Electrostatic-Interaction-Aided Microneedle Patch for Enhanced Glucose-Responsive Insulin Delivery and Three-Meal-Per-Day Blood-Glucose Regulation.

The phenylborate-ester-cross-linked hydrogel microneedle patch (MNP) was promising in the diabetic field for the glucose-responsive insulin-delivering property and simple fabrication process. However, the unfit design of the charging microneedle network limited the improvement of blood-glucose regulating performances. In this work, insulin-loaded phenylborate-ester-cross-linked MNPs, with the polyzwitterion property, were constructed based on the modified ε-polylysine and poly(vinyl alcohol). The relationship between the charging nature of the MNP network and insulin release was verified by regulating the content of postprotonated positively charged amino groups. The elaborately designed MNP possessed improved glucose-responsive insulin-delivering performance. The in vivo study revealed the satisfactory results on blood-glucose regulation by the optimized MNP under the mimic three-meal-per-day mode. Moreover, the insulin bioactivity in the MNP could be maintained for 2 weeks under 25 °C. In summary, this work developed an effective strategy to improve the glucose-responsive phenylborate-ester-cross-linked MNP and enhance its potential for clinical transformation.

Medical service pricing and pharmaceutical supply chain coordination contracts under the zero-markup drug policy.

To implement state policies of zero-markup drug policy and medical service fee adjustment for public hospitals, this study constructed game models of the pharmaceutical supply chain, consisting of a drug supplier and a public hospital. The study obtained the optimal medical service level and pricing under the new state drug policies. In addition, it analyzed the impacts of the degree of public benefit of hospitals on the medical service level, the medical service price, and the drug price. Finally, from the perspective of cooperation between drug suppliers and public hospitals, the specialized coordination contract was designed to maximize overall social welfare. This study found an anomalous but meaningful conclusion: in the background of the zero-markup drug policy, a higher public benefit of hospitals could increase the drug prices, but it could reduce the medical service prices further to cut down on the overall treatment fees for the patients. The novel coordination contract can optimize the pharmaceutical supply chain and achieve a win-win situation for the drug suppliers, public hospitals, and patients. When the public benefit of hospitals is higher, the profit of a decentralized decision-making supply chain is greater than a centralized one, while the pharmaceutical supply chain will not coordinate itself.

Molecular Docking-Guided Design on Glucose-Responsive Nanoparticles for Microneedle Fabrication and "Three-Meal-per-Day" Blood-Glucose Regulation.

It was greatly significant, but difficult, to develop stimulus-responsive polymeric nanoparticles with efficient protein-loading and protein-delivering properties. Crucial obstacles were the ambiguous protein/nanoparticle-interacting mechanisms and the corresponding inefficient trial-and-error strategies, which brought large quantities of experiments in design and optimization. In this work, a molecular docking-guided universal "segment-functional group-polymer" process was proposed to simplify the previous laborious experimental step. The insulin-delivering glucose-responsive polymeric nanoparticles for diabetic treatments were taken as the examples. The molecular docking study obtained insights from the insulin/segment interactions. It was then experimentally confirmed in six functional groups for insulin-loading performances of their corresponding polymers. The optimization formulation was further proved effective in blood-glucose stabilization on the diabetic rats under the "three-meal-per-day" mode. It was believed that the molecular docking-guided designing process was promising in the protein-delivering field.

Uncertainty quantification of CO2 emissions from China's civil aviation industry to 2050.

