A randomized trial on the effect of transcutaneous electrical nerve stimulator on glycemic control in patients with type 2 diabetes.

Transcutaneous electrical nerve stimulator (TENS) has been demonstrated to be beneficial in glycemic control in animal models, but its application in humans has not been well studied. We randomly assigned 160 patients with type 2 diabetes on oral antidiabetic drugs 1:1 to the TENS study device (n = 81) and placebo (n = 79). 147 (92%) randomized participants (mean [SD] age 59 [10] years, 92 men [58%], mean [SD] baseline HbA1c level 8.1% [0.6%]) completed the trial. At week 20, HbA1c decreased from 8.1% to 7.9% in the TENS group (- 0.2% [95% CI - 0.4% to - 0.1%]) and from 8.1% to 7.8% in the placebo group (- 0.3% [95% CI - 0.5% to - 0.2%]) (P = 0.821). Glycemic variability, measured as mean amplitude of glycemic excursion (MAGE) at week 20 were significantly different in the TENS group vs. the placebo group (66 mg/dL [95% CI 58, 73] vs. 79 mg/dL [95% CI 72, 87]) (P = 0.009). Our study provides the clinical evidence for the first time in humans that TENS does not demonstrate a statistically significant HbA1c reduction. However, it is a safe complementary therapy to improve MAGE in patients with type 2 diabetes.

ER ribosomal-binding protein 1 regulates blood pressure and potassium homeostasis by modulating intracellular renin trafficking.

BACKGROUND: Genome-wide association studies (GWASs) have linked RRBP1 (ribosomal-binding protein 1) genetic variants to atherosclerotic cardiovascular diseases and serum lipoprotein levels. However, how RRBP1 regulates blood pressure is unknown. METHODS: To identify genetic variants associated with blood pressure, we performed a genome-wide linkage analysis with regional fine mapping in the Stanford Asia-Pacific Program for Hypertension and Insulin Resistance (SAPPHIRe) cohort. We further investigated the role of the RRBP1 gene using a transgenic mouse model and a human cell model. RESULTS: In the SAPPHIRe cohort, we discovered that genetic variants of the RRBP1 gene were associated with blood pressure variation, which was confirmed by other GWASs for blood pressure. Rrbp1- knockout (KO) mice had lower blood pressure and were more likely to die suddenly from severe hyperkalemia caused by phenotypically hyporeninemic hypoaldosteronism than wild-type controls. The survival of Rrbp1-KO mice significantly decreased under high potassium intake due to lethal hyperkalemia-induced arrhythmia and persistent hypoaldosteronism, which could be rescued by fludrocortisone. An immunohistochemical study revealed renin accumulation in the juxtaglomerular cells of Rrbp1-KO mice. In the RRBP1-knockdown Calu-6 cells, a human renin-producing cell line, transmission electron and confocal microscopy revealed that renin was primarily retained in the endoplasmic reticulum and was unable to efficiently target the Golgi apparatus for secretion. CONCLUSIONS: RRBP1 deficiency in mice caused hyporeninemic hypoaldosteronism, resulting in lower blood pressure, severe hyperkalemia, and sudden cardiac death. In juxtaglomerular cells, deficiency of RRBP1 reduced renin intracellular trafficking from ER to Golgi apparatus. RRBP1 is a brand-new regulator of blood pressure and potassium homeostasis discovered in this study.

The Effects of Bariatric Surgery on Renal, Neurological, and Ophthalmic Complications in Patients with Type 2 Diabetes: the Taiwan Diabesity Study.

