Comparison of insulins detemir and glargine: effects on glucose disposal, hepatic glucose release and the central nervous system

Abstract

Aims: The effects of insulins detemir (Det) and glargine (Glar) on endogenous glucose production (EGP) and net hepatic glucose output (NHGO) were compared.

Methods: Arteriovenous difference and tracer ([3-(3) H]glucose) techniques were employed during a two-step hyperinsulinemic euglycaemic clamp in conscious dogs (6 groups, n = 5-6/group). After equilibration and basal sampling (0-120 min), somatostatin was infused and basal glucagon was replaced intraportally. Det or Glar was infused via portal vein (Po), peripheral vein (IV), or bilateral carotid and vertebral arteries (H) at 0.1 and 0.3 mU/kg/min (low Insulin; Glar vs. Det, respectively, 120-420 min) and 4× the low insulin rate (high insulin; 420-540 min).

Results: NHGO and EGP were suppressed and glucose R(d) and infusion rate were stimulated similarly by Det and Glar at both Low and high insulin with each infusion route. Non-esterified fatty acid (NEFA) concentrations during low insulin were 202 ± 37 versus 323 ± 75 µM in DetPo and GlarPo (p < 0.05) and 125 ± 39 versus 263 ± 48 µM in DetIV and GlarIV, respectively (p < 0.05). In DetH versus GlarH, pAkt/Akt (1.7 ± 0.2 vs. 1.0 ± 0.2) and pSTAT3/STAT3 (1.4 ± 0.2 vs. 1.0 ± 0.1) were significantly increased in the liver but not in the hypothalamus.

Conclusions: Det and Glar have similar net effects on acute regulation of hepatic glucose metabolism in vivo regardless of delivery route. Portal and IV detemir delivery reduces circulating NEFA to a greater extent than glargine, and head detemir infusion enhances molecular signalling in the liver. These findings indicate a need for further examination of Det's central and hepatic effects.

Figure 1

Arterial and hepatic sinusoidal insulin concentrations during the basal period (-30 to 0 min) were endogenous canine insulin, and they did not differ among the six groups. During 0-420 min, the concentrations were for insulin glargine (left panels) and insulin detemir (right panels).

Figure 2

There were no differences between GlarPo vs DetPo, GlarIV vs DetIV, or GlarH vs DetH in regard to arterial plasma glucose, net hepatic glucose balance, endogenous glucose production (EGP), glucose disappearance (R_d), or glucose infusion rate. Data are mean ± SEM; Low Insulin and High Insulin values are the mean of the data during the last h of each insulin infusion period.

Figure 3

Delivery of insulin detemir into the portal vein or a peripheral vein suppressed arterial plasma NEFA significantly more than administration of insulin glargine. Data are mean ± SEM; Low Insulin and High Insulin values are the mean of the data during the last h of each insulin infusion period. *P<0.05 vs insulin glargine via the same route

Figure 4

Infusion of insulin detemir into the carotid and jugular arteries significantly enhanced phosphorylation of Akt and STAT3 in the liver. Graphs show ELISA for pAKT and Western blots of pAkt and pSTAT3 relative to total Akt and STAT3, respectively. Representative gels are shown for the Western blots. Tissues were taken at the end of the High Insulin period. Neg and Pos refer to negative and positive control samples taken in the post-absorptive state and under clamp conditions with 8× basal intraportal infusion of regular human insulin, respectively. Data are mean ± SEM; all data are normalized to the GlarPo group. *P<0.05 vs GlarH