The Effect of the New Oral Hypoglycemic Agent A-4166 on Glucose Turnover in the High Fat Diet-Induced and/or in the Hereditary Insulin Resistance of Rats

Abstract

A-4166, a phenylalanine derivative, is a hypoglycemic agent, which has been shown to improve blood glucose levels mainly due to the rapid and short term stimulation of insulin release. Nevertheless, a possible extrapancreatic action of A-4166 has not yet been investigated. Therefore, insulin action (euglycemic hyperinsulinemic 6.4 mU.kg -1.min -1 clamp plus 3 H-2-deoxyglucose tracer administration) was studied after 3 weeks on either standard (BD) or high fat (HF) diet in normal control (C) or in hereditary insulin resistant (hHTg) rats which were given a single dose of A-4166 (10 mg per kg BW, i.v.) 60 min after clamp commencement. HF feeding reduced the glucose infusion rate (GIR) required to maintain euglycemia to about 50% of C (p < 0.001). In hHTg rats, HF did not further pronounce the pre-existing decrease of GIR of hHTg animals fed BD. A-4166 changed GIR neither in C, nor in the hHTg group. The estimated glucose disposal (Rd) (C-BD: 32.3 ± 1.9 vs C-HF: 25.5 ± 1.9 mg.kg -1.min -1, p < 0.001) and glucose metabolic index (Rg') in skeletal muscles (Q. femoris: C-BD: 25.6 ± 1.5 vs C-HF: 12.3 ± 1.1 mmol.100 g -1.min -1, p < 0.001) were reduced by HF in control rats but were not restored by a concomitant bolus of A-4166. Nevertheless, in hHTg rats fed the HF diet a single dose of A-4166 brought back their Rd (hHTg-HF: 23.5 ± 1.3 vs hHTg-HF plus A-4166: 31.0 ± 3.5 p,< 0.03) and Rg' (Soleus muscle: hHTg-HF: 29.2 ± 3.2 vs hHTg-HF plus A-4166: 41.3 ± 4.0) to values of the control group on BD. In summary, a) a single bolus administration of A-4166 to the control or to the insulin resistant hHTg rats, fed either the BD or HF diets, did not abolish the reduction of GIR required to maintain euglycemia during hyperinsulinemic clamps; b) nevertheless, A-4166 caused a significant increase of the estimat ed plasma glucose disposal (Rd) and skeletal muscle glucose metabolic index (Rg') of hHTG rats fed the HF diet; c) we suggest that A-4166 may have an extrapancreatic action but this needs to be proven using a long-term administration plan of A-4166.