EJE PRIZE 2015: How does insulin resistance arise, and how does it cause disease? Human genetic lessons

Abstract

Insulin orchestrates physiological responses to ingested nutrients; however, although it elicits widely ramifying metabolic and trophic responses from diverse tissues, 'insulin resistance (IR)', a pandemic metabolic derangement commonly associated with obesity, is usually defined solely by blunting of insulin's hypoglycaemic effect. Recent study of monogenic forms of IR has established that biochemical subphenotypes of IR exist, clustering into those caused by primary disorders of adipose tissue and those caused by primary defects in proximal insulin signalling. IR is often first recognised by virtue of its associated disorders including type 2 diabetes, dyslipidaemia (DL), fatty liver and polycystic ovary syndrome (PCOS). Although these clinically observed associations are confirmed by cross-sectional and longitudinal population-based studies, causal relationships among these phenomena have been more difficult to establish. Single gene IR is important to recognise in order to optimise clinical management and also permits testing of causal relationships among components of the IR syndrome using the principle of Mendelian randomisation. Thus, where a precisely defined genetic defect is identified that directly produces one component of the syndrome, then phenomena that are causally linked to that component should be seen. Where this is not the case, then a simple causal link is refuted. This article summarises known forms of monogenic severe IR and considers the lessons to be learned about the pathogenic mechanisms both upstream from common IR and those downstream linking it to disorders such as DL, fatty liver, PCOS and cancer.

MANAGEMENT OF ENDOCRINE DISEASE: Secondary polycystic ovary syndrome: theoretical and practical aspects

“…Notably, it should also be recognized that there has been uncertainty as to whether insulin resistance in PCOS has unique characteristics, since androgen excess per se may explain the development of insulin resistance in the insulin-sensitive tissues, such as fat, muscles and liver (46). In any case, the role of severe insulin resistance and very high circulating insulin in determining the PCOS phenotype in patients with SSIR states is confirmed on both clinical and basic research studies (69). One aspect of the association between PCOS and SSIR is that, in the last two decades, it has become increasingly clear that the responsible genetic factors of PCOS linked to SSIR are quite specific, and completely different with respect to the susceptible genes of the common PCOS, as proposed by recent genome-wide association and linkage studies (22,23).…”

“…A physical sign always present in SSIR is acanthosis nigricans. Other physical signs of SSIR, although not always present, are unusual severe combined dyslipidemia (high triglycerides and low high-density lipoprotein-cholesterol levels) sometimes complicated by unusually severe hepatic steatosis and early-onset hypertension (65,69). The prevalence of PCOS secondary to SSIR has not been formally assessed, though referrals to our center in the last 10 years suggest a rate of approximately 1.5% among patients visiting the out-patient clinic for symptoms of PCOS (oligo-amenorrhea, hirsutism, infertility).…”

“…These findings emphasize the concept that the secondary PCOS to SSIR states is much more common than expected. The identification of these secondary phenotypes of PCOS is of importance also because these patients often benefit from tailored therapies, including specific dietary management as well as insulin sensitizers, particularly thiazolidinediones (pioglitazone) (69,72), which, however, requires the presence of residual adipose depots to achieve metabolic benefit. Finally, in patients with lipodystrophy and low levels of serum leptin, administration of recombinant human leptin may be dramatically beneficial in improving glycemic control, dyslipidemia and lipid accumulation in the liver (73).…”

Definitive diagnosis of mandibular hypoplasia, deafness, progeroid features and lipodystrophy (MDPL) syndrome caused by a recurrent <i>de novo</i> mutation in the <i>POLD1</i> gene

“…However, the patient described by Chen et al [15] showed quite low IGF-1 levels and an atrophic pituitary on MRI. Numerous genomic syndromes associated with short stature are caused by genetic defects in fundamental cellular processes [34,35].…”

Coenzyme Q10, Glucose Homeostasis and the Probable Mediating Role of Adipokines

“…[6][7][8] Many diseases are accompanied with imapired glycemic control and insulin resistance. 9 Phosphorylation of Insulin Receptor Substrates (IRS) is crucial for insulin signalling cascade, which in turn activates the mitogen-activated protein kinase (MAP-Kinase) with major mitogenic effects and phosphatidylinositol-3-Kinase (PI-3K) with prominent metabolic properties including appropriate cellular glucose distribution. 10 Coenzyme Q10 might induce the tyrosine kinase and phosphatidylinositol 3 kinase (PI3k) activity in liver.…”