Alexandra Kautzky-Willer

Pronounced Insulin Resistance and Inadequate β-cell Secretion Characterize Lean Gestational Diabetes During and After Pregnancy

OBJECTIVE To evaluate β-cell secretion and glucose metabolism in lean subjects with gestational diabetes mellitus (GDM) compared with that in subjects with normal pregnancy and obesity. RESEARCH DESIGN AND METHODS Insulin secretion, insulin sensitivity (S1), and hepatic insulin extraction were assessed in pregnant women with GDM before and after delivery and in those with normal glucose tolerance (NGT) in comparison to healthy nonpregnant lean and obese women. Kinetic analysis of glucose, insulin, and C-peptide plasma concentrations during oral and intravenous glucose tolerance tests was performed by mathematical modeling. RESULTS S1 was blunted in pregnant women with GDM by 84% and in those with NGT by 66% compared with lean nonpregnant women (P < 0.005 vs. healthy nonpregnant lean control subjects; P < 0.05, GDM vs. pregnant women with NGT), whereas glucose effectiveness was decreased by 33% in both pregnant groups (P < 0.05 vs. healthy nonpregnant lean control subjects). Insulin secretion was 30% higher (P < 0.05) in subjects with GDM than in pregnant women with NGT or in nonpregnant lean women, but decreased (P < 0.005) when compared with obese women with a comparable degree of insulin resistance. Fractional hepatic insulin extraction was similar in both pregnant groups, being lower (P < 0.0001) by 30% versus nonpregnant females. β-cell sensitivity to glucose for insulin release was decreased in subjects with GDM versus pregnant women with NGT as well as nonpregnant women by 40-50% (P < 0.01). Twelve weeks after delivery, GDM returned to normal glucose tolerance, but S1 remained 50% lower than that in lean nonpregnant women, while β-cell sensitivity to glucose did not change (P < 0.01 vs. healthy nonpregnant lean control subjects). CONCLUSIONS Pregnancy is characterized by insulin resistance, diminished hepatic insulin extraction, and glucose effectiveness. Lean subjects with GDM are additionally characterized by having more pronounced insulin resistance and inadequate insulin secretion, which persist after delivery. Compared with other insulin-resistant prediabetic states like impaired glucose tolerance (IGT), defective insulin secretion seems to be a predominant defect in lean GDM subjects, indicating that it might represent a specific prediabetic condition.

Increased plasma leptin in gestational diabetes

Aims/hypothesis. Insulin resistance as well as marked changes in body weight and energy metabolism are associated with pregnancy. Its impact on plasma leptin is not known and was determined in this longitudinal study in both diabetic and normal pregnancy. Methods. At 28 gestational weeks plasma concentrations of leptin and B-cell hormones were measured at fasting and after an oral glucose load (OGTT:75 g) in women with gestational diabetes and pregnant women with normal glucose tolerance and compared with women who were not pregnant (C). Results. Plasma leptin (ng/ml) was higher (p < 0.001) in women with gestational diabetes (24.9 ± 1.6) than in women with normal glucose tolerance (18.2 ± 1.5) and increased in both groups when compared with the non-pregnant women (8.2 ± 1.3; p < 0.0005). No change in plasma leptin concentrations was induced by OGTT in any group. Basal insulin release was higher (p < 0.05) in women with gestational diabetes compared with the pregnant women with normal glucose tolerance. Marked insulin resistance was confirmed by a 20 % lower (p < 0.05) insulin sensitivity in subgroup analysis and a decrease of almost 40 % in fasting glucose/insulin ratio (p < 0.005) in women with gestational diabetes. Leptin correlated in women with gestational diabetes with basal plasma concentrations of glucose (p < 0.02), insulin (p < 0.004) and proinsulin (p < 0.01) as well as with BMI (p < 0.001) and overall pregnancy induced maternal weight gain (p < 0.009). With normalisation of blood glucose 8 weeks after delivery in women with gestational diabetes their plasma leptin decreased (p < 0.0005) to 17.3 ± 1.9 ng/ml but did not completely normalize (p < 0.05 vs non-pregnant women). Conclusion/interpretation. Our data show that women with gestational diabetes without any change in plasma leptin upon oral glucose loading have increased plasma leptin concentrations during and after pregnancy, a clear association of plasma leptin with the respective concentration of glucose and insulin resistance as well as with changes in body weight, and a failure to normalize spontaneously BMI to the same extent as pregnant women with normal glucose tolerance when compared with matched control subjects. [Diabetologia (2001) 44: 164–172]

