The Anti-Atherosclerosis Effect of Anakinra, a Recombinant Human Interleukin-1 Receptor Antagonist, in Apolipoprotein E Knockout Mice.

Interleukin (IL)-1ß plays an important role in atherosclerosis pathogenesis. We aimed to investigate the effect of anakinra, a recombinant human IL-1 receptor antagonist, on the progression of atherosclerosis in apolipoprotein E knockout (ApoE−/−) mice. ApoE−/− mice (8-week male) were treated with saline (control), anakinra 10, 25, and 50 mg/kg, respectively (n = 10 in each group). Mice were fed a standard chow (4 weeks) followed by an atherogenic diet (35kcal% fat, 1.25% cholesterol, 12 weeks). Atheromatous plaques in ApoE−/− mice and the expression of inflammatory genes and signaling pathways in human umbilical vein endothelial cells (HUVECs), rat aortic smooth muscle cells (RAOSMCs), and 3T3-L1 adipocytes were assessed. Anakinra reduced the plaque size of the aortic arch (30.6% and 25.2% at the 25 mg/kg and 50 mg/kg doses, both p < 0.05) and serum triglyceride in ApoE−/− mice and suppressed inflammatory genes (IL-1ß and IL-6) expressions in HUVECs and RAOSMCs (all p < 0.05). In RAOSMCs, anakinra reduced metalloproteinase-9 expression in a dose-dependent manner and inhibited cell migration. Anakinra-treated mice exhibited trends of lower CD68+ macrophage infiltration in visceral fat and monocyte chemoattractant protein-1 expression was reduced in 3T3-L1 adipocytes. Anakinra could be a useful component for complementary treatment with a standard regimen to reduce the residual cardiovascular risk.

Sequencing Cell-free Fetal DNA in Pregnant Women With GCK-MODY.

CONTEXT: Individuals with monogenic diabetes due to inactivating glucokinase (GCK) variants typically do not require treatment, except potentially during pregnancy. In pregnancy, fetal GCK genotype determines whether treatment is indicated, but noninvasive methods are not clinically available. OBJECTIVE: This work aims to develop a method to determine fetal GCK genotype noninvasively using maternal cell-free fetal DNA. METHODS: This was a proof-of-concept study involving 3 pregnant women with a causal GCK variant that used information from 1) massive parallel sequencing of maternal plasma cell-free DNA, 2) direct haplotype sequences of maternal genomic DNA, and 3) the paternal genotypes to estimate relative haplotype dosage of the pathogenic variant-linked haplotype. Statistical testing of variant inheritance was performed using a sequential probability ratio test (SPRT). RESULTS: In each of the 3 cases, plasma cell-free DNA was extracted once between gestational weeks 24 and 36. The fetal fraction of cell-free DNA ranged from 21.8% to 23.0%. Paternal homozygous alleles that were identical to the maternal GCK variant-linked allele were not overrepresented in the cell-free DNA. Paternal homozygous alleles that were identical to the maternal wild-type-linked allele were significantly overrepresented. Based on the SPRT, we predicted that all 3 cases did not inherit the GCK variant. Postnatal infant genotyping confirmed our prediction in each case. CONCLUSION: We have successfully implemented a noninvasive method to predict fetal GCK genotype using cell-free DNA in 3 pregnant women carrying an inactivating GCK variant. This method could guide tailoring of hyperglycemia treatment in pregnancies of women with GCK monogenic diabetes.

Retinol-binding protein-4 was associated with sensitization to inhalant allergens in the elderly population.

