Insulin gene mutations and diabetes

Abstract

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.

Figure 1

Schematic representation of human insulin gene structure and mutations causing hyperinsulinemia or hyperproinsulinemia. Exons are shown as boxes. Protein coding regions are shown as closed boxes, whereas non‐coding regions are shown as open boxes. Mutations resulting in hyperinsulinemia and hyperproinsulinemia are colored in blue and in pink, respectively. Translation initiation codon (ATG), termination or stop codon (TAG) or dibasic cleavage sites (RR and KR) are shown.

Figure 2

Schematic representation of the amino acid sequence of human preproinsulin showing the positions of mutations. Signal peptide, β‐chain or α‐chain of insulin, and C‐peptide are shown in different colors. Mutations identified in patients with permanent neonatal diabetes mellitus, maturity‐onset diabetes of the young, type 1b‐like, hyperproinsulinemia, hyperinsulinemia or recessive mutation are shown in different colors. Modified from Stoy J, Steiner DF, Park S‐Y et al. Clinical and molecular genetics of neonatal diabetes due to mutations in the insulin gene. Rev Endocr Metab Disord 2010; 11: 205–215.

Figure 3

Schematic representation of the structure of the human insulin gene showing the sites of recessive mutations. Exons are boxed. Coding regions for signal peptide, α‐ and β‐chains of insulin, C‐peptide are shown as S, A, B and C, respectively, and 5′‐ and 3′‐untranslated regions are indicated as 5′ and 3′, respectively. Recessive insulin gene mutations are shown. Modified from Garin I, Edghill EL, Akerman I et al. Recessive mutations in the INS gene result in neonatal diabetes through reduced insulin biosynthesis. Proc Natl Acad Sci USA 2010; 107: 3105–3110.