Sex and Gender Differences in Risk, Pathophysiology and Complications of Type 2 Diabetes Mellitus

The steep rise of type 2 diabetes mellitus (T2DM) and associated complications go along with mounting evidence of clinically important sex and gender differences. T2DM is more frequently diagnosed at lower age and body mass index in men; however, the most prominent risk factor, which is obesity, is more common in women. Generally, large sex-ratio differences across countries are observed. Diversities in biology, culture, lifestyle, environment, and socioeconomic status impact differences between males and females in predisposition, development, and clinical presentation. Genetic effects and epigenetic mechanisms, nutritional factors and sedentary lifestyle affect risk and complications differently in both sexes. Furthermore, sex hormones have a great impact on energy metabolism, body composition, vascular function, and inflammatory responses. Thus, endocrine imbalances relate to unfavorable cardiometabolic traits, observable in women with androgen excess or men with hypogonadism. Both biological and psychosocial factors are responsible for sex and gender differences in diabetes risk and outcome. Overall, psychosocial stress appears to have greater impact on women rather than on men. In addition, women have greater increases of cardiovascular risk, myocardial infarction, and stroke mortality than men, compared with nondiabetic subjects. However, when dialysis therapy is initiated, mortality is comparable in both males and females. Diabetes appears to attenuate the protective effect of the female sex in the development of cardiac diseases and nephropathy. Endocrine and behavioral factors are involved in gender inequalities and affect the outcome. More research regarding sex-dimorphic pathophysiological mechanisms of T2DM and its complications could contribute to more personalized diabetes care in the future and would thus promote more awareness in terms of sex- and gender-specific risk factors.

Proceedings From an International Consensus Meeting on Posttransplantation Diabetes Mellitus: Recommendations and Future Directions

A consensus meeting was held in Vienna on September 8–9, 2013, to discuss diagnostic and therapeutic challenges surrounding development of diabetes mellitus after transplantation. The International Expert Panel comprised 24 transplant nephrologists, surgeons, diabetologists and clinical scientists, which met with the aim to review previous guidelines in light of emerging clinical data and research. Recommendations from the consensus discussions are provided in this article. Although the meeting was kidney‐centric, reflecting the expertise present, these recommendations are likely to be relevant to other solid organ transplant recipients. Our recommendations include: terminology revision from new‐onset diabetes after transplantation to posttransplantation diabetes mellitus (PTDM), exclusion of transient posttransplant hyperglycemia from PTDM diagnosis, expansion of screening strategies (incorporating postprandial glucose and HbA1c) and opinion‐based guidance regarding pharmacological therapy in light of recent clinical evidence. Future research in the field was discussed with the aim of establishing collaborative working groups to address unresolved questions. These recommendations are opinion‐based and intended to serve as a template for planned guidelines update, based on systematic and graded literature review, on the diagnosis and management of PTDM.

Metabolic diseases and associated complications: sex and gender matter!

Background  Clinicians and health professionals are increasingly challenged to understand and consider the different health needs of women and men. The increase of gender awareness and the expanding science of gender medicine will affect more and more clinical practice. This review addresses gender‐specific aspects in metabolic disorders and related complications, which represent an increasing burden of this century and a great challenge to public health.

