Cover Story Current Issue

The year 2021 marks the 100th year of the discovery of insulin, one of the most important discoveries in the history of medical science—in terms of its lasting impact on hundreds of millions of people worldwide and in the development of medical science. This special issue of Molecular Metabolism takes us through the journey over this remarkable century and highlights several aspects of this discovery and its impact – both in diabetes and medical science – in a much broader way.

C. Ronald Kahn

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Current Issue

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

Julie Støy, Elisa De Franco, Honggang Ye, Soo-Young Park, ... Andrew T. Hattersley

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 INSgene has been recognised as a major cause of monogenic diabetes. Both dominant and recessive mutations in the INSgene 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 INSgene 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.

 

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

Julie Støy, Elisa De Franco, Honggang Ye, Soo-Young Park, ... Andrew T. Hattersley

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 INSgene has been recognised as a major cause of monogenic diabetes. Both dominant and recessive mutations in the INSgene 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 INSgene 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.

 

2020 impact factor: 7.4

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