Sex differences in metabolic regulation and diabetes susceptibility

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Abstract

Gender and biological sex impact the pathogenesis of numerous diseases, including metabolic disorders such as diabetes. In most parts of the world, diabetes is more prevalent in men than in women, especially in middle-aged populations. In line with this, considering almost all animal models, males are more likely to develop obesity, insulin resistance and hyperglycaemia than females in response to nutritional challenges. As summarised in this review, it is now obvious that many aspects of energy balance and glucose metabolism are regulated differently in males and females and influence their predisposition to type 2 diabetes. During their reproductive life, women exhibit specificities in energy partitioning as compared with men, with carbohydrate and lipid utilisation as fuel sources that favour energy storage in subcutaneous adipose tissues and preserve them from visceral and ectopic fat accumulation. Insulin sensitivity is higher in women, who are also characterised by higher capacities for insulin secretion and incretin responses than men; although, these sex advantages all disappear when glucose tolerance deteriorates towards diabetes. Clinical and experimental observations evidence the protective actions of endogenous oestrogens, mainly through oestrogen receptor α activation in various tissues, including the brain, the liver, skeletal muscle, adipose tissue and pancreatic beta cells. However, beside sex steroids, underlying mechanisms need to be further investigated, especially the role of sex chromosomes, fetal/neonatal programming and epigenetic modifications. On the path to precision medicine, further deciphering sex-specific traits in energy balance and glucose homeostasis is indeed a priority topic to optimise individual approaches in type 2 diabetes prevention and treatment.

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The online version of this article (10.1007/s00125-019-05040-3) contains a slideset of the figures for download, which is available to authorised users.

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Most cited references 35

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Sex- and gender-related prevalence, cardiovascular risk and therapeutic approach in metabolic syndrome: A review of the literature.

Giacomo Pucci, Riccardo Alcidi, Lisanne Tap … (2017)

Metabolic syndrome (MS), a cluster of metabolic abnormalities linked to insulin-resistance and abdominal obesity, is associated with an increased risk of Type II diabetes mellitus (DM) and cardiovascular (CV) disease. Its prevalence is high, affecting 20%-30% of the general population, and increases with age in a sex-specific manner: in fact, while below 50 years it is slightly higher in men, it reverses after 50 years. The pronounced age-related increase in the prevalence of MS in women occurs as the result of several factors, which may be classified into sex- and gender-related factors. Sex-related factors, linked to genetical and biological pathways, are mainly driven by hyperandrogenism, insulin-resistance, and the associated increase in abdominal obesity and HDL-cholesterol reduction occurring after menopause. Gender-related factors are sensitive to social and cultural behaviors, dietary habits and psychosocial factors. Women are more prone than men to develop MS in response to work stress and low socio-economic status. Sex and gender differences in the prevalence of MS may translate in different CV risk associated. Prospective studies suggest that the CV risk in women with MS is not only equal but also superior to the CV risk of men with MS. This difference is mostly attenuated when adjusting for the presence of overt DM. Despite similar odds for CV events, the number of CV events may be higher in elderly women because of the higher prevalence of MS compared to men in this age group. Men and women may also have a differential response to treatments for MS, such as lifestyle measures and weight loss. Recent observations suggest that men are better responders than women to non-pharmaceutical therapeutic strategies aimed at reducing the prevalence of MS, although this should be confirmed in large-scale studies. The present review describes the impact of sex and gender on the prevalence, clinical presentation, prognostic significance and treatment of the MS. Attention to gender specificities should be a mandatory pre-requisite of clinical and epidemiological research on MS and CV disease, for a better knowledge and development of health strategies.

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Estrogens protect against high-fat diet-induced insulin resistance and glucose intolerance in mice.

Pierre Gourdy, Aurelie Waget, Rémy Burcelin … (2009)

Although corroborating data indicate that estrogens influence glucose metabolism through the activation of the estrogen receptor alpha (ERalpha), it has not been established whether this pathway could represent an effective therapeutic target to fight against metabolic disturbances induced by a high-fat diet (HFD). To this end, we first evaluated the influence of chronic 17beta-estradiol (E2) administration in wild-type ovariectomized mice submitted to either a normal chow diet or a HFD. Whereas only a modest effect was observed in normal chow diet-fed mice, E2 administration exerted a protective effect against HFD-induced glucose intolerance, and this beneficial action was abolished in ERalpha-deficient mice. Furthermore, E2 treatment reduced HFD-induced insulin resistance by 50% during hyperinsulinemic euglycemic clamp studies and improved insulin signaling (Akt phosphorylation) in insulin-stimulated skeletal muscles. Unexpectedly, we found that E2 treatment enhanced cytokine (IL-6, TNF-alpha) and plasminogen activator inhibitor-1 mRNA expression induced by HFD in the liver and visceral adipose tissue. Interestingly, although the proinflammatory effect of E2 was abolished in visceral adipose tissue from chimeric mice grafted with bone marrow cells from ERalpha-deficient mice, the beneficial effect of the hormone on glucose tolerance was not altered, suggesting that the metabolic and inflammatory effects of estrogens can be dissociated. Eventually comparison of sham-operated with ovariectomized HFD-fed mice demonstrated that endogenous estrogens levels are sufficient to exert a full protective effect against insulin resistance and glucose intolerance. In conclusion, the regulation of the ERalpha pathway could represent an effective strategy to reduce the impact of high-fat diet-induced type 2 diabetes.

