Multiple metabolic abnormalities in normal glucose tolerant relatives of NIDDM families.

Non-diabetic first degree relatives of non-insulin-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 pair-matched 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 C-peptide: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.

Features of syndrome X in first-degree relatives of NIDDM patients.

OBJECTIVE: To determine whether the features of syndrome X are more common in first-degree relatives of non-insulin-dependent diabetes mellitus (NIDDM) patients than in control subjects with no family history of diabetes. RESEARCH DESIGN AND METHODS: A total of 154 first-degree relatives from 60 families with two or more NIDDM patients and 154 age- and sex-matched control subjects were studied. All subjects underwent a 75-g oral glucose tolerance test and baseline lipid blood and anthropometric measures. The features of syndrome X that were studied were obesity, hypertension, dyslipidemia (high triglyceride levels and low high-density lipoprotein [HDL] cholesterol concentrations), impaired glucose tolerance (World Health Organization criteria), and insulin resistance (as assessed by the homeostasis model assessment). RESULTS: Relatives were heavier than control subjects (body mass index 27.5 +/- 5.2 vs. 25.2 +/- 4.6 kg/m2, respectively [mean +/- SD], P < 0.0002), had lower HDL cholesterol concentrations (1.2 +/- 0.3 vs. 1.4 +/- 0.4 mmol/l, P < 0.001), were more insulin-resistant (2.3 [0.7-7.6] vs. 1.6 [0.5-5.1], geometric mean [95% confidence intervals], P < 0.0001), and had more individuals classified as having impaired glucose tolerance (28 of 154 [18%] vs. 7 of 154 [7%], chi 2, P < 0.001). The differences in insulin resistance and HDL cholesterol concentrations between the groups were independent of obesity. CONCLUSIONS: Features of syndrome X occur more frequently in relatives of NIDDM patients than in control subjects with no family history of diabetes.

Relapse of medically treated insulinoma following the development of thyrotoxicosis: an assessment of potential mechanisms.

Increased thyroid hormone concentrations have been reported to have disparate effects on insulin sensitivity in man. We describe a 72-year-old lady who initially presented with episodic hypoglycemia secondary to an insulinoma that was controlled by diazoxide. She re-presented 12 months later with a recurrence of the hypoglycemia following the development of thyrotoxicosis. The diazoxide treatment was maintained and propranolol was introduced, which prevented further episodes of hypoglycemia. This appeared to be due to a direct effect of propranolol on endogenous insulin secretion, while whole body insulin sensitivity remained unchanged as assessed using the hyperinsulinemic-euglycemic clamp technique. She was later rendered biochemically euthyroid with a combination of blocking carbimazole therapy and thyroxine replacement, and this was associated with a marked decrease in insulin sensitivity. Thus, the principal effect of thyroid hormone excess in this patient was an increase in insulin sensitivity that led to the clinical relapse of the insulinoma.