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This study was undertaken to clarify the effect of sulphonylurea therapy on beta cell function in 27 subjects with newly diagnosed Type 2 diabetes mellitus. Plasma glucose, insulin, intact and 32/33 split proinsulin were measured at diagnostic OGTT. After 8-12 weeks on a conventional diet, subjects with a fasting glucose > 9 mmol l-1 (n = 12) were commenced on sulphonylurea therapy. At diagnosis, the sulphonylurea requiring group were more hyperglycaemic (p < 0.0001), less obese (p < 0.05) and more insulin deficient with a lower 30 min insulin (p < 0.0002) than the diet group. Following dietary intervention in the sulphonylurea group, weight remained unchanged but there was a reduction in fasting glucose (p < 0.009). Fasting insulin, intact proinsulin, and 32/33 split proinsulin remained unchanged. After 12 weeks of sulphonylurea therapy there was a weight gain of 1.5 kg (p < 0.01), but a reduction in fasting glucose (p < 0.0001). Fasting insulin and intact proinsulin increased (p < 0.004) but 32/33 split proinsulin remained unchanged. There was a significant increase in both the fasting insulin to glucose ratio (p < 0.005), and intact to 32/33 split proinsulin ratio (p < 0.02). Final fasting glucose following sulphonylurea therapy was positively correlated with the initial intact and 32/33 split proinsulin and the fasting glucose following dietary treatment. It is clear from this work that sulphonylureas have a complex effect on beta cell physiology and as well as stimulating release of insulin they increase the release of intact proinsulin but not that of 32/33 split proinsulin, hence they increase the intact to 32/33 split proinsulin ratio.

This paper reports beta cell function as assessed during OGTT using specific IRMAs for insulin, intact and 32/33 split proinsulin in subjects with newly diagnosed Type 2 diabetes matched to normal controls. The relationships between insulin and the proinsulins to risk factors for cardiovascular disease were also examined. Similar fasting insulin concentrations but lower 30-min post-glucose-load insulin concentrations were found in diabetic subjects (mean +/- SEM 143 +/- 12 pmol-1 vs 304 +/- 19 (p < 0.001). Subjects with diabetes had increased fasting intact (10.6 +/- 1.1 pmol-1 vs 3.3 +/- 0.2, p < 0.001) and 32/33 split proinsulin concentrations (8.1 +/- 0.9 pmol-1 vs 2.2 +/- 0.3, p < 0.0001). Beta cell dysfunction, as expressed by a reduction in the 30-min insulin to glucose ratio (9.4 +/- 1 vs 34.8 +/- 2.3, p < 0.0001) and an increase in the fasting percentage of total proinsulin-like to total insulin-like molecules (24.5 +/- 9% vs 11.6 +/- 5, p < 0.001), was present in subjects with diabetes. In diabetic subjects beta cell dysfunction and insulin deficiency increased relative to the degree of fasting hyperglycaemia. It seems clear that beta cell dysfunction and insulin deficiency are major features of Type 2 diabetes. Only the fasting concentration of 32/33 split proinsulin positively correlated with both the waist/hip ratio (r = 0.36, p < 0.001), diastolic blood pressure (r = 0.23, p < 0.01) in addition to plasma triglyceride concentration (r = 0.46, p < 0.001). It is questionable whether hyperinsulinaemia plays a pathogenic role in cardiovascular disease in subjects with glucose intolerance.