Discovery of DiPeptidyl Peptidase-4 Gene Variants and the Associations with Efficacy of Vildagliptin in Patients with Type 2 Diabetes - A Pilot Study

Background: The dipeptidyl peptidase-4 (DPP4) inhibitors have become widely used antidiabetic medication. They control glycemia by interacting with serum DPP4 to interfere catalyzation of incretins. The aim of this pilot study was to discover the DPP4 polymorphisms that could affect the efficacy of vildagliptin, a DPP-4 inhibitor in diabetic patients. Methods: Genetic variations in DPP4 were identified in 48 patients with type 2 diabetes who received vildagliptin treatment at least 12 weeks following metformin monotherapy. Luciferase assay was performed to estimate the effect of the regulatory single nucleotide polymorphism (SNP) on expression of DPP4. Results: Eight tagging SNPs were genotyped in a sample of 24 patients. Additional sample of 24 patients was used to discover further regulatory SNPs and coding SNPs. In all 48 patients, responders (degree of HbA1c and/or fasting glucose level decrease greater than 10% of baseline after 12 weeks of vildagliptin add-on treatment) did not show any significant difference in selected six DPP4 polymorphisms from non-responders. DPP4 expression was not different according to g.-234A/C in luciferase assay. Conclusion: Our pilot study could not find any significant genetic variant which is associated with vildagliptin response in patients with type 2 diabetes. Further studies in large population are warranted.ope

The Effect of DPP-4 Inhibitors on Metabolic Parameters in Patients with Type 2 Diabetes

BACKGROUND: We evaluated the effects of two dipeptidyl peptidase-4 (DPP-4) inhibitors, sitagliptin and vildagliptin, on metabolic parameters in patients with type 2 diabetes mellitus. METHODS: A total of 170 type 2 diabetes patients treated with sitagliptin or vildagliptin for more than 24 weeks were selected. The patients were separated into two groups, sitagliptin (100 mg once daily, n=93) and vildagliptin (50 mg twice daily, n=77). We compared the effect of each DPP-4 inhibitor on metabolic parameters, including the fasting plasma glucose (FPG), postprandial glucose (PPG), glycated hemoglobin (HbA1c), and glycated albumin (GA) levels, and lipid parameters at baseline and after 24 weeks of treatment. RESULTS: The HbA1c, FPG, and GA levels were similar between the two groups at baseline, but the sitagliptin group displayed a higher PPG level (P=0.03). After 24 weeks of treatment, all of the glucose-related parameters were significantly decreased in both groups (P=0.001). The levels of total cholesterol and triglycerides were only reduced in the vildagliptin group (P=0.001), although the sitagliptin group received a larger quantity of statins than the vildagliptin group (P=0.002).The mean change in the glucose- and lipid-related parameters after 24 weeks of treatment were not significantly different between the two groups (P=not significant). Neither sitagliptin nor vildagliptin treatment was associated with a reduction in the high sensitive C-reactive protein level (P=0.714). CONCLUSION: Vildagliptin and sitagliptin exert a similar effect on metabolic parameters, but vildagliptin exerts a more potent beneficial effect on lipid parameters.ope

GPR30-mediated activation of STAT3-anorexigenic pathway by estrogen in the hypothalamus

의과대학/박사Estrogen plays an important role in the control of energy balance in the hypothalamus. Leptin-independent STAT3 activation (phosphorylation of STAT3, pSTAT3) in the hypothalamus is hypothesized as the primary mechanism of the estrogen-induced anorexic response. However, it is unknown which type of estrogen receptor mediates this regulation. In this study, the role of the G protein-coupled receptor 30 (GPR30) in estradiol (E2)-induced STAT3 activation in the hypothalamus was investigated. E2 stimulated pSTAT3 in cells expressing GPR30, but not expressing estrogen receptor ERα and ERβ. E2-induced pSTAT3 activation was inhibited by EGFR inhibitor or pertussis toxin. G-1, a specific agonist of GPR30, induced pSTAT3 and G-15, a specific antagonist of GPR30, inhibited E2-induced pSTAT3 in primary cultures of hypothalamic neurons. Intracerebroventricular (ICV) injection of G-1 increased pSTAT3 in the arcuate nucleus of mice, which was associated with a decrease in food intake and body weight gain. These pSTAT3 signals were colocalized with POMC neurons in the arcuate nucleus. ICV injection of G-15 inhibited G-1-induced pSTAT3 activation and E2-induced decrease in food intake and body weight gain. These results suggest that GPR30 is the estrogen receptor that mediates the anorectic effect of estrogen through the STAT3 pathway in the hypothalamus, which may provide a basis for future therapeutic interventions of obesity.prohibitio