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GLP-1 Response to Oral Glucose Is Reduced in Prediabetes, Screen-Detected Type 2 Diabetes, and Obesity and Influenced by Sex: The ADDITION-PRO Study.

Kristine Færch, Signe Torekov, Dorte Vistisen … (2015)

The role of glucose-stimulated release of GLP-1 in the development of obesity and type 2 diabetes is unclear. We assessed GLP-1 response to oral glucose in a large study population of lean and obese men and women with normal and impaired glucose regulation. Circulating concentrations of glucose, insulin, and GLP-1 during an oral glucose tolerance test (OGTT) were analyzed in individuals with normal glucose tolerance (NGT) (n = 774), prediabetes (n = 525), or screen-detected type 2 diabetes (n = 163) who attended the Danish ADDITION-PRO study (n = 1,462). Compared with individuals with NGT, women with prediabetes or type 2 diabetes had 25% lower GLP-1 response to an OGTT, and both men and women with prediabetes or type 2 diabetes had 16-21% lower 120-min GLP-1 concentrations independent of age and obesity. Obese and overweight individuals had up to 20% reduced GLP-1 response to oral glucose compared with normal weight individuals independent of glucose tolerance status. Higher GLP-1 responses were associated with better insulin sensitivity and β-cell function, older age, and lesser degree of obesity. Our findings indicate that a reduction in GLP-1 response to oral glucose occurs prior to the development of type 2 diabetes and obesity, which can have consequences for early prevention strategies for diabetes.

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Author and article information

Contributors

Pierre Gourdy: pierre.gourdy@inserm.fr

Journal

Journal ID (nlm-ta): Diabetologia

Journal ID (iso-abbrev): Diabetologia

Title: Diabetologia

Publisher: Springer Berlin Heidelberg (Berlin/Heidelberg )

ISSN (Print): 0012-186X

ISSN (Electronic): 1432-0428

Publication date (Electronic): 21 November 2019

Publication date PMC-release: 21 November 2019

Publication date (Print): 2020

Volume: 63

Issue: 3

Pages: 453-461

Affiliations

[1 ]GRID grid.11417.32, ISNI 0000 0001 2353 1689, Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), UMR1048, Team 9, INSERM/UPS, , Université de Toulouse, ; 1 avenue Jean Poulhès, BP 84225, 31432 Toulouse Cedex 4, France

[2 ]GRID grid.411175.7, ISNI 0000 0001 1457 2980, Service de Diabétologie, Maladies Métaboliques et Nutrition, , CHU de Toulouse, ; Toulouse, France

[3 ]GRID grid.414548.8, ISNI 0000 0001 2169 1988, Institut National de la Recherche Agronomique (INRA), Toxalim UMR 1331, ; Toulouse, France

Article

Publisher ID: 5040

DOI: 10.1007/s00125-019-05040-3

PMC ID: 6997275

PubMed ID: 31754750

SO-VID: 59f173da-b91b-4adf-ab90-97cf0a3ca623

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Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

History

Date received : 30 June 2019

Date accepted : 23 September 2019

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ScienceOpen disciplines: Endocrinology & Diabetes

Keywords: diabetes,energy balance,glucose metabolism,oestrogens,review,sex differences

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ScienceOpen disciplines: Endocrinology & Diabetes

Keywords: diabetes, energy balance, glucose metabolism, oestrogens, review, sex differences

Sex differences in metabolic regulation and diabetes susceptibility

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Most cited references 35

Sex- and gender-related prevalence, cardiovascular risk and therapeutic approach in metabolic syndrome: A review of the literature.

Estrogens protect against high-fat diet-induced insulin resistance and glucose intolerance in mice.

GLP-1 Response to Oral Glucose Is Reduced in Prediabetes, Screen-Detected Type 2 Diabetes, and Obesity and Influenced by Sex: The ADDITION-PRO Study.

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