Dorzagliatin is a novel dual-acting allosteric activator of hepatic and beta-cell glucokinase (GCK). Dorzagliatin improved second-phase insulin secretion in type 2 diabetes and heterozygous carriers ...of GCK mutations. We investigated the effects of dorzagliatin on insulin secretion and glucagon suppression during hyperglycemic clamps in individuals with impaired glucose tolerance (IGT) and normal controls. In a double-blind, single-dose, randomized cross-over study, 9 participants with IGT (mean age 55±7.5years, 5 female) and 10 controls (39.5±11.8 years, 5 female) underwent 2-hour 12 mmol/l hyperglycemic clamp following a single dose of dorzagliatin 50mg or matched placebo. Insulin, C-peptide and glucagon were measured at regular intervals. In controls, dorzagliatin significantly increased basal insulin (48.2±26.5 vs 36.8±16.6 pmol/L, p=0.0006) and second-phase insulin area under the curve (AUC) (25164 ± 22525 vs 17533 ± 12043 pmol/L.min, p=0.049) compared with placebo. Glucagon was also significantly suppressed after dorzagliatin (AUC0-120min 161±58 vs 234±70 pmol/L.min, p=0.0009) in the control group. The IGT group showed significantly higher steady-state C-peptide response (2193±531 vs 1768±351 pmol/L, p=0.013) following dorzagliatin, but similar basal, acute insulin secretion and glucagon levels following both treatments. Dorzagliatin did not affect the insulin sensitivity in either subject group. Dorzagliatin increased second-phase insulin secretion in IGT, while additionally suppressing glucagon and enhancing basal insulin secretion in normal controls. Disclosure Z. Bai: None. K. Wang: Employee; Hua Medicine (Shanghai) Ltd., Shanghai, China. T. Yau: None. E.W. Poon: None. A. Luk: Research Support; Novo Nordisk, Amgen Inc., Merck Sharp & Dohme Corp., Roche Pharmaceuticals, Biogen, Boehringer-Ingelheim, Shanghai Junshi Biosciences CO.Ltd. R.C. Ma: Advisory Panel; AstraZeneca. Other Relationship; Bayer Inc., Boehringer-Ingelheim. Advisory Panel; Merck & Co., Inc. Other Relationship; Roche Diagnostics, Novo Nordisk. Advisory Panel; Takeda Pharmaceutical Company Limited. Other Relationship; GemVCare Ltd. A.P. Kong: Speaker's Bureau; Abbott. Advisory Panel; Merck Sharp & Dohme Corp. Speaker's Bureau; Boehringer-Ingelheim, Bayer Inc., AstraZeneca. Other Relationship; Dexcom, Inc. Speaker's Bureau; Eli Lilly and Company, Novo Nordisk, Sanofi. Advisory Panel; Kyowa Kirin Co., Ltd., Abbott. E. Chow: Research Support; Merck KGaA. Speaker's Bureau; AstraZeneca. Advisory Panel; Boehringer-Ingelheim. Research Support; Medtronic. Speaker's Bureau; Zuellig Pharma Holdings Pte. Ltd., Abbott. L. Chen: None. J.C. Chan: Research Support; AstraZeneca, Hua Medicine. Consultant; Sanofi. Research Support; Servier Laboratories. Consultant; Viatris Inc. Research Support; Merck & Co., Inc. Stock/Shareholder; GemVCare Ltd. Board Member; Asia Diabetes Foundation. Speaker's Bureau; Zuellig Pharma Holdings Pte. Ltd. Advisory Panel; Bayer Inc. Speaker's Bureau; Boehringer-Ingelheim. Funding Hua Medicine investigator initiated study grant; Health and Medical Research Fund (CTC-CUHK)
AbstractObjectiveTo update a previous individual participant data meta-analysis and determine the accuracy of the Patient Health Questionnaire-9 (PHQ-9), the most commonly used depression screening ...tool in general practice, for detecting major depression overall and by study or participant subgroups.DesignSystematic review and individual participant data meta-analysis.Data sourcesMedline, Medline In-Process, and Other Non-Indexed Citations via Ovid, PsycINFO, Web of Science searched through 9 May 2018.Review methodsEligible studies administered the PHQ-9 and classified current major depression status using a validated semistructured diagnostic interview (designed for clinician administration), fully structured interview (designed for lay administration), or the Mini International Neuropsychiatric Interview (MINI; a brief interview designed for lay administration). A bivariate random effects meta-analytic model was used to obtain point and interval estimates of pooled PHQ-9 sensitivity and specificity at cut-off values 5-15, separately, among studies that used semistructured diagnostic interviews (eg, Structured Clinical Interview for Diagnostic and Statistical Manual), fully structured interviews (eg, Composite International Diagnostic Interview), and the MINI. Meta-regression was used to investigate whether PHQ-9 accuracy correlated with reference standard categories and participant characteristics.ResultsData from 44 503 total