Christine Winzer

Early possible risk factors for overt diabetes after gestational diabetes mellitus.

OBJECTIVE: To assess a cluster of risk factors, including parameters of the metabolic syndrome, in women with gestational diabetes mellitus (GDM) early after delivery, that features the best prediction for developing diabetes. METHODS: Women with GDM 3–6 months after delivery received a complete metabolic characterization at baseline as well as annually for up to 10 years of follow-up (N=110). We used parameters characterizing the metabolic syndrome as well as demographic variables at baseline to predict diabetes manifestation. RESULTS: Metabolic disturbances and insulin treatment during pregnancy were significantly associated with overt diabetes. Waist circumference of 80 cm or higher failed to show a significant effect on later development of the disease; however, it was significant when 88 cm or more was used as a cutoff value. We identified impaired glucose tolerance (13 [56.5%]; hazard ratio 6.77, confidence interval [CI] 2.96–15.45, P<.001) as well as high-density lipoprotein (HDL) cholesterol less than 50 mg/dL (14 [60.9%]; hazard ratio 2.88, CI 1.24–6.67, P=.010) and age older than 35 years (12 [52.2%]; hazard ratio 3.06, CI 1.32–7.12, P=.006) as the best predictors with additive effects. Women with at least two risk factors had a higher risk to develop the disease as compared with those women who showed only one risk factor (hazard ratio 3.2, CI 1.4–7.7, P=.008). CONCLUSION: Impaired glucose tolerance, HDL cholesterol less than 50 mg/dL, and age older than 35 years were identified as the best predictors of developing diabetes after GDM. LEVEL OF EVIDENCE: II

Body and liver fat mass rather than muscle mitochondrial function determine glucose metabolism in women with a history of gestational diabetes mellitus.

OBJECTIVE Ectopic lipid storage in muscle (intramyocellular lipids [IMCL]) and liver (hepatocellular lipids [HCL]) coexists with impaired myocellular flux through ATP synthase (fATPase) in certain cohorts with increased risk of type 2 diabetes. Because women with a history of gestational diabetes mellitus (pGDM) have elevated ectopic lipids and diabetes risk, we tested whether deteriorated energy metabolism contributes to these abnormalities. RESEARCH DESIGN AND METHODS A total of 23 glucose-tolerant nonobese pGDM and eight women with normal glucose metabolism during pregnancy with similar age, body mass, and physical activity underwent oral glucose tolerance tests (OGTT) and intravenous glucose tolerance tests at 4–5 years after delivery. OGTT values <463 mL ⋅ min−1 ⋅ m−2 were considered to indicate insulin resistance. pGDM were further stratified into insulin-resistant (pGDM-IR) and insulin-sensitive (pGDM-IS) groups. IMCL, HCL, and fATPase were measured with 1H/31P magnetic resonance spectroscopy. RESULTS pGDM had 36% higher fat mass and 12% lower insulin sensitivity. Log-transformed fATPase was lower in pGDM (10.6 ± 3.8 µmol ⋅ mL muscle−1 ⋅ min−1 vs. 12.1 ± 1.4 µmol ⋅ mL muscle−1 ⋅ min−1, P < 0.03) and related to plasma adiponectin after adjustment for body fat (r = 0.44, P < 0.04). IMCL were 61% and 69% higher in pGDM-IR (P < 0.05 vs. pGDM-IS) and insulin resistant women (P < 0.003 vs. insulin sensitive), respectively. HCL were doubled (P < 0.05) in pGDM and insulin resistant women, and correlated positively with body fat mass (r = 0.50, P < 0.01) and inversely with insulin sensitivity (r = −0.46, P < 0.05). CONCLUSIONS Glucose-tolerant pGDM show increased liver fat but only slightly lower muscular insulin sensitivity and ATP synthesis. This suggests that alteration of hepatic lipid storage represents an early and predominant abnormality in this cohort.

Fibrinolytic dysfunction in insulin-resistant women with previous gestational diabetes

Background  Women with a history of gestational diabetes (p‐GDM) are at increased risk of developing type 2 diabetes mellitus (DM2) later in life, and therefore at increased risk for future cardiovascular disease.

Impaired β‐cell function in lean normotolerant former gestational diabetic women

Background  Former gestational diabetes (fGDM) constitutes a risk condition for the development of Type 2 diabetes. Former gestational diabetes is often characterized by obesity and hyperglycaemia, which may be concomitant and independent risk factors.

Elevated concentrations of asymmetric dimethylarginine are associated with deterioration of glucose tolerance in women with previous gestational diabetes mellitus.

