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Disproportionately Elevated Proinsulin Levels Reflect the Degree of Impaired B Cell Secretory Capacity in Patients with Noninsulin-Dependent Diabetes Mellitus¹

Divisions of Metabolism, Endocrinology, and Nutrition and Gerontology and Geriatric Medicine (R.S.S.), Department of Medicine, Veterans Affairs Puget Sound Health Care System, Harborview Medical Center (R.S.S.), and University of Washington, Seattle, Washington 98108

Address all correspondence and requests for reprints to: Michael E. Røder, M.D., Rigshospitalet, Department of Nephrology and Endocrinology P, University of Copenhagen, Blegdamsvej 9, DK-2100 Copenhagen Ø, Denmark. E-mail address: mroder{at}login.dknet.dk

An increased proportion of fasting proinsulin (PI) relative to immunoreactive insulin (IRI; increased PI/IRI) occurs in noninsulin-dependent diabetes mellitus (NIDDM). To determine whether the magnitude of the increase in PI/IRI is an indicator of the degree of reduced B cell secretory capacity, we measured fasting plasma glucose, PI, IRI, and PI/IRI and related them to maximal B cell secretory capacity (AIRmax) in 9 subjects with NIDDM [age, 61 ± 3 yr; body mass index (BMI), 27.5 ± 1.3 kg/m²; duration of NIDDM, 10.8 ± 1.8 yr; mean ± SEM] and in 10 healthy subjects matched for age and BMI (age, 61 ± 6 yr; BMI, 27.9 ± 1.5 kg/m²). AIRmax was quantified as the incremental insulin response to iv arginine at maximal glycemic potentiation (plasma glucose >25 mmol/L).

Mean fasting plasma glucose was 13.7 ± 1.4 mmol/L (range, 7.5–18.3 mmol/L) in NIDDM subjects and 5.0 ± 0.1 mmol/L in the controls. Fasting PI was higher in NIDDM (33.1 ± 5.2) than in controls (9.4 ± 2.5 pmol/L; P < 0.01), but IRI levels were similar (93.4 ± 10.9 vs. 82.8 ± 23.4 pmol/L; P = NS). The PI/IRI ratio was significantly elevated in NIDDM compared to control subjects (35.9 ± 4.1% vs. 12.8 ± 0.8%; P < 0.01). After elevation of the glucose level to 30.3 ± 0.4 mmol/L (NIDDM) and 30.3 ± 0.5 mmol/L (controls), AIRmax was quantified as 622 ± 71 pmol/L in NIDDM and 1997 ± 315 pmol/L in controls, (P < 0.001). The PI/IRI ratio correlated inversely with AIRmax in the NIDDM patients (r = -0.76; P < 0.01).

We conclude that the magnitude of the elevation in fasting PI/IRI is related to the reduction in AIRmax. Thus, the fasting PI/IRI ratio appears to be a marker of the degree of reduced AIRmax in NIDDM.

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