요오드 제한이 무증상 갑상선기능저하증 환자에 미치는 영향

의학과/석사[한글]요오드 과다 섭취는 무증상 갑상선기능저하증의 높은 유병율과 관련되어있다. 본 연구는 요오드 제한이 무증상 갑상선 기능저하증 환자의 갑상선 기능을 호전시킬 수 있는지 확인하기 위해 시행되었다. 한국인 중 64명의 무증상 갑상선기능저하증 환자에게서 반정량 식품섭취빈도 설문지를 통해 계산된 요오드 섭취량을 토대로 세 군으로 나누었다. A군은 요오드 섭취 제한을 하지 않는 군 (13명), B군은 요오드 섭취를 제한하는 군 (33명), C군은 갑상선 호르몬 투여가 필요한 군 (18명) 이었다. 각각의 요오드 섭취 방침에 따라 24시간 소변 요오드량과 갑상선 기능에 변화에 차이가 있는지 조사하였다. 전체 환자들에게서 계산된 요오드 섭취량의 중위값은 290.61 μg/day 였으며, 24시간 소변 요오드량의 중위값은 33.65 μmol/g of creatinine 였다. A군 및 C군과 비교하여 B군의 소변 요오드량은 유의하게 높았다 (P = 0.034 및 P = 0.008). 이 환자들의 주된 요오드 공급원은 해초류였으며, 그 중 다시마로부터 가장 많은 요오드를 섭취하였다 (중위값 177.26 μg/day). 설문지를 통해 계산된 요오드 섭취량은 24시간 요오드량과 유의한 연관관계를 보였다 (P < 0.001). 소변 요오드량이 많은 것과 계산된 요오드 섭취량이 많은 것은 보다 높은 갑상선자극호르몬 수치와 유의한 상관관계를 보였다 (P < 0.001 및 P = 0.027). 요오드 섭취 제한 후 B군은 A군에 비해서 24시간 소변 요오드량 및 갑상선 자극호르몬 수치가 유의하게 감소된 소견을 보였다 (P = 0.017 및 P = 0.013). 결론적으로, 한국인 무증상 갑상선기능저하증 환자에게 있어서 요오드 섭취량과 24시간 소변 요오드량은 갑상선 기능과 상관관계를 보였다. 또한, 이러한 환자에게서 요오드 섭취를 제한하는 것은 갑상선 기능을 호전시킬 수 있었다. [영문]High iodine intake is related to a higher prevalence of subclinical hypothyroidism. We conducted this study to confirm that restriction of daily dietary iodine could improve thyroid function in subclinical hypothyroidism patients. We divided 64 Korean participants into three groups according to their 24-hour urine iodine test results and calculated iodine intake using a semi-quantitative food frequency questionnaire. The groups were as follows: group A had no restriction on dietary iodine (n = 13); group B had a dietary iodine restriction (n = 33); and group C received thyroid hormone replacement (n = 18). We also investigated whether different strategies of iodine restriction lead to variations in 24-hour urine iodine and/or thyroid function. The median calculated amount of iodine intake was 290.61 μg/day, and the median 24-hour urine iodine was 33.65 μmol/g of creatinine. Compared with groups A and C, the baseline urine iodine of group B was significantly higher (P = 0.034 for A vs. B, and P = 0.008 for C vs. B). The major source of dietary iodine in this Korean population was seaweed. Among the different types of dietary seaweed studied, sea tangle had the highest iodine contents (median 177.26 μg/day). The calculated amount of daily dietary iodine was significantly correlated with 24-hour urine iodine (P < 0.001). Higher urine iodine content and calculated amount of iodine intake were related to higher serum TSH levels (P < 0.001 and P = 0.027, respectively). Compared with group A, group B showed significantly decreased contents of 24-hour urine iodine (P = 0.017) and TSH (P = 0.013) after the restriction of excessive iodine intake. In conclusion, iodine intake and 24-hour urine iodine were correlated with thyroid function. Additionally, restriction of daily dietary iodine could reverse thyroid malfunctions in subclinical hypothyroidism patients with excessive iodine intake.ope

