Insulin resistance and impaired insulin secretion are thought to be the primary defects in the pathogenesis of
non-insulin-dependent diabetes mellitus (
NIDDM). Disproportionately increased
proinsulin relative to
insulin levels are suggested to be an early
indicator of a failing pancreas. We examined the relationship of fasting specific
insulin,
proinsulin, and
32, 33 split proinsulin concentrations, and the
proinsulin:
insulin ration to the risk of developing
NIDDM 3.5 years later in 65-74-year-old non-diabetic Finnish subjects participating in a population-based study (n=892) on diabetes and
heart disease. Altogether 69 subjects developed
NIDDM over a 3.5-year follow-up (cases). The cases were compared to randomly-selected gender-matched control subjects (n=69) and control subjects matched for gender,
glucose tolerance status (normal or impaired), and body mass index (n=69). There were no differences in
insulin concentrations between cases and random or matched control subjects [median and interquartile range: 123 (77-154), 108 (74-143), 118 (83-145) pmol/l, p=0.271]. Random control subjects had lower
proinsulin and
32, 33 split proinsulin concentrations and split
proinsulin:
insulin ratios compared to cases [5.7 (3.8-9.0) vs 7.3 (4.8-10.0) pmol/l, p=0.005; 7.3 (4.5-13.0 vs 10.4 (7.1-18.0) pmol/l, p=0.002; 0.073 (0.057-0.110) vs 0.097 (0.060- 0.135), p=0.003]. Matched control subjects had lower
proinsulin concentrations and
proinsulin:
insulin ratios compared to cases [5.9 (4.0-7.7) vs 7.3 (4.8-10.0) pmol/l, p=0.019; 0.048 (0.035-0.071) vs 0.064 (0.045-0.100), p=0.008]. When cases were compared to matched control subjects a 1 SD increase in baseline
proinsulin:
insulin ratio was associated with a 1.37-fold risk (p=0.020) of developing diabetes. Moreover, this association was independent of fasting
glucose concentration at baseline. Thus, in elderly prediabetic subjects disproportionately increased
proinsulin concentration, an
indicator of defective insulin secretion, is associated with conversion to diabetes over a short time period.