Longitudinal study of fasting proinsulin in 148 siblings of patients with insulin-dependent diabetes mellitus. Study Group on Childhood Diabetes in Finland

Abstract

Objective: To follow proinsulin immunoreactive material (PIM) in healthy siblings from the time of diagnosis of insulin-dependent diabetes mellitus (IDDM) in the proband, for at least 2 years. Design and methods: The study comprised 148 siblings representing 112 families. The siblings were recruited from the nationwide 'Childhood Diabetes in Finland' study and tested for immunological markers. If a sibling was found positive for islet cell antibodies (ICA) or insulin autoantibodies (IAA), PIM sampling was extended beyond 2 years. Results: Of the 148 siblings, 12 developed IDDM 3-53 months after the diagnosis in the proband. Eleven of these siblings exhibited initially normal PIM concentrations. In nine siblings, samples were available both more than 6 months and during the last 6 months before the diagnosis of IDDM; PIM concentrations increased in seven, remained unchanged in one, and decreased in one in the period up to the diagnosis of IDDM (P < 0.05). Median PIM concentration did not change significantly during the examination period of 2 years in the 136 siblings who did not contract IDDM. Constantly increased PIM concentrations were found in 12 of the 136 siblings who did not develop IDDM. These 12 siblings were all ICA negative. Conclusion: In healthy siblings of IDDM patients exhibiting an initially low PIM concentration, an abrupt increase in PIM seems to precede the clinical manifestation of IDDM within 0-6 months. However, there were too few patients available to close follow-up to allow calculation of any predictive value of this increase. Persistently increased PIM concentrations were present in some healthy siblings who did not develop IDDM. The reason for that finding remains unclear, but it could be associated with previous B cell damage.

Proinsulin levels and the proinsulin:c-peptide ratio complement autoantibody measurement for predicting type 1 diabetes

“…The discrepancy with the present observation may relate to the use of random vs fasting values, different hormone and antibody assays, and low numbers both in older studies and our control group. However, it does not invalidate our observation of a(n) (further) increase in proinsulin and PI:C closer to diagnosis, which was also noted by others [14,32,33]. In particular, the use of random hormone levels may lead to more overlapping results between groups tested, but remains the only option to screen large groups of active non-diabetic relatives nationwide.…”

“…Up to a 500-fold excess of C-peptide did not interfere in the proinsulin assay. Because of high crossreactivity with conversion intermediates [74% for split (32)(33) proinsulin, 65% for des (31,32) proinsulin, 78% for split(65-66) proinsulin and 99% for des(64,65) proinsulin], the assay was considered to measure total proinsulin immunoreactive material [27]. It comprises two separate overnight incubations allowing the monoclonal antibodies used in the assay to compete with IAA (if present in the plasma tested) for binding to proinsulin.…”

Subtle hyperproinsulinaemia characterises the defective insulin secretory capacity in offspring of glutamic acid decarboxylase antibody-positive patients with latent autoimmune diabetes mellitus in adults

“…These results suggested that the impaired insulin secretory capacity in the offspring of LADA patients (9) is characterised by a subtle defect in the processing of insulin precursors, unlike in the offspring of patients with type 2 diabetes (34). On the other hand, although hyperproinsulinaemia was not so profound as described in first-degree relatives of patients with type 1 diabetes (13)(14)(15)(16)(17)(18)(19) it supports the concept that LADA has metabolic features typical of classical type 1 diabetes. Moreover, hyperproinsulinaemia was observed only in the offspring of GADA-positive LADA patients, providing further evidence that LADA is a heterogeneous disorder (8,10).…”

Elevations in the Fasting Serum Proinsulin–to–C-Peptide Ratio Precede the Onset of Type 1 Diabetes

“…In Finland, an increased PI:C ratio was observed in 11 antibody-positive siblings of persons with type 1 diabetes who exhibited reduced first-phase insulin responses during an intravenous glucose tolerance test (9). Fasting PI-immunoreactive material increased during the 6 months prior to diabetes onset in seven of nine siblings of type 1 diabetes probands who were monitored longitudinally for type 1 diabetes development (28). An elevated random PI:C ratio was also present in Belgian autoantibody positive first-degree relatives in whom type 1 diabetes developed within 11–50 months (10).…”