Non-insulin-dependent diabetes mellitus (NIDDM) is a complex metabolic condition characterised by both impaired insulin secretion and insulin resistance [1]. It is also recognised that elevated circulating proinsulin levels are an important and consistent feature of NIDDM [2][3][4][5], and may represent a specific defect of pancreatic beta-cell function. There is continuing debate as to whether insulin deficiency or insulin resistance represents the primary abnormality which predisposes to the development of NIDDM [6], although it is clear that comparative insulin deficiency is a sine qua non for NIDDM to develop [7].In an attempt to identify the early fundamental abnormalities, non-diabetic first degree relatives of NIDDM patients have been studied, as they have a 40 % lifetime risk of progressing to diabetes [8]. However, such an approach has so far failed to clarify matters, as some studies have found a principal defect of insulin secretion [9-13], several have suggested that Diabetologia (1997Diabetologia ( ) 40: 1185Diabetologia ( -1190 Multiple metabolic abnormalities in normal glucose tolerant relatives of NIDDM families Summary Non-diabetic first degree relatives of noninsulin-dependent diabetic (NIDDM) families are at increased risk of developing diabetes mellitus, and have been studied to identify early metabolic abnormalities. Hormone concentrations measured by specific enzyme immunoassays were assessed in non-diabetic relatives of North European extraction, and control subjects with no family history of diabetes were matched for age, sex and ethnicity. A 75-g oral glucose tolerance test was conducted and those with newly diagnosed NIDDM were excluded. Basal insulin resistance was determined by homeostasis model assessment (HOMA), and hepatic insulin clearance by C-peptide:insulin molar ratio. Relatives (n = 150) were heavier (BMI: p < 0.0001) than the control subjects (n = 152), and had an increased prevalence of impaired glucose tolerance (15 vs 3 %, p < 0.01). The relatives had increased fasting proinsulin levels and decreased C-peptide levels following the glucose load, while insulin levels were increased at all time points. To examine whether the differences in hormone levels were secondary to the differences in glucose tolerance and adiposity, we studied 100 normal glucose tolerant relatives and control subjects pairmatched for age, sex, waist-hip ratio and BMI. The differences in proinsulin levels were no longer apparent. However, the relatives remained more insulin resistant, and had decreased C-peptide levels and Cpeptide:insulin ratios at all time points. In conclusion, we have identified several metabolic abnormalities in the normal glucose tolerant relatives, and propose that the decreased hepatic insulin clearance helps to maintain normoglycaemia in the face of combined insulin resistance and decreased insulin secretion. [Diabetologie (1997[Diabetologie ( ) 40: 1185[Diabetologie ( -1190

Features of syndrome X occur more frequently in relatives of NIDDM patients than in control subjects with no family history of diabetes.

No abstract

Recent evidence suggests that the postprandial hyperglycaemia in impaired glucose tolerance is primarily due to impaired suppression of basal hepatic glucose output. This in turn appears to be secondary to decreased first phase insulin secretion, although decreased hepatic insulin sensitivity, which is a feature of non-insulin-dependent diabetes mellitus, might also play a role. Eight mildly overweight subjects with impaired glucose tolerance and eight closely matched control subjects with normal glucose tolerance underwent an intravenous glucose tolerance test to assess first phase insulin secretion. Insulin sensitivity was examined by a 150-min hyperinsulinaemic-euglycaemic clamp. Somatostatin was infused from 150 min to suppress endogenous insulin secretion, and glucagon and insulin were replaced by constant infusion. Glucose with added dideuterated glucose (labelled infusion technique) was infused to maintain euglycaemia. First phase insulin secretion (delta 0-10 min insulin area divided by delta 0-10 min glucose area) was significantly decreased in the subjects with impaired glucose tolerance (median [range]: 1.2 [0.2-19.4] vs 9.1 [2.6-14.5] mU.mmol-1; p < 0.01). During the clamp, circulating insulin (93 +/- 8 [mean +/- SEM] and 81 +/- 10 mU.l-1) and glucagon (54 +/- 4 and 44 +/- 6 ng.l-1) levels were comparable. Total glucose disposal was decreased in subjects with impaired glucose tolerance (2.78 +/- 0.27 vs 4.47 +/- 0.53 mg.kg-1.min-1; p< 0.02), and was primarily due to decreased non-oxidative glucose disposal. However, hepatic glucose output rates were comparable during the clamp (0.38 +/- 0.10 and 0.30 +/- 0.18 mg.kg-1.min-1).(ABSTRACT TRUNCATED AT 250 WORDS)

The peak cortisol response to CRH was diminished at the higher circulating insulin levels. This was not dependent upon concurrent hypoglycaemia and did not appear to be mediated at the level of the pituitary gland.