Introduction: Sulfonylureas (SUs) are commonly used drugs for type 2 diabetes mellitus (T2DM) in the Philippines. This study aimed to associate genetic variants with poor response to gliclazide and glimepiride among Filipinos. Methodology: Two independent, dichotomous longitudinal substudies enrolled 139 and 113 participants in the gliclazide and glimepiride substudies, respectively. DNA from blood samples underwent customized genotyping for candidate genes using microarray. Allelic and genotypic features and clinical associations were determined using exact statistical methods. Results: Three months after sulfonylurea monotherapy, 18 (13%) were found to be poorly responsive to gliclazide, while 7 (6%) had poor response to glimepiride. Seven genetic variants were nominally associated (p<0.05) with poor gliclazide response, while three variants were nominally associated with poor glimepiride response. For gliclazide response, carboxypeptidase-associated variants (rs319952 and rs393994 of AGBL4 and rs2229437 of PRCP) had the highest genotypic association; other variants include rs9806699, rs7119, rs6465084 and rs1234315. For glimepiride response, 2 variants were nominally associated: CLCN6-NPPA-MTHFR gene cluster – rs5063 and rs17367504 – and rs2299267 from the PON2 loci. Conclusion Genetic variants were found to have a nominal association with sulfonylurea response among Filipinos. These findings can guide for future study directions on pharmacotherapeutic applications for sulfonylurea treatment in this population.
genetic variants ; sulfonylureas ; Filipino ; gliclazide

BACKGROUND: To investigate whether the number of subjects with severe hypoglycemia who are brought to a hospital emergency department is increasing and to identify whether there have been changes in the demographic and clinical characteristics of those subjects. METHODS: We analyzed data from the Emergency Departments of two general hospitals in Seoul, Korea. We included data from all adult subjects with type 2 diabetes who presented to an emergency department with severe hypoglycemia between January 1, 2004 and December 30, 2009. RESULTS: A total of 740 cases of severe hypoglycemia were identified. The mean subject age was 69+/-12 years, mean duration of diabetes was 13.8+/-9.3 years, and 53.2% of subjects were receiving insulin therapy. We observed a sharp rise in the number of cases between 2006 and 2007. Stages 3-5 chronic kidney disease was diagnosed in 31.5% of subjects, and low C-peptide levels (<0.6 ng/mL) were found in 25.5%. The mean subject age, duration of diabetes, HbA1c level, and renal and insulin secretory function values did not change significantly during the study period. The proportion of glimepiride use increased, while use of gliclazide decreased among sulfonylurea users. Use of insulin analogues increased, while use of NPH/RI decreased among insulin users. CONCLUSION: We identified a sharp increase in the number of subjects with severe hypoglycemia presenting to an emergency room since 2006. The clinical characteristics of these subjects did not change markedly during the study period. Nationwide studies are warranted to further clarify this epidemic of severe hypoglycemia.
Adult ; C-Peptide ; Emergencies ; Gliclazide ; Hospitals, General ; Humans ; Hypoglycemia ; Insulin ; Korea ; Renal Insufficiency, Chronic ; Sulfonylurea Compounds

OBJECTIVETo compare the roles of alisma and gliclazide in the treatment of diabetes in Goto-Kakizaki (GK) rats.

METHODSGK rats were randomly divided into alisma group, gliclazide group, and blank group, and Wistar rats were used as the normal group. After two weeks of treatment, body weight, food intake,fasting glucose, impaired glucose tolerance, and other indicators were measured.

RESULTSThe body weight increased after the treatment in the normal group,blank group,and gliclazide group [(241.3 ± 7.0)g vs.(263.5 ± 11.1)g, (242.8 ± 7.1)g vs.(267.9 ± 16.8)g, (243.9 ± 12.2)g vs.(277.9 ± 9.8)g, P<0.05] but decreased in alisma group [(244.6 ± 9.2)g vs.(227.9 ± 13.7)g, P<0.05]. The food intake showed no significant change before and after administration among different groups(P>0.05). Fasting glucose was significantly lower in normal group than in control group,alisma group,and gliclazide group [(4.8 ± 0.2) mmol/L vs.(8.2 ± 1.4) mmol/L,(8.1 ± 0.6) mmol/L, (8.1 ± 0.9)mmol/L, P<0.05] one week after drug administration; it was not significantly different among blank group,alisma group,and gliclazide group before drug administration (P>0.05); however, it significantly decreased in alisma group and gliclazide group two weeks after administration [(6.9 ± 0.7) mmol/L vs.(8.1 ± 0.6) mmol/L; (5.8 ± 0.5) mmol/L vs.(8.1 ± 0.9) mmol/L, P<0.05]; compared with the blank group, the fasting glucose was significantly lower in the alisma group and gliclazide group,and it was also significantly different between these two groups [(6.9 ± 0.7) mmol/L vs.(8.8 ± 0.6) mmol/L,(5.8 ± 0.5)mmol/L vs.(8.8 ± 0.6)mmol/L, (6.9 ± 0.7) mmol/L vs.(5.8 ± 0.5)mmol/L, P<0.05]. Compared with the normal group,glucose tolerance was abnormal in blank group,alisma group,and gliclazide group;after two weeks of treatment,glucose tolerance was significantly improved in alisma group (P<0.05); compared with the pretreatment level and that in the blank group,the glucose tolerance in gliclazide group showed no significant difference (P> 0.05).

