Ammon Handisurya

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.

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.

Sex-Specific differences in metabolic control, cardiovascular risk, and interventions in patients with type 2 diabetes mellitus

BACKGROUND Sex-specific differences appear particularly relevant in the management of type 2 diabetes mellitus (T2DM), with women experiencing greater increases in cardiovascular morbidity and mortality than do men. OBJECTIVE The aim of this article was to investigate the influence of biological sex on clinical care and microvascular and macrovascular complications in patients with T2DM in a Central European university diabetes clinic. METHODS In a cross-sectional study, sex-specific disparities in metabolic control, cardiovascular risk factors, and diabetic complications, as well as concomitant medication use and adherence to treatment recommendations, were evaluated in 350 consecutive patients who were comparable for age, diabetes duration, and body mass index. Study inclusion criteria included age ≤75 years, T2DM, a documented history of presence or absence of coronary heart disease (CHD), and informed consent. Patients were followed in the diabetes outpatient clinic between November 2007 and March 2008. RESULTS Two hundred and one patients with T2DM met inclusion criteria (93 [46.3%] women, 108 [53.7%] men). Women with T2DM had higher mean (SE) systolic blood pressure (155.4 [22.5] vs 141.0 [19.8] mm Hg for men; P < 0.001) and total cholesterol (TC) (5.28 [1.34] vs 4.86 [1.29] mmol/L for men; P < 0.05), but a lower TC:HDL-C ratio (4.1 [1.19] vs 4.5 [1.2] for men; P < 0.05). Slightly more men (32.4%) than women (26.9%) reached the therapeutic goal of <7.0% for glycosylated hemoglobin. Women with shorter diabetes duration (<10 years) received oral antihyperglycemic therapy less frequently (P < 0.05). Women with longer disease duration had hypertension more frequently than did their male counterparts (100% vs 86.0%, respectively; P < 0.01). Despite a similar rate of CHD, men were twice as likely as women to have had coronary interventions (percutaneous transluminal coronary angioplasty/coronary artery bypass graft, 25.0% vs 12.9%, respectively; P < 0.05). Women with CHD also had a higher rate of cerebral ischemia than did men (27.6% vs 5.4%, respectively; P < 0.05) and received aspirin less frequently for secondary prevention (P < 0.001). Men had greater overall adherence to diabetes and cardiovascular risk guidelines than did women (66.4% vs 58.9%, respectively; P < 0.01). CONCLUSIONS In this study of diabetes clinic outpatients, women with T2DM had a worse cardiovascular risk profile and achieved therapeutic goals less frequently than did men. Treatment strategies should be improved in both sexes, but women with diabetes may be in need of more aggressive treatment, especially when cardiovascular disease is present.

The Relationship between Insulin Resistance and the Cardiovascular Biomarker Growth Differentiation Factor-15 in Obese Patients

BACKGROUND Growth differentiation factor-15 (GDF-15) is a stress-responsive cytokine linked to obesity comorbidities such as cardiovascular disease, inflammation, and cancer. GDF-15 also has adipokine properties and recently emerged as a prognostic biomarker for cardiovascular events. METHODS We evaluated the relationship of plasma GDF-15 concentrations with parameters of obesity, inflammation, and glucose and lipid metabolism in a cohort of 118 morbidly obese patients [mean (SD) age 37.2 (12) years, 89 females, 29 males] and 30 age- and sex-matched healthy lean individuals. All study participants underwent a 75-g oral glucose tolerance test; 28 patients were studied before and 1 year after Roux-en-Y gastric bypass surgery. RESULTS Obese individuals displayed increased plasma GDF-15 concentrations (P < 0.001), with highest concentrations observed in patients with type 2 diabetes. GDF-15 was positively correlated with age, waist-to-height ratio, mean arterial blood pressure, triglycerides, creatinine, glucose, insulin, C-peptide, hemoglobin A(1c), and homeostatic model assessment insulin resistance index and negatively correlated with oral glucose insulin sensitivity. Age, homeostatic model assessment index, oral glucose insulin sensitivity, and creatinine were independent predictors of GDF-15 concentrations. Roux-en-Y gastric bypass led to a significant reduction in weight, leptin, insulin, and insulin resistance, but further increased GDF-15 concentrations (P < 0.001). CONCLUSIONS The associations between circulating GDF-15 concentrations and age, insulin resistance, and creatinine might account for the additional cardiovascular predictive information of GDF-15 compared to traditional risk factors. Nevertheless, GDF-15 changes following bariatric surgery suggest an indirect relationship between GDF-15 and insulin resistance. The clinical utility of GDF-15 as a biomarker might be limited until the pathways directly controlling GDF-15 concentrations are better understood.

