We found that β-cell function is already impaired in women with recent GDM, a young at-risk cohort for T2D. In addition, our data suggest that fetuin-A and leptin signaling may be important early contributors to the pathogenesis of T2D, at this disease stage equally or more relevant than ectopic lipids and low-grade inflammation.

Aims/HypothesisLow physical fitness (PF) is a risk factor for type 2 diabetes mellitus (T2D). Women with a history of gestational diabetes (GDM) are at risk for T2D at a young age, but the role of PF in this population is not clear. PF has also been found to correlate inversely with plasma leptin in previous studies. Here, we examine whether women who had GDM have lower PF than women after a normoglycemic pregnancy and, second, whether PF is associated with plasma leptin, independently of body fat mass.MethodsCross-sectional analysis of 236 participants in the PPSDiab Study (cohort study of women 3–16 months after delivery, 152 after gestational diabetes (pGDM), 84 after normoglycemic pregnancy (control subjects); consecutively recruited 2011–16); medical history, physical examination with bioelectrical impedance analysis (BIA), whole body magnetic resonance imaging (MRI) (n = 154), 5-point oral glucose tolerance test, cardiopulmonary exercise testing, clinical chemistry including fasting plasma leptin; statistical analysis with Mann–Whitney U and t -test, Spearman correlation coefficient, multiple linear regression.ResultsWomen pGDM had lower maximally achieved oxygen uptake (VO2peak/kg: 25.7(21.3–29.9) vs. 30.0(26.6–34.1)ml/min/kg; total VO2peak: 1733(1552–2005) vs. 1970(1767–2238)ml/min; p<0.0001 for both), and maximum workload (122.5(105.5–136.5) vs. 141.0(128.5–159.5)W; p<0.0001). Fasting plasma leptin correlated inversely with PF (VO2peak/kg ρ = -0.72 p<0.0001; VO2peak ρ = -0.16 p = 0.015; max. load ρ = -0.35 p<0.0001). These associations remained significant with adjustment for body mass index, or for body fat mass (BIA and MRI).Conclusions/InterpretationWomen with a recent history of GDM were less fit than control subjects. Low PF may therefore contribute to the risk for T2D after GDM. This should be tested in intervention studies. Low PF also associated with increased leptin levels–independently of body fat. PF may therefore influence leptin levels and signaling. This hypothesis requires further investigation.

Background Familial partial lipodystrophies are rare monogenic disorders that are often associated with diabetes. In such cases, it can be difficult to achieve glycaemic control.Case report We report a 34-year old woman with familial partial lipodystrophy type 2 (Dunnigan) and diabetes; her hyperglycaemia persisted despite metformin treatment. A combined intravenous glucose tolerance-euglycaemic clamp test showed severe insulin resistance, as expected, but also showed strongly diminished first-phase insulin secretion. After the latter finding, we added the glucagon-like peptide-1 receptor agonist liraglutide to the patient's treatment regimen, which rapidly normalized plasma glucose levels. HbA 1c values <42 mmol/mol (6.0%) have now been maintained for over 4 years.Conclusion This case suggests that a glucagon-like peptide-1 receptor agonist may be a useful component of glucoselowering therapy in individuals with familial partial lipodystrophy and diabetes mellitus.