Gender differences in non-glycemic responses to improved insulin sensitivity by pioglitazone treatment in patients with type 2 diabetes

Abstract

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.

Sex differences in type 2 diabetes: focus on disease course and outcomes

“…Hypoglycemia98 and fractures68 are more common in women than men on TZDs. We have found pioglitazone to increase basal serum cortisol in women but not in men, although the clinical significance of this is unclear 99. Women treated with rosiglitazone had higher mortality than men, while no differences were seen for other treatments eg, metformin 100…”

40 YEARS OF IGF1: Role of IGF-binding proteins in regulating IGF responses to changes in metabolism

“…showed that pioglitazone improves insulin sensitivity by inhibiting IGFBP1 synthesis thereby increasing free IGF1 and the change in IGFBP1 in subjects with established type II diabetes begun on pioglitazone correlates with a change in adiponectin (Arnetz et al 2014). IGFBP1 was shown to increase beta cell regeneration by promoting alpha to beta cell transdifferentiation in mouse and human islets (Lu et al 2016).…”

Gender differences in the efficacy of pioglitazone treatment in nonalcoholic fatty liver disease patients with abnormal glucose metabolism

“…A Diabetes Outcome Progression Trial (ADOPT) and Rosiglitazone Evaluated for Cardiovascular Outcomes and Regulation of Glycemia in Diabetes (RECORD) reported that obese females had a greater HbA1c reduction with TZDs than that with sulfonylureas (p < 0.001) [29] . Additionally, triglycerides decreased signi cantly in women but not in men with pioglitazone treatment (p = 0.015) [30] . Our previous study showed that after pioglitazone treatment, women experienced a greater drop in blood glucose and insulin (Supplemental data 1).…”