The natural history of type 2 diabetes described above

(1) is depicted by a prospective study carried out by Felber

and colleagues in Lausanne, Switzerland (35) (Fig. 2).
Although the study was originally cross-sectional in nature,
subjects were followed up for 6 years and shown to
progress from one category of glucose intolerance to the
next. All subjects had a euglycemic insulin clamp to
measure tissue sensitivity to insulin and an oral glucose
tolerance test (OGTT) to provide an overall measure of
glucose homeostasis and _-cell function. In lean subjects
with normal glucose tolerance (NGT), the mean plasma
glucose and insulin concentrations during the OGTT were
115 mg/dl and 62 _U/ml, while the mean rate of insulinstimulated
glucose disposal (measured with a 40 mU/m2
per min euglycemic insulin clamp) was 265 mg/m 2 per min.
Obesity was associated with a 29% decline in insulin
sensitivity, but glucose tolerance remained perfectly normal
because of the compensatory increase in insulin
secretion. With time the obese NGT individuals progressed
to IGT in association with a further 28% reduction in
insulin sensitivity (total decrease _ 57% from NGT to IGT).
However, the rise in plasma glucose concentration was
quite modest because of a further compensatory increase
in insulin secretion. However, people with IGT are in a
very precarious position. They are maximally or nearmaximally
insulin resistant, and their _-cells are functioning
at less than maximum capacity. With time the _-cells
cannot continue to produce these very large amounts of
insulin and the obese IGT individual progresses to overt
diabetes. The decline in glucose tolerance is associated
with a marked decrease in insulin secretion without