MOLECULAR EFFECTS OF SULFONYLUREA AGENTS IN CIRCULATING LYMPHOCYTES OF PATIENTS WITH NON-INSULIN-DEPENDENT DIABETES-MELLITUS

Aims In circulating lymphocytes of NIDDM patients pyruvate dehydrogena se (PDH), the major determinant in glucose consumption through oxidati ve pathways, is poorly active. The aim of this study is to examine whe ther sulphonylurea drug treatment revives PDH activity in circulating lymphocytes from NIDDM patients.Methods Twenty normal-weight individua ls with NIDDM were enrolled in this study. They had maintained their g lycaemic levels close to normal by means of a restricted diet that had no longer been successful in the proceeding 2 months. The treatment p rotocol consisted in 160 mg gliclazide daily for 5 weeks. Twenty healt hy subjects, matched for age, body mass index and gender, were enrolle d as a control soup. Patients, before and after treatment, as well as controls were tested for PDH activity in their circulating lymphocytes . Nine other untreated patients and nine healthy subjects, with the ab ove mentioned characteristics, were recruited for the assay of PDH act ivity in their circulating lymphocytes before and after exposure, in v itro, to gliclazide, to insulin, and to gliclazide and insulin in comb ination. Results In gliclazide-treated NIDDM patients, PDH activity in circulating lymphocytes recovered. In vitro, in circulating lymphocyt es of untreated patients and controls insulin at 5 mu U ml(-1) was ine ffective and highly effective, respectively, in raising enzyme activit y; gliclazide at 10 ng ml(-1) was ineffective on PDH in both groups, b ut in combination with insulin at 5 mu U ml(-1) in both groups PDH was as active as in cells of controls exposed to insulin only. In cells o f controls, gliclazide alone at 25-50 ng ml(-1) caused enzyme activati on, whereas above 50 ng ml(-1) it caused inhibition; in cells of patie nts below 50 ng ml(-1) it had no effects, but at 50 ng ml(-1) and abov e raised enzyme activity to the basal level of controls. Conclusions T his study suggests that free gliclazide concentrations determine recov ery of PDH activity in circulating lymphocytes of treated patients thr ough drug-mediated enhanced insulin control over PDH or through the dr ug alone.