participants (27 146 additional from the update) were obtained from 100 of 127 eligible studies (42 additional studies; 79% eligible studies; 86% eligible participants). Among studies with a semistructured interview reference standard, pooled PHQ-9 sensitivity and specificity (95% confidence interval) at the standard cut-off value of ≥10, which maximised combined sensitivity and specificity, were 0.85 (0.79 to 0.89) and 0.85 (0.82 to 0.87), respectively. Specificity was similar across reference standards, but sensitivity in studies with semistructured interviews was 7-24% (median 21%) higher than with fully structured reference standards and 2-14% (median 11%) higher than with the MINI across cut-off values. Across reference standards and cut-off values, specificity was 0-10% (median 3%) higher for men and 0-12 (median 5%) higher for people aged 60 or older.ConclusionsResearchers and clinicians could use results to determine outcomes, such as total number of positive screens and false positive screens, at different PHQ-9 cut-off values for different clinical settings using the knowledge translation tool at www.depressionscreening100.com/phq.Study registrationPROSPERO CRD42014010673.
Summary Aims Sonographic measurement of mesenteric fat thickness (MFT) is a novel, accurate and simple tool to evaluate regional distribution of obesity. We used MFT to determine the optimal waist ...circumference (WC) values and associated risk factors for cardiovascular disease (CVD). Methods 282 healthy Chinese (age 41.8 ± 7.4 years, BMI 23.8 ± 3.3 kg/m2 ) was assessed. High MFT was defined as mean + 1 SD of the cohort. We compared the CVD risks including fatty liver amongst subjects with normal waist, central pre-obesity and central obesity. Results WC of 84.6 cm in men and 75.7 cm in women were the optimal cutoff values to predict high MFT with ROC analysis. Using WC cutoff values ≥85–90 cm and ≥90 cm to define central pre-obesity and obesity in men (≥75–80 cm and ≥80 cm in women), both central obesity and pre-obesity had higher MFT and CVD risk than those with normal waist. The frequencies of fatty liver in these 3 categories were 15.9%, 56.7% and 96.7% in men and 6.9%. 17.9% and 63.2% in women ( p < 0.001 for trend). Conclusion In addition to central obesity, “central pre-obesity” identifies subjects who harbor high CVD risks, fatty liver and excess visceral fat.
The rapid increase in diabetes prevalence globally has contributed to large increases in health care expenditure on diabetic complications, posing a major health burden to countries worldwide. Asians ...are commonly observed to have poorer β-cell function and greater insulin resistance compared to the Caucasian population, which is attributed by their lower lean body mass and central obesity. This “double phenotype” as well as the rising prevalence of young onset diabetes in Asia has placed Asians with diabetes at high risk of cardiovascular and renal complications, with cancer emerging as an important cause of morbidity and mortality. The experience from Hong Kong had demonstrated that a multifaceted approach, involving team-based integrated care, information technological advances, and patient empowerment programs were able to reduce the incidence of diabetic complications, hospitalizations, and mortality. System change and public policies to enhance implementation of such programs may provide solutions to combat the burgeoning health problem of diabetes at a societal level.
Type 2 diabetes mellitus is characterized histopathologically by islet amyloid deposits formed from islet amyloid polypeptide. The aim of this study was to investigate sex difference in islet amyloid ...of type 2 diabetic patients.
Pancreas specimens were collected from 235 autopsies with type 2 diabetes mellitus. Islet amyloid was identified with Congo red stain. The load of islet amyloid deposits was assessed by prevalence (percentage of cases with islet amyloid deposits), frequency (percentage of islets containing amyloid deposits), and severity (percentage of islet area occupied by amyloid deposits).
Women (n = 80) and men (n = 155) had similar age of death, duration of diabetes, body mass index, and hemoglobin (Hb)A1c level. Islet amyloid was found in 30.0% of the women and in 44.5% of the men (P = 0.035). None of 9 women younger than 50 years had islet amyloid. Frequency of amyloid-affected islets was 31.5% +/- 13.1% in women and 41.1% +/- 14.3% in men (P = 0.008). Severity of amyloid-affected islet area was 29.0% +/- 12.5% in women and 38.5% +/- 14.6% in men (P = 0.007).
