Relationships Among Age, Proinsulin Conversion, and β-Cell Function in Nondiabetic Humans

  1. Andreas Fritsche,
  2. Alexander Madaus,
  3. Norbert Stefan,
  4. Otto Tschritter,
  5. Elke Maerker,
  6. Anna Teigeler,
  7. Hans Häring and
  8. Michael Stumvoll
  1. From the Medizinische Klinik, Abteilung für Endokrinologie, Stoffwechsel und Pathobiochemie, Eberhard-Karls-Universität, Tübingen, Germany


    The aim of the present study was to examine the relationships among β-cell function, proinsulin conversion to insulin, and age. We studied insulin and proinsulin secretion in nondiabetic subjects during an oral glucose tolerance test (OGTT) using published indexes of β-cell function (n = 379, age 16–68 years) and a modified hyperglycemic clamp (10 mmol/l, additional glucagon-like peptide [GLP-1] infusion, final arginine bolus; n = 50, age 19–68 years). Proinsulin conversion to insulin was assessed using proinsulin/insulin (PI/I) ratios immediately after an acute stimulus (OGTT, 30 min; hyperglycemic clamp, 2.5–5.0 min after glucose and arginine). There was a negative correlation between age and β-cell function (adjusted for insulin sensitivity, BMI, and fasting glucose) in the OGTT (r = −0.21, P < 0.001) and first phase of the hyperglycemic clamp (r = −0.30, P = 0.03), but not second phase (r = −0.08, P = 0.6) or arginine-induced insulin secretion (r = 0.06, P = 0.7). There was a positive correlation between age and the PI/I ratio in the OGTT (r = 0.24, P < 0.001). Analogously, there was also a positive correlation between age and the PI/I ratio during first phase (r = 0.37, P = 0.009) and arginine stimulation (r = 0.33, P = 0.01) of the hyperglycemic clamp. First-phase insulin secretion of the hyperglycemic clamp was inversely correlated with the PI/I ratio (r = −0.60, P < 0.001). Interestingly, adjusting first-phase secretion rate for the PI/I ratio abolished the linear relationship with age (r = −0.06, P = 0.7). In conclusion, aging is associated with deteriorating β-cell function and deteriorating proinsulin conversion to insulin. The age effect on insulin secretion appears to be attributable at least in part to an impairment of proinsulin conversion to insulin.


    • Address correspondence and reprint requests to michael.stumvoll{at}

      Accepted for publication 12 June 2001.

      AUCI/AUCG, ratio of the insulin over glucose area under the curve; GLP-1, glucagon-like peptide; HOMA, homeostatic model assessment; IGT, impaired glucose tolerant; ISR, insulin secretion rate; IVGTT, intravenous glucose tolerance test; NGT, normal glucose tolerant; OGTT, oral glucose tolerance test; PI/I, proportion of proinsulin to insulin.

      The symposium and the publication of this article have been made possible by an unrestricted educational grant from Servier, Paris.

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