BACKGROUND/AIMS: Recent evidence suggests an association between allergic sensitization and metabolic markers. However, this association has rarely been examined in the elderly. Retinol-binding protein-4 (RBP-4) is a recently identified adipokine that acts on the muscle and liver affecting insulin sensitivity. We evaluated the association between metabolic parameters and allergic sensitization in the elderly. METHODS: We analysed the database of the Korean Longitudinal Study on Health and Aging cohort study conducted during 2005 to 2006. Atopy was identified by inhalant allergen skin prick test. Metabolic conditions were assessed using anthropometric indices and serum biomarkers such as fasting glucose, lipid, adiponectin, and RBP-4. RESULTS: Among the 854 elderly subjects, 17.2% had atopy. Plasma RBP-4 levels were significantly higher in the atopic elderly than nonatopic elderly (p = 0.003). When RBP-4 percentiles were categorized as under three groups, the prevalence of atopy and current rhinitis increased significantly with percentiles of RBP-4 levels (p = 0.019 and p = 0.007, respectively). Log RBP-4 was associated with atopy (odds ratio [OR], 4.10; p = 0.009) and current rhinitis (OR, 2.73; p = 0.014), but not with current asthma (OR, 1.17; p = 0.824). Higher RBP-4 level in atopic elderly was also observed in current rhinitis patients. Atopy, but not current rhinitis, showed significant relationships with log RBP-4 levels in multivariate analyses adjusted for other metabolic markers including body mass index. CONCLUSION: RBP-4 positively associated with atopy in the general elderly population irrespective of other metabolic markers.

A subset of microRNAs in the Dlk1-Dio3 cluster regulates age-associated muscle atrophy by targeting Atrogin-1.

BACKGROUND: The microRNAs (miRNAs) down-regulated in aged mouse skeletal muscle were mainly clustered within the delta-like homologue 1 and the type III iodothyronine deiodinase (Dlk1-Dio3) genomic region. Although clustered miRNAs are coexpressed and regulate multiple targets in a specific signalling pathway, the function of miRNAs in the Dlk1-Dio3 cluster in muscle aging is largely unknown. We aimed to ascertain whether these miRNAs play a common role to regulate age-related muscle atrophy. METHODS: To examine anti-atrophic effect of miRNAs, we individually transfected 42 miRNA mimics in fully differentiated myotubes and analysed their diameters. The luciferase reporter assay using target 3' untranslated region (UTR) and RNA pull-down assay were employed to ascertain the target predicted by the TargetScan algorithm. To investigate the therapeutic potential of the miRNAs in vivo, we generated adeno-associated virus (AAV) serotype 9 expressing green fluorescent protein (GFP) (AAV9-GFP) bearing miR-376c-3p and infected it into the tibialis anterior muscle of old mice. We performed morphometric analysis and measured ex vivo isometric force using a force transducer. Human gluteus maximus muscle tissues (ages ranging from 25 to 80 years) were used to investigate expression levels of the conserved miRNAs in the Dlk1-Dio3 cluster. RESULTS: We found that the majority of miRNAs (33 out of 42 tested) in the cluster induced anti-atrophic phenotypes in fully differentiated myotubes with increasing their diameters. Eighteen of these miRNAs, eight of which are conserved in humans, harboured predicted binding sites in the 3' UTR of muscle atrophy gene-1 (Atrogin-1) encoding a muscle-specific E3 ligase. Direct interactions were identified between these miRNAs and the 3' UTR of Atrogin-1, leading to repression of Atrogin-1 and thereby induction of eIF3f protein content, in both human and mouse skeletal muscle cells. Intramuscular delivery of AAV9 expressing miR-376c-3p, one of the most effective miRNAs in myotube thickening, dramatically ameliorated skeletal muscle atrophy and improved muscle function, including isometric force, twitch force, and fatigue resistance in old mice. Consistent with our findings in mice, the expression of miRNAs in the cluster was significantly down-regulated in human muscle from individuals > 50 years old. CONCLUSIONS: Our study suggests that genetic intervention using a muscle-directed miRNA delivery system has therapeutic efficacy in preventing Atrogin-1-mediated muscle atrophy in sarcopenia.

COVID-19 and older people in Asia: Asian Working Group for Sarcopenia calls to actions.

The coronavirus disease 2019 (COVID-19) pandemic has casted a huge impact on global public health and the economy. In this challenging situation, older people are vulnerable to the infection and the secondary effects of the pandemic and need special attention. To evaluate the impacts of COVID-19 on older people, it is important to balance the successful pandemic control and active management of secondary consequences. These considerations are particularly salient in the Asian context, with its diversity among countries in terms of sociocultural heritage, healthcare setup and availability of resources. Thus, the Asian Working Group for Sarcopenia summarized the considerations of Asian countries focusing on responses and difficulties in each country, impacts of health inequity related to the COVID-19 pandemic and proposed recommendations for older people, which are germane to the Asian context. More innovative services should be developed to address the increasing demands for new approaches to deliver healthcare in these difficult times and to establish resilient healthcare systems for older people. Geriatr Gerontol Int 2020; 9999: n/a-n/a.