Sex is a determinant of the development of islet amyloid in type 2 diabetes mellitus. This sex difference in islet amyloid may be related to a potential benefit of female sex hormones.
In recent years, the application of inductively-coupled plasma mass spectrometry (ICP-MS) has been used increasingly in clinical laboratories for the measurement of various trace elements and heavy ...metals. However, full evaluation of this technique has not been conducted to ensure the transfer of comparable results from conventional cold-vapour atomic absorption spectrophotometry (CVAAS) for blood and urine total mercury (Hg) analysis.
A total of 131 blood and 223 urine samples from both patients and normal healthy subjects were collected from a university-based trace element laboratory and a population survey of healthy school adolescents. Correlation study was conducted for total Hg concentration measured by the traditional on-line digestion with flow injection CVAAS and the newly installed ICP-MS. Reference materials were used for method validation and quality control. Standard addition of fixed amounts of inorganic and methyl Hg standards into blood and urine were performed for recovery study. Bias in total Hg measurement was investigated by re-calibrating both instruments using methyl Hg standards.
The intra- and inter-assay coefficients of variation in the ICP-MS were <6% in the range of 14–259 nmol/L for Hg in blood and urine samples assayed. The detection limit was 1.1 nmol/L and linearity was up to 186 nmol/L. The results from analyses of a range of whole blood and urine reference materials agreed well with the certified values. The correlation study showed a significant correlation between ICP-MS and CVAAS with: ICP-MS=7.36+1.69*CVAAS in blood samples (r=0.84, p<0.0001) and ICP-MS=1.90+1.14*CVAAS in urine samples (r=0.93, p<0.0001) for total Hg. Recovery study showed that the % recovery of inorganic Hg in blood for ICP-MS and CVAAS ranged from 83 to 95% and 77 to 84%, respectively, while that of inorganic Hg in urine for ICP-MS and CVAAS ranged from 92 to 126% and 43 to 93%, respectively. For methyl Hg, the % recovery in blood for ICP-MS and CVAAS ranged from 72 to 89% and 37 to 75%, respectively, while that in urine for ICP-MS and CVAAS ranged from 65 to 85% and 29 to 42%, respectively. When both instruments were re-calibrated using methyl Hg standards, the blood and urinary total Hg results in ICP-MS were corrected at 24% and −11% of CVAAS, respectively.
Analysis of total Hg was underestimated at about 69% in blood and 14% in urine using the traditional CVAAS method compared to ICP-MS, plausibly due to incomplete oxidation and reduction of methyl Hg species in CVAAS method. The normal limit of blood total Hg concentration has been targeted at <50nmol/L based on the traditional CVAAS method, and the in vivo proportion of methyl Hg of individuals mainly depends on the dietary intake of seafood. Therefore, for clinical laboratories preparing to change over to ICP-MS method for total Hg analysis, the local reference interval for blood total Hg should be re-determined using a non-occupationally exposed population. Otherwise, over-diagnosis of Hg intoxication can result. We have found that by using ICP-MS for total Hg analysis, the local reference range in blood was <77nmol/L while in spot urine was <15nmol/L or 1.2nmol/mmol of creatinine.
Precision diagnosis is the keystone of clinical medicine. In East Asians, classical type 1 diabetes is uncommon in patients with youngonset diabetes diagnosed before age of 40, in whom a family ...history, obesity, and beta-cell and kidney dysfunction are key features. Young-onset diabetes affects one in five Asian adults with diabetes in clinic settings; however, it is often misclassified, resulting in delayed or non-targeted treatment. Complex aetiologies, long disease duration, aggressive clinical course, and a lack of evidence-based guidelines have contributed to variable care standards and premature death in these young patients. The high burden of comorbidities, notably mental illness, highlights the numerous knowledge gaps related to this silent killer. The majority of adult patients with youngonset diabetes are managed as part of a heterogeneous population of patients with various ages of diagnosis. A multidisciplinary care team led by physicians with special interest in young-onset diabetes will help improve the precision of diagnosis and address their physical, mental, and behavioral health. To this end, payors, planners, and providers need to align and re-design the practice environment to gather data systematically during routine practice to elucidate the multicausality of young-onset diabetes, treat to multiple targets, and improve outcomes in these vulnerable individuals.
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