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

Objective: We set out to assess whether hyperproinsulinaemia is an early finding in latent autoimmune diabetes in adults (LADA). Research design and methods: We measured plasma proinsulin and C-peptide responses during a 2-h oral glucose tolerance test (OGTT) and in the hyperglycaemic clamp in 21 normoglycaemic offspring of LADA patients testing positive for glutamic acid decarboxylase antibodies (GADA) or islet cell antibodies (ICA), and in 17 healthy control subjects without a family history of diabetes. Results: The study groups had comparable areas under the curves of blood glucose, plasma proinsulin, C-peptide and proinsulin/C-peptide in the OGTT. However, the offspring of LADA patients had higher proinsulin/C-peptide in the hyperglycaemic clamp (P , 0.01 versus the control group). The offspring of GADA-positive LADA patients (n ¼ 9) had higher proinsulin and proinsulin/C-peptide than did the control group in the OGTT (P , 0.05 for both comparisons) and in the hyperglycaemic clamp (P , 0.001 and P , 0.05 respectively). They also had higher proinsulin than the offspring of ICApositive LADA patients (n ¼ 12) (P , 0.001) in the hyperglycaemic clamp. The offspring of ICA-positive LADA patients did not clearly show hyperproinsulinaemia during the tests, but they had lower maximal glucose-stimulated insulin secretory capacity than the control group (P , 0.05) and the offspring of GADA-positive LADA patients (P , 0.05) in the hyperglycaemic clamp. Conclusions: These results suggested that insulin secretion in the offspring of GADA-positive LADA patients is characterised by subtle defects in the processing of insulin precursors. Furthermore, various proinsulin responses among the offspring of LADA patients with different autoimmune markers provided further evidence that LADA is a heterogeneous disorder.