A Randomized Trial Evaluating the Efficacy and Safety of Fast-Acting Insulin Aspart Compared With Insulin Aspart, Both in Combination With Insulin Degludec With or Without Metformin, in Adults With Type 2 Diabetes (ONSET 9).

OBJECTIVE: To evaluate the efficacy and safety of fast-acting insulin aspart (faster aspart) compared with insulin aspart (IAsp), both with insulin degludec with or without metformin, in adults with type 2 diabetes not optimally controlled with a basal-bolus regimen. RESEARCH DESIGN AND METHODS: This multicenter, double-blind, treat-to-target trial randomized participants to faster aspart (n = 546) or IAsp (n = 545). All available information, regardless of treatment discontinuation or use of ancillary treatment, was used for evaluation of effect. RESULTS: Noninferiority for the change from baseline in HbA1c 16 weeks after randomization (primary end point) was confirmed for faster aspart versus IAsp (estimated treatment difference [ETD] -0.04% [95% CI -0.11; 0.03]; -0.39 mmol/mol [-1.15; 0.37]; P < 0.001). Faster aspart was superior to IAsp for change from baseline in 1-h postprandial glucose (PPG) increment using a meal test (ETD -0.40 mmol/L [-0.66; -0.14]; -7.23 mg/dL [-11.92; -2.55]; P = 0.001 for superiority). Change from baseline in self-measured 1-h PPG increment for the mean over all meals favored faster aspart (ETD -0.25 mmol/L [-0.42; -0.09]); -4.58 mg/dL [-7.59; -1.57]; P = 0.003). The overall rate of treatment-emergent severe or blood glucose (BG)-confirmed hypoglycemia was statistically significantly lower for faster aspart versus IAsp (estimated treatment ratio 0.81 [95% CI 0.68; 0.97]). CONCLUSIONS: In combination with insulin degludec, faster aspart provided effective overall glycemic control, superior PPG control, and a lower rate of severe or BG-confirmed hypoglycemia versus IAsp in adults with type 2 diabetes not optimally controlled with a basal-bolus regimen.

Estimated Association Between Cytokines and the Progression to Diabetes: 10-year Follow-Up From a Community-Based Cohort.

CONTEXT: The long-term association between multiple cytokines and progression to diabetes is still uncertain. OBJECTIVE: To identify which cytokines could predict progression to prediabetes and type 2 diabetes over 10 years. METHODS: The study included 912 participants aged 40 to 69 years at baseline from the Ansung cohort, part of the Korea Genome Epidemiology Study. At baseline, a 75-g oral glucose tolerance test and 8 cytokines were measured: plasminogen activator inhibitor 1 (PAI-1), resistin, interleukin 6, leptin, monocyte chemoattractant protein 1, tumor necrosis factor alpha, retinol binding protein 4 (RBP4), and adiponectin. People with normal glucose tolerance (NGT, n = 241) and prediabetes (n = 330) were followed-up biennially for 10 years. Multinomial logistic regression analysis was used to evaluate the predictability of cytokines on the new-onset prediabetes and type 2 diabetes. RESULTS: At 10 years, 38 (15.8%) and 82 (34.0%) of those with NGT had converted to prediabetes and type 2 diabetes, respectively. Of those with prediabetes, 228 (69.1%) had converted to type 2 diabetes. In people with NGT or prediabetes at baseline, the highest tertile of RBP4 was associated with a 5.48-fold and 2.43-fold higher risk of progression to type 2 diabetes, respectively. The odds for converting from NGT to prediabetes in the highest tertile of PAI-1 and the lowest tertile of adiponectin were 3.23 and 3.37, respectively. In people with prediabetes at baseline, those in the highest tertile of resistin were 2.94 time more likely to develop type 2 diabetes (all P < 0.05). CONCLUSIONS: In this 10-year prospective study, NGT with higher serum RBP4 and PAI-1, and with lower adiponectin were associated with new-onset prediabetes and type 2 diabetes.