To mitigate aviation's carbon emissions of the aviation industry, the following steps are vital: accurately quantifying the carbon emission path by considering uncertainty factors, including transportation demand in the post-COVID-19 pandemic period; identifying gaps between this path and emission reduction targets; and providing mitigation measures. Some mitigation measures that can be employed by China's civil aviation industry include the gradual realization of large-scale production of sustainable aviation fuels and transition to 100% sustainable and low-carbon sources of energy. This study identified the key driving factors of carbon emissions by using the Delphi Method and set scenarios that consider uncertainty, such as aviation development and emission reduction policies. A backpropagation neural network and Monte Carlo simulation were used to quantify the carbon emission path. The study results show that China's civil aviation industry can effectively help the country achieve its carbon peak and carbon neutrality goals. However, to achieve the net-zero carbon emissions goal of global aviation, China needs to reduce its emissions by approximately 82%-91% based on the optimal emission scenario. Thus, under the international net-zero target, China's civil aviation industry will face significant pressure to reduce its emissions. The use of sustainable aviation fuels is the best way to reduce aviation emissions by 2050. Moreover, in addition to the application of sustainable aviation fuel, it will be necessary to develop a new generation of aircraft introducing new materials and upgrading technology, implement additional carbon absorption measures, and make use of carbon trading markets to facilitate China's civil aviation industry's contribution to reduce climate change.

Adoption of mobile health services using the unified theory of acceptance and use of technology model: Self-efficacy and privacy concerns.

Mobile health (mHealth) services have been widely used in medical services and health management through mobile devices and multiple channels, such as smartphones, wearable equipment, healthcare applications (Apps), and medical platforms. However, the number of the users who are currently receiving the mHealth services is small. In China, more than 70% of internet users have never used mHealth services. Such imbalanced situation could be attributed to users' traditional concept of medical treatment, psychological factors (such as low self-efficacy) and privacy concerns. The purpose of this study is to explore the direct and indirect effects of mHealth users' self-efficacy and privacy concerns on their intention to adopt mHealth services, providing guidelines for mHealth service providers to enhance users' intention of adoption. A questionnaire was designed by the research team and 386 valid responses were collected from domestic participants in China. Based on the unified theory of acceptance and use of technology (UTAUT) model, a research model integrated self-efficacy and privacy concerns was constructed to investigate their effects on users' intention to adopt mobile mHealth services. The results show that self-efficacy could facilitate users' intention to adopt mHealth services, and had a significantly positive effect on perceived ubiquity, effort expectancy, performance expectancy and subjective norm. This study verifies the direct and indirect effects of self-efficacy and privacy concerns on users' intention to adopt mHealth services, providing a different perspective for studying mHealth adoption behavior. The findings could provide guidelines for mHealth service providers to improve their service quality and enhance users' intention of adoption.

Detection of Chromosomal Segments Introgressed from Wild Species of Carrot into Cultivars: Quantitative Trait Loci Mapping for Morphological Features in Backcross Inbred Lines.

Cultivated carrot is thought to have been domesticated from a wild species, and various phenotypes developed through human domestication and selection over the past several centuries. Little is known about the genomic contribution of wild species to the phenotypes of present-day cultivars, although several studies have focused on identifying genetic loci that contribute to the morphology of storage roots. A backcross inbred line (BIL) population derived from a cross between the wild species Daucus carota ssp. carota "Songzi" and the orange cultivar "Amsterdam forcing" was developed. The morphological features in the BIL population became more diverse after several generations of selfing BC2F1 plants. Only few lines retained features of wild parent. Genomic resequencing of the two parental lines and the BILs resulted in 3,223,651 single nucleotide polymorphisms (SNPs), and 13,445 bin markers were generated using a sliding window approach. We constructed a genetic map with 2027 bins containing 154,776 SNPs; the total genetic distance was 1436.43 cM and the average interval between the bins was 0.71 cm. Five stable QTLs related to root length, root shoulder width, dry material content of root, and ratio of root shoulder width to root middle width were consistently detected on chromosome 2 in both years and explained 23.4-66.9% of the phenotypic variance. The effects of introgressed genomic segments from the wild species on the storage root are reported and will enable the identification of functional genes that control root morphological traits in carrot.

Cross-Linking-Density-Changeable Microneedle Patch Prepared from a Glucose-Responsive Hydrogel for Insulin Delivery.

