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Genetics in endocrinology: genetic forms of severe insulin resistance: what endocrinologists should know.

ABSTRACT: 'Insulin resistance' (IR) is a widely used clinical term. It is usually defined as a state characterised by reduced glucose-lowering activity of insulin, but it is also sometimes used as a shorthand label for a clinical syndrome encompassing major pathologies such as type 2 diabetes, polycystic ovary syndrome, fatty liver disease and atherosclerosis. Nevertheless, the precise cellular origins of IR, the causal links among these phenomena and the mechanisms underlying them remain poorly understood or contentious. Prevalent IR usually results from a genetic predisposition interacting with acquired obesity; however, even in some lean individuals, very severe degrees of IR can be observed. It is important to identify these people as they often harbour identifiable single-gene defects and they may benefit from molecular diagnosis, genetic counselling and sometimes tailored therapies. Observation of people with known single-gene defects also offers the opportunity to make inferences about the mechanistic links between IR and common pathologies. Herein, we summarise the currently known monogenic forms of severe IR, with an emphasis on the practical aspects of their recognition, diagnosis and management. In particular, we draw distinctions among the biochemical subphenotypes of IR that arise from primary adipose tissue dysfunction or from primary insulin signalling defects and discuss the implications of this dichotomy for management.

SUBMITTER: Parker VE

PROVIDER: S-EPMC4359904 | biostudies-literature | 2013 Oct

REPOSITORIES: biostudies-literature

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Genetics in endocrinology: genetic forms of severe insulin resistance: what endocrinologists should know.

Parker Victoria E R VE Semple Robert K RK

European journal of endocrinology 20130912 4

'Insulin resistance' (IR) is a widely used clinical term. It is usually defined as a state characterised by reduced glucose-lowering activity of insulin, but it is also sometimes used as a shorthand label for a clinical syndrome encompassing major pathologies such as type 2 diabetes, polycystic ovary syndrome, fatty liver disease and atherosclerosis. Nevertheless, the precise cellular origins of IR, the causal links among these phenomena and the mechanisms underlying them remain poorly understoo ...[more]

PMID: 23857978

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Project description:BACKGROUND: Alzheimer's disease (AD) pathophysiology is mostly (>95%) not inherited in a Mendelian fashion. Such sporadic AD (sAD) forms do not exhibit familial aggregation and are characterized by complex genetic inheritance. Growing evidence indicates that multiple genes contribute to sAD-characteristic endophenotypes, molecular mechanisms, signaling pathways and biomarker signatures either individually or through complex gene-gene interactions, lifestyle and the environment. DISCUSSION: Under the hypothesis that low-prevalence variants showing moderate-to-high effect size may be associated with risk for sAD, two independent research groups have demonstrated that a rare variant (rs75932628, encoding a substitution of arginine by histidine at residue 47 (R47H), in the TREM2 gene, which encodes the triggering receptor expressed on myeloid cells 2) is significantly associated with an increased susceptibility to sAD. Another study has provided intriguing evidence that a low-frequency variant (rs63750847) in the APP gene is associated with a reduced risk of developing AD and a lower likelihood of age-related cognitive decline in elderly subjects without AD. SUMMARY: Recent years have witnessed tremendous development in genetics technology that has allowed full individualized genome-wide or genomic screening embracing all of the risk and protective variants for sAD, both across populations and within individuals. Hopefully, the integration of neurogenetics with systems biology and high-throughput genotyping will further pave the way to decipher all of the related causes, mechanisms, and biomarkers across the spectrum of distinct AD forms. After an almost lost apprentice decade in AD therapy development, the epoch of individualized asymptomatic screening and progress in primary and secondary prevention of sAD is probably at its dawn. Even though we are more at the beginning than at the end of sAD genetics, there is some reason for optimism given the recent identification of novel risk or protective variants (such as rare TREM2 and APP mutations) showing strong statistical associations with sAD.

Dataset Information

Genetics in endocrinology: genetic forms of severe insulin resistance: what endocrinologists should know.

Publications

Genetics in endocrinology: genetic forms of severe insulin resistance: what endocrinologists should know.

Similar Datasets

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