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Aim: To evaluate the efficacy and safety of dapagliflozin versus placebo as an add‐on in patients with type 2 diabetes who did not achieve adequate glycaemic control with evogliptin and metformin combination. Patients and Methods: In this multicentre, randomized, double‐blind, placebo‐controlled Phase 3 trial, patients with glycated haemoglobin (HbA1c) levels ≥7.0% (≥53 mmol/mol) and ≤10.5% (≤91 mmol/mol) who had received stable‐dose metformin (≥1000 mg) and evogliptin (5 mg) for at least 8 weeks were randomized to receive dapagliflozin 10 mg or placebo once daily for 24 weeks. Participants continued treatment with metformin and evogliptin. The primary endpoint was change in HbA1c level after 24 weeks of treatment from baseline level. Results: In total, 198 patients were randomized, and 195 patients were included in the efficacy analyses (dapagliflozin: 96, placebo: 99). At Week 24, dapagliflozin significantly reduced HbA1c levels. The least squares mean difference in HbA1c level change from baseline after 24 weeks of treatment was −0.70% (−7.7 mmol/mol) (p < 0.0001). The proportion of participants achieving HbA1c <7.0% (≥53 mmol/mol) was higher in the dapagliflozin group than in the placebo group. Compared to placebo, dapagliflozin significantly reduced fasting plasma glucose, mean daily glucose, 2‐h postprandial plasma glucose, fasting insulin, uric acid and gamma‐glutamyl transferase levels, homeostatic model assessment for insulin resistance index, body weight, hepatic steatosis index, and albuminuria. Adiponectin level significantly increased from baseline level after 24 weeks of dapagliflozin treatment. Adverse event rates were similar in the two groups. Conclusion: Dapagliflozin add‐on to evogliptin plus metformin improved glycaemic control and was well tolerated by the target patients. [ABSTRACT FROM AUTHOR]

Objective: The natural course of diabetes of the exocrine pancreas (DEP) is not well established. We aimed to compare the risk of insulin initiation, diabetic complications, and mortality between DEP and type 2 diabetes.Research Design and Methods: Using the Korean National Health Insurance Service-Health Screening Cohort between 2012 and 2017, we divided patients with diabetes into those with diabetes without prior pancreatic disease (indicated type 2 diabetes, n = 153,894) and diabetes with a prior diagnosis of pancreatic disease (indicated DEP, n = 3,629). ICD-10 codes and pharmacy prescription information were used to define type 2 diabetes, DEP, and acute and chronic diabetes complications. Kaplan-Meier curves were produced to compare insulin use over time between groups. We created logistic regression models for odds of progression to diabetic complications and mortality.Results: DEP was associated with a higher risk of insulin use than type 2 diabetes (adjusted hazard ratio 1.38 at 5 years [95% CI 1.30-1.47], P < 0.0001). Individuals with DEP showed higher risks of hypoglycemia (odds ratio 1.85 [1.54-2.21], P < 0.0001), diabetic neuropathy (1.38 [1.28-1.49], P < 0.0001), nephropathy (1.38 [1.27-1.50], P < 0.0001), retinopathy (1.10 [1.01-1.20], P = 0.0347), coronary heart disease (1.59 [1.48-1.70], P < 0.0001), cerebrovascular disease (1.38 [1.28-1.49], P < 0.0001), and peripheral arterial disease (1.34 [1.25-1.44], P < 0.0001). All-cause mortality was higher in those with DEP (1.74 [1.57-1.93], P < 0.0001) than in those with type 2 diabetes.Conclusions: DEP is more likely to require insulin therapy than type 2 diabetes. Hypoglycemia, micro- and macrovascular complications, and all-cause mortality events are higher in DEP compared with type 2 diabetes. [ABSTRACT FROM AUTHOR]

