Insulin Mutations in Diabetes

The Clinical Spectrum

  1. Benjamin Glaser
  1. Endocrinology and Metabolism Service, Internal Medicine Department, Hadassah-Hebrew University Medical School, Jerusalem, Israel
  1. Address correspondence and reprint requests to Benjamin Glaser, MD, Endocrinology and Metabolism, Hadassah Hospital, P.O.B. 12000, Jerusalem 91120, Israel. E-mail: beng{at}

Studies of monogenic disorders of β-cell function have yielded important information on β-cell physiology and have improved the diagnosis and treatment of patients with these rare diseases. These disorders include defects associated with increased insulin secretion, causing hypoglycemia, and decreased insulin secretion, resulting in diabetes. The most common form of monogenic diabetes is so-called maturity-onset diabetes of the young (MODY) syndrome, causing autosomal dominant non–insulin dependent diabetes appearing before the age of 25 years. Mutations in six genes can cause MODY, although in 16–45% of cases the genetic etiology is still unknown (1). Neonatal diabetes mellitus (NDM) is another form of monogenic diabetes, usually defined as overt diabetes diagnosed during the first 6 months of life (2). The disease is rare (incidence 1:300,000–500,000 live births), and ∼50% of patients have transient NDM (TNDM), in which the disease remits after a few months but may reappear months or years later. The other 50% have permanent NDM (PNDM). In a small percentage of these, diabetes is part of a complex clinical syndrome involving organs other than the endocrine pancreas. For those with isolated PNDM, mutations in four different genes have been identified. Inactivating glucokinase mutations were discovered first, but appear to be rather rare causes of this syndrome (3). Activating mutations in either of the two subunits of the β-cell ATP-sensitive K+ channel, ABCC8 and KCNJ11, are more frequently seen (4,5).

In a landmark report last year, Stoy et al. (6) described 16 patients with PNDM caused by insulin gene mutations. These mutations appear to cause abnormal …

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