Insulin Detemir Is Transported From Blood to Cerebrospinal Fluid and Has Prolonged Central Anorectic Action Relative to NPH Insulin

Abstract

Insulin detemir (DET) reduces glycemia comparably to other long-acting insulin formulations but causes less weight gain. Insulin signaling in the brain is catabolic, reducing food intake. We hypothesized that DET reduces weight gain, relative to other insulins, owing to increased transport into the central nervous system and/or increased catabolic action within the brain. Transport of DET and NPH insulin into the cerebrospinal fluid (CSF) was compared over several hours and after the administration of different doses peripherally in rats. DET and NPH had comparable saturable, receptor-mediated transport into the CSF. CSF insulin remained elevated significantly longer after intraperitoneal DET than after NPH. When administered acutely into the 3rd cerebral ventricle, both DET and NPH insulin reduced food intake and body weight at 24 h, and both food intake and body weight remained lower after DET than after NPH after 48 h. In direct comparison with another long-acting insulin, insulin glargine (GLAR), DET led to more prolonged increases in CSF insulin despite a shorter plasma half-life in both rats and mice. Additionally, peripheral DET administration reduced weight gain and increased CSF insulin compared with saline or GLAR in mice. Overall, these data support the hypothesis that DET has distinct effects on energy balance through enhanced and prolonged centrally mediated reduction of food intake.

Figure 1

Mean ± SEM concentration of insulin in plasma and CSF and glucose in plasma 30 min after the intraperitoneal administration of DET or NPH insulin at different doses in rats. Intraperitoneal NPH insulin and DET produced similar levels as a function of dose in plasma (A and D). Likewise, there were dose-dependent increases of CSF insulin with both NPH insulin and DET, with apparent saturation of the CSF insulin levels occurring by the 3 units/kg dose (B and E). Plasma glucose decreased in a dose-dependent manner after intraperitoneal NPH insulin or DET (C and F). Significant differences are described in the text.

Figure 2

Mean ± SEM concentration of insulin in plasma and CSF and glucose in plasma at different time points after 0.5 units/kg i.p. DET or NPH insulin in rats. Plasma insulin rose rapidly after the intraperitoneal injection of NPH insulin, peaking at 5 min and then decreasing (A). CSF insulin levels also rose rapidly after intraperitoneal NPH insulin, the peak occurring at around 40 min and levels returning to baseline by 320 min (B). Plasma glucose dropped sharply after intraperitoneal NPH insulin, returning to baseline by 80 min (C). Intraperitoneal DET also increased plasma insulin after 5 min, and it remained elevated at a relatively constant level throughout the 320 min (D). CSF insulin peaked rapidly after intraperitoneal DET at the 5- and 10-min time points before reducing to a stable but elevated level between 40 and 320 min (E). Plasma glucose was reduced after DET to a constant level for the duration of the experiment (F). Significant differences are described in the text.

Figure 3

i3vt DET and NPH insulin reduce food intake and body weight in rats. i3vt DET and NPH insulin each reduced food intake over a 24-h period (A) relative to control (CON). After 48 h, intake by the DET group remained reduced, whereas that of the NPH group had returned to CON levels (B). Both NPH insulin and DET rats lost weight in the 24-h postinfusion (C); however, only the DET group maintained the weight loss after 48 h (D). Data are means ± SEM. *P < 0.05 vs. control, +P < 0.05 vs. NPH insulin.

Figure 4

Comparison of the appearance of insulin in the plasma and CSF after the subcutaneous administration of two long-acting formulations of insulin, DET, and GLAR in rats. Injection of either DET or GLAR at 0.5 units/kg s.c. led to increased plasma insulin at 6–12 h. By 24 h, only GLAR-treated rats continued to have elevated insulin (A). In contrast, CSF insulin levels were similarly increased in both groups at 6, 12, and 24 h; but at 48 h, DET-treated animals had elevated CSF insulin levels, while CSF insulin of GLAR-treated animals had returned to baseline (B). Plasma glucose levels were reduced at both 6 and 12 h by both DET and GLAR but were lower at 24 h only in GLAR-treated animals (C). Data are means ± SEM.

Figure 5

Chronic subcutaneous administration of DET reduces food intake and body weight relative to subcutaneous GLAR or vehicle in mice. DET reduced weight gain compared with both saline control (CON) and GLAR treatment by week 3. GLAR resulted in increased body weight relative to control at week 6 (A). Total food intake was reduced in the DET group compared with that in both GLAR and control (B). Fat mass was lower in DET and higher in GLAR compared with control (C). Lean mass was not altered by any treatment (D). Data are means ± SEM. *P < 0.05 vs. control, +P < 0.05 vs. GLAR.

Figure 6

Appearance of insulin in plasma and CSF at different times after the administration of subcutaneous DET and GLAR in mice and the effect of chronic DET and GLAR treatment on CSF insulin. Injection of either DET or GLAR (1 unit/kg s.c.) led to increased plasma insulin at 6–12 h. By 24 h, only GLAR-treated animals continued to have elevated plasma insulin (A). In contrast, CSF insulin levels were increased in both groups at 6, 12, and 24 h; but at 48 h, DET-treated animals had elevated CSF insulin levels, whereas CSF insulin of GLAR-treated animals had returned to baseline (B). Twenty-four hours after cessation of chronic treatment with DET or GLAR, mice treated with GLAR continued to have elevated plasma insulin (C), but the reverse occurred in CSF, where DET-treated, but not GLAR-treated, mice had elevated insulin. Data are means ± SEM. *P < 0.05 vs. control, +P < 0.05 vs. GLAR. CON, control.