To simplify the preparation process of a glucose-responsive microneedle patch, a cross-linking-density changeable microneedle patch was designed. The microneedle patch was made up of a hydrogel formed by phenylboronic acid-grafted polyallylamine and poly(vinyl alcohol) (PVA). The gel was cross-linked by boronate ester bonds between phenylboronic acid groups and PVA. It still had fluidity and could be filled into a mold to prepare microneedle patches. Moreover, insulin could be directly loaded into the microneedle patch by mixing with the gel. The boronate ester bond would be broken in the presence of glucose, resulting in a decrease in the cross-linking density. Therefore, the gel could achieve a greater swelling degree and insulin could be released faster. In addition, PVA chains were crystallized by repeatedly freezing and thawing to improve the mechanical strength of the microneedle patch. In terms of glucose-dependent insulin release, the gel showed good glucose-responsive insulin-release ability. Through additional ion cross-linking, the microneedle patch could also control the insulin release according to glucose concentration. In the hypoglycemic experiment of diabetic rats, the microneedle patch effectively pierced the skin and slowly released insulin.

Is diabetes mellitus a risk factor for low bone density: a systematic review and meta-analysis.

BACKGROUND: This systematic review aimed to investigate whether diabetes mellitus is a risk factor for low bone density, as this might be important and necessary for doctors specialized in treating patients with low bone density. METHODS: PubMed, Embase, CINAHL, and SciELO were searched for cohort, case-control, and cross-sectional studies that investigated the effects of diabetes mellitus on bone mineral density till January 2020. Data screening and extraction are done independently, whereas the methodological quality of the studies was assessed according to the Newcastle-Ottawa Scale (NOS). RESULTS: A total of 14 studies that met the eligibility criteria including 24,340 participants were enrolled. The overall quality of the studies had a scale of over 6 points. The overall odds ratio (OR) regarding the risk of diabetes mellitus in low bone density patients was 1.20 [95% confidence interval (CI)0.80-1.79, P = 0.30], and type 2 diabetes mellitus (T2DM) (OR = 0.69 [0.11, 4.55], P = 0.70). Subgroup analysis revealed that whether females or males, developed or developing countries, T2DM, studies after 2015, and quality over 7 points (all P values > 0.05) showed no significant differences with the risk of low bone density, except type 1 diabetes mellitus (T1DM) (OR = 3.83 [1.64, 8.96], P = 0.002), and studies before 2015 (OR = 1.76 [1.06, 2.92], P = 0.03), and quality below 7 points (OR = 2.27 [1.50, 3.43], P = 0.0001). Funnel plot showed no significant asymmetry. CONCLUSIONS: These findings revealed no relationship between T2DM and low bone density, and also, the evidence between T1DM and low bone density is inadequate, requiring further analysis of well-designed cohort studies.

Chitosan reinforced hydrogels with swelling-shrinking behaviors in response to glucose concentration.

Different hydrogels of poly(acrylamide-co-3-acrylamido phenylboronic acid-co-chitosan grafted maleic acid) (P(AM-co-AAPBA-co-CSMA)s) were synthesized using poly(ethylene glycol) diacrylate (PEGDA) as a crosslinker to serve for glucose sensing and insulin delivery. The structure and morphology of the hydrogels, named as CSPBA were studied by FTIR and SEM, while the mechanical properties were tested using dynamic mechanical analysis (DMA) and universal testing machine. The prepared hydrogels shrinked at low glucose concentration due to the 2:1 boronate-glucose binding, and swelled at high glucose concentration because of 1:1 boronate-glucose complexation. Both binding mechanisms are useful for glucose sensing and insulin delivery. The integration of CSMA into hydrogels network not only enhanced the response to glucose at physiological pH, but also improved the mechanical properties and increased the encapsulation efficiency of the prepared hydrogels. These CSPBA may find potential as implantable hydrogels in applications were continuous glucose monitoring and controlled release is beneficial.

Isolated Langerhans cell histiocytosis in the hypothalamic-pituitary region: a case report.

