Gender and T2DM
In the first half of the last century the prevalence of type 2 diabetes was higher among women than among men, but this trend has shifted, so more men than women are now diagnosed with type 2 diabetes . This change in the gender distribution of type 2 diabetes is mainly caused by a more sedentary lifestyle particularly among men, resulting in increased obesity. However, recent data have also shown that men develop diabetes at a lower degree of obesity than women – a finding which adds support to the view that the pathogenesis of type 2 diabetes differs between men and women. Observations of sex differences in body fat distribution, insulin resistance, sex hormones, and blood glucose levels further support this notion.
Body fat distribution
Figure 1: Cross-sectional abdominal magnetic resonance image of an obese woman and an obese man . Obesity is one of the main risk factors for type 2 diabetes, and especially the abdominal visceral fat is associated with increased type 2 diabetes risk. Body fat distribution differs by sex , and in general men have more abdominal fat, whereas women have more peripheral fat – also denoted as “apple” versus “pear” shape. Looking into the abdominal fat, men also tend to have more visceral and hepatic fat than women, whereas women have more subcutaneous fat than men (Figure 1). In contrast to visceral fat, subcutaneous fat is associated with improved insulin sensitivity and is therefore protective against type 2 diabetes. Thus, the phenomenon that men develop diabetes at a lower body mass index than women  can be explained by the fact that men have more visceral fat for a given body mass index than women and thereby a higher relative risk for developing type 2 diabetes.
Insulin resistance and blood glucose levels
The sex differences in body fat distribution are closely related to sex differences in insulin resistance. Men are in general more insulin resistant than women, which can be explained by their higher proportion of visceral and hepatic fat compartments associated with insulin resistance .
Figure 2: Trajectories of fasting plasma glucose (a), fasting serum insulin (b), 2-hour plasma glucose (c) and 2-hour serum insulin (d). For men (blue) and women (pink) who developed diabetes and men (light blue) and women (light pink) without diabetes from 18 years before time of diagnosis or last clinical examination in a diabetes free population (the Whitehall II study). Solid lines indicate estimated trajectories and dashed lines are 95% confidence limits. Trajectories are shown for a hypothetical male and female participant age 55 years. Black bars at the bottom indicate data distribution over the follow-up period [*7].In addition to sex differences in insulin resistance it is also well documented that more men than women have elevated fasting glucose levels (impaired fasting glycaemia, IFG), whereas more women than men have elevated 2-hour glucose concentrations (impaired glucose tolerance, IGT) . It has been suggested that part of the sex differences in 2-hour glucose and insulin concentrations is related to the different body sizes of men and women . In general, women have a smaller body mass than men, which means it may take them longer time to metabolise the 75 g of glucose given during a standard oral glucose tolerance test (OGTT). On the other hand, the sex differences in glucose concentrations in the fasting state are likely to be caused by physiological differences, e.g. sex hormones.
Sex hormones and sex hormone binding globulin
Some of the observed sex differences in body composition, insulin resistance and blood glucose levels are partly due to the effect of sex hormones. After menopause, insulin sensitivity declines, indicating that oestrogen may exert beneficial effects on insulin sensitivity in women. Oestrogen has also a beneficial effect on adipose tissue distribution. The preferential deposition of adipose tissue in the subcutaneous fat compartments in women compared with the visceral compartments in men seem to be related to the higher oestrogen levels in women compared with men. In contrast, testosterone levels are significantly associated with central fat accumulation in both men and women .
Observational studies have also found associations of low concentrations of sex hormone binding globulin with increased risk of insulin resistance and type 2 diabetes independent of the concentrations of circulating sex hormones. The association between sex hormone binding globulin and insulin resistance is stronger in women than in men, and stronger in postmenopausal than in premenopausal women. However, it is not clear whether sex hormone binding globulin leads to insulin resistance or whether the reversal pathway is the case.
In general, men have higher absolute risk of coronary heart disease than women. However, the relative risk of coronary heart disease associated with diabetes is greater in women than in men , indicating that diabetes exerts a greater adverse effect on cardiovascular risk in women compared with men. This suggestion is supported by the finding that cardiovascular risk factors differ more between women with and without diabetes than between diabetic and non-diabetic men . Because of the higher absolute risk for coronary heart disease among men and the higher relative risk among diabetic women, the absolute risk for coronary heart disease is comparable between men and women with diabetes.
When blood glucose concentrations are analysed as continuous variables the effect of post-OGTT glucose concentrations and HbA1c on CVD risk seem to be stronger among women than among men . However, among pre-diabetic individuals with IFG there is no difference in the relative risk of CVD between men and women 14, so there are insufficient data to suggest a sex difference in the association between pre-diabetes and CVD risk.
^ Geer EB, Shen W (2009) Gender differences in insulin resistance, body composition, and energy balance. Gend.Med 6 Suppl 1: 60-75
^ Logue J, Walker J, Colhoun H, et al (2011) Do men develop type 2 diabetes at lower body mass indices than women? Diabetologia 54: 3003-3006
^ Færch K, Borch-Johnsen K, Vaag A, Jørgensen T, Witte D (2010) Sex differences in glucose levels: a consequence of physiology or methodological convenience? The Inter99 study. Diabetologia 53: 858-865
^ Perreault L, Ma Y, Dagogo-Jack S, et al (2008) Sex Differences in Diabetes Risk and the Effect of Intensive Lifestyle Modification in the Diabetes Prevention Program. Diabetes care 31: 1416-1421
^ Sicree RA, Zimmet PZ, Dunstan DW, Cameron AJ, Welborn TA, Shaw JE (2008) Differences in height explain gender differences in the response to the oral glucose tolerance test- the AusDiab study. DIABETIC MED. 25: 296-302
^ Rathmann W, Strassburger K, Giani G, Döring A, Meisinger C (2008) Differences in height explain gender differences in the response to the oral glucose tolerance test. Diabet Med 25: 1374-1375
^ Vistisen D, Witte DR, Tabak AG, Brunner EJ, Kivimaki M, Faerch K (2012) Sex differences in glucose and insulin trajectories prior to diabetes diagnosis: the Whitehall II study. Acta Diabetol
^ Wallace IR, McKinley MC, Bell PM, Hunter SJ (2013) Sex hormone binding globulin and insulin resistance. Clin Endocrinol (Oxf) 78: 321-329
^ Huxley R, Barzi F, Woodward M (2006) Excess risk of fatal coronary heart disease associated with diabetes in men and women: meta-analysis of 37 prospective cohort studies. BMJ 332: 73-78
^ Wannamethee SG, Papacosta O, Lawlor DA, et al (2012) Do women exhibit greater differences in established and novel risk factors between diabetes and non-diabetes than men? The British Regional Heart Study and British Women's Heart Health Study. Diabetologia 55: 80-87
^ Kodama S, Saito K, Tanaka S, et al (2012) Fasting and Post-Challenge Glucose as Quantitative Cardiovascular Risk Factors: A Meta-Analysis. J Atheroscler.Thromb.
^ Park S, Barrett-Connor E, Wingard DL, Shan J, Edelstein S (1996) GHb is a better predictor of cardiovascular disease than fasting or postchallenge plasma glucose in women without diabetes. The Rancho Bernardo Study. Diabetes care 19: 450-456
^ Ford ES, Zhao G, Li C (2010) Pre-diabetes and the risk for cardiovascular disease: a systematic review of the evidence. J Am.Coll.Cardiol. 55: 1310-1317