Insulin reverts macrosomia in a mouse model of gestational diabetes

Abstract

Background and aims: SOCS2 (Suppressor of Cytokine Signaling 2) protein modulates cytokine-mediated metabolism of lipids, carbohydrates and growth. SOCS2 ablation in mice (Socs2-/-) generates gigantism, insulin-resistance and spontaneous gestational diabetes (GDM) with macrosomia. As both conditions in Socs2-/- show high maternal (88%) and neonatal mortality rates, we aimed to evaluate the effect of insulin treatment on macrosomia. Materials and methods: Fasting glycemia was measured (Glucomen Aero, Menarini) at every gestational third (7, 14 and 18 days (d)) in 8 Socs2-/- and 8 C57BI/6J control pregnant females (age: 210 ± 11 days). In addition, 8 Socs2-/- mothers received insulin (Socs2-/-- ins) (0.5 U/kg, Glargine) from day 10 once daily, during pregnancy. All females were followed and offspring, if born, were evaluated for macrosomia (39 Socs2-/- postmortem-neonates, vs 41 C57-neonates vs 44-neonates from Socs2-/--ins). Macrosomia was previously defined as > 1.43 g birth weight. Besides, glucose metabolism was characterised in the offspring of Socs2-/--ins at 90 days, following an oral glucose tolerance test (OGTT) (2 g glucose/kg) and an intra-peritoneal insulin tolerance test (ITT) (0.5 U/Kg). Results were compared with previously obtained data from C57 and Socs2-/- females. Mann-Whitney’s U, Student’s and Chi2 test were used for comparisons. Results: Fasting glycemia during pregnancy tends to be higher in Socs2-/- (7d: 146 ± 17.6 ; 14d: 138.5 [131,5-145,5]; 18d: 114.8 ± 21.4mg/dL) than in C57 (7d: 133.9 ± 29.0; 14d: 113.6 ± 26.5; 18d: 109 [98-120] mg/dL) (p = 0.059). During treatment, mean glycemia of Socs2-/--ins was 135.6 ± 9.7 mg/dL. Neonates from Socs2-/- were heavier than neonates from Socs2-/--ins and C57 (1.5 ± 0.03 vs 1.2 ± 0.2 vs 1.3 ± 0.1 g, respectively) (p < 0.01) and the prevalence of macrosomia was higher too (61.1 % vs 2.8 % vs 2.4%, respectively) (p < 0.01). We previously described mild glucose intolerance in 90d Socs2-/- females compared to C57. At 90d Socs2-/--ins female offspring show a clear worsening of this impairment, with higher glucose values for each timepoint, glucose peak and AUC, compared to C57, but also to Socs2-/- (peak (mg/dL): 332 ± 33.1 vs 260.7 ± 27.8 vs 286.7 ± 33.5, respectively); AUC (a.u.): 265.1 ± 15.7 vs 201 ± 20.7 vs 223.81 [212,8-234,8], respectively) (p < 0.05). Further, insulin resistance was also observed following ITT, shown by higher AUC and 15 minutes glucose compared to C57 and Socs2-/- (AUC (a.u.): 112.8 ± 25.5 vs 89.7 ± 14.8 vs 85.7 ± 6.1, respectively; 15 min. glucose (mg/dL): 73 [31-115] vs 57.4 ± 7.6 vs 56.8 ± 6.2, respectively) (p < 0.05). Conclusion: Socs2-/- females develop gestational hyperglycemia compared to C57 controls. Insulin administration during pregnancy in Socs2-/- normalizes birth weight. However, the offspring of the treated females show enhanced hyperglycemia and insulin resistance, compared to controls and untreated Socs2-/-. The relationship of hyperglycemia with SOCS2 mechanisms in the development of GDM, the role of insulin treatment in the resolution of macrosomia but worsening glucose intolerance in the offspring, generates a paradox that needs to be further explored.