BACKGROUND: Langerhans cell histiocytosis (LCH) is a rare disease that mainly affects children, but this disease is significantly rarer in patients who are older than 15 years. In this disease, any organ can be involved. The skeleton, skin and lung are commonly affected, and isolated hypothalamic-pituitary (HP) involvement is relatively rare. Here we report a 17-year-old adolescent with isolated HP-LCH of enlarged pituitary stalk presented with central diabetes insipidus (CDI). CASE PRESENTATION: A 17-year-old male adolescent with polydipsia and polyuria accompanied with elevated serum sodium level and low urine osmolality for 3 weeks was referred to our hospital. After admission, hormonal evaluation showed that his growth hormone (GH) was slightly elevated, and serum osmolality and glucose were normal. The fluid deprivation-vasopressin test demonstrated CDI. Imaging examination showed an obvious thickening of the pituitary stalk. Lymphocytic hypophysitis, sarcoidosis and granulation tissue lesions were suspected. After oral 1-deamino-8-Darginine vasopressin (DDAVP) and prednisone were administered for 2 months, symptoms were relieved, and he discontinued taking the drugs by himself. On reexamination, imaging revealed changes in the size and shape of the pituitary stalk, with thickened nodules. Then, a diagnostic biopsy of the pituitary stalk lesion was performed. Immunohistochemistry confirmed the definitive diagnosis of LCH. The clinical symptoms subsided with oral hormone replacements. CONCLUSION: CDI is a rare symptom in children and adolescents. Most of the causes are idiopathic, while others are caused by central nervous system (CNS) disorders. Meanwhile, lymphocytic hypophysitis, germinoma, LCH and other CNS disorders can all present as thickening of the pituitary stalk, diffuse enlargement of the pituitary gland, and weakening of high signal intensity in the neurohypophysis on magnetic resonance imaging (MRI). The differential diagnosis among these diseases depends on immunohistochemistry evidence.

PPWD1 is associated with the occurrence of postmenopausal osteoporosis as determined by weighted gene co­expression network analysis.

Postmenopausal osteoporosis (PMO) is the most common type of primary osteoporosis (OP), a systemic skeletal disease. Although many factors have been revealed to contribute to the occurrence of PMO, specific biomarkers for the early diagnosis and therapy of PMO are not available. In the present study, a weighted gene co­expression network analysis (WGCNA) was performed to screen gene modules associated with menopausal status. The turquoise module was verified as the clinically significant module, and 12 genes (NUP133, PSMD12, PPWD1, RBM8A, CRNKL1, PPP2R5C, RBM22, PIK3CB, SKIV2L2, PAPOLA, SRSF1 and COPS2) were identified as 'real' hub genes in both the protein­protein interaction (PPI) network and co­expression network. Furthermore, gene expression analysis by microarray in blood monocytes from pre­ and post­menopausal women revealed an increase in the expression of these hub genes in postmenopausal women. However, only the expression of peptidylprolyl isomerase domain and WD repeat containing 1 (PPWD1) was correlated with bone mineral density (BMD) in postmenopausal women. In the validation set, a similar expression pattern of PPWD1 was revealed. Functional enrichment analysis revealed that the fatty acid metabolism pathway was significantly abundant in the samples that exhibited a higher expression of PPWD1. Collectively, PPWD1 is indicated as a potential diagnostic biomarker for the occurrence of PMO.

Hepatic steroid sulfatase critically determines estrogenic activities of conjugated equine estrogens in human cells in vitro and in mice.

