[Show abstract][Hide abstract] ABSTRACT: Introduction:
A1chieve(®) (ClinicalTrials.gov identifier NCT00869908) was a 24-week observational study evaluating certain insulin analogs and not insulin analogs in general in 66,726 people with type 2 diabetes (T2D) in routine clinical care in 28 non-Western countries. This study demonstrated that insulin analogs improved self-management and metabolic control in patients with T2D. We investigated the effectiveness and clinical characteristics of patients with T2D showing better response to basal insulin (BI) (detemir), using data from the A1chieve study performed in Korea.
Subjects were classified into two groups according to the achievement of target glycated hemoglobin (A1c) level of <7.5%. Multivariate logistic regression analysis was performed to determine the variables independently associated with the achievement of target A1c level.
Baseline A1c, postprandial glucose (PPG), difference between PPG and fasting plasma glucose, and duration of diabetes were independently associated with better response to BI after adjusting for other risk factors. Compared to patients with BI use at evening, those who took BI in the morning demonstrated a larger reduction in A1c level.
Once-daily BI therapy appears to be effective in Korean subjects with type 2 diabetes who had a shorter duration of diabetes and a smaller postprandial glucose excursion.
Novo Nordisk Pharma Korea and Novo Nordisk International Operations.
[Show abstract][Hide abstract] ABSTRACT: This trial was conducted to compare the efficacy and safety of combination therapy with basal insulin glargine plus mitiglinide to that of basal insulin glargine plus voglibosein patients with type 2 diabetes. This was a 20-week, randomized, multicenter non-inferiority trial. Patients with HbA1c levels over 7.0% were randomly assigned to receive either mitiglinide (10 mg tid) or voglibose (0.2 mg tid) concurrent with insulin glargine for 16 weeks after a 4-week of basal insulin glargine monotherapy. The intention-to-treat population included 156 patients; 79 were placed in the mitiglinide group, and 77 were placed in the voglibose group. At 20 weeks, there was no significant difference between the mitiglinide group and the voglibose group in terms of the mean HbA1c level or the mean decrease of the HbAlc level from baseline (-0.9% [-7.5 mmol/mol] and -0.7%, [-5.3 mmol/mol] respectively). The mean fasting plasma glucose level and data of self-monitoring blood glucosewere significantly decreased from baseline to week 20 in both groups, but there was no significant difference between the two groups. The changes in the basal insulin requirements of each group were not significant. The prevalence of adverse events and the risk of hypoglycemia were similar for both groups. Combination therapy with mitiglinide plus basal insulin glargine was non-inferior to voglibose plus basal insulin glargine in terms of the effect on overall glycemic control.
[Show abstract][Hide abstract] ABSTRACT: Background:
A substantial percentage of patients have undiagnosed diabetes. We investigated the demographic characteristics and cardiometabolic profiles of subjects with undiagnosed diabetes.
A cross-sectional study with nationally representative samples of 25490 subjects aged ≥ 20 years from the KHNANES 2008 to 2011, which applied a complex, multistage, probability proportional to size sampling design. Subjects were categorized as having normal glucose (n = 16880), impaired fasting glucose (n = 5771), undiagnosed diabetes (n = 713), or diagnosed diabetes (n = 2126). Hyper low-density lipoprotein cholesterolemia was individually evaluated by the 2004 Adult Treatment Panel III guidelines and predicted risk of cardiovascular disease was estimated from the Framingham model.
Among overall subjects with diabetes, the prevalence of undiagnosed diabetes was markedly increased in younger adults compared to older adults (49% in diabetic subjects <50 years vs 23% in diabetic subjects ≥50 years, P < .001), suggesting significant discrepancies in age-based screening. Patients with undiagnosed diabetes were also more likely to have undiagnosed or uncontrolled hypertension and hyper-low-density lipoprotein cholesterolemia. Individuals with undiagnosed diabetes had a significantly higher predicted 10-year Framingham cardiovascular disease risk than those with diagnosed diabetes (11% vs 8% in <50 years, 33% vs 30% in ≥50 years; both P < .001). Patients with undiagnosed diabetes were also more likely to have multiple cardiovascular risk factors including obesity, smoking and uncontrolled hypertension.
