Total immunoreactive proinsulin, immunoreactive insulin and specific insulin in relation to conversion to NIDDM: the Mexico City Diabetes Study

Abstract

Non-insulin-dependent diabetes mellitus (NIDDM) is characterized by peripheral insulin resistance, beta-cell failure, and increased hepatic glucose production [1]. In diabetic subjects, these metabolic abnormalities interact in a complex fashion to cause and sustain hyperglycaemia. However, there continues to be controversy about which of these abnormalities is primary. Both insulin resistance [2] and deficient insulin secretion [3] have been postulated as antecedents of NIDDM. Prospective studies are useful in elucidating the complex relationship between abnormal insulin secretion and peripheral insulin resistance in the pathogenesis of NIDDM.Previous prospective studies have shown that hyperinsulinaemia is a strong predictor of NIDDM [4][5][6][7][8][9][10][11]. Insulin resistance has been inferred on the basis of hyperinsulinaemia in these studies of prediabetic subjects; in non-diabetic subjects, there is a Diabetologia (1997) Summary Although insulin resistance and decreased insulin secretion are characteristic of established non-insulin-dependent diabetes mellitus (NIDDM), which of these metabolic abnormalities is the primary determinant of NIDDM is still controversial. A disproportionate increase in the proinsulin to insulin ratio has been proposed as a marker of compromised insulin secretion. We examined the association of fasting immunoreactive insulin (which cross-reacts with proinsulin), specific insulin (which does not cross-react with proinsulin), total immunoreactive proinsulin (or insulin precursors), and the fasting proinsulin/specific insulin ratio to the risk of developing NIDDM in the 3.25-year follow-up of the Mexico City Diabetes Study. These measurements were made in 85 subjects who subsequently converted to NIDDM (prediabetic subjects) and in 85 age and gender matched subjects who remained non-diabetic at follow-up (control subjects). Immunoreactive insulin, proinsulin and the proinsulin/specific insulin ratio were significantly higher in prediabetic than in control subjects. However, the relation between specific insulin and the development of NIDDM was weaker than for proinsulin or immunoreactive insulin. After further adjustment for obesity, body fat distribution and glucose tolerance status, proinsulin and the proinsulin/specific insulin ratio, but not specific or immunoreactive insulin, predicted conversion to NIDDM. A high proinsulin/specific insulin ratio predicted conversion to NIDDM both in subjects with normal and those with impaired glucose tolerance at baseline. We conclude that in prediabetic subjects increased proinsulin, a marker of islet cell distress or compromised insulin secretion, is associated with rapid conversion (within 3.25 years) to NIDDM even in obese populations. [Diabetologia (1997) 40: 830-837]

Increased Proinsulin Levels and Decreased Acute Insulin Response Independently Predict the Incidence of Type 2 Diabetes in the Insulin Resistance Atherosclerosis Study

“…A similar phenomenon was reported by Lillioja et al (7) in a prospective study of Pima Indians. Our observation that elevated baseline PI concentration, a measure of ␤-cell dysfunction, was a significant independent predictor of diabetes is consistent with previous studies that were conducted in populations of European white (18,19,23), Asian (17,22), Asian-American (20), and Mexican origin (21). The present results contribute to this body of literature in a number of ways.…”

“…PI and its split products circulate in high concentrations in subjects with diabetes and gestational diabetes (12)(13)(14), as well as (in some studies) among individuals with IGT or a diabetic first-degree relative (12,15,16). In addition, a limited number of investigations have reported that elevated absolute and relative concentrations of PI and its split products are prospectively associated with risk of diabetes (17)(18)(19)(20)(21)(22)(23). Finally, recent studies have shown that PI and the PI-to-insulin ratio correlate significantly with AIR (24,25).…”

Beta cell function and its relation to insulin action in humans: a critical appraisal

“…This measurement is commonly regarded as a marker of inappropriate intracellular processing of pro-hormone to insulin and, by extension, as a generic index of beta cell dysfunction. Interestingly, fasting proinsulin is already markedly elevated in subjects with normal glucose tolerance who develop diabetes at follow-up [23].…”

Proinsulin-to-C-peptide ratio versus proinsulin-to-insulin ratio in the prediction of incident diabetes: the Insulin Resistance Atherosclerosis Study (IRAS)

“…Although the cause of disproportional hyperproinsulinaemia in diabetes is unknown, it may arise from inefficient proinsulin processing within the beta cell secretory granule or the premature release of proinsulin as a result of increased demand for insulin in insulin-resistant states [4]. Elevations in the ratio of proinsulin to insulin as well as absolute proinsulin concentrations adjusted for fasting insulin have been proposed as early markers of beta cell dysfunction [5].…”