Background. Sodium-glucose cotransporter 2 (SGLT2) and dipeptidyl peptidase-4 (DPP-4) inhibitors are glucose-lowering drugs whose anti-inflammatory properties have recently become useful in tackling metabolic syndromes in chronic inflammatory diseases, including diabetes and obesity. We investigated whether empagliflozin (SGLT2 inhibitor) and gemigliptin (DPP-4 inhibitor) improve inflammatory responses in macrophages, identified signalling pathways responsible for these effects, and studied whether the effects can be augmented with dual empagliflozin and gemigliptin therapy. Methods. RAW 264.7 macrophages were first stimulated with lipopolysaccharide (LPS), then cotreated with empagliflozin, gemigliptin, or empagliflozin plus gemigliptin. We conducted quantitative RT-PCR (qRT-PCR) to determine the most effective anti-inflammatory doses without cytotoxicity. We performed ELISA and qRT-PCR for inflammatory cytokines and chemokines and flow cytometry for CD80, the M1 macrophage surface marker, to evaluate the anti-inflammatory effects of empagliflozin and gemigliptin. NF-κB, MAPK, and JAK2/STAT signalling pathways were examined via Western blotting to elucidate the molecular mechanisms of anti-inflammation. Results. LPS-stimulated CD80+ M1 macrophages were suppressed by coincubation with empagliflozin, gemigliptin, and empagliflozin plus gemigliptin, respectively. Empagliflozin and gemigliptin (individually and combined) inhibited prostaglandin E2 (PGE2) release and COX-2, iNOS gene expression in LPS-stimulated RAW 264.7 macrophages. These three treatments also attenuated the secretion and mRNA expression of proinflammatory cytokines, such as TNF-α, IL-1β, IL-6, and IFN-γ, and proinflammatory chemokines, such as CCL3, CCL4, CCL5, and CXCL10. All of them blocked NF-κB, JNK, and STAT1/3 phosphorylation through IKKα/β, MKK4/7, and JAK2 signalling. Conclusions. Our study demonstrated the anti-inflammatory effects of empagliflozin and gemigliptin via IKK/NF-κB, MKK7/JNK, and JAK2/STAT1 pathway downregulation in macrophages. In all cases, combined empagliflozin and gemigliptin treatment showed greater anti-inflammatory properties. [ABSTRACT FROM AUTHOR]

Background: Sodium-glucose cotransporter 2 (SGLT2) and dipeptidyl peptidase-4 (DPP-4) inhibitors are glucose-lowering drugs whose anti-inflammatory properties have recently become useful in tackling metabolic syndromes in chronic inflammatory diseases, including diabetes and obesity. We investigated whether empagliflozin (SGLT2 inhibitor) and gemigliptin (DPP-4 inhibitor) improve inflammatory responses in macrophages, identified signalling pathways responsible for these effects, and studied whether the effects can be augmented with dual empagliflozin and gemigliptin therapy.Methods: RAW 264.7 macrophages were first stimulated with lipopolysaccharide (LPS), then cotreated with empagliflozin, gemigliptin, or empagliflozin plus gemigliptin. We conducted quantitative RT-PCR (qRT-PCR) to determine the most effective anti-inflammatory doses without cytotoxicity. We performed ELISA and qRT-PCR for inflammatory cytokines and chemokines and flow cytometry for CD80, the M1 macrophage surface marker, to evaluate the anti-inflammatory effects of empagliflozin and gemigliptin. NF-κB, MAPK, and JAK2/STAT signalling pathways were examined via Western blotting to elucidate the molecular mechanisms of anti-inflammation.Results: LPS-stimulated CD80+ M1 macrophages were suppressed by coincubation with empagliflozin, gemigliptin, and empagliflozin plus gemigliptin, respectively. Empagliflozin and gemigliptin (individually and combined) inhibited prostaglandin E2 (PGE2) release and COX-2, iNOS gene expression in LPS-stimulated RAW 264.7 macrophages. These three treatments also attenuated the secretion and mRNA expression of proinflammatory cytokines, such as TNF-α, IL-1β, IL-6, and IFN-γ, and proinflammatory chemokines, such as CCL3, CCL4, CCL5, and CXCL10. All of them blocked NF-κB, JNK, and STAT1/3 phosphorylation through IKKα/β, MKK4/7, and JAK2 signalling.Conclusions: Our study demonstrated the anti-inflammatory effects of empagliflozin and gemigliptin via IKK/NF-κB, MKK7/JNK, and JAK2/STAT1 pathway downregulation in macrophages. In all cases, combined empagliflozin and gemigliptin treatment showed greater anti-inflammatory properties. [ABSTRACT FROM AUTHOR]

Aim: To examine the real‐world cardiovascular effectiveness and safety associated with sodium‐glucose co‐transporter‐2 (SGLT2) inhibitor compared with dipeptidyl peptidase‐4 (DPP‐4) inhibitor treatment in older adults with type 2 diabetes. Materials and Methods: In this retrospective cohort study, older adults with type 2 diabetes (aged ≥65 years) were identified in the Korean National Health Insurance Service database from September 2014 to December 2016. In total, 408 506 new users of an SGLT2 inhibitor or DPP‐4 inhibitor were propensity score matched. Cox regression was used to estimate the hazard ratios (HR) and 95% confidence interval (CI) for outcomes of interest: hospitalization for heart failure (HHF), all‐cause death, myocardial infarction, stroke, diabetic ketoacidosis (DKA), bone fracture, severe hypoglycaemia, genital infection and urinary tract infection (UTI). Results: Compared with DPP‐4 inhibitors, new users of SGLT2 inhibitors had a lower risk of HHF (HR 0.86; 95% CI 0.76‐0.97), all‐cause death (HR 0.85; 95% CI 0.75‐0.98) and stroke (HR 0.86; 95% CI 0.77‐0.97), but a similar risk of myocardial infarction (HR 0.95; 95% CI 0.77‐1.19). The risks of DKA, bone fracture and severe hypoglycaemia were similar between both groups, although genital infection (HR 2.44; 95% CI 2.22‐2.67) and UTI (HR 1.05; 95% CI 1.00‐21.11) were more frequent among new users of SGLT2 inhibitors compared with DPP‐4 inhibitors. Conclusion: Our findings suggest that initiation of SGLT2 inhibitors offers cardiovascular disease protection and can be used safely in older adults with type 2 diabetes. [ABSTRACT FROM AUTHOR]

