SummaryOBJECTIVENon‐insulin‐dependent diabetes is a heterogeneous disorder, the basis of which may differ in different ethnic groups. In order to investigate early metabolic abnormalities occurring during the development of the condition we assessed insulin secretion and insulin action in subjects predisposed to the later development of non‐insulin‐dependent diabetes from two different ethnic groups.DESIGNSubjects were studied on two separate occasions by an oral glucose tolerance test and a short insulin tolerance test.PATIENTSTwenty‐four glucose‐tolerant first‐degree relatives of patients with non‐insulin‐dependent diabetes (12 of European and 12 of Asian origin) were compared with 24 ethnically matched control subjects with no family history of diabetes.MEASUREMENTSInsulin, proinsulin, glucose and intermediary metabolites were measured during a 75‐g oral glucose tolerance test. Insulin sensitivity was assessed using a 15‐minute insulin tolerance test (0.05 units/kg).RESULTSAsian relatives compared to Asian controls had significantly higher fasting levels of immunoreactive insulin (83 ± 17 vs 40 ± 6 pmol/l,P<0 05), which were not due to increased proinsulin. Blood glycerol concentrations were elevated (83 ± 9 vs 51 ± 4μmol/l,P<0.005), but fasting glucose and non‐esterified fatty acid (NEFA) concentrations were similar. Relatives of European origin did not differ from their European controls in any of these measurements.The glucose response to oral glucose was similar in relatives and controls, irrespective of ethnic group. The insulin responses were non‐significantly greater in relatives from both ethnic groups. Proinsulin levels were not significantly different. Asian relatives had higher circulating glycerol and NEFA levels after oral glucose than Asian controls, but these differences were not observed in the European group. Insulin sensitivity was reduced in the Asian relatives compared to their controls (183 ± 7 vs 139 ± 12μmol/l/min,P<0.01) but there was no difference in insulin sensitivity between the European relatives and European controls (167 ± 11 vs 160 ± 11μmol/l/min).CONCLUSIONSFirst‐degree relatives of non‐insulin‐dependent diabetic patients of Asian, but not of European, origin are insulin insensitive in terms of both glucose metabolism and lipolysis, and have true hyperinsulinaemia. This suggests that insulin insensitivity may be an early abnormality in the development of non‐insuli