Objective.  Women with previous gestational diabetes mellitus (GDM) have a high risk for development of type 2 diabetes mellitus. The endogenous nitric oxide synthase inhibitor asymmetric dimethylarginine (ADMA) could be related to disorders of the glucose metabolism. To evaluate if ADMA predicts deterioration of glucose tolerance in women with previous GDM and to assess concentration changes we analysed ADMA in women with previous GDM after delivery and after a median follow‐up of 2.75 years (interquartile range: 1.47–4.60).

Glucose Absorption in Gestational Diabetes Mellitus During an Oral Glucose Tolerance Test

OBJECTIVE Women with gestational diabetes mellitus (GDM) show reduced insulin sensitivity and markedly elevated glucose excursions. After delivery, GDM mostly reverts to normal glucose tolerance (NGT), although leaving an increased risk of type 2 diabetes. Because gastrointestinal function changes during pregnancy causing vomiting, constipation, or reduced motility, we thought that gut glucose absorption in GDM or pregnancy might be altered to affect circulating glucose excursions. RESEARCH DESIGN AND METHODS By undergoing 180-min oral glucose tolerance tests (OGTTs), pregnant women with GDM (GDMpreg; n = 15, BMI = 32 ± 2 kg/m2, aged 33 ± 1 years) were compared with NGT women (NGTpreg; n = 7, BMI = 28 ± 1 kg/m2, aged 34 ± 2 years), matching for major anthropometric characteristics (each P > 0.2). After delivery (6–7 months later), both groups were studied the same way. We computed and mathematically modeled gut glucose absorption from insulin-mediated glucose disappearance and endogenous glucose production (EGP). Whole-body insulin sensitivity was calculated using the Clamp-like Index. RESULTS GDMpreg showed 16–25% higher plasma glucose concentrations (P < 0.04) during the final 2 h of OGTT, similar EGP, but lower (P < 0.01) insulin sensitivity (2.7 ± 0.2 mg · kg−1 · min−1 vs. NGTpreg: 4.5 ± 0.8 mg · kg−1 · min−1). In GDMpreg, gut glucose absorption rates were ≤52% lower from 30 to 120 min (P < 0.03 vs. conditions after delivery or NGTpreg). In contrast, glucose absorption rates in NGTpreg were comparable during and after pregnancy. None of the studied women developed diabetes after delivery. CONCLUSIONS In GDMpreg, OGTT gut glucose absorption is markedly lower during hyperglycemia, whereas both glycemia and glucose absorption in NGTpreg are comparable between pregnant and postpartum states. Thus, hyperglycemia in GDM does not seem to result from too rapid or increased glucose absorption.

Impaired vascular nitric oxide bioactivity in women with previous gestational diabetes

ZusammenfassungHINTERGRUND: Eine Dysfunktion des Gefäß-Endothels, die vaskulären Erkrankungen und Typ 2 Diabetes vorausgehen kann, zeigt sich bei Patientinnen nach Gestationsdiabetes. Es ist allerdings nicht geklärt ob Adipositas, asymetrisches Dimethylarginin (ADMA), ein endogener Stickstoffmonoxid (NO) Synthese Inhibitor oder Insulin-Resistenz die beobachteten Gefäß-Veränderungen bei diesen Patientinnen zusätzlich verstärken. Ziel dieser Studie war es daher, Faktoren zu finden, die die Gefäß-Dysfunktion zusätzlich zum Gestationsdiabetes beeinträchtigen. METHODEN: 7 übergewichtige und 5 normalgewichtigen Patientinnen nach Gestationsdiabetes wurden in diese Studie eingeschlossen. Die Gefäß-Funktion wurde durch Änderungen des Unterarm-Blutflusses auf den Endothel-abhängigen Vasodilatator Acetylcholin (ACh), den Endothel-unabhängigen Vasodilatator Nitroglycerin (GTN), den Vasokonstriktor Norepinephrin (NE) und den NO-Synthase Inhibitor N(G)-monomethyl-L-arginine (L-NMMA) gemessen. ADMA wurde aus venösen Blutproben bestimmt und die Insulin-Resistenz wurde mittels eines modifizierten intravenösen Glukose-Toleranz Tests abgeschätzt. 20 gesunde, männliche Probanden dienten als historische Kontroll-Gruppe. RESULTATE: Verglichen mit Normalgewichtigen war die Reaktion des Unterarm-Blutflusses auf ACh bei übergewichtigen Frauen gestört (p < 0.05); ebenso war die Antwort auf den Vasokonstriktor NE tendenziell bei dieser Gruppe verringert. Weiters gab es signifikante Korrelationen zwischen der vaskulären Antwort auf ACh beziehungsweise L-NMMA und Body Mass Index, Serum ADMA Konzentrationen und stimulierten Glukose Werten (alle p < 0.05). Normalgewichtigen Patientinnen hatten mit der gesunden Kontrollgruppe vergleichbares Ansprechen auf ACh und ADMA Konzentrationen. SCHLUSSFOLGERUNG: Faktoren wie Übergewicht, erhöhte ADMA Werte und Insulin-Resistenz dürften starken Einfluss auf die Endotheliale Dysfunktion bei Patientinnen nach Gestationsdiabetes haben.SummaryBACKGROUND: Dysfunction of the vascular endothelium, preceding vascular morbidity and type 2 diabetes, is present in women with previous gestational diabetes (GDM). However, it is unknown whether excess weight, insulin resistance, and asymmetric dimethylarginine (ADMA) – an endogenous nitric oxide (NO) synthase inhibitor – also contribute to the vascular changes observed in these patients. The aim of this study was therefore to identify factors other than GDM that impair vascular function. METHODS: Seven overweight and five non-overweight women with previous GDM were included in this study. Vascular function was assessed from forearm blood-flow responses to the endothelium-dependent vasodilator acetylcholine (ACh), the endothelium-independent vasodilator glyceryltrinitrate, the vasoconstrictor norepinephrine and the NO synthase inhibitor N(G)-monomethyl-L-arginine (L-NMMA). ADMA was measured in venous blood, and insulin resistance was estimated from a modified intravenous glucose tolerance test. Twenty healthy male volunteers served as a historical control group. RESULTS: Vasodilation of forearm resistance vessels in response to ACh was impaired in overweight women when compared with non-overweight women (P < 0.05); similarly, vasoconstrictor reactivity tended to be smaller in the overweight group. In addition, there was a significant relationship between vascular responsiveness to ACh and L-NMMA, body-mass index, serum ADMA concentrations and stimulated glucose levels (all P < 0.05). ACh responses and ADMA levels in non-overweight women were similar to those of healthy controls. CONCLUSION: Factors such as obesity, increased ADMA levels and insulin resistance appear to be strong contributors to endothelial dysfunction observed in women with GDM.