BACKGROUND: Bariatric surgery has been shown to improve glycemic control in patients with type 2 diabetes. However, less is known whether it can also reduce diabetic renal, neurological, and ophthalmic complications. METHODS: This prospective multicenter cohort study compared renal, ophthalmic, and neurological complications between 49 patients with obesity/overweight receiving bariatric surgery and 338 patients receiving standard medical treatment after follow-up for 2 years. Patients received neurological examinations including toe tuning fork vibration test, ankle tendon reflex test, 10-g monofilament test, and ophthalmic examinations including visual acuity measurement and fundus examinations. Multiple regressions, propensity score weighting, and matching were employed to adjust for baseline differences. RESULTS: After 2 years of follow-up, patients with type 2 diabetes receiving bariatric surgery had greater reduction in BMI, HbA1c, and urine albumin-creatinine ratio, greater improvement in estimated glomerular filtration rate, and greater increase in tuning fork test score of right and left toes compared with the medical group. However, there is no improvement in 10 g-monofilament test, visual acuity, diabetic non-proliferative retinopathy, and proliferative retinopathy. Similar results were obtained using multiple regression adjustment, propensity-score weighting, or comparing age-, sex-, and BMI-matched subjects. CONCLUSIONS: After 2-year follow-up, patients with obesity/overweight and type 2 diabetes receiving bariatric surgery have increased glomerular filtration rate, reduced albuminuria, and improved tuning folk vibration sensation.

Trends in antidiabetic medical treatment from 2005 to 2014 in Taiwan.

BACKGROUND/PURPOSE: Several new antidiabetic drugs have been introduced in Taiwan. However, the trends in antidiabetic treatment remain unexamined. METHODS: We studied data from the Taiwan National Health Insurance Database to identify outpatient prescriptions for antidiabetic drugs from 2005 to 2014. The patterns in antidiabetic treatment and the number of different classes of antidiabetic drugs were analyzed. The proportions of prescriptions of antidiabetic monotherapy, combination therapy, or insulin therapy were further analyzed. RESULTS: The total and mean prescriptions gradually increased during the study period. Prescription of oral antidiabetic drugs (OADs) only or insulin-only therapy decreased slightly. Prescriptions of monotherapy and dual therapy decreased, whereas those of triple or higher order combinations increased. Prescriptions of sulfonylureas (SUs) decreased, whereas those of metformin and dipeptidyl peptidease-4 (DPP4) inhibitors increased. Insulin prescriptions increased but accounted for only 13.07% of prescriptions in 2014. Among monotherapy prescriptions, SU prescriptions decreased, but metformin and DPP4 inhibitor prescriptions increased. Among dual OAD prescriptions, those including SUs decreased, and those of metformin and DPP4 inhibitors increased. Although prescriptions of the metformin-SU combination decreased, they remained the most common among all dual OAD prescriptions, followed by the metformin-DPP4 inhibitor combination. Prescriptions of human insulin decreased and those of insulin analogs increased considerably; those of basal insulin increased, and those of mixed insulin decreased. However, mixed insulin was prescribed more than basal-bolus insulin. CONCLUSION: Antidiabetic treatment has become complex in Taiwan. Although combination therapy would become the major treatment strategy gradually, the underuse of insulin therapy must improve.

Thiazolidinediones and reduced risk of incident bacterial abscess in adults with type 2 diabetes: A population-based cohort study.

AIM: Previous research has suggested that peroxisome proliferator-activated receptor-gamma (PPAR-γ) may play an important role in immunomodulation. We aimed to examine the association between thiazolidinediones, PPAR-γ agonists and incidence of bacterial abscess among patients with type 2 diabetes. MATERIALS AND METHODS: This retrospective cohort study between 2000 and 2010 included 46 986 propensity (PS)-matched patients diagnosed with type 2 diabetes. We compared the incidence of bacterial abscess, including liver and non-liver abscesses, between patients treated with metformin plus a thiazolidinedione (M + T, N = 7831) or metformin plus a sulfonylurea (M + S, N = 39 155). Data were retrieved from a population-based Taiwanese database. We applied Cox proportional hazard regression models to estimate hazard ratios (HRs) and 95% confidence intervals (CIs), comparing M + T and M + S after PS matching. RESULTS: During a median follow-up of 4.5 years, the incidence rate of bacterial abscess was lower with M + T than with M + S treatment (1.89 vs 3.15 per 1000 person-years) in the PS-matched cohort. M + T was associated with a reduced risk of bacterial abscess (HRs after PS matching, 0.58; 95% CI, 0.42-0.80 for total bacterial abscess; 0.54; 95% CI, 0.28-1.07 for liver abscess; 0.59; 95% CI, 0.41-0.85 for non-liver abscess). Results did not change materially after accounting for unmeasured confounding factors using high-dimenional PS matching and differential censoring between regimen groups. Rosiglitazone and pioglitazone, in combination with metformin, produced similar reductions in risk of all abscess outcomes. CONCLUSION: We found that M + T may provide a protective benefit in reducing the incidence of bacterial abscesses. These findings merit further investigation.