Introduction: We examined whether circulating adiponectin levels are associated with further cardiovascular events in patients with type 2 diabetes. Methods: Between December 2004 and February 2005, 349 patients with type 2 diabetes were enrolled and followed-up until December 2015. Blood levels of total, middle-molecular weight and high-molecular weight adiponectin were measured at baseline. The primary composite outcome was the occurrence of the following events: cardiovascular death, non-fatal myocardial infarction, non-fatal stroke or hospitalization for unstable angina and heart failure. Results: During a median follow-up of 9 years, cardiovascular events occurred in 14% of patients (50/349, 1.9% per year). Median blood levels of total, middle-molecular weight and high-molecular weight adiponectin were 4.8, 3.2 and 1.8 μg/mL, respectively. The cumulative incidence of cardiovascular events was not significantly different between the three groups based on total, middle-molecular weight, high-molecular weight or high-molecular weight/total adiponectin. After adjustment for potential confounding factors, blood adiponectin levels were positively associated with an increased number of cardiovascular events, but between tertiles, there was no significant difference. Conclusion: This observational cohort study suggested that blood adiponectin levels are not related to further cardiovascular events in patients with type 2 diabetes. [ABSTRACT FROM AUTHOR]

Abstract: Aims/Introduction: We investigated the failure of monotherapy in patients with type 2 diabetes mellitus in real practice settings. Materials and Methods: The Korean National Diabetes Program was a prospective, multicenter observational cohort study of type 2 diabetes mellitus patients in Korea. Of the 3,950 patients enrolled in the study, we studied 998 who were continuously maintained on monotherapy for at least 90 days at six participating centers. To balance the baseline characteristics of patients in each group, we used propensity matching at a 1:1 ratio (metformin vs sulfonylureas) and 4:1 ratio (metformin vs meglitinides and metformin vs alpha‐glucosidase inhibitors [aGIs]). The hazard ratios (HRs) of treatments (compared with metformin) were determined by Cox's proportional hazards regression modeling. Results: The median follow‐up time was 56 months, and monotherapy failed in 45% of all patients. The annual incidences of failure were 15.6%, 21.3%, 27% and 9.6% in the metformin, sulfonylurea, meglitinide and aGI groups. Compared with metformin, sulfonylureas and meglitinides were associated with higher risks of monotherapy failure (HR 1.39, 95% confidence interval [CI] 1.08–1.80; HR 1.92, 95% CI 1.13–3.27), and aGIs with risks similar to that of metformin (HR 0.80, 95% CI 0.44–1.45). When analyzed by failure type, sulfonylureas, meglitinides and aGIs were associated with a higher risk of a switch to other agents (HR 4.43, 95% CI 2.14–9.17; HR 18.80, 95% CI 6.21–56.93; HR 4.25, 95% CI 1.49–12.13), and aGIs with a lower risk of prescription of add‐on second agents (HR 0.16, 95% CI 0.04–0.64). Conclusions: Metformin was associated with a lower failure risk than were sulfonylureas and meglitinides, but a comparable aGI failure rate. [ABSTRACT FROM AUTHOR]

Background. Information on the risk of acute pancreatitis in patients receiving dipeptidyl-peptidase IV inhibitors (DPP-4i) is limited and controversial. One study suggested that the differences in findings between these meta-analyses were attributed to whether they included large randomized control trials with cardiovascular outcomes or not. The aim of our study was to determine whether the use of DPP-4i increases the risk of acute pancreatitis compared with sulfonylurea (SU) and whether the risk is higher in patients with underlying cardiovascular disease (CVD). Methods. A population-based cohort study was performed using Korean National Health Insurance Service-National Sample Cohort data. We included 33,395 new users of SU and DPP-4i from 1 January 2008 to 31 December 2015. SU-treated patients and DPP-4i-treated patients were matched by 1 : 1 propensity score matching. We used Kaplan–Meier curves and Cox proportional hazards regression analysis to calculate the risk of acute pancreatitis. Results. The hazard ratio (HR) of hospitalization for acute pancreatitis was 0.642 (95% confidence interval (CI): 0.535–0.771) in DPP-4i-treated patients compared with SU-treated patients. The HR of DPP-4i use was also lower than that of SU use in patients without underlying CVD (HR: 0.591; 95% CI: 0.476–0.735) but not in patients with underlying CVD (HR: 0.727; 95% CI: 0.527–1.003). Conclusion. Our findings suggest that DPP-4i is less likely to cause drug-induced pancreatitis than SU. This finding was not evident in patients with CVD, but DPP-4i was not more likely to induce pancreatitis in these patients than SU was. [ABSTRACT FROM AUTHOR]

