INSULIN-RESISTANCE IN OBESE SUBJECTS AND NEWLY-DIAGNOSED NIDDM PATIENTS AND DERANGEMENTS OF PYRUVATE-DEHYDROGENASE IN THEIR CIRCULATING LYMPHOCYTES

BACKGROUND: In circulating lymphocytes of individuals with insulin res istance and overt hyperglycaemia (NIDDM patients), alterations, affect ing pyruvate dehydrogenase (PDH), the key enzyme in glucose oxidative breakdown, have been observed. They include below normal enzyme activi ty and, in vitro, no enzyme response to insulin at low physiological l evels (5 mu U/ml) as well as activation up to the basal values of cont rols with insulin at high physiological levels (50 mu U/ml), instead o f activation and inhibition respectively, as in controls. OBJECTIVE: T o investigate whether these alterations characterize circulating lymph ocytes of individuals with insulin resistance in whom derangements of glucose homeostasis are absent (obese subjects with normal glucose tol erance), or present but still controllable (nonobese and obese newly d iagnosed NIDDM patients on an appropriate diet). SUBJECTS: Thirty obes e subjects (BMI 36 +/- 31 responding normally to an oral glucose toler ance (OGT) test; 60 newly diagnosed NIDDM patients (30 nonobese, BMI 2 2 +/- 4 and 30 obese, BMI 38 +/- 2); 30 nonobese (BMI 21 +/- 5) and no ndiabetic subjects, with no family history for NIDDM, served as contro ls. METHODS: Evaluation of PDH activity in circulating lymphocytes bef ore and after exposure to insulin at 5 and 50 mu U/ml, and of clinical parameters before and during an OGT test. RESULTS: 1) In circulating lymphocytes of obese nondiabetic subjects as well as obese and nonobes e newly diagnosed NIDDM patients, PDH activity was significantly below normal. In vitro, enzyme response to insulin at 5 mu U/ml was reduced in nonobese NIDDM patients with respect to controls, and absent in ob ese nondiabetic subjects and obese NIDDM patients. Enzyme response to insulin at 50 mu U/ml was reversed in all individuals, which allowed e nzyme activity to recover up to the basal level of controls. 2) In NID DM patients and obese nondiabetic subjects, undergoing an OGT test, th e area under the glycaemic curve (g-AUC) was as expected; the area und er the insulinaemic curve (I-AUG) was increased in both groups with re spect to controls, but significantly only in the latter. CONCLUSION: I n individuals with insulin resistance PDH activity in their circulatin g lymphocytes rises up to basal revels of controls, only if these cell s are exposed to insulin at high physiological concentrations, and g-A UC is normal only in those subjects who have significantly increased i -AUC. This suggests that with insulin at sufficiently high concentrati ons both parameters can be corrected. We conclude that the derangement s responsible for the alterations of the two parameters share common f eatures and thus the described PDH alterations in circulating lymphocy tes reflect systemic insulin resistance whether accompanied by hypergl ycaemia or not.