Comparison of glucose metabolism and anthropometry in women with previous gestational diabetes treated with metformin vs. insulin: 9-year follow-up of two randomized trials.

INTRODUCTION: The main aim was to study whether the long-term incidences of type 2 diabetes, pre-diabetes and metabolic syndrome differed between women who were treated with metformin or insulin for gestational diabetes. MATERIAL AND METHODS: This 9-year follow-up study of two open-label randomized trials compares metformin and insulin treatments of gestational diabetes. In all, 165 women, 88 previously treated with insulin and 77 treated with metformin in the index pregnancy, were included in the analyses. An oral glucose tolerance test was performed, and measures of anthropometry, glucose metabolism, serum lipids and inflammatory markers were compared between the treatment groups. Disorders of glucose metabolism (pre-diabetes and type 2 diabetes) at the 9-year follow-up was the primary outcome of this study. This study was registered at ClinicalTrials.gov: NCT02417090. RESULTS: The incidences of pre-diabetes and type 2 diabetes (40.3% vs. 46.6%, odds ratio [OR] 0.77, 95% CI 0.40-1.50, p = 0.51), type 2 diabetes (14.3% vs. 15.9%, OR 0.88, 95% CI 0.34-2.26, p = 0.94), pre-diabetes (26.0% vs. 30.7%, OR 0.79, 95% CI 0.38-1.65, p = 0.62), and metabolic syndrome (45.9% vs. 55.2%, OR 0.69, 95% CI 0.35-1.35, p = 0.31) were comparable between the metformin and insulin groups. Moreover, there were no evident differences in the individual measures of anthropometry, glucose metabolism including HOMA-insulin resistance, serum lipids or inflammatory markers between the two treatment groups. CONCLUSIONS: Treatment of gestational diabetes with metformin vs. insulin during pregnancy is unlikely to have diverging long-term effects on maternal anthropometry, glucose metabolism or serum lipids. From this perspective, both treatments may be considered in gestational diabetes.

Metformin and insulin treatment of gestational diabetes: effects on inflammatory markers and IGF-binding protein-1 - secondary analysis of a randomized controlled trial.

BACKGROUND: Gestational diabetes mellitus (GDM) is characterized by disturbed glucose metabolism and activation of low-grade inflammation. We studied whether metformin treatment has favorable or unfavorable effects on inflammatory markers and insulin-like growth factor-binding protein 1 (IGFBP-1) in GDM patients compared with insulin, and whether these markers associate with major maternal or fetal clinical outcomes. METHODS: This is a secondary analysis of a previous randomized controlled trial comparing metformin (n = 110) and insulin (n = 107) treatment of GDM. Fasting serum samples were collected at the time of diagnosis (baseline, mean 30 gestational weeks [gw]) and at 36 gw. Inflammatory markers serum high-sensitivity CRP (hsCRP), interleukin-6 (IL-6), matrix metalloproteinase-8 (MMP-8) and glycoprotein acetylation (GlycA) as well as three IGFBP-1 phosphoisoform concentrations were determined. RESULTS: In the metformin and insulin groups combined, hsCRP decreased (p = 0.01), whereas IL-6 (p = 0.002), GlycA (p < 0.0001) and all IGFBP-1 phosphoisoforms (p < 0.0001) increased from baseline to 36 gw. GlycA (p = 0.02) and non-phosphorylated IGFBP-1 (p = 0.008) increased more in patients treated with metformin than those treated with insulin. Inflammatory markers did not clearly associate with pregnancy outcomes but non-phosphorylated IGFBP-1 was inversely associated with gestational weight gain. CONCLUSIONS: Metformin had beneficial effects on maternal serum IGFBP-1 concentrations compared to insulin, as increased IGFBP-1 related to lower total and late pregnancy maternal weight gain. GlycA increased more during metformin treatment compared to insulin. The significance of this observation needs to be more profoundly examined in further studies. There were no evident clinically relevant relations between inflammatory markers and pregnancy outcome measures. TRIAL REGISTRATION: The trial comparing metformin and insulin treatment was registered in ClinicalTrials.gov ( NCT01240785 ) November 3, 2010. Retrospectively registered.