Dipeptidyl Peptidase-4 Inhibitor Use Is Not Associated With Acute Pancreatitis in High-Risk Type 2 Diabetic Patients: A Nationwide Cohort Study.

To analyze the association between use of DPP-4 inhibitors and acute pancreatitis in high-risk type 2 diabetic patients. A retrospective nationwide cohort study was conducted using the Taiwan National Health Insurance claim database. The risk associated with sitagliptin was compared to that with acarbose, a second-line antidiabetic drug prescribed for patients with similar diabetes severity and with a known neutral effect on pancreatitis. Between January 1, 2009 and December 31, 2010, a total of 8526 sitagliptin initiators and 8055 acarbose initiators who had hypertriglyceridemia or prior hospitalization history for acute pancreatitis were analyzed for the risk of hospitalization due to acute pancreatitis stratified for baseline propensity score. In the crude analysis, sitagliptin was associated with a decreased risk of acute pancreatitis (hazard ratio [HR] 0.74; 95% confidence interval [CI]: 0.62-0.88) compared to acarbose in diabetic patients with prior history of hospitalization for pancreatitis or hypertriglyceridemia. The association was abolished after stratification for propensity score quintiles (adjusted HR 0.95; 95% CI: 0.79-1.16). Similar results were found separately in both patients' histories of prior hospitalization of acute pancreatitis (adjusted HR 0.97; 95% CI: 0.76-1.24) and those with hypertriglyceridemia (adjusted HR 0.86; 95% CI: 0.65-1.13). No significant association was found for different durations or accumulative doses of sitagliptin. In the stratified analysis, no significant effect modification was found in relation to patients' characteristics. Use of sitagliptin was not associated with an increased risk of acute pancreatitis in high-risk diabetic patients with hypertriglyceridemia or with history of acute pancreatitis.

Association of insulin resistance with serum ferritin and aminotransferases-iron hypothesis.

AIM: To investigate the relationship of iron indices with diabetes mellitus (DM) in those without hemochromatosis. METHODS: This cross-sectional study examined data collected during the Third National Health and Nutrition Examination Survey (NHANES III). Only those who fasted properly and were not anemic with transferrin saturation < 45% were included (n = 6849). Insulin sensitivity and beta cell function were calculated from fasting glucose and insulin concentrations. Indices of iron metabolism were examined in the presence or absence of DM. We examined the relationship of insulin sensitivity and beta cell function with serum ferritin concentration. The influence of C-reactive protein and liver enzymes was also investigated. RESULTS: Serum ferritin concentration was significantly higher in diabetic subjects (P = 0.0001 to < 0.000001). The difference remained significant after adjustment for age, body mass index, alcohol consumption, and mineral/iron supplement (P = 0.03 to < 0.000001). In those who did not take insulin, serum ferritin concentration was negatively associated with insulin sensitivity (P = 0.05 to 0.00001), but not with beta cell function. The alanine aminotransferase was correlated with serum ferritin concentration (P = 0.02 to < 0.000001) but not with insulin sensitivity, suggesting the role of the liver in iron-associated insulin resistance. CONCLUSION: As most of diabetes is type 2 diabetes and insulin resistance is a cardinal feature of type 2 diabetes, disordered iron metabolism could play a role in the pathogenesis of insulin resistance and type 2 diabetes through its effect on liver function.

Roux-en-Y gastric bypass for diabetes (the Diabetes Surgery Study): 2-year outcomes of a 5-year, randomised, controlled trial.