Conjugated equine estrogens (CEEs), whose brand name is Premarin, are widely used as a hormone-replacement therapy (HRT) drug to manage postmenopausal symptoms in women. Extracted from pregnant mare urine, CEEs are composed of nearly a dozen estrogens existing in an inactive sulfated form. To determine whether the hepatic steroid sulfatase (STS) is a key contributor to the efficacy of CEEs in HRT, we performed estrogen-responsive element (ERE) reporter gene assay, real-time PCR, and UPLC-MS/MS to assess the STS-dependent and inflammation-responsive estrogenic activity of CEEs in HepG2 cells and human primary hepatocytes. Using liver-specific STS-expressing transgenic mice, we also evaluated the effect of STS on the estrogenic activity of CEEs in vivo We observed that CEEs induce activity of the ERE reporter gene in an STS-dependent manner and that genetic or pharmacological inhibition of STS attenuates CEE estrogenic activity. In hepatocytes, inflammation enhanced CEE estrogenic activity by inducing STS gene expression. The inflammation-responsive estrogenic activity of CEEs, in turn, attenuated inflammation through the anti-inflammatory activity of the active estrogens. In vivo, transgenic mice with liver-specific STS expression exhibited markedly increased sensitivity to CEE-induced estrogenic activity in the uterus resulting from increased levels of liver-derived and circulating estrogens. Our results reveal a critical role of hepatic STS in mediating the hormone-replacing activity of CEEs. We propose that caution needs to be applied when Premarin is used in patients with chronic inflammatory liver diseases because such patients may have heightened sensitivity to CEEs due to the inflammatory induction of STS activity.

A rare case of pure testosterone-secreting adrenal adenoma in a postmenopausal elderly woman.

BACKGROUND: Hyperandrogenemia is more common in puberty and reproductive age, but relatively rare in postmenopausal women. Postmenopausal virilization may result from androgen-producing tumors. Androgen-secreting adrenal tumors are rare in clinical practice and are diagnosed as adrenocortical carcinoma, most of which can co-secrete androgen and cortisol. Highly elevated serum testosterone level with normal adrenal androgens such as dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEAS) and androstenedione is usually regarded as ovary origin. Here we describe an unusual case of a postmenopausal woman with markedly elevated serum testosterone level, while DHEAS, androstenedione, 17-hydroxyprogesterone and cortisol were within the normal range. CASE PRESENTATION: A 67-year-old postmenopausal woman with hirsutism in the upper lip and armpit, accompanied by clitoromegaly for 5 months. Hormonal evaluation showed markedly elevated serum testosterone level (714.8 ng/ml), whereas DHEAS, androstenedione, 17-hydroxyprogesterone, and cortisol were within the normal range. Imaging examination showed a mass of 1.5 cm in diameter in the left adrenal gland and normal appearance of both ovaries. PET-CT indicated that it was a case of benign adrenal adenoma and excluded ovarian abnormalities and other ectopic tumors. Thus, a pure testosterone-secreting adrenal tumor was suspected and then adrenalectomy was performed. Histology and immunohistochemistry furtherly confirmed the benign adrenocortical adenoma with immunohistochemistry positive for inhibin α, melan A, ß-captenin, SYN (focal), Ki-67(< 3%), and negative for chromogranin (CgA), cytokeratin (CK), S-100, P53. After surgery, the level of testosterone returned to normal range and the clinical symptoms also subsided. CONCLUSIONS: Pure testosterone-secreting adrenal adenomas are extremely rare, but it can induce severe hyperandrogenism and virilization. The source identification of hyperandrogenemia only based on the levels of testosterone, DHEAS and androstenedione is limited. It is important to evaluate not only ovaries but also adrenals in all women with virilization particularly during menopause, even their androstenedione, DHEA and DHEAS level are normal.

Preparation, properties and challenges of the microneedles-based insulin delivery system.

Microneedle technology relates to pharmacy, polymer chemistry and micromachining. Microneedle can effectively deliver insulin into systemic circulation across the skin. This process does not affect the activity of insulin. Compared to subcutaneous injection, microneedles cause less pain for their special structure. This review thoroughly discusses the preparation technologies of the microneedles-based insulin delivery system including solid, hollow, dissolving, phase transition, glucose-responsive microneedle patches. In the meantime, the properties, challenges and clinical/commercial status of the microneedles-based insulin delivery system are also discussed in this review.

An ovarian Leydig cell tumor of ultrasound negative in a postmenopausal woman with hirsutism and hyperandrogenism: A case report.