People with undiagnosed diabetes have a higher predicted risk for cardiovascular disease compared to those with diagnosed diabetes. Intensive screening for diabetes in younger adults should be stressed in public healthcare to reduce the burden of modifiable cardiometabolic risk among individuals with undiagnosed diabetes.
American heart journal 09/2015; 170(4):760-769.e2. DOI:10.1016/j.ahj.2015.07.024 · 4.46 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Statins (HMGCR/HMG-CoA reductase [3-hydroxy-3-methylglutaryl-CoA reductase] inhibitors) are widely used to lower blood cholesterol levels but have been shown to increase the risk of type 2 diabetes mellitus. However, the molecular mechanism underlying diabetogenic effects remains to be elucidated. Here we show that statins significantly increase the expression of key gluconeogenic enzymes (such as G6PC [glucose-6-phosphatase] and PCK1 (phosphoenolpyruvate carboxykinase 1 [soluble]) in vitro and in vivo and promote hepatic glucose output. Statin treatment activates autophagic flux in HepG2 cells. Acute suppression of autophagy with lysosome inhibitors in statin treated HepG2 cells reduced gluconeogenic enzymes expression and glucose output. Importantly, the ability of statins to increase gluconeogenesis was impaired when ATG7 was deficient and BECN1 was absent, suggesting that autophagy plays a critical role in the diabetogenic effects of statins. Moreover autophagic vacuoles and gluconeogenic genes expression in the liver of diet-induced obese mice were increased by statins, ultimately leading to elevated hepatic glucose production, hyperglycemia, and insulin resistance. Together, these data demonstrate that chronic statin therapy results in insulin resistance through the activation of hepatic gluconeogenesis, which is tightly coupled to hepatic autophagy. These data further contribute to a better understanding of the diabetogenic effects of stains in the context of insulin resistance.
[Show abstract][Hide abstract] ABSTRACT: Aims/IntroductionTo determine the efficacy and safety of ipragliflozin in combination with metformin in Asian patients with type 2 diabetes mellitus.Materials and Methods
This phase 3, multicenter, placebo-controlled, double-blind, parallel-group study was conducted at 18 sites in Korea and 12 sites in Taiwan. After an 8-week washout period for patients using drugs other than metformin and a 2-week run-in period, patients were randomized to either 50 mg ipragliflozin or placebo for 24 weeks while continuing metformin. Efficacy outcomes included the changes in hemoglobin A1c (HbA1c), fasting plasma glucose (FPG), and body weight from baseline to the end of treatment (with last observation carried forward). Safety outcomes included treatment-emergent adverse events (TEAEs).ResultsBetween November 2011 and January 2013, 171 patients were randomized to and administered ipragliflozin (n = 87) or placebo (n = 83). The mean changes (SD) in HbA1c were −0.94% (0.75%) and −0.47% (0.81%) in the ipragliflozin and placebo groups, respectively (between-group difference: −0.46%, P< 0.001). The changes in FPG and body weight were also significantly greater in the ipragliflozin group, with between-group differences of −14.1 mg/dL and −1.24 kg, respectively (both P< 0.001). The most common TEAEs (ipragliflozin vs. placebo) were upper respiratory tract infection (9.2% vs. 12.0%) and urinary tract infection (6.9% vs. 2.4%).Conclusions
These results indicate that ipragliflozin is effective and well tolerated when used in combination with metformin in Asian patients with type 2 diabetes mellitus.This article is protected by copyright. All rights reserved.
[Show abstract][Hide abstract] ABSTRACT: Type 1 diabetes is associated with more severe glycemic variability and more frequent hypoglycemia than type 2 diabetes. Glycemic variability is associated with poor glycemic control and diabetic complications. In this study, we demonstrate the clinical usefulness of serum 1,5-anhydroglucitol (1,5-AG) for assessing changes in glycemic excursion in type 1 diabetes.
Seventeen patients with type 1 diabetes were enrolled in this study. A continuous glucose monitoring system (CGMS) was applied twice at a 2-week interval to evaluate changes in glycemic variability. The changes in serum glycemic assays, including 1,5-AG, glycated albumin and hemoglobin A1c (HbA1c), were also evaluated.
