Sex and Gender Differences in Risk, Pathophysiology and Complications of Type 2 Diabetes Mellitus

Abstract

The steep rise of type 2 diabetes mellitus (T2DM) and associated complications go along with mounting evidence of clinically important sex and gender differences. T2DM is more frequently diagnosed at lower age and body mass index in men; however, the most prominent risk factor, which is obesity, is more common in women. Generally, large sex-ratio differences across countries are observed. Diversities in biology, culture, lifestyle, environment, and socioeconomic status impact differences between males and females in predisposition, development, and clinical presentation. Genetic effects and epigenetic mechanisms, nutritional factors and sedentary lifestyle affect risk and complications differently in both sexes. Furthermore, sex hormones have a great impact on energy metabolism, body composition, vascular function, and inflammatory responses. Thus, endocrine imbalances relate to unfavorable cardiometabolic traits, observable in women with androgen excess or men with hypogonadism. Both biological and psychosocial factors are responsible for sex and gender differences in diabetes risk and outcome. Overall, psychosocial stress appears to have greater impact on women rather than on men. In addition, women have greater increases of cardiovascular risk, myocardial infarction, and stroke mortality than men, compared with nondiabetic subjects. However, when dialysis therapy is initiated, mortality is comparable in both males and females. Diabetes appears to attenuate the protective effect of the female sex in the development of cardiac diseases and nephropathy. Endocrine and behavioral factors are involved in gender inequalities and affect the outcome. More research regarding sex-dimorphic pathophysiological mechanisms of T2DM and its complications could contribute to more personalized diabetes care in the future and would thus promote more awareness in terms of sex- and gender-specific risk factors.

Figure 1.

Lifelong impact and interaction between sex and gender on development and outcomes of T2DM: social conditions (upper) and biological factors (lower) influence the development of germ cells, fetal programming, the newborn, puberty, reproductive age, ageing, and the manifestation of T2DM in men and women as well as the progression of its complications and comorbidities. Modified from Gender in cardiovascular diseases: impact on clinical manifestations, management, and outcomes, by EUGenMed Cardiovascular Clinical Study Group, Regitz-Zagrosek V, Oertelt-Prigione S, et al. Eur Heart J. 2016;37:24–34 with permission.

Figure 2.

Prevalence of prediabetes, diabetes, and overweight/obesity in men and women. A, Percent of women (pink) and men (blue) (age 25+) with fasting glucose more than or equal to 126 mg/dL (7.0 mmol/L) or on medication for raised blood glucose (age-standardized estimate) in 2014 (348). B, Prevalence of IGT and diabetes by age and sex in 2013 (11). C, Prevalence of overweight and obesity by age and sex in 2013 (2).

Figure 3.

Overview of physiological and pathological sex differences in metabolism and energy homeostasis in men (left) and women (right). Blue arrows indicate higher or lower levels or impact in men compared with women. Red arrows indicate higher or lower levels or impact in women compared with men. Fat mass: red, SAT; orange, VAT; purple, BAT. ARC POMC, arcuate nucleus POMC; FFA, free fatty acid; RR, relative risk. These facts are described in more detail in the main text, eg, in the sections II and V, respectively.

Figure 4.

Sex differences in fat distribution. MR image showing area between L5 and L4 at the lumbar spine in a male and female young healthy, normal-weight subject of comparable age and BMI (A and B) and a male and female patient with T2DM of comparable age and BMI (C and D). A, Man, 23 years old, BMI 25 kg/m², VAT from area L2 to L5 216 cm², SAT 649 cm², liver fat 1.9%. B, Woman, 19 years old, BMI 24 kg/m², VAT from area L2 to L5 138 cm², SAT 807 cm², liver fat 1.1%. C, Man, 59 years old, BMI 33, VAT from area L2 to L5 901 cm², sc 879 cm², liver fat 9.6%. D, Woman, 57 years old, BMI 34, VAT from area L2 to L5 712 cm², SAT 2158 cm², liver fat 5.1%.

Figure 5.

Insulin secretion and sensitivity in men and women with NGT, IGM (IGT and/or IFG), and overt T2DM relationships between insulin sensitivity, calculated as oral glucose insulin sensitivity (OGIS) (m⁻² mL/min) (367), and insulin secretion, as the AUC of insulin (min U/L), from oral glucose tolerance test (OGTT) data. Continuous lines represent the normal metabolic condition (NGT) in both nonobese and obese males and females, ie, for declining insulin sensitivity, there is an increase of insulin secretion to compensate for insulin resistance, maintaining NGT (200). The location of the various categories of subjects is positioned by the different symbols according to their combination of insulin sensitivity and secretion. In general, the “good” area is that above the curves for the nonobese subjects, whereas the “bad” one is below and especially in the low left corner characterized by low insulin sensitivity and inadequate secretion. Original data derived from different studies carried out by the authors (199, 200).