Identifying Pathogenic Variants of Monogenic Diabetes Using Targeted Panel Sequencing in an East Asian Population.

PURPOSE: Monogenic diabetes is a specific type of diabetes in which precision medicine could be applied. In this study, we used targeted panel sequencing to investigate pathogenic variants in Korean patients with clinically suspected monogenic diabetes. METHODS: The eligibility criteria for inclusion were patients with nontype 1 diabetes with age at onset ≤30 years and body mass index (BMI) ≤30 kg/m2. Among the 2090 patients with nontype 1 diabetes, 109 had suspected monogenic diabetes and underwent genetic testing. We analyzed 30 monogenic diabetes genes using targeted panel sequencing. The pathogenicity of the genetic variants was evaluated according to the American College of Medical Genetics and Genomics and Association for Molecular Pathology guidelines. RESULTS: Among the 109 patients with suspected monogenic diabetes, 23 patients (21.1%) harbored pathogenic/likely pathogenic variants. A total of 14 pathogenic/likely pathogenic variants of common maturity-onset diabetes of the young (MODY) genes were identified in GCK, HNF1A, HNF4A, and HNF1B. Other pathogenic/likely pathogenic variants were identified in WFS1, INS, ABCC8, and FOXP3. The mitochondrial DNA 3243A>G variant was identified in five participants. Patients with pathogenic/likely pathogenic variants had a significantly higher MODY probability, a lower BMI, and a lower C-peptide level than those without pathogenic/likely pathogenic variants (P = 0.007, P = 0.001, and P = 0.012, respectively). CONCLUSIONS: Using targeted panel sequencing followed by pathogenicity evaluation, we were able to make molecular genetic diagnoses for 23 patients (21.1%) with suspected monogenic diabetes. Lower BMI, higher MODY probability, and lower C-peptide level were characteristics of these participants.

Progression to Gestational Diabetes Mellitus in Pregnant Women with One Abnormal Value in Repeated Oral Glucose Tolerance Tests.

BACKGROUND: Women with one abnormal value (OAV) in a 100 g oral glucose tolerance test (OGTT) during pregnancy are reported to have an increased risk of adverse pregnancy outcomes. However, there is limited data about whether women with OAV will progress to gestational diabetes mellitus (GDM) when the OGTT is repeated. METHODS: To identify clinical and metabolic predictors for GDM in women with OAV, we conducted a retrospective study and identified women with OAV in the OGTT done at 24 to 30 weeks gestational age (GA) and repeated the second OGTT between 32 and 34 weeks of GA. RESULTS: Among 137 women with OAV in the initial OGTT, 58 (42.3%) had normal, 40 (29.2%) had OAV and 39 (28.5%) had GDM in the second OGTT. Maternal age, prepregnancy body mass index, weight gain from prepregnancy to the second OGTT, GA at the time of the OGTT, and parity were similar among normal, OAV, and GDM groups. Plasma glucose levels in screening tests were different (151.8±15.7, 155.8±14.6, 162.5±20.3 mg/dL, P<0.05), but fasting, 1-, 2-, and 3-hour glucose levels in the initial OGTT were not. Compared to women with screen negative, women with untreated OAV had a higher frequency of macrosomia. CONCLUSION: We demonstrated that women with OAV in the initial OGTT significantly progressed to GDM in the second OGTT. Clinical parameters predicting progression to GDM were not found. Repeating the OGTT in women with OAV in the initial test may be helpful to detect GDM progression.

Pregnancy Outcomes of Women Additionally Diagnosed as Gestational Diabetes by the International Association of the Diabetes and Pregnancy Study Groups Criteria.

