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Introduction: Gremlin-1 is a peptide that functions as an antagonist to bone morphogenic proteins and is overexpressed in obesity and type 2 diabetes mellitus. Gremlin-1 has not yet been investigated in pregnancy, pregnancy-related insulin resistance or gestational diabetes mellitus (GDM). Patients and methods: Gremlin-1 levels were measured throughout the pregnancy of 58 women at high risk for GDM at the Medical University of Vienna. Furthermore, an oral glucose tolerance test, fasting insulin, fasting glucose, sex hormones, blood lipids, liver and renal parameters, and markers of bone development were evaluated at two points during pregnancy (< 20 weeks of gestation (GW), GW 24–28) and 12–14 weeks postpartum. Results: Gremlin-1 levels decreased from < 20 GW (mean = 9.2 pg/ml, SD = 8.4 pg/ml) to GW 24–28 (mean = 6.7 pg/ml, SD = 5.7 pg/ml, p = 0.033) and increased again postpartum, albeit not significantly (mean = 10.7 pg/ml, SD = 13.1 pg/ml, p = 0.339). During pregnancy, Gremlin-1 levels correlated negatively with osteocalcin and procollagen type I aminoterminal propeptide (P1NP), markers of bone health. Concerning glucose metabolism, Gremlin-1 levels were inversely related to the Insulinogenic Index at GW < 20. However, Gremlin-1 levels were not significantly different between women with normal glucose tolerance and GDM during pregnancy. Postpartum, Gremlin-1 was associated with the fatty liver index, osteocalcin levels, diastolic blood pressure and weight. Conclusion: Gremlin-1 levels decreased significantly during pregnancy. The biomarker is not related to GDM status, but correlates negatively with the Insulinogenic Index, an index related to beta cell function. Trial Registry Number ACTRN12616000924459. [ABSTRACT FROM AUTHOR]

Glypican-4 (GPC-4) is an adipokine that enhances insulin receptor signaling. Plasma concentrations were found to be elevated in patients with prediabetes but reduced in type 2 diabetes mellitus. No study on Glypican-4 in pregnancy and pregnancy-related insulin resistance has been published yet. GPC-4 levels were investigated in 59 overweight women throughout their pregnancy at the Medical University of Vienna. GPC-4 levels, fasting insulin, fasting glucose, estradiol, liver and renal parameters, and markers of bone development were assessed before the < 21st week of gestation (GW), and at GW 35–37. GPC-4 levels increased from < 21 GW (mean = 2.38 pg/ml, SD = 0.68 pg/ml) to GW 35–37 (mean = 2.96 pg/ml, SD = 0.77 pg/ml, p < 0.001). At the same time, GPC-4 levels correlated negatively with estimated glomerular filtration rate (eGFR), serum protein and serum albumin levels and were positively related to creatinine and uric acid levels at GW 35–37. Concerning glucose metabolism, GPC-4 levels were inversely related to ISSI-2, fasting insulin and HOMA-IR, however, not significantly different between women with normal glucose tolerance (NGT) and GDM (p = 0.239). In conclusion, GPC-4 levels rose significantly during pregnancy, correlated negatively with fasting insulin and HOMA-IR but might not be related to gestational diabetes mellitus status. [ABSTRACT FROM AUTHOR]