Plasma Osteopontin Increases After Bariatric Surgery and Correlates with Markers of Bone Turnover But Not with Insulin Resistance

CONTEXT Osteopontin (OPN) is a multifunctional protein involved in bone metabolism, cardiovascular disease, diabetes, and obesity. OPN levels are elevated in the plasma and adipose tissue of obese subjects, and are decreased with diet-induced weight loss. OBJECTIVE We investigated the effect of bariatric surgery on plasma OPN concentrations in morbidly obese patients. SETTING The study was performed at a university hospital. SUBJECTS We investigated 40 obese patients aged 43.1 +/- 1.8 yr, scheduled to undergo bariatric surgery. Roux-en-Y gastric bypass (RYGB) was performed in 30 subjects (27 females, three males), and laparoscopic adjustable gastric banding (LAGB) in 10 subjects (eight females, two males). STUDY DESIGN All patients were studied before and 1 yr (10.3-14.8 months) after the intervention. MAIN OUTCOME MEASURES OPN, leptin, C-reactive protein, insulin, the homeostatic model assessment insulin resistance index, calcium, 25-hydroxyvitamin D, C telopeptide, and osteocalcin were determined. RESULTS Both bariatric procedures significantly reduced body weight, body mass index, insulin, leptin, and C-reactive protein 1 yr after surgery. Plasma OPN increased from 31.4 +/- 3.8 to 52.8 +/- 3.7 ng/ml after RYGB (P < 0.001) and from 29.8 +/- 6.9 to 46.4 +/- 10.6 ng/ml after LAGB (P = 0.042). Preoperative OPN correlated with age, insulin, the homeostatic model assessment insulin resistance index, and postoperative OPN. Postoperative OPN correlated with C telopeptide and osteocalcin. CONCLUSIONS One year after RYGB and LAGB, plasma OPN levels significantly increased and correlated with biomarkers of bone turnover. Unlike other proinflammatory cytokines, OPN does not normalize but increases further after bariatric surgery.

Effects of T4 replacement therapy on glucose metabolism in subjects with subclinical (SH) and overt hypothyroidism (OH)

Objective  To evaluate β‐cell function and insulin sensitivity in subjects with overt (OH) and subclinical hypothyroidism (SH) before and after T4 replacement therapy.

Sex-Specific Differences in Glycemic Control and Cardiovascular Risk Factors in Older Patients With Insulin-Treated Type 2 Diabetes Mellitus

BACKGROUND Because women have been excluded from many study populations in investigations of diabetes care, there is insufficient information on sex-specific differences in glycemic control. OBJECTIVE The aim of the present study was to assess whether treatment goals for glycemic and cardiovascular risk factor control are achieved equally in older, Central European, female and male patients with type 2 diabetes mellitus (T2DM). METHODS In a retrospective cross-sectional study, data were analyzed from consecutive older (aged ≥60 years) female and male patients with insulin-treated T2DM who attended a diabetes outpatient clinic between January 2007 and April 2008 at the Medical University of Vienna, Austria. Sex-specific differences in glycosylated hemoglobin (HbA₁(c)) levels were assessed as the primary outcome. LDL-C and HDL-C, as well as systolic and diastolic blood pressure (SBP and DBP, respectively), were assessed as secondary outcomes and were adjusted for age, duration of diabetes, duration of insulin treatment, body mass index, insulin units per kilogram per day, and secondary causes of diabetes. P values were adjusted using the Bonferroni correction. RESULTS Data were analyzed from 183 female and 209 male patients with insulin-treated T2DM. In multivariate linear regression models, women had significantly higher levels of LDL-C (P = 0.008), HDL-C (P < 0.001), SBP (P < 0.001), and DBP (P = 0.034), but not HbA₁(c) (P = NS). Multivariate logistic regression models revealed that women were significantly less likely to meet treatment goals for blood pressure (SBP, P = 0.044; DBP, P = 0.024), but not for cholesterol or HbA₁(c) levels (P = NS for LDL-C, HDL-C, and HbA₁(c)). CONCLUSION In this study of older patients with insulin-treated T2DM, whereas glycemic control was comparable between women and men, a more adverse cardiovascular risk factor profile was observed in female patients.

