HOMA-beta in the UKPDS and ADOPT. Is the natural history of type 2 diabetes characterised by a progressive and inexorable loss of insulin secretory function? Maybe? Maybe not?

Abstract

Introduction In 1995 the investigators of the United Kingdom Prospective Diabetes Study (UKPDS) published the results of 6 years of therapy with a variety of blood glucose-lowering drugs in patients with 2DM. Although the major goal of the study was to evaluate the relationship between glycaemic control and the development of diabetic complications, the report contained metabolic data which have had a substantial impact on general views as to the pathophysiology of 2DM. Specifically, using HOMA-beta, a surrogate estimate of pancreatic beta-cell function based on measurements of fasting plasma glucose and insulin concentrations, it was concluded that approximately 50% of insulin secretory capacity had been lost in these patients prior to initiation of the study. Following enrolment, there was a progressive deterioration of glycaemic control over the next 6 years in all groups, including those assigned to ‘intensive’ glycaemic intervention. beta-cell function as estimated by HOMA-beta also decreased continuously over the study period, leading the authors to conclude that ‘progressively increasing hyperglycaemia, associated with decreasing beta-cell function, was a marked feature irrespective of the therapy used.’ HOMA-beta has continued to be used as an estimate of beta-cell function in the years following the publication of the UKPDS report, with essentially similar conclusions as to the progressive loss of insulin secretory function over the natural history of 2DM. For example, HOMA-beta was used in the recent study 3 A Diabetes Outcome Progression Trial (ADOPT) to assess changes in beta-cell function over time in patients with 2DM assigned to monotherapy with rosiglitazone, metformin or glyburide. The major conclusion of ADOPT was that although the three drugs differed in length of time for monotherapy to fail, the data were consistent with the UKPDS results in that the initial improvement in glycaemic control was followed by a progressive increase in glycated haemoglobin and fasting plasma glucose concentration. The effect of treatment on the estimate of beta-cell function was somewhat more complicated than reported by the UKPDS, consisting of an initial improvement following initiation of drug treatment, but after this ‘levels of beta-cell function declined in all three groups.’ The notion of a progressive and inexorable loss of beta-cell function as part of the natural history of 2DM has been buttressed by results suggesting that in order to attain glycaemic control in patients with 2DM over time additional pharmacological agents must continually be added. This point was initially made in one of the reports of the UKPDS, but is echoed in the findings of the ADOPT study. The remainder of this analysis will be devoted to consideration of the appropriateness of HOMA-beta as an assessment of insulin secretory function, as well as the notion that glycaemic control inexorably declines with duration of 2DM.