CONCLUSIONSBoth alisma and gliclazide monotherapy is effective in lowering fasting blood glucose. As a single-target drug,gliclazide has stronger effecacy in lowering fasting glucose. However, alisma, as a mixture, can also control weight and improve glucose intolerance.

Alisma ; Animals ; Blood Glucose ; Body Weight ; Diabetes Mellitus, Experimental ; Gliclazide ; Rats ; Rats, Wistar

Permanent neonatal diabetes mellitus (PNDM) is caused by mutations in the ATP-sensitive potassium channel (K(ATP) channel) subunits. Developmental delay, epilepsy, and neonatal diabetes (DEND) syndrome is the most severe form of PNDM and is characterized by various neurologic features. We report on a patient with DEND syndrome following initial misdiagnosis with type 1 DM, who was successfully switched from insulin to sulfonylurea therapy. A 50-day-old male presented with fever and seizure, complicated by persistent hyperglycemia. Insulin therapy was initiated. At 10 months of age, the patient was unable to hold his head up and make eye contact with others. At 17.9 years of age, direct sequencing of KCNJ11 identified a heterozygous mutation of c.602G>A (p.R201H). Since then, treatment with gliclazide was initiated and the insulin dose was gradually reduced. Following 3 months, insulin was discontinued with a gliclazide dose of 2.4 mg/kg. The patient continued to have excellent glycemic control with a glycated hemoglobin (HbA1c) level of 5.8% after 5 months. However, the patient's psychomotor retardation did not improve. This study reports the first case of DEND syndrome in Korea caused by a KCNJ11 mutation and emphasizes the necessity to screen mutations in KATP channel genes in patients with neonatal diabetes.
Diabetes Mellitus ; Diagnostic Errors ; Epilepsy ; Fever ; Gliclazide ; Head ; Hemoglobin A, Glycosylated ; Humans ; Hyperglycemia ; Insulin ; Korea ; Male ; Potassium Channels ; Seizures

A conference was convened by the Korean Diabetes Association and the Korean Endocrine Society on September 7, 2009 to discuss and organize the results of research on intensive glucose control for the prevention of cardiovascular disease in patients with type 2 diabetes. Professor Kyung Soo Park led the conference, and Professors Kwang Won Kim and Ho Young Son acted as chairmen. Professors Doo Man Kim, Tae Sun Park, and Bong Soo Cha reported on intensive glucose control and diabetic complications, including the UK Prospective Diabetes Study (UKPDS), Diabetes Control and Complication Trial (DCCT) research results, the recently published Action to Control Cardiovascular Risk in Diabetes (ACCORD), Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE), and Veterans Affairs Diabetes Trial (VADT) research, as well as meta-analyses. Professor Jeong-Taek Woo reported on the manuscript written by the committee for the Korean Diabetes Association which dealt with the treatment of diabetes mellitus. Professors Kyung Soo Ko, Joong Yeol Park, Hyun Shik Son, Moon-Kyu Lee, Dong-Won Byun, and Yoon-Sok Chung participated in the discussion and collected information for the manuscript from all of the participants. The aim of the debate was to determine how to establish target goals for intensive glucose control and how to individualize those goals. The participants concluded that there was no need to modify the recommendation of maintaining an HbA1c under 6.5%, the current blood glucose treatment goal that is recommended by the Korean Diabetes Association. In addition, individual target goals for glucose control were recommended depending on the situation of each patient. We report on the consensus statement from the meeting.
Blood Glucose ; Cardiovascular Diseases ; Consensus ; Diabetes Complications ; Diabetes Mellitus ; Drug Combinations ; Gliclazide ; Glucose ; Humans ; Indapamide ; Perindopril ; Solar System ; Veterans