Plasma neuropeptide Y levels differ in distinct diabetic conditions

Neuropeptide Y (NPY) is an important hormone in appetite regulation. Although the contribution of NPY to metabolic disease has been previously demonstrated, there are only a few reports addressing NPY plasma levels under distinct diabetic conditions. In this study we evaluated NPY plasma levels in diabetes mellitus type 2 (DM2) patients with (n=34) and without (n=34) diabetic polyneuropathy (PNP) and compared these with age and gender matched healthy controls (n=34). We also analyzed NPY plasma levels in gestational diabetes mellitus (GDM) patients with age and pregnancy-week matched controls with normal glucose tolerance (NGT). NPY concentration was determined using a commercially available radioimmunoassay kit. In addition, metabolic parameters of DM2 and GDM patients were recorded. One-way ANOVA tests with appropriate post hoc corrections showed elevated levels of NPY in DM2 patients with and without PNP when compared with those of healthy controls (122.32±40.86 and 117.33±29.92 vs. 84.65±52.17 pmol/L; p<0.001, p<0.005, respectively). No significant difference was observed between diabetic patients with and without PNP. The NPY levels were similar in the GDM group and in pregnant women with NGT (74.87±14.36 vs. 84.82±51.13 pmol/L, respectively). Notably, the NPY concentration correlated positively with insulin levels in DM2 patients (R=0.35, p<0.01). Our data suggest a potential involvement of circulating NPY in DM2 pathology.

Risk Factor Profile and Pregnancy Outcome in Women with Type 1 and Type 2 Diabetes Mellitus

OBJECTIVE To assess differences in congenital anomalies, infant mortality, and obstetrical complications as well as risk factors associated with an adverse pregnancy outcome in women with type 1 (T1DM) and type 2 diabetes mellitus (T2DM). METHODS This observational study was performed at a university clinic and included a total of 200 singleton pregnancies between January 1995 and December 2006. Outcome measures comprise the prevalence of major congenital malformations, fetal losses, stillbirths, and neonatal deaths as well as the combined end point, adverse pregnancy outcome, and obstetrical complications. RESULTS Despite changes in prevailing risk factors, the rate of congenital anomalies and embryonic as well as perinatal death was comparable in type 1 diabetic women over time as well as between women with T1DM and T2DM. Outcome measures and risk factor profile were similar in women with preconception and newly diagnosed T2DM. Glycemic control and increased body mass index (BMI) during the first trimester were the strongest predictors of an adverse pregnancy outcome. Hemoglobin A1c (HbA1c) was higher in T1DM than in T2DM but similar in women with T1DM over time. BMI was highest in women with T2DM, followed by T1DM women of the most recent time period. CONCLUSIONS In addition to HbA1c, other risk factors, especially high BMI, strongly influence pregnancy outcome. The higher prevalence of these risk factors in T2DM might compensate for the better glycemic control, resulting in a pregnancy outcome comparable to that of T1DM. Pregnancy outcome in T1DM remained unchanged over time, possibly because of the missing amelioration of HbA1c levels and the increasing BMI.

Plasma MR-proADM Correlates to BMI and Decreases in Relation to Leptin After Gastric Bypass Surgery

Adrenomedullin (ADM) is a vasoactive peptide found to be related to obesity and its comorbidities: type 2 diabetes, hypertension, atherosclerosis, and coronary heart disease. ADM is increased both in plasma and in adipose tissue of obese individuals when compared to lean subjects and is considered as a member of the adipokine family. We determined plasma midregional proadrenomedullin (MR‐proADM) concentrations in a cohort of 357 subjects with BMI ranging from 17.5 to 42.3 kg/m2 and no additional medical history. In parallel, 28 severely obese patients scheduled to undergo laparoscopic Roux‐en‐Y gastric bypass (RYGB) surgery were studied at two time points: before and 1 year after surgery. Outcome measurements were: MR‐proADM, cortisol, leptin, C‐reactive protein (CRP) thyroid‐stimulating hormone (TSH), creatinine and metabolic parameters. BMI correlated significantly to plasma MR‐proADM levels (r = 0.714, P < 0.001), also after adjustment for age and gender (r = 0.767, P < 0.001). In obese subjects, there was a positive relationship between MR‐proADM and leptin (r = 0.511, P = 0.006). Following RYGB, plasma MR‐proADM decreased from 0.76 ± 0.03 to 0.62 ± 0.02 pg/ml (P < 0.0001). RYGB‐induced changes in MR‐proADM correlated significantly to changes in leptin (r = 0.533, P = 0.004) and in CRP (r = 0.429, P = 0.023). We conclude that BMI is an independent predictor of circulating MR‐proADM levels. Weight loss after RYGB is associated with a significant decrease in plasma MR‐proADM, which is related to surgery‐induced changes in both circulating leptin and systemic inflammation.