Abstract
AimsThe two predominant pathophysiological defects resulting in glucose intolerance are beta-cell dysfunction and insulin insensitivity. This study aimed to re-examine beta-cell function and insulin sensitivity across a continuum from normal glucose tolerance (NGT) to early type 2 diabetes (T2DM) employing highly specific insulin, C-peptide and intact proinsulin assays.Materials and methodsA total of 104 persons with NGT, 85 with impaired glucose tolerance (IGT) and 554 with newly diagnosed T2DM were investigated. Following an overnight fast, all underwent a 4-h standardised mixed meal tolerance test (MTT), and on a second day, a sub-group underwent a frequently sampled insulin-modified intravenous glucose tolerance test (FSIVGTT) over a 3-h period. The participants were stratified according to fasting glucose and BMI for analysis.ResultsThe MTT revealed that increasing FPG was accompanied by progressively elevated and delayed postprandial glucose peaks. In parallel, following an initial compensatory increase in fasting and postprandial insulin responses there followed a progressive demise in overall beta-cell secretory capacity. FSIVGTT demonstrated a major reduction in the early insulin response to IV glucose in persons with IGT accompanied by a dramatic fall in insulin sensitivity. Beyond pre-diabetes, ever-increasing fasting and postprandial hyperglycaemia resulted predominantly from a progressively decreasing beta-cell secretory function.ConclusionThis study utilising improved assay technology re-affirms that beta-cell dysfunction is evident throughout the spectrum of glucose intolerance, whereas the predominant fall in insulin sensitivity occurs early in its evolution.
Highlights
Glucose homeostasis is regulated by a feedback loop, involving beta-cell secretion and insulin sensitivity to maintain glucose concentrations within a tight range [1, 2]
The reported influence of these defects, can depend on multiple factors including the stage of development of glucose intolerance, assay methodology and challenge tests employed and the clinical circumstances of the individual under investigation
We present here an assessment of the glycaemic and hormonal responses to two different carbohydrate challenge tests, with derived indices to represent both beta-cell function and insulin sensitivity, applied across a spectrum of participants with normal glucose tolerance (NGT), impaired glucose tolerance (IGT) and newly diagnosed, treatment naïve T2DM, collected over a period of over 20 years
Summary
Glucose homeostasis is regulated by a feedback loop, involving beta-cell secretion and insulin sensitivity to maintain glucose concentrations within a tight range [1, 2]. Betacell function as measured by disposition index dramatically fell in the early period of glucose intolerance (Fig. 3b) with IGT displaying only approximately 20% that of NGT and continued to fall by half in each increasing glucose-intolerant FPG sub-group (Table 2).
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