglycemia in Type 1 Diabetes

Abstract

Hypoglycemia limits optimal glycemic control in type 1 diabetes mellitus (T1DM), making novel strategies to mitigate it desirable. We hypothesized that portal (Po) vein insulin delivery would lessen hypoglycemia. In the conscious dog, insulin was infused into the hepatic Po vein or a peripheral (Pe) vein at a rate four times of basal. In protocol 1, a full counterregulatory response was allowed, whereas in protocol 2, glucagon was fixed at basal, mimicking the diminished α-cell response to hypoglycemia seen in T1DM. In protocol 1, glucose fell faster with Pe insulin than with Po insulin, reaching 56 ± 3 vs. 70 ± 6 mg/dL (P = 0.04) at 60 min. The change in area under the curve (ΔAUC) for glucagon was similar between Pe and Po, but the peak occurred earlier in Pe. The ΔAUC for epinephrine was greater with Pe than with Po (67 ± 17 vs. 36 ± 14 ng/mL/180 min). In protocol 2, glucose also fell more rapidly than in protocol 1 and fell faster in Pe than in Po, reaching 41 ± 3 vs. 67 ± 2 mg/dL (P < 0.01) by 60 min. Without a rise in glucagon, the epinephrine responses were much larger (ΔAUC of 204 ± 22 for Pe vs. 96 ± 29 ng/mL/180 min for Po). In summary, Pe insulin delivery exacerbates hypoglycemia, particularly in the presence of a diminished glucagon response. Po vein insulin delivery, or strategies that mimic it (i.e., liver-preferential insulin analogs), should therefore lessen hypoglycemia.

Reduced peripheral activity leading to hepato‐preferential action of basal insulin peglispro compared with insulin glargine in patients with type 1 diabetes

“…Although the percentage suppression of EGP was statistically different between insulins, this measure is dependent on baseline EGP. The baseline EGP in this study is not necessarily physiologic as it is dependent on the peripheral infusion of human insulin that results in a state of relative peripheral hyperinsulinism in patients with T1D and is not analogous to the fasting state in healthy subjects . In addition this insulin infusion was discontinued at least 1 hour prior to the clamp and may have contributed to non‐steady state conditions.…”

“…Euglycemia under normal treatment conditions may therefore be achieved at the expense of under‐insulinization of the liver and over‐insulinization of the periphery . In the fasting state, this may predispose patients to hypoglycemia and its associated complications, and insulin therapies which attempt to replicate the normal hepatic‐to‐peripheral insulin gradient may lessen this risk . In addition a hepato‐preferentially acting insulin therapy could potentially lessen the weight effects of over‐insulinization of the periphery.…”

Basal insulin peglispro: Overview of a novel long‐acting insulin with reduced peripheral effect resulting in a hepato‐preferential action

“…Significant unmet needs for currently available insulin therapy remain and include “closing the loop” (ie, regulating insulin delivery according to ambient glycaemia), restoring the glucagon‐response to hypoglycaemia, and restoring the hepatic‐peripheral insulin gradient wherein more insulin is delivered to the liver than the peripheral adipose and muscle tissue as observed in normal physiology. Peripheral (non‐portal) administration of insulin therapy results in similar circulating concentrations to the liver and the peripheral target tissues eliminating the insulin distribution gradient of normal physiology . Consequently, with conventional insulin therapies, the liver is relatively under‐insulinized, and the periphery is over‐insulinized.…”

Finding the right route for insulin delivery – an overview of implantable pump therapy

“…A recent proof of concept study demonstrated that in the setting of induced hypoglycaemia, by either dose-matched portal or peripheral insulin administration, glucose utilisation and the consequent fall in glucose levels were significantly more pronounced by the subcutaneous as opposed to portal route[26]. Although the effect of portal compared to subcutaneous insulin delivery on glucose disposal is known, the evidence of its effect on hepatic glucose output is inconsistent.…”