Insulin Resistance Is Associated with an Unfavorable Serum Lipoprotein Lipid Profile in Women with Newly Diagnosed Gestational Diabetes.

BACKGROUND: Gestational diabetes (GDM) is associated with various degrees of insulin resistance-a feature related to increased risk of adverse perinatal outcomes. We aimed to determine the previously poorly investigated associations between maternal insulin resistance and serum fasting metabolome at the time of GDM diagnosis. METHODS: Serum lipoprotein and amino acid profile was analyzed in 300 subjects with newly diagnosed GDM using a validated nuclear magnetic resonance spectroscopy protocol. Associations between insulin resistance (homeostasis model assessment of insulin resistance, HOMA2-IR) and serum metabolites were examined with linear regression. RESULTS: We found insulin resistance to be associated with a distinct lipid pattern: increased concentration of VLDL triglycerides and phospholipids and total triglycerides. VLDL size was positively related and LDL and HDL sizes were inversely related to insulin resistance. Of fatty acids, increased total fatty acids, relative increase in saturated and monounsaturated fatty acids, and relative decrease in polyunsaturated and omega fatty acids were related to maternal insulin resistance. CONCLUSIONS: In newly diagnosed GDM, the association between maternal insulin resistance and serum lipoprotein profile was largely as described in type 2 diabetes. Lifestyle interventions aiming to decrease insulin resistance from early pregnancy could benefit pregnancy outcomes via more advantageous lipid metabolism.

Prediction of pre-diabetes and type 2 diabetes nine years postpartum using serum metabolome in pregnant women with gestational diabetes requiring pharmacological treatment.

AIMS: We examined the association between serum metabolome in women with pharmacologically treated gestational diabetes (GDM) and measures of glucose metabolism 9 years postpartum. METHODS: Serum targeted metabolome, adiponectin, inflammatory markers, and insulin-like growth factor-binding protein-1 phosphoisoforms were analyzed at the time of diagnosing GDM. Glucose metabolism and insulin resistance were assessed at 9 years postpartum. Data from 119 subjects were available for analyses. Associations between baseline measures and future measures of glycemia were examined with univariate regressions and multivariate prediction models. This is a secondary analysis of a previous prospective trial (NCT02417090). RESULTS: Baseline serum markers were most strongly related to measures of insulin resistance at 9-years follow-up. In multivariate analyses combination of IDL cholesterol, early gestational weight gain and in oral glucose tolerance test fasting and 2-h glucose predicted development of disorders of glucose metabolism (pre-diabetes and/or type 2 diabetes) better than clinical predictors alone (ROC-AUC 0.75 vs. 0.65, p = 0.020). CONCLUSIONS: Serum metabolome in pregnancy in women with GDM is related to future glucose metabolism and insulin resistance. Compared to clinical variables alone metabolome might result in better prediction of future disorders of glucose metabolism and could facilitate personalized risk stratification for postpartum interventions and follow-up.

Cord serum metabolome and birth weight in patients with gestational diabetes treated with metformin, insulin, or diet alone.