Objective: Little is known about possible sex and gender differences in post-stroke neurorehabilitation outcomes. We aimed to analyze if functional performance, prevalence and impact of comorbidities at admission, and success of inpatient stroke-neurorehabilitation differ between men and women. Methods: Retrospective cohort analysis of 1,437 men and 907 women with prior cerebral infarction treated at a neurorehabilitation clinic between 2012 and 2017; multiple linear regression was used to examine the influence of sex/gender as well as multiple confounders on health and functional outcomes. The main outcome measures were Barthel index (BI) at admission and its change during 4 weeks inpatient neurorehabilitation. Results: Men had been diagnosed with osteoporosis less frequently than women but more often with type 2 diabetes mellitus, coronary artery or chronic kidney disease (p ≤ 0.01). Although twice as many women presented with pre-stroke depression compared to men, the risk of post-stroke depression detected during rehabilitation was comparable. Men were more likely to have less than 30 days between diagnosis and neurorehabilitation start than women (p < 0.03). At admission, women exhibited less autonomy, a lower BI, a higher pain score and worse 2-min walk test (2′WT) compared to men (p < 0.001). Among males osteoporosis and peripheral artery disease independently predicted BI at admission, in women it was pre-stroke depression, dementia, and arterial fibrillation. During neurorehabilitation, both sexes improved regarding BI, pain and walk tests (p < 0.001). Despite comparable rehabilitation effectiveness, women still had worse functional outcomes than males at discharge. Time after stroke to start of neurorehabilitation and length of the stay but, most strongly, the simple 2′WT at admission, and in women, pain intensity independently predicted post-stroke functional status and recovery. Conclusion: Women presented with worse functional status at admission to neurorehabilitation. Although men and women showed similar rehabilitation effectiveness, women still displayed worse clinical outcome measures and higher levels of pain at discharge. Early access and gender-sensitive, personalized post-stroke care with more focus on different comorbidities and psychosocial factors like pain levels and management, could further improve neurorehabilitation outcomes. [ABSTRACT FROM AUTHOR]

Aims: To investigate the potential synergistic effects of combined exenatide (EXE) and dapagliflozin (DAPA) versus (PLAC) placebo and DAPA on hepatocellular lipid (HCL) reduction after 24 weeks of treatment. Materials and methods: Thirty patients with type 2 diabetes were randomized to weekly EXE and daily DAPA (n = 16) or weekly PLAC and daily DAPA (n = 14). Inclusion criteria were glycated haemoglobin (HbA1c) 48 to 97 mmol/mol (6.5‐11%), age 18 to 75 years, body mass index (BMI) ≥25 kg/m2 and metformin ≥1000 mg. The primary endpoint, HCL levels, were measured at baseline and after 24 weeks of treatment using magnetic resonance spectroscopy. Between‐group effects were analysed using general linear models, adjusted for baseline outcome variables, age, sex and BMI. Within‐group differences were assessed using a paired t‐test. Results: After 24 weeks, HCLs were reduced in both treatment groups (absolute change from baseline: EXE + DAPA −4.4%, 95% confidence interval [CI] −8.2, −0.7, P < 0.05; PLAC + DAPA −3.9%, 95% CI −6.0, −1.7, P < 0.01; relative change: EXE + DAPA −35.6%, PLAC + DAPA −32.3%) with no difference between groups. Similar findings were observed for subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT). HbA1c (EXE + DAPA −17.8 mmol/mol, [95% CI −24.8, −10.8], P <0.001; PLAC + DAPA −6.9 mmol/mol, [95% CI −10.5, −3.3], P = 0.001) and fasting glucose significantly decreased in both groups, although EXE + DAPA achieved better glycaemic control than PLAC + DAPA (adjusted difference: HbA1c −6.0 mmol/mol [95% CI −9.7, −2.2], P < 0.01). Body weight was reduced in both treatment groups (EXE + DAPA −7.3 kg, 95% CI −9.9, −4.8, P <0.001; PLAC + DAPA −4.6 kg, 95% CI −7.4, −1.8, P <0.01) with comparable results between groups. Changes in HCLs and weight, hip and waist circumference, VAT and SAT were positively associated. Conclusion: After 24 weeks, HCLs were significantly but comparably reduced in the EXE + DAPA and PLAC + DAPA groups, despite significantly better glycaemic control in the combined group EXE + DAPA. Changes in HCLs were associated with weight loss and reduction of visceral adiposity, but not with glucose control. Further studies are necessary to evaluate possible additional long‐term effects of a combined treatment. [ABSTRACT FROM AUTHOR]

