Hepatogenous Diabetes: A Primer.

As liver is one of the primary organs involved in glucose homeostasis, it is not surprising that patients with liver dysfunction in chronic liver disease usually develop impaired glucose tolerance and subsequently overt diabetes later in their natural course. Diabetes that develops after the onset of cirrhosis of liver is usually referred to as hepatogenous diabetes (HD). It is an underrecognized and a hallmark endocrinological event in chronic liver disease. HD is associated with a higher risk of developing hepatic decompensations, such as ascites, variceal bleeding, hepatic encephalopathy, renal dysfunction, refractory ascites, and hepatocellular carcinoma along with reduced survival rates than normoglycemic patients with cirrhosis of liver. It is quite different from type 2 diabetes mellitus with the absence of classical risk factors, dissimilar laboratory profiles, and decreased incidence of microvascular complications. Furthermore, the management of patients with HD is challenging because of altered pharmacokinetics of most antidiabetic drugs and increased risk of hypoglycemia and other adverse effects. Hence, a clear understanding of the epidemiology, pathophysiology, clinical implications, laboratory diagnosis, and management of HD is essential for both hepatologists as well as endocrinologists, which is narrated briefly in this review.

Diagnostic Strategies for Gestational Diabetes Mellitus: Review of Current Evidence.

PURPOSE OF REVIEW: Currently, the diagnosis of gestational diabetes mellitus (GDM) lacks uniformity. Several controversies are still under debate, especially on the method of screening and diagnosis. This review focuses on recent literature and provides current evidence for the screening and diagnosis of GDM. RECENT FINDINGS: Selective screening would miss a significant number of women with GDM. In contrast, universal screening has been shown to be cost-effective, compared with selective screening, and is recommended by many medical societies. For the diagnostic methods for GDM, most observational cohort studies reported that the one-step method is associated with improved pregnancy outcomes and is cost-saving or cost-effective, compared with the two-step method, although these findings should be confirmed in the upcoming randomized controlled trials which compare the performance of one-step and two-step methods. On the other hand, the methods of early screening or diagnosis of GDM are varied, and current evidence does not justify their use during early pregnancy. In conclusion, current evidence favors universal screening for GDM using the one-step method. Early screening for GDM is not favorably supported by the literature.

Insulin Resistance in Polycystic Ovary Syndrome Improved by Chinese Medicine Dingkun Pill (): A Randomized Controlled Clinical Trial.

OBJECTIVE: To assess the efficacy and safety of the Chinese medicine Dingkun Pill (, DKP) on insulin resistance in women with polycystic ovary syndrome (PCOS). METHODS: A total of 117 women with PCOS were randomly assigned to Group A (38 women), Group B (40 women), or Group C (39 women) in a randomization sequence with SAS software and a 1:1:1 allocation ratio using random block sizes of 6, and were given 7 g of oral DKP daily (Group A), 1 tablet of Diane-35 orally daily (Group B), or 7 g of oral DKP daily plus 1 tablet of Diane-35 orally daily (Group C). Patients took all drugs cyclically for 21 consecutive days, followed by 7 drug-free days. The treatment course for the 3 groups was continued for 3 consecutive months. Oral glucose tolerance tests (OGTT) were performed before treatment and again after 2 and 3 months of therapy, respectively, and homeostasis model assessment for insulin resistance (HOMA-IR) and quantitative insulin sensitivity check index (QUICKI) were calculated. RESULTS: Of 117 women with PCOS, 110 completed the entire course of therapy: 35 in Group A, 36 in Group B, and 39 in Group C. After treatment, all three groups showed significant decreases in fasting glucose: at 1 h glucose decreased significantly in Group A (by 0.5 ± 1.4 mmol/L, P=0.028) and Group C (by 0.5 ± 1.2 mmol/L, P=0.045); while showing a tendency to increase in Group B (by 0.4 ± 1.9 mmol/L, P=0.238). HOMA-IR decreased significantly in Group C [by 0.5 (-2.2 to 0.5) mIU mmol/L2, P=0.034]. QUICKI was significantly increased in Groups A and C (by 0.009 ± 0.02, P=0.033 and by 0.009 ± 0.027, P=0.049, respectively), while no change was observed in Group B. Repeated-measure ANOVA showed that the absolute changes in all parameters (except for glucose at 1 h), including glucose and insulin levels at all time-points during OGTT and in HbA1c, HOMA-IR, and QUICKI, were not significantly different among the 3 groups after treatment (P>0.05). CONCLUSION: DKP or DKP combined with Diane-35 produce a slight improvement in insulin sensitivity compared with Diane-35 alone in PCOS patients (Trial Registration: ClinicalTrials.gov, NCT03264638).