Nationwide survey of acromegaly in South Korea

CONTEXT: It was previously reported in Korea that there were 1.4 case per million per year of acromegaly. This was low in comparison with the extrapolated values of Western European countries. We expected that the incidence of acromegaly would be much higher now because of recently improved medical facilities, diagnostic tools and coverage of medical insurance to all the population of South Korea. OBJECTIVE: The purpose of this nationwide survey was to examine the incidence and prevalence of patients with acromegaly, mode of treatment and outcome of surgical treatment of recent 5 years. DESIGN AND PATIENTS: We requested and collected the medical records of all possible patients with acromegaly from 74 secondary or tertiary medical institutes in Korea from 2003 to 2007 retrospectively. MEASUREMENTS: Date of diagnosis and treatment, tumour size, pre- and postoperative hormonal level, treatment modality and usage of medication were collected. RESULTS: During 5 years, 1350 patients with acromegaly had been registered. The average annual incidence was 3.9 cases per million during this period, and prevalence had increased up to 27.9 cases per million in 2007. Male/female ratio was 1:1.2, and mean age at diagnosis was 44.1 years. Macroadenoma was dominant (82.9%). Transsphenoidal adenoidectomy was used the most as primary treatment (90.4%). CONCLUSIONS: This Korean acromegaly survey offers a realistic overview of the predominant epidemiological characteristics of acromegaly in Korea. Annual incidence was at a similar level with western countries. Efforts to diagnose and control the disease earlier are recommended.ope

mGluR5 in the nucleus accumbens is critical for promoting resilience to chronic stress

Resilience to aversive events has a central role in determining whether stress leads to the development of depression. mGluR5 has been implicated in the pathophysiology of depression, but the effect of mGluR5 activity on stress resilience remains unexplored. We found that mGluR5(-/-) (also known as Grm5(-/-)) mice displayed more depression-like behaviors (for example, learned helplessness, social withdrawal and anhedonia) than control mice following exposure to various stressful stimuli. Lentiviral 'rescue' of mGluR5 in the nucleus accumbens (NAc) decreased these depression-like behaviors in mGluR5(-/-) mice. In the NAc, ΔFosB, whose induction promotes stress resilience, failed to be upregulated by stress in mGluR5(-/-) mice. Notably, targeted pharmacological activation of mGluR5 in the NAc increased ΔFosB expression. Our findings point to an essential role for mGluR5 in promoting stress resilience and suggest that a defect in mGluR5-mediated signaling in the NAc may represent an endophenotype for stress-induced depression.ope

