Some mutations of the insulin gene cause hyperinsulinemia or hyperproinsulinemia. Replacement of biologically important amino acid leads to defective receptor binding, longer half-life and hyperinsulinemia. Three mutant insulins have been identified: (i) insulin Chicago (F49L or PheB25Leu); (ii) insulin Los Angeles (F48S or PheB24Ser); (iii) and insulin Wakayama (V92L or ValA3Leu). Replacement of amino acid is necessary for proinsulin processing results in hyperproinsulinemia. Four types have been identified: (i) proinsulin Providence (H34D); (ii) proinsulin Tokyo (R89H); (iii) proinsulin Kyoto (R89L); and (iv) proinsulin Oxford (R89P). Three of these are processing site mutations. The mutation of proinsulin Providence, in contrast, is thought to cause sorting abnormality. Compared with normal proinsulin, a significant amount of proinsulin Providence enters the constitutive pathway where processing does not occur. These insulin gene mutations with hyper(pro)insulinemia were very rare, showed only mild diabetes or glucose intolerance, and hyper(pro)insulinemia was the key for their diagnosis. However, this situation changed dramatically after the identification of insulin gene mutations as a cause of neonatal diabetes. This class of insulin gene mutations does not show hyper(pro)insulinemia. Mutations at the cysteine residue or creating a new cysteine will disturb the correct disulfide bonding and proper conformation, and finally will lead to misfolded proinsulin accumulation, endoplasmic reticulum stress and apoptosis of pancreatic β-cells. Maturity-onset diabetes of the young (MODY) or an autoantibody-negative type 1-like phenotype has also been reported. Very recently, recessive mutations with reduced insulin biosynthesis have been reported. The importance of insulin gene mutation in the pathogenesis of diabetes will increase a great deal and give us a new understanding of β-cell biology and diabetes. (J Diabetes Invest, doi: 10.1111/j.2040-1124.2011.00100.x, 2011).
Keywords: Endoplasmic reticulum stress; Insulin gene mutation; Neonatal diabetes.