Risk factors for abnormal postpartum glucose outcome in women with gestational diabetes mellitus diagnosed by modified The International Association of the Diabetes and Pregnancy Study Groups criteria.

AIM: To characterize postpartum glycemic outcome and related risk factors in women diagnosed with gestational diabetes mellitus (GDM) by modified The International Association of the Diabetes and Pregnancy Study Groups (IADPSG) criteria. METHODS: This is a cohort study of 583 patients with GDM diagnosed by modified IADPSG criteria for Chinese women from 2016 to 2017. According to their oral glucose tolerance tests (OGTT) results at 6-12 weeks postpartum, the subjects were categorized into normal glucose tolerance (NGT) and abnormal glucose tolerance (AGT) groups using the World Health Organization criteria. Multivariate pregestational and gestational factors were compared between the NGT and AGT groups. RESULTS: A total of 174 (29.9%) and 17 (2.9%) subjects were found to have AGT and diabetes, respectively. Multivariate logistic regression analysis showed that elevated 2 h postprandial plasma glucose (PPG) at the diagnosis of GDM (odds ratio [OR], 1.485; 95% confidence interval [CI], 1.253-1.760) and multigravida (OR, 2.187; 95% CI, 1.152-4.150) were independent predictors of AGT in GDM women. Subjects with elevated OGTT 2 h PPG at gestational 24-28 weeks had a 2.254-fold increased risk (95% CI, 1.439-3.530) of developing AGT. Presence of multigravida further increased the risk to 7.329 (95% CI, 2.879-18.659). Women with two or three elevated glucose levels at OGTT had higher risk for postpartum dysglycemia. There was a robust and continuous association of OGTT 2 h PPG at gestational 24-28 weeks with abnormal postpartum glycemic outcomes. CONCLUSION: In GDM women, OGTT 2 h PPG at gestational 24-28 weeks appear to confer a continuously increased risk for postpartum dysglycemia, which is further increased by the presence of multigravida. Multigravida and women with two or three elevated glucose levels during OGTT have higher risks of impaired postpartum glucose metabolism.

Insulin Resistance in Polycystic Ovary Syndrome Improved by Chinese Medicine Dingkun Pill (): A Randomized Controlled Clinical Trial / 中国结合医学杂志