GPR30 mediates anorectic estrogen-induced STAT3 signaling in the hypothalamus

OBJECTIVE: Estrogen plays an important role in the control of energy balance in the hypothalamus. Leptin-independent STAT3 activation (i.e., tyrosine(705)-phosphorylation of STAT3, pSTAT3) in the hypothalamus is hypothesized as the primary mechanism of the estrogen-induced anorexic response. However, the type of estrogen receptor that mediates this regulation is unknown. We investigated the role of the G protein-coupled receptor 30 (GPR30) in estradiol (E2)-induced STAT3 activation in the hypothalamus. MATERIALS/METHODS: Regulation of STAT3 activation by E2, G-1, a specific agonist of GPR30 and G-15, a specific antagonist of GPR30 was analyzed in vitro and in vivo. Effect of GPR30 activation on eating behavior was analyzed in vivo. RESULTS: E2 stimulated pSTAT3 in cells expressing GPR30, but not expressing estrogen receptor ERα and ERβ. G-1 induced pSTAT3, and G-15 inhibited E2-induced pSTAT3 in primary cultures of hypothalamic neurons. A cerebroventricular injection of G-1 increased pSTAT3 in the arcuate nucleus of mice, which was associated with a decrease in food intake and body weight gain. CONCLUSIONS: These results suggest that GPR30 is the estrogen receptor that mediates the anorectic effect of estrogen through the STAT3 pathway in the hypothalamus.ope

Increments of alpha-dystroglycan expression in liver metastasis correlate with poor survival in gastric cancer

BACKGROUND: Dystroglycan (DG) is a recently focused adhesion molecule with possible roles in cancer development and progression. We investigated correlations between alpha-DG expression and prognosis in gastric carcinoma with liver metastasis. METHODS: For 40 patients with gastric adenocarcinoma and liver-only metastasis, alpha-DG expression was determined by immunohistochemistry in paraffin-embedded surgical specimens of resected stomach tumor, resected liver metastasis, and their normal counterpart tissues. Correlations between alpha-DG expression and prognosis were retrospectively analyzed. RESULTS: alpha-DG expression was higher in primary gastric cancer (P = 0.006) and lower in liver metastasis (P = 0.002) than in each normal counterpart. In primary stomach cancer, patients who had lower alpha-DG expression in tumors than in normal counterparts showed poor overall survival (OS) (P = 0.028). In contrast, in the liver, patients who had higher alpha-DG expression in tumors than in normal counterparts showed poor OS (P = 0.022). Also, higher alpha-DG expression in liver metastasis than in stomach tumors led to poor recurrence-free survival (P = 0.023) and OS (P = 0.056). CONCLUSIONS: This approach may be used to further understanding of the pathogenesis of liver metastasis from gastric cancer. Further studies are warranted to reveal the mechanisms of alpha-DG dysregulation in liver metastasis.ope

HMG CoA Reductase Inhibitor Treatment Induces Dysglycemia in Renal Allograft Recipients

BACKGROUND: Dysglycemia and dyslipidemia are important metabolic complications of organ transplantation. Statins are widely used to control dyslipidemia; however, long-term use of statins is related to diabetes mellitus (DM) and impaired fasting glucose (IFG). The aim of this study was to evaluate the influence of statins on the development of dysglycemia (IFG and/or DM) in renal allograft recipients. METHODS: A total of 394 patients without previously known DM or IFG who underwent kidney transplantation were enrolled. Patients were grouped into the two groups according to the use of statin (control, n=149; statin, n=245). The major statins used were fluvastatin (80 mg/d, n=134) and atorvastatin (20 mg/d, n=111). We compared the incidence of IFG or DM during the follow-up period. RESULTS: The incidence of IFG was higher in the statin group than that in the control group (28.6% vs. 8.7%, P<0.001). The incidence of dysglycemia was significantly higher in the statin group (40.0% vs. 15.4%, P=0.001). Time to development of dysglycemia after transplantation was shorter in the statin group than in the control group (38.8±29.7 vs. 47.2±23.3 months, P=0.002). Statin use was associated with an increased risk for dysglycemia after adjustment for age, sex, body mass index, hypertension, cholesterol levels, hepatitis C infection, and type of immunosuppressant (hazard ratio=3.08, 95% confidence interval=1.91-4.98). The dysglycemic effect was more profound in the patients who used atorvastatin than in those who used fluvastatin (hazard ratio=2.21, 95% confidence interval=1.02-4.76). CONCLUSION: Statin treatment is associated with an elevation in fasting plasma glucose and in the development of dysglycemia in renal allograft recipients.ope