RATIONALE: The incidence of severe hyperandrogenism associated with masculinity in women is very low. While rare and difficult to diagnose, androgen secreting tumors should be suspected in women with hyperandrogenism and hirsutism, especially in the postmenopausal population. Herein we present one case of ovarian Leydig cell tumor (LCT) with markedly elevated serum testosterone levels and frank hirsutism. PATIENT CONCERNS: A 60-year-old woman, presented with increased hair growth and androgenic alopecia and the hormonal laboratory examination showed that she had elevated serum testosterone level and normal dehydroepiandrosterone sulfate (DHEAS), androstenedione, 17- hydroxyprogesterone, cortisol and thyroid stimulating hormone (TSH). DIAGNOSES: The diagnosis of possible testosterone secreting tumor was performed when pelvic computed tomography (CT) and magnetic resonance image (MRI) showed a right adnexal mass of 15mm×16mm indicative of sex cord- stromal tumors. INTERVENTIONS: The patient received laparoscopic total abdominal hysterectomy and bilateral salpingo-oophorectomy. OUTCOMES: After operation, testosterone got back to the normal level and clinical symptoms subsided. LESSONS: It is common that postmenopausal androgen excess is a state of relative or absolute androgen excess originating from the adrenal gland and/or ovaries. In either case, doctors need to assess such patients and exclude relatively rare potential causes of tumors. Any woman who has hirsutism or frank evidence of markedly increased testosterone should exclude this kind of possibility of androgen producing tumors. It is possible to determine the origin of androgen hypersecretion with the severity of symptoms, the extent of androgen excess, and the relevant imaging studies. Since LCT are rare ovarian sex-cord stromal tumors, it can be beneficial for diagnosis with careful research of patient history of the defeminization followed by virilization, and a CT and MRI image.

Metabolic Profiling of Plasma in Gestational Diabetes Mellitus Using Liquid Chromatography and Q-TOF Mass Spectrometry.

BACKGROUND: To delineate the metabolomic profiling and identify early diagnostic biomarkers in maternal plasma from the pregnant women who subsequently developed gestational diabetes mellitus (GDM) using liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (LC-Q-TOF MS). METHODS: Plasma samples were collected from GDM pregnant women (n = 30) and healthy controls (n = 30) at the 20th gestational week in Huzhou Central Hospital and Huzhou Maternal and Child Health Hospital. The principle component analysis (PCA), partial least-squares discriminant analysis (PLS-DA), and orthogonal PLS (OPLS) were sequentially applied to discover the differential metabolites for GDM diagnosis. Further, we analyzed the identified biomarkers in the MetPA database in order to reveal the key relevant metabolism in GDM. RESULTS: Twenty-four out of 975 aligned metabolites were distinguished among GDM plasma and healthy controls. In particular, the level of linolenic acid and arachidonic acid was significantly elevated in GDM. CONCLUSIONS: The linolenic acid and arachidonic acid could be selected as new potent biomarkers for GDM diagnosis and prognosis in early pregnancy; however, they still need to be confirmed from large samples in future.

Efficacy and safety of alogliptin in patients with type 2 diabetes mellitus: A multicentre randomized double-blind placebo-controlled Phase 3 study in mainland China, Taiwan, and Hong Kong.

BACKGROUND: This study determined the efficacy and safety of once-daily oral alogliptin in patients from mainland China, Taiwan, and Hong Kong with type 2 diabetes mellitus. METHODS: In this Phase 3 multicenter double-blind placebo-controlled 16-week trial, 506 patients were randomized to receive once-daily alogliptin 25 mg or placebo: 185 in the monotherapy group, 197 in the add-on to metformin group, and 124 in the add-on to pioglitazone group. The primary efficacy variable was the change from baseline (CFB) in HbA1c at Week 16; other efficacy measures included CFB to Week 16 in fasting plasma glucose (FPG), incidence of marked hyperglycemia (FPG ≥11.1 mmol/L), and the incidence of clinical HbA1c ≤6.5 % (48 mmol/mol) and ≤7.0 % (53 mmol/mol) at Week 16. Safety was assessed throughout the trial. RESULTS: Alogliptin monotherapy provided a significantly greater decrease in HbA1c from baseline to Week 16 compared with placebo (-0.58 %; 95 % confidence interval [CI] -0.78 %, -0.37 %; P < 0.001). As an add-on to metformin or pioglitazone, alogliptin also significantly decreased HbA1c compared with placebo (-0.69 % [95 % CI -0.87 %, -0.51 %; P < 0.001] and -0.52 % [95 % CI -0.75 %, -0.28 %; P < 0.001], respectively). In any treatment group versus placebo, alogliptin led to greater decreases in FPG (P ≤ 0.004) and a higher percentage of patients who achieved an HbA1c target of ≤6.5 % and ≤7.0 % (P ≤ 0.003). No weight gain was observed in any treatment group. A similar percentage of patients experienced drug-related, treatment-emergent adverse events in the alogliptin and placebo arms. Four and two patients in the alogliptin and placebo arms, respectively, experienced mild or moderate hypoglycemia. CONCLUSIONS: Alogliptin 25 mg once daily reduced HbA1c and FPG and enhanced clinical response compared with placebo when used as monotherapy or as an add-on to metformin or pioglitazone. Therapy with alogliptin was well tolerated.