BACKGROUND: Conventional treatments for patients with type 2 diabetes are often inadequate. We aimed to assess outcomes of diabetes control and treatment risks 2 years after adding Roux-en-Y gastric bypass to intensive lifestyle and medical management. METHODS: We report 2-year outcomes of a 5-year randomised trial (the Diabetes Surgery Study) at four teaching hospitals (three in the USA and one in Taiwan). At baseline, eligible participants had to have HbA1c of at least 8·0% (64 mmol/mol), BMI between 30·0 and 39·9 kg/m(2), and type 2 diabetes for at least 6 months, and be aged 30-67 years. We randomly assigned participants to receive either intensive lifestyle and medical management alone (lifestyle and medical management), or lifestyle and medical management plus standard Roux-en-Y gastric bypass surgery (gastric bypass). Staff from the clinical centres had access to data from individual patients, but were masked to other patients' data and aggregated data until the 2-year follow-up. Drugs for hyperglycaemia, hypertension, and dyslipidaemia were prescribed by protocol. The primary endpoint was achievement of the composite treatment goal of HbA1c less than 7·0% (53 mmol/mol), LDL cholesterol less than 2·59 mmol/L, and systolic blood pressure less than 130 mm Hg at 12 months; here we report the composite outcome and other pre-planned secondary outcomes at 24 months. Analyses were done on an intention-to-treat basis, with multiple imputations for missing data. This study is registered with ClinicalTrials.gov, number NCT00641251, and is still ongoing. FINDINGS: Between April 21, 2008, and Nov 21, 2011, we randomly assigned 120 eligible patients to either lifestyle and medical management alone (n=60) or with the addition of gastric bypass (n=60). One patient in the lifestyle and medical management group died (from pancreatic cancer), thus 119 were included in the primary analysis. Significantly more participants in the gastric bypass group achieved the composite triple endpoint at 24 months than in the lifestyle and medical management group (26 [43%] vs eight [14%]; odds ratio 5·1 [95% CI 2·0-12·6], p=0·0004), mainly through improved glycaemic control (HbA1c <7·0% [53 mmol/mol] in 45 [75%] vs 14 [24%]; treatment difference -1·9% (-2·5 to -1·4); p=0·0001). 46 clinically important adverse events occurred in the gastric bypass group and 25 in the lifestyle and medical management group (mainly infections in both groups [four in the lifestyle and medical management group, eight in the gastric bypass group]). With a negative binomial model adjusted for site, the event rate for the gastric bypass group was non-significantly higher than the lifestyle and medical management group by a factor of 1·67 (95% CI 0·98-2·87, p=0·06). Across both years of the study, the gastric bypass group had seven serious falls with five fractures, compared with three serious falls and one fracture in the lifestyle and medical management group. All fractures happened in women. Many more nutritional deficiencies occurred in the gastric bypass group (mainly deficiencies in iron, albumin, calcium, and vitamin D), despite protocol use of nutritional supplements. INTERPRETATION: The addition of gastric bypass to lifestyle and medical management in patients with type 2 diabetes improved diabetes control, but adverse events and nutritional deficiencies were more frequent. Larger and longer studies are needed to investigate whether the benefits and risk of gastric bypass for type 2 diabetes can be balanced. FUNDING: Covidien, National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases Nutrition Obesity Research Centers, and the National Center for Advancing Translational Sciences.

Loss of Egr-1 sensitizes pancreatic ß-cells to palmitate-induced ER stress and apoptosis.