BACKGROUND: We investigated the pregnancy outcomes in women who were diagnosed with gestational diabetes mellitus (GDM) by the International Association of the Diabetes and Pregnancy Study Groups (IADPSG) criteria but not by the Carpenter-Coustan (CC) criteria. METHODS: A total of 8,735 Korean pregnant women were identified at two hospitals between 2014 and 2016. Among them, 2,038 women participated in the prospective cohort to investigate pregnancy outcomes. Diagnosis of GDM was made via two-step approach with 50-g glucose challenge test for screening followed by diagnostic 2-hour 75-g oral glucose tolerance test. Women were divided into three groups: non-GDM, GDM diagnosed exclusively by the IADPSG criteria, and GDM diagnosed by the CC criteria. RESULTS: The incidence of GDM was 2.1% according to the CC criteria, and 4.1% by the IADPSG criteria. Women diagnosed with GDM by the IADPSG criteria had a higher body mass index (22.0±3.1 kg/m² vs. 21.0±2.8 kg/m², P<0.001) and an increased risk of preeclampsia (odds ratio [OR], 6.90; 95% confidence interval [CI], 1.84 to 25.87; P=0.004) compared to non-GDM women. Compared to neonates of the non-GDM group, those of the IADPSG GDM group had an increased risk of being large for gestational age (OR, 2.39; 95% CI, 1.50 to 3.81; P<0.001), macrosomia (OR, 2.53; 95% CI, 1.26 to 5.10; P=0.009), and neonatal hypoglycemia (OR, 3.84; 95% CI, 1.01 to 14.74; P=0.049); they were also at an increased risk of requiring phototherapy (OR, 1.57; 95% CI, 1.07 to 2.31; P=0.022) compared to the non-GDM group. CONCLUSION: The IADPSG criteria increased the incidence of GDM by nearly three-fold, and women diagnosed with GDM by the IADPSG criteria had an increased risk of adverse pregnancy outcomes in Korea.

Oral Glucose Tolerance Testing Allows Better Prediction of Diabetes in Women with a History of Gestational Diabetes Mellitus.

BACKGROUND: We aimed to identify the postpartum metabolic factors that were associated with the development of diabetes in women with a history of gestational diabetes mellitus (GDM). In addition, we examined the role of the oral glucose tolerance test (OGTT) in the prediction of future diabetes. METHODS: We conducted a prospective study of 179 subjects who previously had GDM but did not have diabetes at 2 months postpartum. The initial postpartum examination including a 75-g OGTT and the frequently sampled intravenous glucose tolerance test (FSIVGTT) was performed 12 months after delivery, and annual follow-up visits were made thereafter. RESULTS: The insulinogenic index (IGI30) obtained from the OGTT was significantly correlated with the acute insulin response to glucose (AIRg) obtained from the FSIVGTT. The disposition indices obtained from the OGTT and FSIVGTT were also significantly correlated. Women who progressed to diabetes had a lower insulin secretory capacity including IGI30, AIRg, and disposition indices obtained from the FSIVGTT and OGTT compared with those who did not. However, the insulin sensitivity indices obtained from the OGTT and FSIVGTT did not differ between the two groups. Multivariate logistic regression analysis showed that the 2-hour glucose and disposition index obtained from the FSIVGTT were significant postpartum metabolic risk factors for the development of diabetes. CONCLUSION: We identified a crucial role of ß-cell dysfunction in the development of diabetes in Korean women with previous GDM. The 2-hour glucose result from the OGTT is an independent predictor of future diabetes. Therefore, the OGTT is crucial for better prediction of future diabetes in Korean women with previous GDM.

Nonsynonymous Variants in PAX4 and GLP1R Are Associated With Type 2 Diabetes in an East Asian Population.

We investigated ethnicity-specific exonic variants of type 2 diabetes (T2D) and its related clinical phenotypes in an East Asian population. We performed whole-exome sequencing in 917 T2D case and control subjects, and the findings were validated by exome array genotyping in 3,026 participants. In silico replication was conducted for seven nonsynonymous variants in an additional 13,122 participants. Single-variant and gene-based association tests for T2D were analyzed. A total of 728,838 variants were identified by whole-exome sequencing. Among nonsynonymous variants, PAX4 Arg192His increased risk of T2D and GLP1R Arg131Gln decreased risk of T2D in genome-wide significance (odds ratio [OR] 1.48, P = 4.47 × 10-16 and OR 0.84, P = 3.55 × 10-8, respectively). Another variant at PAX4 192 codon Arg192Ser was nominally associated with T2D (OR 1.62, P = 5.18 × 10-4). In T2D patients, PAX4 Arg192His was associated with earlier age at diagnosis, and GLP1R Arg131Gln was associated with decreased risk of cardiovascular disease. In control subjects without diabetes, the PAX4 Arg192His was associated with higher fasting glucose and GLP1R Arg131Gln was associated with lower fasting glucose and HbA1c level. Gene-based analysis revealed that SLC30A8 was most significantly associated with decreased risk of T2D (P = 1.0 × 10-4). In summary, we have identified nonsynonymous variants associated with risk of T2D and related phenotypes in Koreans.