Aim: We investigated the association between combined changes of visceral fat and thigh muscle over 5 years and incident type 2 diabetes in a prospective study of Japanese Americans.Methods: We followed 420 nondiabetic Japanese American subjects for 5 years and assessed visceral fat and thigh muscle by computed tomography (CT) at baseline and at 5 years. We categorized study subjects into 4 body composition change groups: visceral fat loss/thigh muscle gain (VF-loss/TM-gain), visceral fat loss/thigh muscle loss (VF-loss/TM-loss), visceral fat gain/thigh muscle gain (VF-gain/TM-gain), and visceral fat gain/thigh muscle loss (VF-gain/TM-loss) by combining changes from baseline in CT measured visceral fat and estimated thigh muscle areas. We fit a logistic regression model to examine the association between body composition categories and the development of incident type 2 diabetes at 5 years.Results: Cumulative incidence of type 2 diabetes was 9.8% at 5 years. VF-gain/TM-gain and VF-loss/TM-loss groups had higher risk for incident type 2 diabetes in a model adjusted for age, sex, family history of diabetes, and body mass index compared to VF-loss/TM-gain group as the reference category (OR=6.83 (1.85-25.17), 4.55 (1.06-19.48), respectively). However, the VF-gain/TM-loss group did not show a significant association with the odds of incident diabetes (3.24; 95% CI. 0.78-13.47).Conclusions: Concordant gain or loss in visceral fat and thigh muscle was related to higher risk of incident type 2 diabetes compared to the reference combination of loss of visceral fat and gain of thigh muscle in Japanese Americans. [ABSTRACT FROM AUTHOR]

Aim: Because the incidence of type 2 diabetes in Korea has not been clearly defined, we examined the incidence of this condition and its association with impaired fasting glucose (IFG), impaired glucose tolerance (IGT), and other risk factors in a 12-year follow-up Korean community-based prospective cohort study.Methods: We recruited 7542 subjects aged 40-69years without diabetes at baseline examination from the Korean Genome and Epidemiology Study and followed these subjects for 12years biennially. Diabetes was defined according to the 2010 American Diabetes Association criteria. The incidence of type 2 diabetes and the predictors of progression to diabetes were analyzed according to baseline glucose tolerance.Results: The overall incidence of type 2 diabetes was 22.1 per 1000person-years. Subjects with combined IFG-IGT at baseline had the highest incidence of diabetes, which was more than two-fold that of individuals with isolated IFG or isolated IGT (114.4 vs. 51.3 vs. 53.1 per 1000person-years). A multivariate Cox proportional hazards model analysis showed that combined IFG-IGT, which were strong predictors of diabetes, as well as age, urban residence, family history of diabetes, smoking status, abdominal obesity, hypertension, high triglycerides and low HDL cholesterols were also independently associated with progression to diabetes.Conclusions: The incidence of type 2 diabetes is relatively high in our Korean community-based sample. Combined IFG-IGT are strong predictors of type 2 diabetes. Measurement of 2-hour plasma glucose in addition to fasting plasma glucose is necessary for the detection of individuals at high risk for development of diabetes. [ABSTRACT FROM AUTHOR]

Abstract: Objective: Atherosclerosis in patients with type 2 diabetes has been linked to oxidative stress. NADP[1]:quinone oxidoreductase 1 (NQO1) plays a key role in cellular antioxidant defense. Recent reports suggest that highly expressed and inducible endogenous NQO1 from cardiovascular cells may act as a potential superoxide scavenger. We examined the relationship between the risk of NQO1 C609T polymorphism and carotid artery atherosclerosis in patients with type 2 diabetes. Methods: We recruited 601 (Seoul set) and 233 (Koyang set) unrelated patients with type 2 diabetes from independent groups. The C609T variant of NQO1 was genotyped by Taqman RT-PCR. Mean and maximum carotid intima-media thickness (IMT) and carotid artery plaques were measured by high-resolution ultrasonography. Results: Patients with the T allele exhibited a higher prevalence of atherosclerotic plaques than non-T allele carriers in both sets (Seoul set vs. Koyang set, p =0.021, p =0.023, respectively). After adjusting for age, sex, duration of diabetes, systolic blood pressure, body mass index, current smoking, HDL-cholesterol, LDL-cholesterol and HbA1c, subjects with the T allele had a significantly higher risk of carotid artery plaques (Seoul set vs. Koyang set, OR=1.65, p =0.015; OR=2.00, p =0.037, respectively) than subjects with the CC genotype. Conclusion: These results suggest that the C609T polymorphism of NQO1 is associated with carotid artery plaques in type 2 diabetic patients. [Copyright &y& Elsevier]