UNLABELLED: Pancreatic ß-cells are particularly susceptible to fatty-acid-induced endoplasmic reticulum (ER) stress and apoptosis. To understand how ß-cells sense fatty acid stimuli and translate into a long-term adaptive response, we investigated whether palmitic acid (PA) regulates early growth response-1 (Egr-1), an immediate-early transcription factor, which is induced by many environmental stimuli and implicated in cell proliferation, differentiation, and apoptosis. We found that Egr-1 was rapidly and transiently induced by PA in MIN6 insulinoma cells, which was accompanied by calcium influx and ERK1/2 phosphorylation. Calcium chelation and MEK1/2 inhibition blocked PA-induced Egr-1 upregulation, suggesting that PA induces Egr-1 expression through a calcium influx-MEK1/2-ERK1/2 cascade. Knockdown of Egr-1 increased PA-induced caspase-3 activation and ER stress markers and decreased PA-induced Akt phosphorylation and insulin secretion and signaling. Akt replenishment and insulin supplementation rescued PA-induced apoptosis in Egr-1 knockdown cells. These results suggest that the absence of Egr-1 loses its ability to couple the short-term insulin/Akt pathway to long-term survival adaptation. Finally, Egr-1-deficient mouse islets are more susceptible to ex vivo stimuli of apoptosis. In human pancreatic tissues, EGR1 expression correlated with expression of ER stress markers and anti-apoptotic gene. In conclusion, Egr-1 is induced by PA and further attempts to rescue ß-cells from ER stress and apoptosis through improving insulin/Akt signaling. Our study underscores Egr-1 as a critical early sensor in pancreatic ß-cells to translate fatty acid stimuli into a cellular adaptation mechanism. KEY MESSAGE: PA stimulates Egr-1 expression via a calcium influx-MEK1/2-ERK1/2-Elk-1 cascade. Egr-1 attenuates PA-induced ER stress and apoptosis. Egr-1 maintains Akt survival pathway to protect ß-cells from PA-induced apoptosis. Egr-1-deficient islets are prone to ex vivo stimuli of apoptosis. Human EGR1 expression correlates with genes for ER stress and anti-apoptosis.

Comparison of thrice-daily premixed insulin (insulin lispro premix) with basal-bolus (insulin glargine once-daily plus thrice-daily prandial insulin lispro) therapy in east Asian patients with type 2 diabetes insufficiently controlled with twice-daily premixed insulin: an open-label, randomised, controlled trial.

BACKGROUND: Unlike in western countries, premixed insulin is widely used as the starter insulin in Asian patients instead of basal insulin. The use of basal-bolus therapy as an intensification regimen is not common in Asia despite poor glycaemic control after starting insulin therapy. An alternative insulin intensification regimen with a similar efficacy and safety profile to basal-bolus therapy, but of higher convenience, is urgently needed. The efficacy and safety of insulin lispro mix thrice-daily was compared with basal-bolus therapy in Asian patients with type 2 diabetes who were insufficiently controlled on twice-daily premixed insulin. METHODS: This open-label, randomised, active comparator-controlled, parallel-group trial was done at 24 centres in China, Taiwan, and South Korea. Patients with type 2 diabetes who were inadequately controlled on twice-daily premixed insulin were randomly assigned (1:1) to receive either insulin lispro mix (mix 50 before breakfast and lunch plus mix 25 before dinner) or basal-bolus therapy (insulin glargine at bedtime plus prandial insulin lispro thrice-daily) for 24 weeks. Randomisation was done by a computer-generated random sequence and was stratified by country or region and baseline HbA1c. Treatment assignments were masked from the study team assessing outcomes but not from investigators and patients. The primary outcome was change from baseline in HbA1c at week 24 in all randomly assigned patients who received at least one dose of study drug. Analysis was by modified intention to treat, with the per-protocol population used as a supportive analysis. This study is registered with ClinicalTrials.gov, number NCT01175811. FINDINGS: Between Feb 7, 2011, and Nov 7, 2012, 402 patients were enrolled (199 in the premix group, 203 in the basal-bolus group) and 399 were included in the primary analysis (197 in the premix group, 202 in the basal-bolus group). HbA1c change at week 24 was -1.1% for both treatment groups. The least squares mean difference between groups in HbA1c change from baseline was 0% (95% CI -0.1 to 0.2). Insulin lispro mix was non-inferior to basal-bolus therapy based on the prespecified margin of 0.4%. The frequency of adverse events, and the incidences and 30-day rates of nocturnal and overall hypoglycaemia were comparable between groups. No severe hypoglycaemia was reported. INTERPRETATION: A premixed insulin lispro regimen thrice-daily was non-inferior to basal-bolus therapy in terms of overall glycaemic control and thus could be an option for intensified insulin regimen in Asian patients with type 2 diabetes who are inadequately controlled with twice-daily premixed insulin.