Comparison of pancreatic volume and fat amount linked with glucose homeostasis between healthy Caucasians and Koreans.

AIM: To compare pancreatic volume and fat amount, and their associations with glucose homeostasis, in a Korean and a white population. MATERIALS AND METHODS: In 43 healthy Korean and 43 healthy white people, matched for age (±3 years) and body mass index (BMI; ±1 kg/m2 ), we measured pancreatic volume and fat amount in the pancreas and abdomen using computed tomography. Pancreatic ß-cell function and insulin resistance were estimated according to biochemical characteristics and a 75-g oral glucose tolerance test. Body composition and resting energy expenditure (REE) were examined using bioimpedance and indirect calorimetry, respectively. RESULTS: The mean ±SD age of the participants was 29.9 ± 5.9 years and 30.0 ± 5.2 years, and BMI was 24.0 ±3.7 and 24.1 ±3.2 kg/m2 in the white participants and the Korean participants, respectively. Pancreatic volume in the white participants was greater than that in Korean participants (77.8 ±11.6 vs 68.2 ±12.1 cm3 ; P < .001). Pancreatic fat content in Korean participants was 22.8% higher than in white participants (P = .051). Insulinogenic index, disposition index, muscle mass and REE were significantly lower in Korean participants. Pancreatic volume was positively associated with indices linked to ß-cell function; fat content in the pancreas was negatively associated with such indices, and positively with insulin resistance after adjusting for relevant variables including REE. CONCLUSIONS: A smaller pancreas and higher fat deposition might be crucial determinants of vulnerability to diabetes in Korean people compared with white people with similar BMI and body fat levels.

Rosiglitazone increases endothelial cell migration and vascular permeability through Akt phosphorylation.

BACKGROUND: Thiazolidinediones (TZDs), peroxisome proliferator-activated receptor-γ (PPAR-γ) agonists, exhibit anti-inflammatory and antioxidant properties and inhibit endothelial inflammation and dysfunction, which is anti-atherogenic. However, fluid retention, which may lead to congestive heart failure and peripheral edema, is also a concern, which may result from endothelial cell leakage. In the current study, we examined the effects of PPAR-γ agonists on vascular endothelial cell migration and permeability in order to determine its underlying mechanisms. METHODS: We used rosiglitazone and conducted cell migration assay and permeability assay using HUVEC cells and measured vascular permeability and leakage in male C57BL/6 mice. RESULTS: Rosiglitazone significantly promoted endothelial cell migration and induced permeability via activation of phosphatidylinositol-3-kinase (PI3K) - Akt or protein kinase C (PKC)ß. In addition, rosiglitazone increased vascular endothelial growth factor (VEGF) expression and suppressed expression of tight junction proteins (JAM-A and ZO-1), which might promote neovascularization and vascular leakage. These phenomena were reduced by Akt inhibition. CONCLUSIONS: Vascular endothelial cell migration and permeability change through Akt phosphorylation might be a mechanism of induced fluid retention and peripheral tissue edema by TZD.

Carbohydrate Composition Associated with the 2-Year Incidence of Metabolic Syndrome in Korean Adults.

The aim of this study was to investigate the association between macronutrient composition and metabolic syndrome (MetS) incidence in Korean adults. Data were obtained from a cohort of 10,030 members aged 40 to 69 years who were enrolled from the 2 cities (Ansung and Ansan) between 2001 and 2002 to participate in the Korean Genome Epidemiology Study. Of these members, 5,565 participants, who were free of MetS and reported no diagnosis of cardiovascular disease at baseline, were included in this study. MetS was defined using the criteria of the National Cholesterol Education Program-Adult Treatment Panel III and Asia-Pacific criteria for waist circumference. MetS incidence rate were identified during a 2-year follow-up period. Baseline dietary information was obtained using a semi-quantitative food frequency questionnaire. Multivariate logistic regression analysis was used to evaluate the association between the quartiles of percentages of total calorie from macronutrients consumed and MetS incidence. In analyses, baseline information, including age, sex, body mass index, income status, educational status, smoking status, alcohol drinking status, and physical activity level was considered as confounding variables. Participants with the second quartile of the percentages of carbohydrate calorie (67%-70%) had a 23% reduced odds ratio (95% confidence interval, 0.61-0.97) for MetS incidence compared with those with the fourth quartile after adjusting for confounding variables. The findings suggest that middle aged or elderly Korean adults who consume approximately 67%-70% of calorie from carbohydrate have a reduced risk of MetS.