Background: Type 2 diabetes is related to an increased risk of dementia. Preclinical studies of dipeptidyl peptidase-IV inhibitors (DPP-4i) for dementia have yielded promising results. Therefore, we investigated the risk of dementia in elderly patients with type 2 diabetes on DPP-4is and sulfonylureas (SU). Methods: Using a claims database called the Korean National Health Insurance Service Senior cohort, new users of DPP-4is and SUs were matched by 1:1 propensity score matching using 49 confounding variables (7552 new DPP-4is users and 7552 new SU users were matched by 1:1 propensity score matching; average age 75.4; mean follow-up period: 1361.9 days). Survival analysis was performed to estimate the risk of dementia. Results: The risk of all-cause dementia was lower in the DPP-4i group compared to the SU group (hazard ratio (HR) 0.66; 95% confidence interval (CI) 0.56–0.78; p < 0.001). Particularly, DPP-4i use showed a significantly lower risk of Alzheimer's disease (HR 0.64; 95% CI 0.52–0.79; p < 0.001) and a lower risk, albeit non-significant, of vascular dementia compared to SU use (HR 0.66; 95% CI 0.38–1.14; p = 0.139). Conclusion: Our findings suggest that DPP-4i use decreases the risk of dementia compared to SU use in elderly patients with type 2 diabetes in a real-world clinical setting. [ABSTRACT FROM AUTHOR]

Cardiovascular disease is responsible for 75% of all deaths in diabetic patients, so it is important to predict cardiovascular morbidity in type 2 diabetes (T2DM). Endothelial dysfunction of coronary arteries can be detected as coronary flow reserve (CFR). Relaxation abnormality, characterized by reduced early (E) and increased late diastolic flow (A), is an early sign of cardiac diastolic dysfunction. The objective of this study is to determine the relationship of CFR and diastolic dysfunction and to evaluate the risk factors predicting these abnormalities in T2DM patients. 61 T2DM patients and 16 normal glucose tolerance (NGT) control without evidence of coronary artery disease (CAD) were measured CFR and diastolic function using non-invastive transthoracic echocardiography. CFR (hyperemic/resting diastolic flow velocity ratio) was measured by 90-second intravenous adenosine infusion (140 µg/kg/min). The mitral inflow velocity (transmitral E/A ratio) was measured to evaluate cardiac diastolic dysfunction. Diabetic peripheral neuropathy was assessed by history, physical examination and nerve conduction velocity (NCV). CFR was decreased in T2DM patients (2.35 ± 0.66 vs 2.89 ± 1.00; p=0.029). E (0.67 ± 0.18 m/sec) and E/A ratio (0.88 ± 0.32) were also reduced in T2DM patients. There was a significant correlation between CFR and E/A ratio (r=0.323, p=0.017) in T2DM patients. Age (r=-0.269, p=0.036), male sex (0.592, p<0.001), triglyceride (r=-0.261, p=0.023), free fatty acid (r=-0.324, p=0.036) and the presence of diabetic neuropathy (-0.346, p=0.016) were significantly correlated with CFR. In addition, age (r=0.329, p=0.010), male sex (r=0.394, p=0.003), waist-hip ratio (r=-0.392, p=0.005), leptin (r=-0.318, p=0.040) and the presence of diabetic neuropathy (r=0.467, p=0.001) were significantly correlated with E/A ratio. In summary, the reduced coronary microcirculation in T2DM may play an important role of diastolic dysfunction and diabetic cardiomyopathy, causing myocardial ischemia. Furthermore, diabetic neuropathy may be a significant predictor in coronary microcirculation and diastolic dysfunction in T2DM. We suggest that CFR may be a good indicator to estimate diastolic dysfunction, and diabetic neuropathy is a useful marker of estimating cardiovascular morbidity in T2DM without CAD. [ABSTRACT FROM AUTHOR]

Abstract: We evaluated incretin secretion and dipeptidyl peptidase (DPP)-IV activity in Korean type 2 diabetic patients compared with non-diabetic subjects. Type 2 diabetic patients showed intact GLP-1 and total GIP levels similar to those in non-diabetic subjects. Serum DPP-IV activity was significantly higher in type 2 diabetic patients (p =0.022). [ABSTRACT FROM AUTHOR]