OBJECTIVE@#To assess the efficacy and safety of the Chinese medicine Dingkun Pill (, DKP) on insulin resistance in women with polycystic ovary syndrome (PCOS).@*METHODS@#A total of 117 women with PCOS were randomly assigned to Group A (38 women), Group B (40 women), or Group C (39 women) in a randomization sequence with SAS software and a 1:1:1 allocation ratio using random block sizes of 6, and were given 7 g of oral DKP daily (Group A), 1 tablet of Diane-35 orally daily (Group B), or 7 g of oral DKP daily plus 1 tablet of Diane-35 orally daily (Group C). Patients took all drugs cyclically for 21 consecutive days, followed by 7 drug-free days. The treatment course for the 3 groups was continued for 3 consecutive months. Oral glucose tolerance tests (OGTT) were performed before treatment and again after 2 and 3 months of therapy, respectively, and homeostasis model assessment for insulin resistance (HOMA-IR) and quantitative insulin sensitivity check index (QUICKI) were calculated.@*RESULTS@#Of 117 women with PCOS, 110 completed the entire course of therapy: 35 in Group A, 36 in Group B, and 39 in Group C. After treatment, all three groups showed significant decreases in fasting glucose: at 1 h glucose decreased significantly in Group A (by 0.5 ± 1.4 mmol/L, P=0.028) and Group C (by 0.5 ± 1.2 mmol/L, P=0.045); while showing a tendency to increase in Group B (by 0.4 ± 1.9 mmol/L, P=0.238). HOMA-IR decreased significantly in Group C [by 0.5 (-2.2 to 0.5) mIU mmol/L, P=0.034]. QUICKI was significantly increased in Groups A and C (by 0.009 ± 0.02, P=0.033 and by 0.009 ± 0.027, P=0.049, respectively), while no change was observed in Group B. Repeated-measure ANOVA showed that the absolute changes in all parameters (except for glucose at 1 h), including glucose and insulin levels at all time-points during OGTT and in HbA1c, HOMA-IR, and QUICKI, were not significantly different among the 3 groups after treatment (P>0.05).@*CONCLUSION@#DKP or DKP combined with Diane-35 produce a slight improvement in insulin sensitivity compared with Diane-35 alone in PCOS patients (Trial Registration: ClinicalTrials.gov, NCT03264638).

Comparison of metabolic responses to the mixed meal tolerance test vs the oral glucose tolerance test after successful clinical islet transplantation.

Following islet transplantation, mixed meal tolerance tests (MMTs) are routinely utilized to assess graft function, but how the 90-minute MMTT glucose value relates to a 120-minute glucose concentration of ≥11.1 mmol/L used to diagnose diabetes following a standardized 75 g-OGTT, is not known. We examined this relationship further. Thirteen subjects with Type 1 diabetes and stable transplant grafts, not on exogenous insulin with HbA1c < 7% (53 mmol/mol), were studied on 17 occasions with paired OGTTs and MMTTs. Receiver operating characteristic (ROC) curves were constructed to derive the 90-minute MMTT glucose threshold associated with a 120-minute glucose concentration following a 75 g-OGTT (OGTT120 ) ≥11.1 mmol/L and their diagnostic accuracy. Studies with OGTT120 ≥11.1 mmol/L (n = 5) had diminished C-peptide: glucose, greater integrated glucose and diminished insulin: glucose area under the curve (AUC) ratios (0-120 minutes) and disposition indices; all P < .05, contrasting with MMTTs where no difference in the 90-minute glucose concentrations, C-peptide:glucose, integrated glucose, C-peptide and C-peptide: glucose AUCs (0-90 minutes) was seen; all P > .05. A 90-minute MMTT glucose concentration ≥8.0 mmol/L demonstrated a sensitivity and specificity of ≥80% for the diagnosis of OGTT120 ≥11.1 mmol/L; area under ROC curve (mean ± SEM) 73 ± 13%. A 90-minute MMTT glucose ≥8.0 mmol/L, identifies islet transplant recipients who may require closer monitoring for graft dysfunction.

135-Day Interventions of Yam Dioscorin and the Dipeptide Asn-Trp (NW) To Reduce Weight Gains and Improve Impaired Glucose Tolerances in High-Fat Diet-Induced C57BL/6 Mice.