Objective: Recent studies indicate that sodium-glucose cotransporter 2 (SGLT-2) inhibition increases endogenous glucose production (EGP), potentially counteracting the glucose-lowering potency, and stimulates lipid oxidation and lipolysis. However, the acute effects of SGLT-2 inhibition on hepatic glycogen, lipid, and energy metabolism have not yet been analyzed. We therefore investigated the impact of a single dose of dapagliflozin (D) or placebo (P) on hepatic glycogenolysis, hepatocellular lipid (HCL) content and mitochondrial activity (kATP).Research Design and Methods: Ten healthy volunteers (control [CON]: age 30 ± 3 years, BMI 24 ± 1 kg/m2, HbA1c 5.2 ± 0.1%) and six patients with type 2 diabetes mellitus (T2DM: age 63 ± 4 years, BMI 28 ± 1.5 kg/m2, HbA1c 6.1 ± 0.5%) were investigated on two study days (CON-P vs. CON-D and T2DM-P vs. T2DM-D). 1H/13C/31P MRS was performed before, 90-180 min (MR1), and 300-390 min (MR2) after administration of 10 mg dapagliflozin or placebo. EGP was assessed by tracer dilution techniques.Results: Compared with CON-P, EGP was higher in CON-D (10.0 ± 0.3 vs. 12.4 ± 0.5 μmol kg-1 min-1; P < 0.05) and comparable in T2DM-D and T2DM-P (10.1 ± 0.7 vs. 10.4 ± 0.5 μmol kg-1 min-1; P = not significant [n.s.]). A strong correlation of EGP with glucosuria was observed (r = 0.732; P < 0.01). The insulin-to-glucagon ratio was lower after dapagliflozin in CON-D and T2DM-D compared with baseline (P < 0.05). Glycogenolysis did not differ between CON-P and CON-D (-3.28 ± 0.49 vs. -2.53 ± 0.56 μmol kg-1 min-1; P = n.s.) or T2DM-P and T2DM-D (-0.74 ± 0.23 vs. -1.21 ± 0.33 μmol kg-1 min-1; P = n.s.), whereas gluconeogenesis was higher after dapagliflozin in CON-P compared with CON-D (6.7 ± 0.6 vs. 9.9 ± 0.6 μmol kg-1 min-1; P < 0.01) but not in T2DM. No significant changes in HCL and kATP were observed.Conclusions: The rise in EGP after SGLT-2 inhibition is due to increased gluconeogenesis, but not glycogenolysis. Changes in glucagon and the insulin-to-glucagon ratio are not associated with an increased hepatic glycogen breakdown. HCL and kATP are not significantly affected by a single dose of dapagliflozin. [ABSTRACT FROM AUTHOR]

Keywords: genotype; GDM; therapy; prediction; precision medicine; BMI; LGA EN genotype GDM therapy prediction precision medicine BMI LGA 1 5 5 04/24/20 20200421 NES 200421 Introduction Genome-wide association studies (GWASs) are reliable tools to identify novel gene variant-trait (disease) associations. Association of MTNR1B rs10830963 Gene Variant and Diabetes Mellitus Traits Type 2 Diabetes Mellitus (T2DM) Development The I MTNR1B i rs10830963 associated effects on non-autoimmune diabetes mellitus (DM) traits are discussed as an example, more specifically the differences in the genetic effect sizes for T2DM development and GDM development/therapy. Our response as clinicians should already be triggered in any case when a meaningful outcome, such as antenatal insulin treatment in GDM is assessed in a precisely defined clinical trait and the exposure results in an OR value over 5, even in the case of a single risk gene variant without the use of a challenging PRS/PHS. Genotype, GDM, therapy, prediction, precision medicine, BMI, LGA. [Extracted from the article]