Insulin, secretion, insulin sensitivity and hepatic insulin extraction in primary hyperparathyroidism before and after surgery

OBJECTIVE Primary hyperparathyroidism (pHPT) is associated with hypertension, hyperinsulinaemia, and insulin resistance. The present study investigated the causes of these metabolic disturbances by quantifying insulin sensitivity and glucose effectiveness, and by assessing the time course of β‐cell insulin secretion and hepatic insulin extraction, during a dynamic condition such as after an intravenous glucose load. In addition, we evaluated the possible link between metabolic disorders and high blood pressure.

Role of islet amyloid polypeptide secretion in insulin-resistant humans

SummaryAlthough it is generally accepted that islet amyloid polypeptide is cosecreted with insulin, relatively few data on its kinetics are available. We therefore studied the dynamics of islet amyloid polypeptide release following oral and frequently sampled intravenous glucose tolerance tests in comparison to insulin and C-peptide using mathematical model techniques in 14 control subjects, 10 obese and 11 hyper-tensive patients. The fractional clearance rate of islet amyloid polypeptide (0.034 ±0.004 min−1 in control subjects, 0.058 ± 0.008 in the obese and 0.050 ± 0.008 in the hypertensive patients) was significantly different (p < 0.01) in each group compared with that of insulin (0.14 ± 0.03 min−1) and similar to that of C-peptide (0.061 ± 0.007 min−1), at least in the insulin-resistant subjects. Based on the insulin sensitivity index derived from the minimal model analysis of intravenous glucose tolerance test data, both the hypertensive (2.4 ±0.4 min−1/(μU/ml); p < 0.0005) and the obese (2.7 ±0.5; p < 0.001) patients demonstrated severe insulin resistance compared to control subjects (8.1 ± 1.3). Marked insulin hypersecretion was found in the hypertensive (57.6 ± 5.2 nmol · 1−1 in 180 min; p < 0.001) and obese (60.8 ± 10.1; p < 0.003) patients in comparison with control subjects (32.4 ± 3.2). The release of islet amyloid polypeptide was significantly higher in the hypertensive (83.1 ± 16.6 pmol/1 in 180 min; p < 0.02) and obese (78.6 ± 13.1; p < 0.005) patients than in control subjects (40.5 ± 6.4). No correlation was found between islet amyloid polypeptide release and the insulin sensitivity index in any group. We conclude that, due to a significantly slower clearance of islet amyloid polypeptide in comparison to insulin, reliance on molar ratios between these two peptides might be misleading in the interpretation of islet amy-loid polypeptide secretion especially under non-steady-state conditions.

Improved usability of the Minimal Model of insulin sensitivity based on automated approach and Genetic Algorithms for parameter estimation

Minimal model analysis of glucose and insulin data from an IVGTT (intravenous glucose tolerance test) is widely used to estimate insulin sensitivity; however, the use of the model often requires intervention by a trained operator and some problems can occur in the estimation of model parameters. In the present study, a new method for minimal model analysis, termed GAMMOD, was developed based on genetic algorithms for the estimation of model parameters. Such an algorithm does not require the fixing of initial values for the parameters (that may lead to unreliable estimates). Our method also implements an automated weighting scheme not requiring manual intervention of the operator, thus improving the usability of the model. We studied a group of 170 women with a history of previous gestational diabetes. Results obtained by GAMMOD were compared with those obtained by MINMOD (a traditional gradient-based algorithm for minimal model analysis). Insulin sensitivity by GAMMOD was (3.86+/-0.19) compared with (4.33+/-0.20) x 10(-4) micro-units.ml(-1) x min(-1) by MINMOD; glucose effectiveness was 0.0236+/-0.0005 compared with 0.0229+/-0.0005 min(-1) respectively. The difference in the estimation by the two methods was within the precision expected for such metabolic parameters and is probably of no clinical relevance. Moreover, both the coefficient of variation of the estimated parameters and the error of fit were generally lower in GAMMOD, despite the fact that it does not require manual intervention. In conclusion, the GAMMOD approach for parameter estimation in the minimal model provides a reliable estimation of the model parameters and improves the usability of the model, thus facilitating its further use and application in a clinical context.