AMP-activated protein kinase (AMPK) is activated under a variety of conditions that signify cellular stress, usually in response to a change in the intracellular ATP-to-AMP ratio. This is well known as a major drug target of diabetes. Ginseng has been shown to antidiabetic properties in many clinical and experimental studies. In previous our study, Panax ginseng (Korean red ginseng :KRG) showed improvement of insulin resistance and preventive effect on type 2 diabetes. Here, we evaluated the hypothesis that the insulin-sensitizing effect of KRG is mediated through the action of AMPK. To investigate the chronic effect of KRG on AMPK regulation in skeletal muscle and liver in vivo, OLETF rats were randomly allocated into two experimental groups: control and KRG. KRG was given orally once daily at a dose of 200 mg/kg to 10 week-old male OLETF rats for 32 weeks. To investigate the acute effect ofKRG on AMPK signaling in skeletal muscle and liver in vitro, L6 myotubles and HepG2 cells were incubated for 1hr, 6hr and 24 hr with KRG. Western blot analysis was performed to evaluate the expression of AMPK; ACC, PPARα and glucose transport (GLUT)-4. Thr 172 phosphorylation of AMPKα was significantly decreased in liver and skeletal muscle (gastrocnemius) of untreated OLETF rats. However, KRG treatment resulted in increased phosphorylation of AMPK in both tissues. Similarly, Ser79 acetyl-coA carbosylase (ACC) phosphorylation was increased in KRG-treated OLETF rats. The expression of PPARα was also increased in skeletal muscle and liver of KRG treated OLETF rats. In addition, the expression of GLUT4 was increased in skeletal muscle. In HepG2 cell line, KRG treatment during 1hr, 6hr and 24 hr was increased phosphorylation of AMPK. This effect mimicked those of metformin 2mM. ACC phosphorylation also increased in KRG treatment. Similarly, KRG treatment was increased phoshorylation of AMPK and ACC in differentiated L6 myotubules. In summary, KRG may enhance fatty acid oxidation via the activation of AMPK in skeletal muscle and liver, which contribute to the improvement of hyperglycemia, hyperlipidemia and insulin resistance. We suggest that KRG may have potential role in treatment and prevention of metabolic syndrome and type 2 diabetes. [ABSTRACT FROM AUTHOR]

Abstract: Lipin1 protein, a product of the LPIN1 gene, is required for normal adipose tissue development and metabolism. Lipin1 deficiency results in immature adipocyte development in cases of mouse fatty liver dystrophy and human lipodystrophy. Recently, pioglitazone has been reported to increase human adipocyte lipin1 expression. We evaluated the effects of LPIN1 polymorphisms on rosiglitazone response in patients with type 2 diabetes (T2DM). A total of 262 patients were treated with 12 weeks of rosiglitazone (4mg/day) in addition to their previous drug regimen medications. Six single nucleotide polymorphisms (SNPs) at the LPIN1 locus were genotyped: rs11693809, rs10192566, rs2278513, rs2577262, rs2716610, and rs1050800. Because rs11693809, rs10192566, and rs2278513 are in nearly complete linkage disequilibrium (D′>0.958, r 2 >0.882), we analyzed rs10192566, rs2577262, rs2716610, and rs1050800. Rs10192566 was significantly associated with rosiglitazone treatment response. Patients with the G allele in rs10192566 had a larger decrease in fasting plasma glucose, 2-h postprandial glucose, and HbA1c than those without. This genetic effect remained significant after adjustment for age, sex, and initial body weight. No other SNPs were associated with response. These data suggest that LPIN1 genetic variations can affect rosiglitazone treatment response in T2DM. [Copyright &y& Elsevier]

