Extrapancreatic action of truncated glucagon-like peptide-I in otsuka long-evans tokushima fatty rats, an animal model for non—insulin-dependent diabetes mellitus☆

Abstract 

To clarify the mechanism(s) of the antidiabetic effects of truncated glucagon-like peptide-1 (GLP-1) in diabetics, we examined its insulinotropic and extrapancreatic effects in a newly established strain of spontaneously non—insulin-dependent diabetic (NIDDM) rats, Otsuka Long-Evans Tokushima Fatty (OLETF) rats, that received a continuous infusion of truncated GLP-1 620 pmol/d/kg (G group, n = 12) or of vehicle (V group, n = 12) for 4 weeks by Alzet pump. Nonfasting plasma glucose levels were significantly lower (P < .05) in the G group than in the V group (7.0 ± 0.67 v 9.1 ± 1.7 mmol/L), and fasting plasma immunoreactive insulin (IRI) levels were lower in the former than in the latter (0.63 ± 0.31 v 0.78 ± 0.25 nmol/L). At day 15 of infusion, the G group showed an attenuated plasma glucose response to an oral glucose load, but had plasma IRI levels comparable to those in the V group. A long-term infusion of truncated GLP-1 increased the glucose infusion rate (GIR) significantly (P < .05) during a euglycemic-hyperinsulinemic clamp test (59.0 ± 14.8 μmol/kg/min for group G v 38.9 ± 12.2 for group V), but hepatic glucose output (HGO) did not differ significantly for either group. Uptake of 2-deoxy-d-glucose (2DG) by peripheral muscles in the G group was as much as 2.4-fold higher than in the V group (5.52 ± 2.04 v 2.29 ± 0.97 μmol/100 g muscle weight/min). We conclude from these data that truncated GLP-1, in addition to its well-known incretin effect, is capable of augmenting insulin action in peripheral tissues of diabetics, which can contribute, in part, to improve glucose intolerance in OLETF rats.

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