INTRODUCTION: Recent research has demonstrated the benefits of metformin treatment in gestational diabetes (GDM) on short-term pregnancy outcomes (including excessive fetal growth and pre-eclampsia), but its effects on fetal metabolism remain mostly unknown. Our aim was to study the effects of metformin treatment compared with insulin or diet on the cord serum metabolome and also to assess how these metabolites are related to birth weight (BW) in pregnancies complicated by GDM. RESEARCH DESIGN AND METHODS: Cord serum samples were available from 113, 97, and 98 patients with GDM treated with diet, insulin, and metformin, respectively. A targeted metabolome was measured using nuclear magnetic resonance spectroscopy. The patients in the metformin and insulin groups had participated in a previous randomized trial (NCT01240785). RESULTS: Cord serum alanine was elevated in the metformin group (0.53 mmol/L) compared with the insulin (0.45 mmol/L, p<0.001) and the diet groups (0.46 mmol/L, p<0.0001). All other measured metabolites were similar between the groups. The triglyceride (TG)-to-phosphoglyceride ratio, average very low-density lipoprotein particle diameter, docosahexaenoic acid, omega-3 fatty acids (FAs), and ratios of omega-3 and monounsaturated FA to total FA were inversely related to BW. The omega-6-to-total-FA and omega-6-to-omega-3-FA ratios were positively related to BW. Cholesterol in very large and large high-density lipoprotein (HDL) was positively (p<0.01) associated with BW when adjusted for maternal prepregnancy body mass index, gestational weight gain, glycated hemoglobin, and mode of delivery. CONCLUSIONS: Metformin treatment in GDM leads to an increase in cord serum alanine. The possible long-term implications of elevated neonatal alanine in this context need to be evaluated in future studies. Although previous studies have shown that metformin increased maternal TG levels, the cord serum TG levels were not affected. Cord serum HDL cholesterol and several FA variables are related to the regulation of fetal growth in GDM. Moreover, these associations seem to be independent of maternal confounding factors. TRIAL REGISTRATION NUMBER: NCT01240785.

Serum lipids and their association with birth weight in metformin and insulin treated patients with gestational diabetes.

AIMS: To compare the effects of metformin and insulin treatment on maternal serum lipids in patients with gestational diabetes (GDM), and to analyse the associations between individual lipids and birth weight (BW). METHODS: This is a secondary analysis of a randomized trial comparing metformin (n = 110) and insulin (n = 107) treatment of GDM. Fasting serum lipidome was measured at baseline (the time of diagnosis, mean 30 gestational weeks, gw) and at 36 gw using nuclear magnetic resonance spectroscopy. RESULTS: Total and VLDL triglycerides, and VLDL cholesterol increased from baseline to 36 gw in both treatment groups. The rise in triglycerides was greater in the metformin treated patients (p < 0.01). Baseline total and VLDL triglycerides, VLDL cholesterol, and apolipoprotein B to A-1 ratio (apoB/apoA-1) associated positively with BW, more strongly in the metformin group. Among patients in the highest baseline VLDL cholesterol or apoB/apoA-1 quartile, those treated with insulin had lower BWs than those treated with metformin (p < 0.03). CONCLUSION: Compared to insulin, metformin treatment of GDM led to higher maternal serum concentrations of triglyceride-rich lipoproteins. Especially triglycerides and cholesterol in VLDL were positively associated with BW. Women with high VLDL cholesterol or high apoB/apoA-1 may benefit from insulin treatment over metformin with respect to offspring BW.

Amino acid profile in women with gestational diabetes mellitus treated with metformin or insulin.

AIMS: We compared the effects of metformin and insulin treatments of gestational diabetes mellitus (GDM) on amino acid metabolism. METHODS: 217 pregnant women diagnosed with GDM were randomized to receive either metformin or insulin. 1H nuclear magnetic spectroscopy was used to determine serum concentrations of alanine, glutamine, glycine, isoleucine, leucine, valine, histidine, phenylalanine, tyrosine, glucose and lactate at the time of diagnosis and at 36 gestational weeks (gw). RESULTS: Majority of the amino acid concentrations increased from 30 to 36 gw. The rise in alanine (16% vs. 8%, p < 0.0001), isoleucine (11% vs. 5%, p = 0.035) and lactate (29% vs. 14% p = 0.015) was larger in the metformin group compared to insulin group. Baseline alanine, glycine, isoleucine, leucine, valine and tyrosine were positively related to slightly earlier delivery. Alanine at 36 gw was positively associated with birth weight and glutamine with gestational hypertension or preeclampsia. Lactate at 36 gw was not associated with any adverse outcome. CONCLUSIONS: Compared to insulin metformin caused a greater increase in serum alanine, isoleucine and lactate concentrations. Although the observed differences in the metabolic variables were relatively small and not outright concerning, additional studies and follow-up data are required to ensure the safety of metformin use in pregnancy. The trial was registered in Clinicaltrials.gov, NCT01240785; http://clinicaltrials.gov/ct2/show/NCT01240785.