Most subjects showed severe glycemic excursions, including hypoglycemia and hyperglycemia. The change in 1,5-AG level was significantly correlated with changes in the glycemic excursion indices of the standard deviation (SD), mean amplitude of glucose excursion (MAGE), lability index, mean postmeal maximum glucose, and area under the curve for glucose above 180 mg/dL (r=-0.576, -0.613, -0.600, -0.630, and -0.500, respectively; all P<0.05). Changes in glycated albumin were correlated with changes in SD and MAGE (r=0.495 and 0.517, respectively; all P<0.05). However, changes in HbA1c were not correlated with any changes in the CGMS variables.
1,5-AG may be a useful marker for the assessment of short-term changes in glycemic variability. Furthermore, 1,5-AG may have clinical implications for the evaluation and treatment of glycemic excursions in type 1 diabetes.
[Show abstract][Hide abstract] ABSTRACT: Objective
To evaluate the safety and efficacy of a plasmid (VM202) containing two human hepatocyte growth factor isoforms given by intramuscular injections in patients with painful diabetic neuropathy.Methods
In a double-blind, placebo-controlled study, patients were randomized to receive injections of 8 or 16 mg VM202 per leg or placebo. Divided doses were administered on Day 0 and Day 14. The prospective primary outcome was change in the mean pain score measured by a 7 day pain diary. Secondary outcomes included a responder analysis, quality of life and pain measures, and intraepidermal nerve fiber density.ResultsThere were no significant adverse events attributable to VM202. Eighty-four patients completed the study. Patients receiving 8 mg VM202 per leg improved the most in all efficacy measures including a significant (P = 0.03) reduction at 3 months in the mean pain score and continued but not statistically significant reductions in pain at 6 and 9 months. Of these patients, 48.4% experienced a ≥50% reduction in pain compared to 17.6% of placebo patients. There were also significant improvements in the brief pain inventory for patients with diabetic peripheral neuropathy and the questionnaire portion of the Michigan Neuropathy Screening Instrument. Patients not on pregabalin or gabapentin had the largest reductions in pain.InterpretationVM202 was safe, well tolerated and effective indicating the feasibility of a nonviral gene therapy approach to painful diabetic neuropathy. Two days of treatment were sufficient to provide symptomatic relief with improvement in quality of life for 3 months. VM202 may be particularly beneficial for patients not taking gabapentin or pregabalin.
[Show abstract][Hide abstract] ABSTRACT: We aimed to compare the efficacy and safety of lobeglitazone and pioglitazone as add-ons to metformin in patients with type 2 diabetes. Patients who were inadequately controlled by metformin were randomized and treated once daily with either lobeglitazone (0.5 mg, n = 128) or pioglitazone (15 mg, n=125) for 24 weeks, with a 28-week extension of lobeglitazone treatment in patients who consented. The primary endpoint was the change in HbA1c level between baseline and week 24. At week 24, the mean change from baseline HbA1c was −0.74% for the lobeglitazone group and −0.74% for the pioglitazone group, with a mean difference of 0.01% [95% confidence interval (CI) of difference, −0.16 to 0.18]. The effects of lobeglitazone on lipid parameters and adverse events associated with lobeglitazone were similar to those achieved with pioglitazone. Lobeglitazone was not inferior to pioglitazone as an add-on to metformin in terms of the efficacy and safety.
[Show abstract][Hide abstract] ABSTRACT: We recently reported that glycated albumin (GA) is increased in subjects with longer duration of diabetes and with decreased insulin secretory function. Based on this, we investigated whether GA increases with time relative to glycated hemoglobin (HbA1c) and the association between GA and beta-cell function. We analyzed 340 type 2 diabetes patients whose serum GA and HbA1c levels had been repeatedly measured over 4 years. We assessed the pattern of changes with time in glycemic indices (GA, HbA1c, and GA/HbA1c ratio) and their relationship with beta-cell function. In all patients, glycemic indices decreased and maintained low levels around 15 and 27 months. However, from 39 months to 51 months, GA significantly increased but HbA1c tended to increase without statistical significance. We defined ΔGA/HbA1c as the difference between the nadir point (at 15 to 27 months) and the end point (at 39 to 51 months) and found that ΔGA/HbA1c was positively correlated with diabetes duration and negatively related to beta-cell function. In multivariable linear regression analyses, ΔGA/HbA1c was independently associated with diabetes duration. In conclusion, this study demonstrated that serum GA levels increase relative to HbA1c levels with time.
