Metformin in gestational diabetes mellitus

METFORMIININ KÄYTTÖ RASKAUSDIABETEKSESSA Raskausdiabeteksella tarkoitetaan sokeriaineenvaihdunnan häiriötä, joka todetaan ensimmäisen kerran raskauden aikana. Hoidolla voidaan vähentää raskausdiabetekseen liittyviä äidin ja vastasyntyneen haittoja. Lääkitystä tarvitaan, jos ruokavaliohoidolla ei saavuteta hyvää sokeritasapainoa. Perinteisesti lääkityksenä on käytetty insuliinia, mutta metformii¬nin käyttöä insuliinin vaihtoehtona on ehdotettu. Metformiini läpäisee istukan, mutta sen läpäisymekanismi ei ole selvillä. Tämän tutkimuskokonaisuuden pääasiallisin tarkoitus oli verrata metformiinin tehokkuutta ja turvallisuutta insuliiniin raskausdiabeteksen hoidossa selvittämällä lääkkeen vaiku¬tusta äitiin ja vastasyntyneeseen. Lisäksi haluttiin tutkia, mitkä tekijät ennustavat insulii¬nin tarvetta metformiinin lisänä, jotta saavutettaisiin hyvä sokeritasapaino. Metformiinin annoksen vaikutus äitiin ja vastasyntyneeseen arvioitiin mittaamalla metformiinin pitoisuus äidistä, ja sikiön puolelta napanuoran veressä. Tässä tutkimuksessa selvitettiin myös aktiivisen kuljetusproteiinin (OCT) merkitystä metformiinin kulkeutumiseen istukan läpi perfusiomalla istukkaa ex vivo . Ex vivo istukkaperfuusiotutkimuksen tulokset viittasivat siihen, että OCT-kuljetusproteiinilla ei ollut todennäköisesti merkittävää osuutta metformiinin kulkeutumisessa istukan läpi. Metformiinin pitoisuusmittaukset synnytyksen yhteydessä osoittivat metformiinin siirtyvän sikiöön istukan läpi suuressa määrin (96 %) kertymättä kuitenkaan sikiön verenkiertoon. Metformiinin pitoisuudella ei ollut vaikutusta vastasyntyneen hyvinvointiin. Maksi¬maalisella metformiinin annostuksella ja korkealla metformiinipitoisuudella todettiin olevan suotuisa vaikutus äidin painon nousuun raskauden aikana. Insuliiniin verrattuna metformiini ei lisännyt äidin, sikiön tai vastasyntyneen haittatapahtumia, eikä sillä ollut vaikutusta synnytystapaan. Sokeritasapaino insuliini- ja metformiinilääkityksen aikana oli yhtäläinen arvioitaessa sitä HbA1c- ja fruktosamiinimittauksilla, mutta 21 % metformiinin käyttäjistä tarvitsi lisäksi insuliinia hyvän sokeritasapainon saavuttamiseksi. Tutkimuksesssa todettiin, että mitä iäkkäämpi äiti oli, mitä varhaisemmassa raskauden vaiheessa sokerirasitus oli tehty ja lääkitys aloitettu, ja mitä korkeammat HbA1c ja fruktosamiinipitoisuudet olivat, sitä suuremmalla todennäköisyydellä metformiinin lisänä tarvittiin insuliinia.Gestational diabetes mellitus (GDM) is a state of impaired glucose tolerance with onset or first recognized during pregnancy. Treatment of GDM is important, since adequate treatment reduces maternal and neonatal adverse effects. GDM is associated with an elevated risk of maternal blood pressure problems during pregnancy, cesarean deliveries and it raises the risk of type 2 diabetes later in life. The fetus has an increased risk of macrosomia, delivery complications and neonatal hypoglycemia. Medication is needed if adequate glycemic control is not achieved by diet. Insulin is the traditional medication for GDM but metformin as an oral drug has been suggested to be an alternative. Metformin crosses the placenta, but the transfer mechanism is not clear. The main aim of this study was to compare the efficacy and safety of metformin and insulin in the treatment of GDM patients by evaluating the influence of medication on maternal and fetal outcomes in a retrospective and a randomized controlled trial (RCT). Predictors of the need for additional insulin with metformin to meet good glycemic control were evaluated. The impact of metformin exposure on maternal and fetal outcomes was studied by assessment of metformin concentrations in maternal serum and umbilical cord serum. The mechanism of metformin placental transfer and the role of active organic cationic transporters (OCT) in metformin transfer were studied by ex vivo placental perfusion. Measurements of metformin concentrations at birth indicated that there is a high degree of placental transfer of metformin from the mother to the fetus (96%). Metformin does not seem to accumulate in the fetus. The ex vivo placental perfusion study indicated that OCTs may not have a significant role on the placental transfer of metformin. Metformin concentration levels were not related to fetal outcome. Higher metformin concentrations and a maximum clinical dose of metformin had a favorable effect on retarding maternal weight gain during pregnancy. Compared to insulin, metformin did not increase the maternal, fetal or neonatal risks of adverse events, and the delivery modes were unaffected. Glycemic control evaluated by HbA1c and serum fructosamine levels was similar during metformin and insulin therapies. However, 21% of the metformin-treated patients needed additional insulin to obtain good glycemic control. High maternal age, performing the oral glucose tolerance test and initiation of medication early during pregnancy and high HbA1c and fructosamine values are associated with a need of additional insulin.Siirretty Doriast