A conference was convened by the Korean Diabetes Association and the Korean Endocrine Society on September 7, 2009 to discuss and organize the results of research on intensive glucose control for the prevention of cardiovascular disease in patients with type 2 diabetes. Professor Kyung Soo Park led the conference, and Professors Kwang Won Kim and Ho Young Son acted as chairmen. Professors Doo Man Kim, Tae Sun Park, and Bong Soo Cha reported on intensive glucose control and diabetic complications, including the UK Prospective Diabetes Study (UKPDS), Diabetes Control and Complication Trial (DCCT) research results, the recently published Action to Control Cardiovascular Risk in Diabetes (ACCORD), Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE), and Veterans Affairs Diabetes Trial (VADT) research, as well as meta-analyses. Professor Jeong-Taek Woo reported on the manuscript written by the committee for the Korean Diabetes Association which dealt with the treatment of diabetes mellitus. Professors Kyung Soo Ko, Joong Yeol Park, Hyun Shik Son, Moon-Kyu Lee, Dong-Won Byun, and Yoon-Sok Chung participated in the discussion and collected information for the manuscript from all of the participants. The aim of the debate was to determine how to establish target goals for intensive glucose control and how to individualize those goals. The participants concluded that there was no need to modify the recommendation of maintaining an HbA1c under 6.5%, the current blood glucose treatment goal that is recommended by the Korean Diabetes Association. In addition, individual target goals for glucose control were recommended depending on the situation of each patient. We report on the consensus statement from the meeting.
Blood Glucose ; Cardiovascular Diseases ; Consensus ; Diabetes Complications ; Diabetes Mellitus ; Drug Combinations ; Gliclazide ; Glucose ; Humans ; Indapamide ; Perindopril ; Solar System ; Veterans

OBJECTIVETo compare the influence of different sulfonylureas on the myocardial protection effect of ischemic preconditioning (IPC) in isolated rat hearts, and ATP-sensitive potassium channel current (IK(ATP)) of rat ventricular myocytes.

METHODSIsolated Langendorff perfused rat hearts were randomly assigned to five groups: (1) control group, (2) IPC group, (3) IPC + glibenclamide (GLB, 10 micromol/L) group, (4) IPC + glimepiride (GLM, 10 micromol/L) group, (5) IPC + gliclazide (GLC, 50 micromol/L) group. IPC was defined as 3 cycles of 5-minute zero-flow global ischemia followed by 5-minute reperfusion. The haemodynamic parameters and the infarct size of each isolated heart were recorded. And the sarcolemmal IK(ATP) of dissociated ventricular myocytes reperfused with 10 micromol/L GLB, 1 micromol/L GLM, and 1 micromol/L GLC was recorded with single-pipette whole-cell voltage clamp under simulated ischemic condition.

RESULTSThe infarct sizes of rat hearts in IPC (23.7% +/- 1.3%), IPC + GLM (24.6% +/- 1.0%), and IPC + GLC (33.1% +/- 1.3%) groups were all significantly smaller than that in control group (43.3% +/- 1.8%; P < 0.01, n = 6). The infarct size of rat hearts in IPC + GLB group (40.4% +/- 1.4%) was significantly larger than that in IPC group (P < 0.01, n=6). Under simulated ischemic condition, GLB (10 micromol/L) decreased IK(ATP) from 20.65 +/- 7.80 to 9.09 +/- 0.10 pA/pF (P < 0.01, n=6), GLM (1 micromol/L) did not significantly inhibit IK(ATP) (n=6), and GLC (1 micromol/L) decreased IK(ATP) from 16.73 +/- 0.97 to 11. 18 +/- 3.56 pA/pF (P < 0.05, n=6).

CONCLUSIONSGLM has less effect on myocardial protection of IPC than GLB and GLC. Blockage of sarcolemmal ATP-sensitive potassium channels in myocardium might play an important role in diminishing IPC-induced protection of GLM, GLB, and GLC.

Animals ; Gliclazide ; pharmacology ; Glyburide ; pharmacology ; Heart ; drug effects ; Ischemic Preconditioning ; Male ; Rats ; Rats, Sprague-Dawley ; Sulfonylurea Compounds ; pharmacology

