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OBJECTIVEHeterozygous mutations in the human preproinsulin (INS) gene are a cause of nonsyndromic neonatal or early-infancy diabetes. Here, we sought to identify INS mutations associated with maturity-onset diabetes of the young (MODY) or nonautoimmune diabetes in mid-adult life, and to explore the molecular mechanisms involved.RESEARCH DESIGN AND METHODSThe INS gene was sequenced in 16 French probands with unexplained MODY, 95 patients with nonautoimmune early-onset diabetes (diagnosed at <35 years) and 292 normoglycemic control subjects of French origin. Three identified insulin mutants were generated by site-directed mutagenesis of cDNA encoding a preproinsulin–green fluorescent protein (GFP) (C-peptide) chimera. Intracellular targeting was assessed in clonal β-cells by immunocytochemistry and proinsulin secretion, by radioimmunoassay. Spliced XBP1 and C/EBP homologous protein were quantitated by real-time PCR.RESULTSA novel coding mutation, L30M, potentially affecting insulin multimerization, was identified in five diabetic individuals (diabetes onset 17–36 years) in a single family. L30M preproinsulin-GFP fluorescence largely associated with the endoplasmic reticulum (ER) in MIN6 β-cells, and ER exit was inhibited by ∼50%. Two additional mutants, R55C (at the B/C junction) and R6H (in the signal peptide), were normally targeted to secretory granules, but nonetheless caused substantial ER stress.CONCLUSIONSWe describe three INS mutations cosegregating with early-onset diabetes whose clinical presentation is compatible with MODY. These led to the production of (pre)proinsulin molecules with markedly different trafficking properties and effects on ER stress, demonstrating a range of molecular defects in the β-cell.

OBJECTIVENeonatal diabetes secondary to mutations in potassium-channel subunits is a rare disease but constitutes a paradigm for personalized genetics-based medicine, as replacing the historical treatment with insulin injections with oral sulfonylurea (SU) therapy has been proven beneficial. SU receptors are widely expressed in the brain, and we therefore evaluated potential effects of SU on neurodevelopmental parameters, which are known to be unresponsive to insulin. RESEARCH DESIGN AND METHODSWe conducted a prospective single-center study. Nineteen patients (15 boys aged 0.1-18.5 years) were switched from insulin to SU therapy. MRI was performed at baseline. Before and 6 or 12 months after the switch, patients underwent quantitative neurological and developmental assessments and electrophysiological nerve and muscle testing. RESULTSAt baseline, hypotonia, deficiencies in gesture conception or realization, and attention disorders were common. SU improved HbA 1c levels (median change 21.55% [range 23.8 to 0.1]; P < 0.0001), intelligence scores, hypotonia (in 12 of 15 patients), visual attention deficits (in 10 of 13 patients), gross and fine motor skills (in all patients younger than 4 years old), and gesture conception and realization (in 5 of 8 older patients). Electrophysiological muscle and nerve tests were normal. Cerebral MRI at baseline showed lesions in 12 patients, suggesting that the impairments were central in origin. CONCLUSIONSSU therapy in neonatal diabetes secondary to mutations in potassium-channel subunits produces measurable improvements in neuropsychomotor impairments, which are greater in younger patients. An early genetic diagnosis should always be made, allowing for a rapid switch to SU.Neonatal diabetes is a rare condition that develops during the first months of life with an estimated incidence of 1 in 90,000 newborns (1,2). Neonatal diabetes can be permanent or transient, relapsing around puberty after a period of remission. We recently reported that 42% of patients in a large cohort had a heterozygous