The C57BL/6J mice were fed a 135-day normal diet or a high-fat diet (HFD) without, or concurrent with, a single yam dioscorin (80 mg/kg) or dipeptide NW (40 mg/kg) intervention every day. The final body weights (g) of mice were 26.1 ± 1.4, 34.97 ± 2.1, 31.75 ± 2.6, and 31.66 ± 3.1, respectively, for normal diet-fed, HFD-fed, dioscorin-intervened, and NW-intervened group. The mice in both intervened groups showed similar less weight gains and had significant differences (P < 0.05) compared to those in the HFD group under the same cumulative HFD intakes. The blood biochemical index of mice with dioscorin interventions showed significantly lower contents in total cholesterol and low-density lipoprotein, and NW interventions showed significantly lower total triglyceride contents compared to those of the HFD group (P < 0.05). Both intervened mice exhibited similar reductions in total visceral lipid contents and have significant differences compared to those of the HFD group (P < 0.05). The dioscorin intervention was better than NW interventions in lowering blood glucose levels by oral glucose tolerance tests and both showed significant differences (P < 0.05) compared to those in the HFD group. Yam dioscorin or dipeptide NW will potentially be used for preventive functional foods of less body weight gains and impaired glucose tolerance controls, which require further clinical trial investigations.

Risk factors for postpartum glucose intolerance in women with gestational diabetes mellitus.

OBJECTIVES: To determine the risk factors for glucose intolerance (GI) during the postpartum period in women with gestational diabetes mellitus (GDM). METHODS: This prospective cohort study included 72 Japanese women with GDM who underwent 75 g oral glucose tolerance tests (OGTT) at 12 weeks after delivery. These women were divided into the GI group and the normal group based on postpartum OGTT. Risk factors for GI, including levels of blood glucose (BG), area under the curve (AUC) of glucose, AUC insulin, HbA1c, homeostasis model assessment-insulin resistance (HOMA-IR), HOMA-ß, insulinogenic index (II) and the oral disposition index (DI) in antepartum OGTT, were analyzed by logistic regression analyses. RESULTS: Of the 72 women, 60 (83.3%) were normal and 12 (16.7%) had GI. By univariate logistic regression analyses, fasting BG, AUC glucose, HOMA-ß, II and oral DI were selected as risk factors for GI. Multivariate logistic regression analysis revealed that the level of II in antepartum OGTT was a significant factor that predicted GI after delivery (odds ratio, 0.008; 95% CI, 0.0001-0.9; p < 0.05). CONCLUSIONS: II measured by OGTT during pregnancy might be a useful predictor of GI within the early postpartum period in women with GDM.

Chromanol 293B, an inhibitor of KCNQ1 channels, enhances glucose-stimulated insulin secretion and increases glucagon-like peptide-1 level in mice.

Glucose-stimulated insulin secretion (GSIS) is a highly regulated process involving complex interaction of multiple factors. Potassium voltage-gated channel subfamily KQT member 1 (KCNQ1) is a susceptibility gene for type 2 diabetes (T2D) and the risk alleles of the KCNQ1 gene appear to be associated with impaired insulin secretion. The role of KCNQ1 channel in insulin secretion has been explored by previous work in clonal pancreatic ß-cells but has yet to be investigated in the context of primary islets as well as intact animals. Genetic studies suggest that altered incretin glucagon-like peptide-1 (GLP-1) secretion might be a potential link between KCNQ1 variants and impaired insulin secretion, but this hypothesis has not been verified so far. In the current study, we examined KCNQ1 expression in pancreas and intestine from normal mice and then investigated the effects of chromanol 293B, a KCNQ1 channel inhibitor, on insulin secretion in vitro and in vivo. By double-immunofluorescence staining, KCNQ1 was detected in insulin-positive ß-cells and GLP-1-positive L-cells. Administration of chromanol 293B enhanced GSIS in cultured islets and intact animals. Along with the potentiated insulin secretion during oral glucose tolerance tests (OGTT), plasma GLP-1 level after gastric glucose load was increased in 293B treated mice. These data not only provided new evidence for the participation of KCNQ1 in GSIS at the level of pancreatic islet and intact animal but also indicated the potential linking role of GLP-1 between KCNQ1 and insulin secretion.