Insulin sensitivity during oral glucose tolerance test and its relations to parameters of glucose metabolism and endothelial function in type 2 diabetic subjects under metformin and thiazolidinedione.

Aim:  This study was designed to assess the usefulness of a model‐based index of insulin sensitivity during an oral glucose tolerance test (OGTT) in the identification of possible changes in this metabolic parameter produced by pharmacological agents known to be potent insulin sensitizers, that is metformin (M) and thiazolidinedione (T). The association of these agents with several other factors related to glucose metabolism was also investigated, as well as the relation of insulin sensitivity and secretion with markers of endothelial function such as different adhesion molecules (cAMs), that is vascular cell adhesion molecule‐1, intercellular adhesion molecule‐1 and E‐Selectin.

The impact of recurrent gestational diabetes on maternal metabolic and cardiovascular risk factors

The development of overt diabetes in women with prior gestational diabetes mellitus (priorGDM) has been linked to several risk factors including age, obesity and insulin therapy during pregnancy; the role of recurrent GDM as a further risk factor remains unclear. As studies examining detailed metabolic consequences of recurrent GDM are missing and the role of recurrent GDM on cardiovascular risk is unknown, our aim was to investigate the impact of recurrent GDM (within 5 years after an index pregnancy) on metabolic and cardiovascular parameters.

Hidden metabolic disturbances in women with normal glucose tolerance five years after gestational diabetes.

Background. The study aimed to assess whether women with prior gestational diabetes (pGDM), despite maintenance of normal glucose tolerance (NGT) five years after delivery, display metabolic disturbances compared to healthy controls. Methods. 45 pGDM with NGT were compared to 18 women without a history of GDM (CON), matched for age (37.0 ± 4.1 versus 35.2 ± 5.3, P = ns) and BMI (24.3 ± 3.1 versus 23.3 ± 3.3, P = ns). Metabolic parameters were derived from oral and intravenous glucose tolerance tests; furthermore lipid profile, C-reactive protein (CRP), adiponectin, leptin, and glucagon were assessed. Results. Five years postpartum, pGDM had increased glucose concentrations during the OGTT (AUC: 1.12 ± 0.15 versus 1.0 ± 0.12 mol/L ∗ min, P = 0.003) and insulin sensitivity was decreased compared to CON (OGIS: 467.2 ± 64.1 versus 510.6 ± 53.1 mL/min ∗ m2, P = 0.01). pGDM had lower adiponectin (8.1 ± 2.6 versus 12.6 ± 5.3, P < 0.008) but increased waist circumference and CRP compared to CON. Conclusions. Despite diagnosis of normal glucose tolerance, pGDM are characterized by hyperglycemia and insulin resistance compared to healthy controls, accompanied by decreased adiponectin and increased CRP concentrations, thus linking metabolic disturbances to an increased cardiovascular risk in pGDM.