BackgroundWomen with type 2 diabetes (T2D) are less likely to reach the goals for hemoglobin A1c compared with men, and have higher all-cause mortality. The risk of cardiovascular disease is elevated among both men and women with T2D, however, the risk has declined among men over recent years while it remains stationary in women. Reasons for these sex differences remain unclear, and guidelines for diabetes treatment do not differentiate between sexes. Possible causes for varying outcome include differences in physiology, treatment response, and psychological factors. This review briefly outlines sex differences in hormonal pathophysiology, and thereafter summarizes the literature to date on sex differences in disease course and outcome.MethodsSystematic searches were performed on PubMed using “sex”, “gender”, and various glucose-lowering therapies as keywords. Earlier reviews are summarized and results from individual studies are reported. Reference lists from studies were used to augment the search.ResultsThere is an increased risk of missing the diagnosis of T2D when screening women with only fasting plasma glucose instead of with an oral glucose tolerance test. The impact of various risk factors for complications may differ by sex. Efficacy and side effects of some glucose-lowering drugs differ between men and women. Men with T2D appear to suffer more microvascular complications, while women have higher morbidity and mortality in cardiovascular disease and also fare worse psychologically.ConclusionFew studies to date have focused on sex differences in T2D. Several questions demand further study, such as whether risk factors and treatment guidelines should be sex-specific. There is a need for clinical trials designed specifically to evaluate sex differences in efficacy and outcome of the available treatments.

The efficacy of low-dose aspirin in type 2 diabetes mellitus (T2DM) has been questioned. We tested if twice daily dosing of aspirin would be more effective in T2DM, possibly due to increased platelet turnover. A randomised cross-over study compared 75 mg aspirin OD, 75 mg BID and 320 mg OD (≥ 2 week treatment periods) in 25 patients with T2DM and micro- or macrovascular complications. Platelet responses were examined by impedance aggregometry (WBA) and the IMPACT-R aspirin test in whole blood, light transmittance aggregometry in platelet-rich plasma (LTA), and urinary 11-dehydro-thromboxane B2 (TxM). Aspirin 75 mg BID decreased arachidonic acid (AA)-induced WBA compared to 75 mg OD (9.7 ± 4.5 vs. 12.6 ± 3.5 ohm; p = 0.003) or to 320 mg OD (11.5 ± 4.2 Ohms; p = 0.049). WBA responses to collagen were similarly attenuated by BID or high dosing (by 12-14%; p = 0.02 for both). The IMPACT-R showed a better response to 75 mg BID compared to 75 mg OD (p = 0.049), but not to 320 mg OD. AA-induced aggregation by LTA was <6.5% on all occasions, with no differences between aspirin dosages. TxM was reduced after 320 mg OD (p = 0.002), but not 75 mg BID (p = 0.07). Reticulated platelets were highly correlated with mean platelet volume (MPV; r2 = 0.74, p<0.0001). Both markers for platelet turnover were correlated with AA-induced WBA, but neither identified patients who benefited from BID dosing dependably. In conclusion, twice daily dosing improved laboratory responses to aspirin in high risk T2DM patients. Studies of whether BID dosing of aspirin can improve clinical outcomes in such patients are of interest.

Excess cortisol and GH induce insulin resistance, a central feature of type 2 diabetes (T2D). To study whether the insulin sensitizer pioglitazone affects basal cortisol levels and the GH-IGF-I axis in patients with T2D. Forty-eight patients with T2D (men/women = 28:20, age 61 ± 1 years, BMI 31 ± 0.6 kg/m(2)) were treated for 26 weeks with pioglitazone 30-45 mg daily in addition to their preexisting therapy. Insulin, proinsulin, HbA(1c), IGF-I, IGFBP-1, and basal cortisol were analyzed before and after treatment. Pioglitazone decreased proinsulin/insulin ratio and HbA(1c) decreased (HbA(1c) from 7.8 ± 0.2 to 6.6 ± 0.2% in men and from 7.6 ± 0.2 to 6.1 ± 0.2% in women, p < 0.001 in both). There was a redistribution of fat but no change in waist circumference. IGF-I and adiponectin increased (p ≤ 0.001) in both genders. IGFBP-1 increased but significantly only for the whole group (p = 0.033). Triglycerides decreased significantly in women only (p = 0.015). Before treatment, women had lower basal cortisol (p = 0.045). Basal cortisol increased in women (from 390 ± 26 to 484 ± 32 nmol/L, p = 0.020) but not in men and did not differ between genders at week 26. ΔIGFBP-1 correlated with Δcortisol (r = 0.458; p = 0.049) and Δadiponectin (r = 0.600; p = 0.005) in women only. In addition to the known effect of improving insulin sensitivity, pioglitazone increased IGF-I regardless of gender and in women also increased basal cortisol. Increased IGF-I may contribute to improved insulin sensitivity after treatment. There seems to be gender differences in treatment responses to pioglitazone on lipid metabolism and basal cortisol, perhaps correcting different mechanisms of insulin resistance between genders.

Sitagliptin therapy does not appear to be related to activation of the arginine vasopressin system.