Cardiovascular risk associated with acarbose versus metformin as the first-line treatment in patients with type 2 diabetes: a nationwide cohort study.

CONTEXT: Metformin is the first-line oral therapy for type 2 diabetes with proven benefits against cardiovascular risk. Recent evidence suggested that acarbose might be similar to metformin in glucose-lowering efficacy and cardiovascular risk reduction. Therefore, international guidelines have suggested the use of acarbose as alternative first-line antidiabetic therapy. OBJECTIVE: To compare the cardiovascular outcomes in the first-line users of acarbose vs metformin. DESIGN, SETTING, PATIENTS, AND OUTCOME MEASURES: A nationwide cohort study was conducted by analyzing the Taiwan National Health Insurance (NHI) Database. A total of 17,366 acarbose initiators and 230,023 metformin initiators were identified between January 1, 2009 and December 31, 2010. The primary outcome is hospitalization due to any cardiovascular events, including acute myocardial infarction, congestive heart failure, and ischemic stroke. The propensity score method was used to adjust for baseline differences between the two groups. Patients were followed from drug initiation to the earliest of outcome occurrence, death or disenrollment from NHI, or study termination. RESULTS: In intention-to-treat analyses, acarbose was associated with a higher risk of any cardiovascular event (adjusted hazard ratio [HR]: 1.05; 95% confidence interval [CI], 1.01-1.09), heart failure (HR, 1.08; 95% CI, 1.00-1.16), and ischemic stroke (HR, 1.05, 95% CI, 1.00-1.10) than metformin. No significant difference in risk was found in subgroups of patients with or without underlying hypertension, ischemic heart disease, or cerebrovascular disease. Similar results were found in auxiliary as-treated analyses or analyses stratified by propensity score quintiles. CONCLUSION: Our data do not support that acarbose has a cardio-protective effect similar to metformin as a first-line antidiabetic agent.

Severe hepatic injury associated with different statins in patients with chronic liver disease: a nationwide population-based cohort study.

BACKGROUND AND AIM: The hepatotoxicity of statins in patients with chronic liver diseases remains unclear. In this study, we aimed to estimate the risk of severe hepatic injury associated with different statins in patients with chronic liver disease. METHODS: A nationwide population-based cohort study was conducted by analyzing the Taiwan National Health Insurance database. A total of 37,929 subjects with chronic liver disease who started statin therapy were identified during the period of January 1, 2005 to December 31, 2009. Outcome was defined as hospitalization due to liver injury. RESULTS: During a total of 118,772 person-years of follow-up, 912 incident cases of hospitalization due to hepatic injury are identified. The incidence rate was 2.95, 2.49, 2.92, 1.94, 2.65, and 2.52 per 100,000 person-days for atorvastatin, lovastatin, fluvastatin, pravastatin, simvastatin, and rosuvastatin initiators, respectively. Overall, there was no difference in the incidence associated with different statins. However, when each statin was further categorized to high (≧ 0.5 defined daily dose) or low (< 0.5 defined daily dose) mean daily dose, only high-dose atorvastatin was significantly associated with increased risk of hospitalization due to hepatic injury (hazard ratio, 1.62; 95% confidence interval, 1.29, 2.03) as compared with low-dose atorvastatin. CONCLUSION: The overall incidence of hospitalization due to severe hepatic injury was low among statin initiators with chronic liver disease. Only high-dose atorvastatin was associated with increased risk.

Hypoglycemic constituents of Gynura divaricata subsp. formosana.

Gynura divaricata Kitam. subsp. formosana is a folk medicine used as a hypoglycemic agent for diabetes patients in Taiwan. Guided by the hexose transport assay, the hypoglycemic constituents of the aerial part of this plant were disclosed through chromatographic methods. They are fructooligosaccharides, including beta-D-fructofuranose, sucrose, 1-kestose, nystose, and 1(F)-beta-fructofuranosylnystose. The hexose transport assay indicated that nystose was the most potent among these compounds, showing a 46.7% difference from pinitol in the stimulation index at a concentration of 0.5 mg/mL.