Prevention of type 2 diabetes mellitus in women with previous gestational diabetes mellitus.

Gestational diabetes mellitus (GDM), defined as any degree of glucose intolerance with onset or first recognition during pregnancy, is characterized by underlying maternal defects in the ß-cell response to insulin during pregnancy. Women with a previous history of GDM have a greater than 7-fold higher risk of developing postpartum diabetes compared with women without GDM. Various risk factors for postpartum diabetes have been identified, including maternal age, glucose levels in pregnancy, family history of diabetes, pre-pregnancy and postpartum body mass index, dietary patterns, physical activity, and breastfeeding. Genetic studies revealed that GDM shares common genetic variants with type 2 diabetes. A number of lifestyle interventional trials that aimed to ameliorate modifiable risk factors, including diet, exercise, and breastfeeding, succeeded in reducing the incidence of postpartum diabetes, weight retention, and other obesity-related morbidities. The present review summarizes the findings of previous studies on the incidence and risk factors of postpartum diabetes and discusses recent lifestyle interventional trials that attempted to prevent postpartum diabetes.

Vildagliptin reduces plasma stromal cell-derived factor-1α in patients with type 2 diabetes compared with glimepiride.

AIMS/INTRODUCTION: Dipeptidyl peptidase-4 inhibitors might have pleiotropic protective effects on cardiovascular disease (CVD), in contrast to sulfonylureas. Therefore, we compared various CVD risk factors between vildagliptin and glimepiride. MATERIALS AND METHODS: We carried out a randomized, prospective and crossover trial. A total of 16 patients with type 2 diabetes whose glycated hemoglobin was >7% were randomized to add vildagliptin or glimepiride. After 12-week treatment, each drug was replaced with the other for another 12 weeks. Before and after each treatment, glucose homeostasis and CVD risk factors were assessed, and the continuous glucose monitoring system was applied to calculate glycemic variability. RESULTS: The mean age of the participants was 60 years, 31% were men, body mass index 25.5 kg/m2 and HbA1c 8.41%. Both vildagliptin and glimepiride significantly decreased glycated hemoglobin and glycemic variability indices. Despite the improved glucose homeostasis, favorable change of CVD markers was not prominent in both the arms, along with significant weight gain. Only plasma stromal cell-derived factor (SDF)-1α decreased by 30% in the vildagliptin arm. According to regression analyses, the reduction of SDF-1α was independently associated with vildagliptin usage and serum interleukin-6 changes, but white blood cells were not related with the SDF-1α changes. CONCLUSION: Compared with glimepiride, vildagliptin arrestingly decreased plasma SDF-1α, and its clinical implications should be further investigated.

Metabolic syndrome independently predicts future diabetes in women with a history of gestational diabetes mellitus.