BACKGROUND: Diabetes mellitus (DM) is one of the most important chronic diseases in public health, thus optimal management of this condition is crucial. For this purpose, oral hypoglycemic agents (OHA) are commonly prescribed with their consistent use being mandatory to maintain adequate blood glucose levels. We aimed to evaluate the compliance with OHA in patients with DM, and to determine the factors associated with compliance. METHODS: From March 2006 to December 2007, we enrolled patients with type 2 DM who were newly diagnosed or had discontinued OHAs for more than four weeks. For OHA, diamicron was prescribed to the participants and response to medication was evaluated by physicians after 12 weeks. Compliance was defined as patients taking diamicron continuously or stopping the medication due to well-controlled blood sugar levels. Demographic characteristics, anthropometric measurements, fasting glucose, and lipid profiles were collected and analyzed. RESULTS: The mean age of our 326 subjects was 56.0+/-9.9 years and 74.5% was defined to be compliant. Logistic regression analysis adjusting for age and sex revealed that combined medication use (odd ratio [OR], 2.03; 95% confidence interval [CI], 1.04-3.97) and diabetes-related nutritional education (OR, 2.08; 95% CI, 1.08-4.03) (P<0.05) were factors associated with compliance with OHA. CONCLUSIONS: About three quarters of the DM patients in our study, using diamicron for the first time, showed compliance after 12 weeks of treatment. Concomitant medications and diabetes-related nutrition education were associated with compliance.
Blood Glucose ; Chronic Disease ; Compliance* ; Diabetes Mellitus ; Diabetes Mellitus, Type 2 ; Education ; Fasting ; Gliclazide* ; Glucose ; Humans ; Hypoglycemic Agents ; Logistic Models ; Patient Education as Topic ; Public Health

BACKGROUND: Sulfonylurea drugs have been used for many decades as one of the main families of drugs for the treatment of type 2 diabetes mellitus. Even though there are many opportunities to medicate sulfonylurea drugs concomitantly with many other drugs, and furthermore there have been several case reports on drug interactions with sulfonylurea drugs, there has been no clear demonstration revealing the mechanisms that cause these interactions. We therefore evaluated inhibitory potential of sulfonylurea drugs, including glibenclamide, glipizide and gliclazide, on the cytochrome P450 (CYP)-catalyzing enzymes using human liver microsomes. METHODS: The inhibitory effects of glibenclamide, glipizide and gliclazide, on the CYP-catalyzing reaction, were evaluated for CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4 using human liver microsomes, and probe drugs for each. RESULTS: Glibenclamide showed relative potent inhibitory effects on the CYP2C9- and CYP3A4-catallyzed reaction (IC50; 11.3 ( microM and 59.0 ( microM). The other CYP isoforms tested showed only weak inhibitory effects by due to glibenclamide (IC50 > 112 ( microM). Glipizide showed potent inhibitory effect on CYP3A4-catalyzed reaction only (IC50; 11.2 ( microM), and weak, or no, inhibitory effects on each on the other CYP isoforms tested (IC50 > 276 ( microM). CONCLUSION: The sulfonylurea drugs showed inhibitory potential on the CYP-catalyzing reaction in human liver microsomes. The results obtained in the present study provide insights into the potential of the drug interaction to ward drugs co-administered with sulfonylureas. It will be necessary to take into consideration the control of blood glucose, as well as therapeutic drug monitoring, to reduced toxicities when sulfonylurea drugs are co-administered with drugs of a narrow therapeutic range, or with severe dose-dependent toxicities.
Blood Glucose ; Cytochrome P-450 CYP1A2 ; Cytochrome P-450 CYP2D6 ; Cytochrome P-450 Enzyme System ; Cytochromes* ; Diabetes Mellitus, Type 2 ; Drug Interactions ; Drug Monitoring ; Gliclazide ; Glipizide ; Glyburide ; Humans* ; Liver* ; Microsomes, Liver* ; Protein Isoforms

OBJECTIVETo observe the effect of Kaixin Capsule (KXC) on myocardial ischemia and plasma endothelin (ET) level in patients with diabetic heart disease (DHD).

METHODSThe 72 subjects for observation were randomly selected from inpatients whose diagnosis fit to the standard of DHD. The 32 patients allocated in the control group were treated with conventional Western medicine, and the 40 patients in the treated group were treated with conventional Western medicine in combination with KXC, with the therapeutic course for both groups as 60 days.

RESULTSOn ECG, the total effective rate and markedly effective rate in the treated group was 85.0% and 37.5% respectively, higher than those in the control group's 68.7% and 28.1% respectively, and showing significant difference between the two groups (P < 0.05). The level of ET in patients in both groups was significantly higher than normal range, after treatment, but reduced to different extent, and the comparison between them also showed that the difference was significant (P < 0.05).

CONCLUSIONKXC might, by way of inhibiting and blocking the release of ET, lower its level in plasma so as to improve the myocardial ischemic condition of patients with DHD.

Adult ; Blood Glucose ; Diabetes Complications ; blood ; drug therapy ; Diabetes Mellitus, Type 2 ; complications ; Drugs, Chinese Herbal ; administration & dosage ; Electrocardiography ; Endothelins ; blood ; Female ; Gliclazide ; administration & dosage ; Humans ; Hypoglycemic Agents ; administration & dosage ; Male ; Middle Aged ; Myocardial Ischemia ; blood ; drug therapy ; etiology