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.Peer reviewe

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

Abstract 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

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

AimsTo 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).MethodsThis 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.ResultsTotal 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 ConclusionCompared 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.</p

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

AbstractIntroductionRecent 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 methodsCord 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).ResultsCord serum alanine was elevated in the metformin group (0.53 mmol/L) compared with the insulin (0.45 mmol/L, pConclusionsMetformin 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.</p

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 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.</p

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 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.</div

Dietary quality influences body composition in overweight and obese pregnant women

BACKGROUND & AIMS: Excessive adiposity and gestational weight gain (GWG) have been linked with maternal and offspring morbidity. We investigated the relation of maternal diet, physical activity and GWG on body composition in overweight and obese pregnant women.METHODS: Fat mass (FM) and fat free mass (FFM) of 110 overweight and obese pregnant women were measured by air displacement plethysmography in early and late pregnancy (mean 13.5 and 35.3 gestational weeks). At the same time points, the quality of overall diet was assessed by validated index of diet quality (IDQ) questionnaire (score < 10/15 denotes poor dietary quality and score ≥ 10/15 denotes good dietary quality), nutrient intakes by 3-day food diaries, and physical activity by questionnaire. Weight gain between early and late pregnancy was compared to the gestational weight gain guidelines issued by Institute of Medicine.RESULTS: Of the women, 77% gained more weight than recommended; this was related to greater dietary fat consumption (80 ± 21 g/day vs. 67 ± 11 g/day, p = 0.010) and greater increase in FM (2.7 ± 3.0 kg vs. -1.0 ± 2.4 kg, p < 0.001) compared to women with ideal GWG. Dietary protein intake (g) correlated positively with FFM at both time points (early pregnancy: r = 0.31, p < 0.002, late pregnancy: r = 0.39, p < 0.001). Women with higher dietary quality index score had more FFM, compared to women with lower dietary quality (early pregnancy FFM: 48.8 ± 5.8 kg vs. 45.8 ± 4.7 kg, p = 0.004, late pregnancy FFM: 56.1 ± 6.4 kg vs. 53.4 ± 5.6 kg, p = 0.025). No correlations were detected between total energy intake or physical activity and FM or FFM at early or late pregnancy.CONCLUSIONS: Body composition changes from early to late pregnancy were related to the amount of weight gained and overall dietary quality during pregnancy. Higher dietary quality and protein intake were associated with greater FFM, while dietary fat intake was related to excess weight gain. Identification of these dietary determinants of body composition and weight offers new targets for dietary counseling of pregnant women and thus potential for ensuing health benefits through reduced adiposity.</p

Body composition measurement by air displacement plethysmography in pregnancy: Comparison of predicted versus measured thoracic gas volume

ObjectivesBody composition measurements with air displacement plethysmography (ADP) define body volume, which must be corrected for thoracic gas volume (TGV). We hypothesized that physiologic changes owing to pregnancy could affect the accuracy of predicted TGV and introduce errors into body composition measurements.MethodsWe investigated the effect of measuring versus predicting TGV on the accuracy of body composition calculations measured with ADP in overweight and obese pregnant women. The fat and fat-free masses of 110 women were determined with ADP with predicted and measured TGV.ResultsMeasured TGV decreased from early to late pregnancy (P = 0.0002). Compared with measured TGV, predicted TGV was 6.3% higher during early gestation and 12.6% higher during late gestation (both P ≤ 0.001). The use of predicted instead of measured TGV in body composition calculations resulted in an overestimation of fat mass by 0.8% during the early stage, and 2.6% during the late stage of pregnancy (both P ≤ 0.001).ConclusionsMeasuring TGV increases the accuracy of body composition measurement by ADP in overweight and obese women, particularly during the late stage of pregnancy.</div

A healthy dietary pattern with a low inflammatory potential reduces the risk of gestational diabetes mellitus

Purpose An optimal diet for lowering the risk of gestational diabetes mellitus (GDM) is still to be defined, but may comprise of nutrient intakes, dietary patterns, diet quality, and eating frequency. This study was designed to investigate the contribution of diet in developing GDM in a comprehensive way. Methods The dietary intake of overweight or obese women, a risk group for GDM (n = 351), was assessed using 3-day food diaries and diet quality questionnaires in early pregnancy. Eating frequency and nutrient intakes were calculated, and dietary patterns identified using principal component analysis. The inflammatory potential of the diet was determined by calculating the dietary inflammatory index (DII(R)) and energy-adjusted DII (E-DII (TM)). GDM was diagnosed with an oral glucose tolerance test at 24-28 gestational weeks. Results Higher adherence to 'healthier dietary pattern' characterized by consumptions of vegetables and rye bread associated with a reduced risk of GDM (adjusted OR 0.27, 95% CI 0.11-0.70). Higher E-DII score, indicating pro-inflammatory diet, was associated with a 27% higher risk of GDM (adjusted OR 1.27; 95% CI 1.08-1.49) for each E-DII point. In the evaluation of nutrient intakes, total fat, saturated fatty acids (SFAs), and trans fatty acids were higher and fiber lower in women developing GDM compared to women not developing GDM (all p < 0.05). Intakes of total fat, SFAs, and trans fatty acids were also significant predictors for GDM (all p < 0.05). Conclusions The results emphasize the importance of an overall healthy diet and limitation of foods with SFAs, and other nutrients with a high inflammatory potential in reducing the risk of GDM.Peer reviewe