Polymorphisms in TCF7L2 gene are associated with gestational diabetes mellitus in Chinese Han population.

This study aimed to investigate the possible association between diabetes susceptibility gene transcription factor 7-like 2 (TCF7L2) and gestational diabetes mellitus (GDM) in a Chinese Han population. A total of 556 GDM patients and 500 Non-GDM were included. Eighteen single nucleotide polymorphisms (SNPs) were evaluated. Fifteen tag SNPs were selected from HapMap CHB database with a minor allele frequency of >0.2 and r(2) of >0.8. Three additional SNPs were also chosen because these SNPs are associated with type 2 diabetes in East Asians. TCF7L2 rs290487, rs6585194, and rs7094463 polymorphisms were found to be significantly associated with GDM. In multivariate analysis, rs290487 genetic variation (OR = 2.686 per each C allele, P = 0.002), pre-BMI > 24 kg/m(2) (OR = 1.592, P = 0.018), age > 25 years (OR = 1.780, P = 0.012) and LDL-C > 3.6 mmol/L (OR = 2.034, P = 0.009) were identified as independent risk factors of GDM, rs7094463 genetic variation (OR = 0.429 per each G allele, P = 0.005) was identified as independent protect factor of GDM. This finding suggests that TCF7L2 rs290487, and rs7094463 were a potential clinical value for the prediction of GDM.

TCF7L2 involvement in estradiol- and progesterone-modulated islet and hepatic glucose homeostasis.

To evaluate the role of TCF7L2, a key regulator of glucose homeostasis, in estradiol (E2) and progesterone (P4)-modulated glucose metabolism, mouse insulinoma cells (MIN6) and human liver cancer cells (hepG2 and HUH7) were treated with physiological concentrations of E2 or P4 in the up- and down-regulation of TCF7L2. Insulin/proinsulin secretion was measured in MIN6 cells, while glucose uptake and production were evaluated in liver cancer cells. E2 increased insulin/proinsulin secretion under both basal and stimulated conditions, whereas P4 increased insulin/proinsulin secretion only under glucose-stimulated conditions. An antagonistic effect, possibly concentration-dependent, of E2 and P4 on the regulation of islet glucose metabolism was observed. After E2 or P4 treatment, secretion of insulin/proinsulin was positively correlated with TCF7L2 protein expression. When TCF7L2 was silenced, E2- or P4-promoted insulin/proinsulin secretion was significantly weakened. Under glucotoxicity conditions, overexpression of TCF7L2 increased insulin secretion and processing. In liver cancer cells, E2 or P4 exposure elevated TCF7L2 expression, enhanced the activity of insulin signaling (pAKT/pGSK), reduced PEPCK expression, subsequently increased insulin-stimulated glucose uptake, and decreased glucose production. Silencing TCF7L2 eliminated effects of E2 or P4. In conclusion, TCF7L2 regulates E2- or P4-modulated islet and hepatic glucose metabolism. The results have implications for glucose homeostasis in pregnancy.