The latest estimates for global diabetes prevalence will no doubt concentrate the thoughts of healthcare officials in many countries 1. Global age-standardized diabetes prevalence increased from 4.3% (95% credible interval 2.4–7.0) in 1980 to 9.0% (7.2–11.1) in 2014 in men, and from 5.0% (2.9–7.9) to 7.9% (6.4–9.7) in women. Thus, over a quarter of a century, the prevalence of diabetes more than doubled in men. The increase seen in women was less pronounced at 60%. These data are consistent with other reports that support a shift from an excess prevalence in women in the earlier part of the 20th century to a consistently higher male prevalence 2,3. The male predominance in type 2 diabetes has implications for cardiometabolic disease prevention strategies that extend to population screening. For example, in the Rancho Bernardo Study, more women than men had isolated postchallenge (oral glucose tolerance test) hyperglycaemia as the only evidence of diabetes; the incidence of diabetes was higher in men than in women, with higher fasting but lower postchallenge glucose levels compared with women 3. The prevalence of prediabetes syndromes – that is, impaired fasting glucose and impaired glucose tolerance – also differs by sex, with impaired fasting glucose being more prevalent in men and impaired glucose tolerance being more frequent in women 4.
Since the pioneering observations of Jean Vague more than 70 years ago, it has been recognized that men are at intrinsically higher risk for the adverse cardiovascular and metabolic consequences of obesity manifested as a higher risk for atherothrombotic disease and type 2 diabetes 5. Differences in insulin sensitivity and regional fat deposition appear to be the most evident drivers of sexual dimorphism in metabolic disease. In parentheses, it is noteworthy that type 1 diabetes is the only major organ-specific autoimmune disorder without a clear female bias 2. The classic differences in adult body composition between the sexes are primarily attributable to the action of sex steroid hormones 6. Oestrogens protect against weight gain by increasing energy expenditure 7 and women have a thermogenic advantage conferred by metabolically active brown adipose tissue mass and activity 8. The classic regional differences in adiposity – central and visceral in men and lower body subcutaneous in women – are accompanied by higher levels of the fat-derived adipocytokines leptin and adiponectin in women compared with men 4. Men tend to develop diabetes at lower levels of BMI compared with women 9. Regional fat deposition may mediate this effect, with visceral adiposity being associated with cardiometabolic disease 5. Visceral fat is regarded as an ectopic lipid store reflecting the limited capacity of subcutaneous adipose tissue to accommodate excess calories as triglycerides 10. As far as nonalcoholic fatty liver disease – a major determinant of whole-body insulin action – is concerned, the current literature is conflicting on whether a sex difference exists in this prevalence of this highly prevalent manifestation of ectopic lipid storage 11.
Intermediary metabolism is subject to sex-specific regulation 12. Compared with men, healthy women have greater adipose mass, higher intramyocellular lipid content and nonesterified fatty acid levels and lower skeletal muscle mass. These factors would predict insulin resistance in whole-body insulin sensitivity in glucose metabolism. Nevertheless, when quantified using techniques such as the hyperinsulinaemic euglycaemic clamp this is not confirmed 13,14. 17β-Oestradiol is the most important female sex hormone with the presence of oestradiol receptors in skeletal muscle supporting a role in the regulation of substrate metabolism 12. Although effects of the follicular versus luteal phases of the menstrual cycle on insulin sensitivity may have contributed to a minor degree to inconsistencies between studies in the literature, higher rates of insulin-mediated glucose uptake in skeletal muscle offer an explanation for higher insulin sensitivity in women 12,14,15. Other metabolic differences are apparent between men and women. For example, whole-body insulin clearance is greater in women 16. Women also appear to be relatively protected against insulin resistance induced by nonesterified fatty acids 17. During fasting, the decrement in blood glucose and increase in lipid metabolites is significantly greater in women than in men 14. From a teleological perspective, it has been tempting to speculate that women preferentially store fat in the gluteal–femoral region to provide energy stores for pregnancy 4 and to prepare the adipose tissue mobilization required for lactation 7.