Metabolic syndrome (MetS) is an established predisposing condition for type 2 diabetes mellitus (T2DM). However, it is not thoroughly evaluated whether MetS increases the risk of T2DM in women with a previous history of gestational diabetes mellitus (GDM) who already at high risk of T2DM compared with the general population. We investigated the impact of MetS on the development of postpartum diabetes in women with a history of GDM.This was a multicenter, prospective cohort study of women diagnosed with GDM. The follow-up evaluations, including the oral glucose tolerance test, were completed at 6 weeks postpartum and annually thereafter. MetS was diagnosed at the initial postpartum evaluation according to the revised criteria of the National Cholesterol Education Program-Adult Treatment Panel III. The risk of developing type 2 diabetes (T2DM) in the follow-up period was analyzed based on the presence of MetS, and the adjusted risk was calculated using a Cox proportional hazards model.A total of 412 women without diabetes at the initial postpartum evaluation participated in the annual follow-up for median 3.8 years. MetS was prevalent in 66 (19.2%) women at the initial postpartum evaluation. The incidences of diabetes in women with and without MetS were 825 and 227 per 10,000 person-years, respectively (P < 0.001). The presence of MetS was an independent risk factor for T2DM, with a hazard ratio (HR) of 2.23 (95% confidence interval 1.04-5.08) in multivariate analysis after adjustment for clinical and metabolic parameters. When we considered MetS and impaired fasting glucose (IFG) separately, women with MetS, IFG, or both had an increased risk of T2DM, with HRs of 4.17, 4.36, and 6.98, respectively.The presence of MetS during the early postpartum period is an independent risk factor for the development of T2DM in women with a previous history of GDM.

Rg3 Improves Mitochondrial Function and the Expression of Key Genes Involved in Mitochondrial Biogenesis in C2C12 Myotubes.

BACKGROUND: Panax ginseng has glucose-lowering effects, some of which are associated with the improvement in insulin resistance in skeletal muscle. Because mitochondria play a pivotal role in the insulin resistance of skeletal muscle, we investigated the effects of the ginsenoside Rg3, one of the active components of P. ginseng, on mitochondrial function and biogenesis in C2C12 myotubes. METHODS: C2C12 myotubes were treated with Rg3 for 24 hours. Insulin signaling pathway proteins were examined by Western blot. Cellular adenosine triphosphate (ATP) levels and the oxygen consumption rate were measured. The protein or mRNA levels of mitochondrial complexes were evaluated by Western blot and quantitative reverse transcription polymerase chain reaction analysis. RESULTS: Rg3 treatment to C2C12 cells activated the insulin signaling pathway proteins, insulin receptor substrate-1 and Akt. Rg3 increased ATP production and the oxygen consumption rate, suggesting improved mitochondrial function. Rg3 increased the expression of peroxisome proliferator-activated receptor γ coactivator 1α, nuclear respiratory factor 1, and mitochondrial transcription factor, which are transcription factors related to mitochondrial biogenesis. Subsequent increased expression of mitochondrial complex IV and V was also observed. CONCLUSION: Our results suggest that Rg3 improves mitochondrial function and the expression of key genes involved in mitochondrial biogenesis, leading to an improvement in insulin resistance in skeletal muscle. Rg3 may have the potential to be developed as an anti-hyperglycemic agent.

Weight Gain and Progression to Type 2 Diabetes in Women With a History of Gestational Diabetes Mellitus.

CONTEXT: The effect of weight gain on the development of type 2 diabetes after gestational diabetes mellitus (GDM) is not fully understood in Asian women who have a relatively low body mass index (BMI). OBJECTIVE: We investigated the effect of postpartum longitudinal BMI change on the development of diabetes in Korean women with a history of GDM. DESIGN AND SETTING: The study included a hospital-based, multicenter, prospective cohort with median follow-up of 4.0 years. PARTICIPANTS: A total of 418 women with previous GDM or gestational impaired glucose tolerance were recruited and underwent an oral glucose tolerance test at 6 weeks postpartum and annually thereafter. MAIN OUTCOME MEASURE: The risk of diabetes was analyzed according to the tertiles of BMI change. Changes in BMI were calculated between the initial postpartum visit and the last follow-up or at the onset of diabetes. RESULTS: The BMI change in each tertile was -1.8 ± 1.1, -0.2 ± 0.3, and 1.6 ± 1.2 kg/m(2), respectively. We observed an increased risk of incident diabetes as the tertile of BMI change increased (8.6%, 12.6%, and 16.9%, P = .039). Postpartum BMI change was an independent predictor of diabetes in a multivariate Cox analysis (hazard ratio 1.27, 95% confidence interval 1.04-1.56, P = .021), even after adjusting for BMI at the last follow-up. In the highest tertile group, there was a significant deterioration in cardiovascular risk factors including blood pressure, lipid profile, and insulin sensitivity. CONCLUSIONS: Postpartum increase in BMI is significantly associated with a risk of diabetes and deterioration of metabolic phenotypes in Korean GDM women.