Background Increased hepatic fat and cardiac fat are common in patients with type 2 diabetes mellitus (T2 DM) and are associated with a greater risk of liver fibrosis and cardiovascular ( CV) events. Sex-specific differences of dipeptidyl peptidase-four ( DPP-4) inhibitor effects on hepatic ( HCL) and myocardial fat content ( MYCL) have not yet been evaluated. Method Forty-one T2 DM patients (20 male, 21 female) received a gliptin add-on therapy if HbA1c goals were not reached under metformin monotherapy. They underwent cardiac and liver magnetic resonance tomography and spectroscopy before and 6 months after therapy initiation. Plasma samples were analysed for the growth differentiation factor 15 ( GDF-15), a novel marker for cardiovascular risk. Results Thirty-eight patients on gliptin therapy completed the study. We observed a positive correlation between MYCL and HCL before therapy ( R = 0·41, P = 0·05). After 6 months of therapy, we noticed a significant weight reduction in women only ( P = 0·02) whereas waist circumference decreased similarly in both sexes. HbA1c sunk significantly in both sexes ( P = 0·002). HCL decreased significantly ( P = 0·0004), with women featuring higher basal HCL ( P < 0·05). MYCL decreased in women only ( P = 0·01) and GDF-15 comparably in both sexes ( P < 0·05). Conclusions 6 months of DPP-4-therapy led to a significant overall decrease in HCL and body weight such as a reduction of MYCL only in women. This preliminary data set could implicate that gliptin may be a feasible therapy option in fatty liver patients with diabetes potentially including positive effects on cardiovascular function particularly in women. [ABSTRACT FROM AUTHOR]

Clinical guidelines for the management of type 2 diabetes recommend individual therapy considering age, duration of disease, presence of complication and risk of hypoglycaemia. However, at present, the patient's sex has no impact on clinical decisions. Yet, there is mounting data pointing at biological and psychosocial differences between men and women with great impact on progression of disease and complications. Moreover, choices and preferences of therapeutic strategies as well as adherence to lifestyle and pharmacological interventions differ in both sexes. In addition, drug therapy may have sex-specific side effects. Therefore, there is need of more research on biological differences and of evidence-based individualised targeted sex-sensitive therapeutic concepts. Clinical guidelines must consider relevant sex-differences. Development and implementation of sex-specific programs may help to improve adherence to therapy and to reduce progression of disease and development of complications. A more gender-sensitive clinical approach may improve quality of life and increase health and life expectancy in men and women with type 2 diabetes. [ABSTRACT FROM AUTHOR]

Secretagogin (SCGN) is a calcium binding protein related to insulin release in the pancreas. Although SCGN is not co-released with insulin, plasma concentrations have been found to be increased in type 2 diabetes mellitus patients. Until now, no study on SCGN levels in pregnancy or patients with gestational diabetes mellitus (GDM) has been published. In 93 women of a high-risk population for GDM at the Medical University of Vienna, secretagogin levels of 45 GDM patients were compared to 48 women with a normal glucose tolerance (NGT). Glucose tolerance, insulin resistance and secretion were assessed with oral glucose tolerance tests (OGTT) between the 10th and 28th week of gestation (GW) and postpartum. In all women, however, predominantly in women with NGT, there was a significant positive correlation between SCGN levels and Stumvoll first (rp = 0.220, p = 0.032) and second phase index (rp = 0.224, p = 0.028). SCGN levels were not significantly different in women with NGT and GDM. However, SCGN was higher postpartum than during pregnancy (postpartum: 88.07 ± 35.63 pg/mL; pregnancy: 75.24 ± 37.90 pg/mL, p = 0.004). SCGN was directly correlated with week of gestation (rp = 0.308; p = 0.021) and triglycerides (rp = 0.276; p = 0.038) in women with GDM. Therefore, SCGN is related to insulin secretion and hyperinsulinemia during pregnancy; however, it does not display differences between women with NGT and GDM. [ABSTRACT FROM AUTHOR]