Design, synthesis and biological evaluation of 4-fluoropyrrolidine-2-carbonitrile and octahydrocyclopenta[b]pyrrole-2-carbonitrile derivatives as dipeptidyl peptidase IV inhibitors.

Based on the previous work in our group and the principle of computer-aided drug design, a series of novel ß-amino pyrrole-2-carbonitrile derivatives was designed and synthesized. Compounds 8l and 9l were efficacious and selective DPP4 inhibitors resulting in decreased blood glucose in vivo. Compound 8l had moderate DPP4 inhibitory activity (IC50 = 0.05 µM) and good oral bioavailability (F = 53.2%). Compound 9l showed excellent DPP4 inhibitory activity (IC50 = 0.01 µM), good selectivity (selective ratio: DPP8/DPP4 = 898.00; DPP9/DPP4 = 566.00) against related peptidases, and good efficacy in an oral glucose tolerance tests in ICR mice and moderate PK profiles (F = 22.8%, t1/2 = 2.74 h). Moreover, compound 9l did not block hERG channel and exhibited no inhibition of liver metabolic enzymes such as CYP2C9.

Multiple intravenous infusions of bone marrow mesenchymal stem cells reverse hyperglycemia in experimental type 2 diabetes rats.

The worldwide rapid increase in diabetes poses a significant challenge to current therapeutic approaches. Single-dose mesenchymal stem cell (MSC) infusion ameliorates hyperglycemia but fails to restore normoglycemia in diabetic animals. We therefore hypothesized that multiple intravenous MSC infusions may reverse hyperglycemia in type 2 diabetes (T2D) rats. We administered serial allogenous bone-marrow derived MSC infusions (1 × 10(6)cells/infusion) via the tail vein once every 2 weeks to T2D rats, induced by high-fat diet and streptozocin (STZ) administration. Hyperglycemia decreased only transiently after a single infusion in early-phase (1 week) T2D rats, but approximated normal levels after at least three-time infusions. This normal blood level was maintained for at least 9 weeks. Serum concentrations of both insulin and C-peptide were dramatically increased after serial MSC infusions. Oral glucose tolerance tests revealed that glucose metabolism was significantly ameliorated. Immunofluorescence analysis of insulin/glucagon staining revealed the restoration of islet structure and number after multiple MSC treatments. When multiple-MSC treatment was initiated in late-phase (5 week) T2D rats, the results were slightly different. The results of this study suggested that a multiple-MSC infusion strategy offers a viable clinical option for T2D patients.

Effects of Teucrium Polium Aerial Parts extract on oral glucose tolerance tests and pancreas histopathology in Streptozocin-induced diabetic rats.

Teucrium polium can reduce serum glucose. There are few reports in the literature related to this subject and the resolution of this mechanism requires further experiments. The aim of the present study was to evaluate the effects of Teucrium polium aerial parts extracts on oral glucose tolerance tests and pancreas histology in streptozocin-induced diabetic rats. In order to prepare the aqueous concentrate, aerial parts extract was dissolved in distilled water and was boiled for 30 minutes. For the preparation of ethanolic solution, powder was dissolved in ethanol and mixed by a shaker. Diabetic rats were induced with single IP injection of streptozotocin (STZ) at a dose of 50 mg/kg body weight dissolved in normal saline just before use to the 16 hr fast rats. Both groups, diabetic and normal were sacrificed by ether anesthesia. The tissue samples were formalin fixed and paraffin embedded for microscopic examination in accordance with routine laboratory procedures. Blood was collected from the tail vein of the rats. Serum glucose levels were then measured by commercial kits by using a glucose oxidized method. There were no biochemical abnormalities or histological changes in the pancreas of control rats. Post treatment of Teucrium polium aerial parts extract reduced the severity of streptozotocin diabetic pancreases. Our histopathological investigation along with the biochemical evaluations showed a significant effect on histological changes in the pancreas of induced diabetic rats upon Teucrium polium aerial parts extract treatment (P<0.05).