Background and aims Sarpogrelate, a 5-hydroxytryptamine type 2A antagonist, is a potential antiplatelet agent. We performed a randomized study to evaluate the effect of sarpogrelate on vascular health in Korean patients with diabetes. Methods Forty diabetic patients aged 58.6 ± 6.8 years with 10–75% coronary artery stenosis, as assessed by coronary computed tomography angiography, were randomly assigned to sarpogrelate 300 mg/day plus aspirin 100 mg/day (SPG + ASA group) or aspirin 100 mg/day alone (ASA group) for 6 months. The primary endpoint of this study was the change in coronary artery disease including the calcium score (CACS), maximal stenosis, and plaque volume (calcified vs. noncalcified). The secondary endpoints were changes in biochemical parameters related to glucose and lipid metabolism, and in subclinical atherosclerosis assessed by ankle–brachial index and pulse wave velocity. Results After 6-month treatment, there was no significant difference in the changes in CACS, coronary stenosis, ankle–brachial index, and pulse wave velocity, between groups. The total plaque volume decreased from 82.4 ± 14.5 mm 3 to 74.6 ± 14.4 mm 3 in the SPG + ASA group, but increased from 64.9 ± 16.0 mm 3 to 68.6 ± 16.3 mm 3 in the ASA group ( p < 0.05), mainly driven by changes in the noncalcified component (SPG + ASA group 15.6 ± 4.6 mm 3 to 11.2 ± 3.7 mm 3 vs . ASA group 21.2 ± 6.2 mm 3 to 22.8 ± 6.6 mm 3 , p < 0.01). Serum C-reactive protein levels and homeostasis model assessment of insulin resistance tended to decrease in the SPG + ASA group, but they were not altered in the ASA group. Conclusions The present study demonstrated that sarpogrelate treatment may decrease coronary artery plaque volume, particularly the noncalcified portion, in patients with diabetes. [ABSTRACT FROM AUTHOR]

High levels of plasma free fatty acid are thought to contribute to the loss of pancreatic beta-cells in type 2 diabetes. In particular, saturated fatty acid such as palmitate or stearate can induce apoptosis in cultured beta cells (lipotoxicity). Endoplasmic reticulum stress is a critical mediator of free fatty acid-induced lipotoxicity. Recently, disorders in mitochondrial respiratory metabolism have been linked to lipotoxicity. Since iron is a critical component of respiratory metabolism, this study is initiated to determine whether abnormal iron metabolism is involved in palmitate-induced beta cell death. Immunoblotting analysis showed that treatment of INS-1 beta cells with palmitate reduced the level of transferrin receptor 1 (TfR1), but increased the level of heavy chain ferritin (FTH). In addition, palmitate reduced intracellular labile iron pool. Whereas iron depletion through treatment with iron-chelators deferoxamine or deferasirox augmented palmitate-induced cell death, iron supplementation with ferric chloride, ferrous sulfate, or holo-transferrin significantly protected cells against palmitate-induced death. Furthermore, overexpression of TfR1 reduced palmitate-induced cell death, whereas knockdown of TfR1 augmented cell death. In particular, treatment with deferoxamine increased the level of endoplasmic reticulum (ER) stress markers phospho-PERK, phospho-eIF2α, CHOP and phospho-c-Jun N-terminal kinase. Treatment with chemical chaperone significantly protected cells against deferoxamine-induced apoptosis. Iron supplementation also protected cells against palmitate-induced primary islet death. These data suggest that iron depletion plays an important role in palmitate-induced beta cell death through inducing ER stress. Therefore, attempts to block iron depletion might be able to prevent beta cell loss in type 2 diabetes. [ABSTRACT FROM AUTHOR]

Abstract: Loss of beta cells is a pathogenic cause for the development of type 2 diabetes. High glucose/free fatty acid (HG/FFA)-induced glucolipotoxicity was thought to play a role in the beta cell loss. Thus, application of small molecules capable of preventing HG/FFA-induced glucolipotoxicty to beta cells could be an avenue for a therapeutic intervention for the development of type 2 diabetes. We screened a representative library supplied from Korean Chemical Bank for prevention of high glucose/palmitate (HG/PA)-induced viability reduction of INS-1 beta cells and were able to identify a new small molecule (DW1182v) with a function to protect HG/PA-induced glucolipotoxicity. The protective effect was specific to HG/PA-induced beta cell death since DW1182v did not protect streptozotocin- or cytokine-induced INS-1 cell death. The protective effect by DW1182v was likely due to the reduction of death-promoting endoplasmic reticulum (ER) stress responses such as phospho-C-Jun N-terminal kinase (JNK) and C/EBP homologous protein (CHOP). Treatment of obese diabetic db/db mice with DW1182v preserved islet integrity and thus increased insulin secretion and lowered blood glucose after glucose infusion. These results suggest that a small molecule protecting HG/PA-induced glucolipotoxicity to beta cells can be a new therapeutic candidate to prevent the development of type 2 diabetes. [Copyright &y& Elsevier]

Abstract: Aims: Fibroblast growth factor 21 (FGF21) is an important regulator of glucose/lipid metabolism. Although there are studies examining the relationship between serum FGF21 levels and glucose homeostasis, the role of FGF21 remains unclear. The objective of this study was to examine whether serum FGF21 levels are associated with metabolic parameters in subjects with varying degrees of obesity and glucose tolerance and with complications in subjects with type2 diabetes mellitus (T2DM). Methods: The study consisted of 213 subjects who were lean and had normal glucose tolerance (lean NGT), were overweight with NGT, had impaired glucose tolerance (IGT) or had T2DM. Serum FGF21 levels and their associations with the parameters of adiposity, glucose tolerance and the presence of diabetic complications were examined. Results: The serum FGF21 levels in T2DM were higher than in lean NGT. Serum FGF21 levels showed a positive correlation with the urine albumin-to-creatinine ratio (ACR) in all subjects except for the T2DM subjects, who showed a correlation after adjustment of age, gender and body mass index. Moreover, the subjects with carotid artery plaque showed higher serum FGF21 levels than those without complications. Conclusion: Serum FGF21 levels were associated with the urine ACR and diabetic complications including carotid artery plaque. [Copyright &y& Elsevier]

