In celebration of a century with insulin - Update of insulin gene mutations in diabetes

TY - JOUR

T1 - In celebration of a century with insulin - Update of insulin gene mutations in diabetes

AU - Støy, Julie

AU - De Franco, Elisa

AU - Ye, Honggang

AU - Park, Soo-Young

AU - Bell, Graeme I

AU - Hattersley, Andrew T

N1 - Copyright © 2021 The Author(s). Published by Elsevier GmbH.. All rights reserved.

PY - 2021/10

Y1 - 2021/10

N2 - Background: While insulin has been central to the pathophysiology and treatment of patients with diabetes for the last 100 years, it has only been since 2007 that genetic variation in the INS gene has been recognised as a major cause of monogenic diabetes. Both dominant and recessive mutations in the INS gene are now recognised as important causes of neonatal diabetes and offer important insights into both the structure and function of insulin. It is also recognised that in rare cases, mutations in the INS gene can be found in patients with diabetes diagnosed outside the first year of life. Scope of Review: This review examines the genetics and clinical features of monogenic diabetes resulting from INS gene mutations from the first description in 2007 and includes information from 389 patients from 292 families diagnosed in Exeter with INS gene mutations. We discuss the implications for diagnosing and treating this subtype of monogenic diabetes. Major Conclusions: The dominant mutations in the INS gene typically affect the secondary structure of the insulin protein, usually by disrupting the 3 disulfide bonds in mature insulin. The resulting misfolded protein results in ER stress and beta-cell destruction. In contrast, recessive INS gene mutations typically result in no functional protein being produced due to reduced insulin biosynthesis or loss-of-function mutations in the insulin protein. There are clinical differences between the two genetic aetiologies, between the specific mutations, and within patients with identical mutations.

AB - Background: While insulin has been central to the pathophysiology and treatment of patients with diabetes for the last 100 years, it has only been since 2007 that genetic variation in the INS gene has been recognised as a major cause of monogenic diabetes. Both dominant and recessive mutations in the INS gene are now recognised as important causes of neonatal diabetes and offer important insights into both the structure and function of insulin. It is also recognised that in rare cases, mutations in the INS gene can be found in patients with diabetes diagnosed outside the first year of life. Scope of Review: This review examines the genetics and clinical features of monogenic diabetes resulting from INS gene mutations from the first description in 2007 and includes information from 389 patients from 292 families diagnosed in Exeter with INS gene mutations. We discuss the implications for diagnosing and treating this subtype of monogenic diabetes. Major Conclusions: The dominant mutations in the INS gene typically affect the secondary structure of the insulin protein, usually by disrupting the 3 disulfide bonds in mature insulin. The resulting misfolded protein results in ER stress and beta-cell destruction. In contrast, recessive INS gene mutations typically result in no functional protein being produced due to reduced insulin biosynthesis or loss-of-function mutations in the insulin protein. There are clinical differences between the two genetic aetiologies, between the specific mutations, and within patients with identical mutations.

KW - Genetics

KW - Insulin biosynthesis

KW - Insulin gene

KW - Monogenic diabetes

KW - Neonatal diabetes

KW - Pathophysiology

U2 - 10.1016/j.molmet.2021.101280

DO - 10.1016/j.molmet.2021.101280

M3 - Review

C2 - 34174481

SN - 2212-8778

VL - 52

JO - Molecular Metabolism

JF - Molecular Metabolism

M1 - 101280

ER -