After the menopause, when serum oestrogen concentrations fall, body composition alters and insulin resistance develops 18. Oestrogens are protective against cardiovascular disease with comparable rates occurring in women 10 years later in life relative to men 19,20. This protection rapidly wanes after menopause. Moreover, it is well recognized that the advantage attributable to female sex in premenopausal women relative to their male counterparts in coronary heart disease risk is eroded by the presence of diabetes, with higher mortality rates for women 3. Deficiency of androgens in men and androgen excess in women further modulate cardiometabolic health in men and women. In men, testosterone has multiple protective effects against diabetes, including enhancing insulin sensitivity through cellular androgen receptors, preventing the development of visceral adiposity and maintaining skeletal muscle mass 21,22. Low testosterone levels, arising, for example, as a consequence of androgen-deprivation therapy or age-related hypogonadism predisposes affected men to type 2 diabetes and cardiovascular disease 23. Conversely, hyperandrogenism in women, usually recognized as polycystic ovary syndrome, is associated with increased risk for diabetes, the metabolic syndrome, and adverse effects on cardiovascular risk factors 24. The association between components of the metabolic syndrome and testosterone levels in men with hypogonadism and women with hyperandrogenism, displays a dose–response relationship 3.
Physiological and psychosocial factors unique to women may also affect cardiovascular risk, such as aspects of reproductive history 25. Accordingly, initiatives to improve the understanding of sex differences in clinical cardiovascular research and healthcare delivery for women and men have been proposed 25. Sex-related differences in biomarkers for cardiovascular disease – the leading cause of premature death among patients with diabetes – have long been recognized, with women having more favourable profiles. Reported differences between the sexes in cardiac metabolism and functional responses to glucose-lowering drugs warrant further investigation, given the inferior outcomes of heart disease in women 26. Although there has been uncertainty about the use of statins in women, intriguing recent data suggest that statin-induced regression of coronary atheroma may be more pronounced in women 27. Novel biomarkers for cardiovascular disease that are being assessed in women include nonclassic lipids, B-type natriuretic peptides, high-sensitivity troponin, coronary artery calcium and genetic markers 19. When standardizing clinical research and ultimately clinical practice the influence of the menstrual cycle on biomarkers for cardiovascular disease needs to be taken into consideration as changing levels may result in reclassification of risk 28.
Beyond cardiovascular disease, type 2 diabetes is also associated with an increased risk for several forms of cancer 29. Sex hormones may influence this risk, with diabetes being a stronger risk factor for colorectal cancer in women than in men and bladder cancer being more common in men with type 2 diabetes 30. In this context, it is noteworthy that the long-established glucose-lowering drug metformin is currently being evaluated in clinical trials as a novel anticancer agent for breast, endometrial and prostate cancer 31.
In the quest for effective personalized diabetes therapy, established biomarkers and emerging pharmacogenomics are the focus of much attention 32. In addition, sex-related differences in pathogenesis and therapy perhaps merit more consideration. From the preceding discussion it is plausible that differences in responses to glucose-lowering agents might be evident between men and women (Table 1). Risk-to-benefit ratios of diabetes drugs may be altered not only through differences in pharmacokinetics 33 and metabolic pathways but also through particular sex-related comorbidities. For example, compared with men, older women are more prone to thiazolidinedione-associated skeletal fractures 30. Tolerability may differ between the sexes as evidenced by women treated with metformin to prevent type 2 diabetes in the Diabetes Prevention Program, reporting more adverse events than men (15 vs. 10%) and being less adherent to treatment 34. Certain subgroups of women with type 2 diabetes may be less likely to reach glycaemic targets whilst being more susceptible to severe and nocturnal hypoglycaemia during insulin treatment 35. In some studies, counter-regulatory hormone responses to hypoglycaemia have been shown to be lower in women; the effects of antecedent hypoglycaemia on recovery from hypoglycaemia also reportedly differ between men and women 14.
What are the implications of sexual dimorphism for research? A recent systematic review and meta-analysis did not reveal differences in beneficial preventive effects of lifestyle or pharmacological interventions on the incidence of type 2 diabetes and weight gain between men and women 36. However, it should be borne in mind that, in diabetes research, as in other medical disciplines, equal representation of both sexes in epidemiological studies and clinical trials is a relatively modern phenomenon 3. Women now account for approximately half of all participants in clinical research funded by the US National Institutes of Health. The National Institutes of Health now expects sex as a biological variable to be factored into research designs, analyses and reporting in vertebrate animal and human studies 37. It has been argued that sex remains a relatively neglected dimension of medicine 38. The available evidence supports application of this principle to diabetes and its long-term vascular complications 39.
Conflicts of interest
There are no conflicts of interest.
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