Abstract: Aims: We evaluated the use and annual cost of complementary and alternative medicine (CAM) compared to conventional medicine in type 2 diabetes mellitus (DM) in the Korean population. Methods: We analyzed the database of 2752 DM patients obtained from the Korean National Diabetes Program (KNDP). The cost data of conventional medicine starting 1-year before enrolment of the KNDP were obtained from the hospital electronic database. The cost data of CAM over the same period were obtained from questionnaires. Results: Among the 2752 subjects, 677 patients (24.6%) used CAM, with the most common type being red ginseng and herbal medicine. Patients with a higher income, neuropathy, and self-monitoring of blood glucose (SMBG) were more likely to use CAM. Men, those with a higher education level and income, no cerebrovascular accident (CVA) history, and SMBG showed a relatively higher cost of CAM of total medical cost. The independent predictors for CAM were a higher income, the existence of diabetic neuropathy, no CVA history, and SMBG. Conclusions: Use and cost of CAM varied depending on income, accompanying complications and SMBG. To evaluate the total medical costs in DM patients, a comprehensive approach considering not only conventional cost but also CAM is required. [Copyright &y& Elsevier]

Abstract: Intake of whole grains has been associated with lower risks of type 2 diabetes and cardiovascular disease. Brown rice is unrefined whole grain and is produced by removing the outermost layers containing the germ and bran, which are rich in nutrients including dietary fiber, vitamins, minerals, and other unmeasured dietary constituents. The lees of brown rice (LB) are by-products of its fermentation in the process of manufacturing takju, a Korean turbid rice wine. In this study, we hypothesized that intake of LB would reduce waist circumference, a strong risk factor for cardiovascular disease in type 2 diabetic patients. A randomized, double-blind, placebo-controlled study was scheduled for 12 weeks. Thirty subjects were randomly assigned to receive a supplement prepared from the LB or from a mixed-grain dietary product (MG). Body weight, waist circumference, body composition, lipid profiles, and other laboratory parameters were measured. The LB group showed greater reduction in waist circumference (LB: 87.9 ± 8.8 to 85.1 ± 9.0 cm; MG: 86.9 ± 8.8 to 86.0 ± 9.3 cm; P = .032). In addition, the consumption of LB resulted in a significantly greater decrease in the level of aspartate transaminase (LB: 25.4 ± 8.5 to 21.0 ± 5.1 IU/mL; MG: 22.5 ± 5.3 to 22.4 ± 5.7 IU/mL; P = .044) and alanine transaminase (LB: 28.6 ± 11.3 to 21.9 ± 8.2 IU/mL; MG: 24.4 ± 7.5 to 24.5 ± 9.9 IU/mL; P = .038). Consumption of the LB was associated with a decreased waist circumference in type 2 diabetic patients. Further study is required to evaluate the metabolic effect of the extract of the LB in type 2 diabetes. [Copyright &y& Elsevier]

Abstract: Lithospermic acid B (LAB), an active component isolated from Salvia miltiorrhizae, has been reported to have renoprotective effects in type 1 diabetic animal models. In the present study we investigated the effects of LAB on the prevention of diabetic nephropathy in type 2 diabetic Otsuka Long-Evans-Tokushima Fatty (OLETF) rats. LAB (20 mg/kg) was given orally once daily to 10-week-old male OLETF rats for 28 weeks. Treatment of OLETF rats with LAB had little effects on body weight and blood glucose levels. Treatment with LAB resulted in significant reduction in blood pressure. LAB markedly attenuated albuminuria and significantly lowered levels of lipid peroxidation, monocyte chemoattractant protein-1 (MCP-1), and transforming growth factor-β (TGF-β1) expression in renal tissues of OLETF rats. In addition, LAB inhibited the progression of glomerular hypertrophy, mesangial expansion, and expansion of the extracellular matrix in the renal cortex. Collectively, these results suggest that LAB has beneficial effects on the diabetic nephropathy in OLETF rats by decreasing blood pressure, oxidative stress, and MCP-1 expression. Our results suggest that LAB might be a new therapeutic agent for the prevention of nephropathy in type 2 diabetes. [Copyright &y& Elsevier]