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

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 te rm 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 H-3-2-deoxygl ucose tracer administration) was studied after 3 weeks on either standard ( BD) or high fat (HF) diet in normal control (C) or in hereditary insulin re sistant (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 i nfusion 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 ED. 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-H F: 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 w ere not restored by a concomitant bolus of A-4166. Nevertheless, in hHTg ra ts 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 val ues of the control group on ED. In summary, a) a single bolus administratio n of A-4166 to the control or to the insulin resistant hHTg rats, fed eithe r the ED or HF diets, did not abolish the reduction of GIR required to main tain euglycemia during hyperinsulinemic clamps; b) nevertheless, A-4166 cau sed a significant increase of the estimated plasma glucose disposal (Rd) an d skeletal muscle glucose metabolic index (Rg') of hHTG rats fed the HF die t; c) we suggest that A-4166 may have an extrapancreatic action but this ne eds to be proven using a long-term administration plan of A-4166.