BioMed Research International 01/2015; 2015. DOI:10.1155/2015/576306 · 2.71 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The ratio of glycated albumin to glycated hemoglobin (GA/A1c) is known to be elevated in subjects with type 2 diabetes mellitus (T2DM) who had decreased insulin secretion. Additionally, the carotid intima media thickness (IMT) is greater in T2DM patients with higher GA/A1c ratios. We investigated whether increased GA/A1c ratio and IMT are also associated in type 1 diabetes mellitus (T1DM), which is characterized by lack of insulin secretory capacity.
In this cross-sectional study, we recruited 81 T1DM patients (33 men, 48 women; mean age 44.1±13.0 years) who underwent carotid IMT, GA, and HbA1c measurements.
The mean GA/A1c ratio was 2.90. Based on these results, we classified the subjects into two groups: group I (GA/A1c ratio <2.90, n=36) and group II (GA/A1c ratio ≥2.90, n=45). Compared with group I, the body mass indexes (BMIs), waist circumferences, and IMTs were lower in group II. GA/A1c ratio was negatively correlated with BMI, urine albumin to creatinine ratio (P<0.001 for both), and both the mean and maximal IMT (P=0.001, both). However, after adjusting the confounding factors, we observed that IMT was no longer associated with GA/A1c ratio.
In contrast to T2DM, IMT was not significantly related to GA/A1c ratio in the subjects with T1DM. This suggests that the correlations between GA/A1c ratio and the parameters known to be associated with atherosclerosis in T2DM could be manifested differently in T1DM. Further studies are needed to investigate these relationships in T1DM.
[Show abstract][Hide abstract] ABSTRACT: Non-alcoholic fatty liver disease affects approximately one-third of the population worldwide, and its incidence continues to increase with the increasing prevalence of other metabolic disorders such as type 2 diabetes. As non-alcoholic fatty liver disease can progress to liver cirrhosis, its treatment is attracting greater attention. The pathogenesis of non-alcoholic fatty liver disease is closely associated with insulin resistance and dyslipidemia, especially hypertriglyceridemia. Increased serum levels of free fatty acid and glucose can cause oxidative stress in the liver and peripheral tissue, leading to ectopic fat accumulation, especially in the liver. In this review, we summarize the mechanism underlying the progression of hepatic steatosis to steatohepatitis and cirrhosis. We also discuss established drugs that are already being used to treat non-alcoholic fatty liver disease, in addition to newly discovered agents, with respect to their mechanisms of drug action, focusing mainly on hepatic insulin resistance. As well, we review clinical data that demonstrate the efficacy of these drugs, together with improvements in biochemical or histological parameters.
World Journal of Hepatology 11/2014; 6(11):800-811. DOI:10.4254/wjh.v6.i11.800
[Show abstract][Hide abstract] ABSTRACT: Metformin activates both PRKA and SIRT1. Furthermore, autophagy is induced by either the PRKA-MTOR-ULK1 or SIRT1-FOXO signaling pathways. We aimed to elucidate the mechanism by which metformin alleviates hepatosteatosis by examining the molecular interplay between SIRT1, PRKA, and autophagy. ob/ob mice were divided into 3 groups: one with ad libitum feeding of a standard chow diet, one with 300 mg/kg intraperitoneal metformin injections, and one with 3 g/d caloric restriction (CR) for a period of 4 wk. Primary hepatocytes or HepG2 cells were treated with oleic acid (OA) plus high glucose in the absence or presence of metformin. Both CR and metformin significantly improved body weight and glucose homeostasis, along with hepatic steatosis, in ob/ob mice. Furthermore, CR and metformin both upregulated SIRT1 expression and also stimulated autophagy induction and flux in vivo. Metformin also prevented OA with high glucose-induced suppression of both SIRT1 expression and SIRT1-dependent activation of autophagy machinery, thereby alleviating intracellular lipid accumulation in vitro. Interestingly, metformin treatment upregulated SIRT1 expression and activated PRKA even after siRNA-mediated knockdown of PRKAA1/2 and SIRT1, respectively. Taken together, these results suggest that metformin alleviates hepatic steatosis through PRKA-independent, SIRT1-mediated effects on the autophagy machinery.