1560-P: Combining Glucagon with Insulin Can Lessen the Hypoglycemic Potential of Insulin

Abstract

We showed previously in people with T1D that by infusing glucagon along with insulin can buffer insulin’s hypoglycemic effect without worsening its ability to limit hyperglycemia. Our aim was to determine in the conscious dog the mechanisms by which glucagon limits the insulin driven fall in glucose. Somatostatin was infused to disable the endocrine pancreas and insulin and glucagon were infused into a leg vein at basal rates. After a 140 min control period, the insulin infusion rate was increased 4-7-fold for 3h to induce hypoglycemia. Glucagon was also infused into a leg vein, then was either increased proportionately to insulin (constant I/G molar ratio, HiGGN), or in a second study on the same dog, it was kept at its basal rate (Ba GGN). Hepatic sinusoidal insulin levels rose from 11±2 to 65±17 μU/ml regardless of the glucagon level, which remained basal in BaGGN (50±10pg/mL) but rose from 52±8 pg/ml to 238±50pg/ml in HiGGN. Plasma glucose fell over the first hour, reaching a nadir of 45±2 mg/dl when glucagon was basal, and fell more slowly when glucagon was elevated (nadir of 50±2 mg/dl). This difference was due to a greater increase in net hepatic glucose output in the HiGGN group (1.4 ± 0.2 vs 2.4 ± 0.2 mg/kg/min in BaGGN and HiGGN respectively). Interestingly the rise in plasma cortisol and epinephrine were reduced by 33 and 39%, respectively, in the group with elevated glucagon. Further, this lessening in the counterregulatory response was associated with reductions in lipolysis and lactate production by muscle. Thus, by maintaining a fixed I/G molar ratio the hypoglycemic potential of insulin is buffered. This could allow more aggressive insulin treatment which would in turn increase time in range for glucose. Disclosure G.Kraft: None. M.Scott: None. M.S.Smith: None. B.Farmer: None. D.S.Edgerton: None. A.D.Cherrington: Advisory Panel; Metavention, vTv Therapeutics, Diakard, Sekkei Bio, Sensulin Labs, LLC, Other Relationship; Fractyl Health, Inc., Novo Nordisk, Abvance Therapeutics, Research Support; Cellular Longevity, Inc, dba Loyal, Senda Biosciences.