Mode of action of ipomoea batatas (caiapo) in type 2 diabetic patients

We have previously reported the beneficial effects of Caiapo, the extract of white-skinned sweet potato (ipomoea batatas), on fasting plasma glucose, as well as on total and low-density lipoprotein (LDL) cholesterol in type 2 diabetic patients. The present study aimed to describe the underlying mechanism responsible for the improvement in metabolic control following administration of Caiapo in those type 2 subjects. A total of 18 male patients (age=58+/-8 years, body mass index [BMI]=27.7+/-2.7 kg/m2, mean +/- SEM) treated only by diet were randomized into 3 groups (placebo, low-dose Caiapo, 2 g/d, and high-dose, 4 g/d). Parameters related to glucose tolerance, glucose disappearance, and insulin secretion were obtained by performing both frequently sampled intravenous glucose tolerance test (FSIGT) and oral glucose tolerance test (OGTT) before and after 6 weeks of treatment with Caiapo. Following treatment with high dose Caiapo, insulin sensitivity significantly ameliorated when assessed both with OGTT (from 308+/-13 mg/min/m2 to 334+/-10, P=.048) and FSIGT (from 1.21+/-0.32 10(4) min(-1)/(microU/mL) to 1.73+/-0.40, P=.021). Improvement of insulin sensitivity with the low dose was observed only with the FSIGT (from 2.02+/-0.70 10(4) min(-1)/(microU/mL) to 2.76+/-0.89, P<.05). Glucose effectiveness did not change. While no changes in glucose tolerance were observed in the placebo and low-dose groups, it increased from 0.85+/-0.13 %min(-1) to 1.46+/-0.13 (P<.02) in patients on high dose. No significant changes were seen in any of the parameters related to insulin dynamics: insulin secretion (from C-peptide), distribution, clearance, and hepatic extraction remained virtually the same after the treatment. In conclusion, short-term treatment with 4 g/d of the nutraceutical Caiapo consistently improved metabolic control in type 2 diabetic patients by decreasing insulin resistance without affecting body weight, glucose effectiveness, or insulin dynamics. No side effects related to the treatment were observed. Thus these results indicate that Caiapo could potentially play a role in the treatment of type 2 diabetes.

Osteocalcin Is Related to Enhanced Insulin Secretion in Gestational Diabetes Mellitus

OBJECTIVE There is growing evidence that osteocalcin, an osteoblast-derived protein locally acting on bone formation, can increase insulin secretion as well as insulin sensitivity and thus prevent the development of obesity and diabetes in experimental animals. In humans, osteocalcin has been reported to be decreased in patients with type 2 diabetes. Because gestational diabetes mellitus (GDM) can serve as a model of pre–type 2 diabetes, the aim of this study was to investigate osteocalcin in GDM. RESEARCH DESIGN AND METHODS Osteocalcin measurement and an oral glucose tolerance test were performed in 78 pregnant women (26 women had GDM and 52 women had normal glucose tolerance [NGT] during pregnancy; women were matched for age and BMI) and in 34 women postpartum. RESULTS During pregnancy osteocalcin was significantly higher in the women with GDM than in the women with NGT (15.6 ± 6.4 vs. 12.6 ± 4.0 ng/ml; P < 0.015), whereas no difference was observed between the two groups at 12 weeks postpartum (36.2 ± 10.2 vs. 36.2 ± 13.0 ng/ml), when osteocalcin was found to be increased compared with the level in the pregnant state in all women (+145 ± 102% in GDM vs. +187 ± 119% in NGT; P < 0.0001). Moreover, osteocalcin showed a significant correlation with basal and total insulin secretion in the whole study group (R = 0.3, P < 0.01). CONCLUSIONS In GDM osteocalcin was higher and thus less restrained than in women with NGT during pregnancy and furthermore correlated with insulin secretion parameters. Therefore, it could be hypothesized that osteocalcin can enhance insulin secretion in insulin-resistant states; alternatively an effect of hyperinsulinemia on osteocalcin secretion cannot be excluded.