Permanent neonatal diabetes mellitus refers to diabetes that occurs before the age of 6 months and persists through life. It is a rare disorder affecting one in 0.2-0.5 million live births. Mutations in the gene KCNJ11, encoding the subunit Kir6.2, and ABCC8, encoding SUR1 of the ATP-sensitive potassium (K(ATP)) channel, are the most common causes of permanent neonatal diabetes mellitus. Sulfonylureas close the K(ATP) channel and increase insulin secretion. KCNJ11 and ABCC8 mutations have important therapeutic implications because sulfonylurea therapy can be effective in treating patients with mutations in the potassium channel subunits. The mutation type, the presence of neurological features, and the duration of diabetes are known to be the major factors affecting the treatment outcome after switching to sulfonylurea therapy. More than 30 mutations in the KCNJ11 gene have been identified. Here, we present our experience with a patient carrying a novel p.H186D heterozygous mutation in the KCNJ11 gene who was successfully treated with oral sulfonylurea.
Diabetes Mellitus* ; Humans ; Insulin ; Live Birth ; Potassium ; Potassium Channels ; Sulfonylurea Compounds ; Treatment Outcome

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

BACKGROUND: To evaluate the clinical efficacy of sitagliptin for reducing plasma glucose levels in Korean subjects with type 2 diabetes mellitus during a 14-week treatment period. METHODS: Our study design involved the addition of 100 mg sitagliptin once-daily to three ongoing combination therapy regimens and changing from glimepiride and metformin to sitagliptin and metformin. RESULTS: The addition of sitagliptin 100 mg/day produced a statistically significant reduction in mean HbA1c level (mean HbA1c reduction of 0.99+/-0.85%, P<0.01). In the group taking a combination of sitagliptin and metformin (n=143, initial mean HbA1c level=7.48%), the reductions in HbA1c, 2-hour postprandial glucose, and fasting glucose levels were 0.72+/-0.76% (P<0.01), 47+/-65 mg/dL (P<0.01), and 15+/-44 mg/dL (P<0.01), respectively. In the group taking a combination of sitagliptin, glimepiride, and metformin (n=125, initial mean HbA1c level=8.42%), the reductions in HbA1c, 2-hour postprandial glucose, and fasting glucose levels were 1.09+/-0.86% (P<0.01), 62+/-64 mg/dL (P<0.01), and 31+/-45 mg/dL (P<0.01), respectively. In the group taking a combination of sitagliptin, glimepiride, metformin, and alpha-glucosidase inhibitor (n=63, initial mean HbA1c level=9.19%), the reductions in HbA1c, 2-hour postprandial glucose, and fasting glucose levels were 1.27+/-0.70% (P<0.01), 72+/-65 mg/dL (P<0.01), and 35+/-51 mg/dL (P<0.01), respectively. In the group that had previous hypoglycemic events and that changed from glimepiride to sitagliptin, HbA1c level did not change but fasting glucose increased significantly (14+/-29 mg/dL, P<0.01). CONCLUSION: Sitagliptin combination therapy for 14 weeks significantly improved glycemic control and was well-tolerated in Korean subjects with type 2 diabetes mellitus.
alpha-Glucosidases ; Diabetes Mellitus, Type 2 ; Fasting ; Glucose ; Metformin ; Plasma ; Pyrazines ; Sulfonylurea Compounds ; Triazoles ; Sitagliptin Phosphate

OBJECTIVETo explore the effect of glimepiride on the glucose uptake as well as glucose transporter (GLUT)-1 and GLUT-3 expression levels of rat mandibular osteoblasts in hyperglycemia.

METHODSPrimary osteoblasts were isolated and cultured. Then, the cells were placed in an osteogenic medium containing two glucose concentrations (5.5 and 16.5 mmol X L(-1)), with or without glimepiride (10 micromol x L(-1)). Glucose uptake was determined by employing 18F-deoxyglucose (18F-FDG) in the cells, and GLUT-1 and GLUT-3 expression levels were evaluated by Western blot analysis.

RESULTSGlucose at 16.5 mmol x L(-1) significantly inhibited 18F-FDG uptake and downregulated GLUT-3 protein expression in osteoblasts. Hyperglycemia increased GLUT-1 protein expression. Glimepiride significantly increased glucose uptake and upregulated GLUT-1 and GLUT-3.

CONCLUSIONGlimepiride enhance the glucose transporter in rat osteoblasts at two different glucose concentrations.

Animals ; Fluorodeoxyglucose F18 ; Glucose ; Glucose Transporter Type 1 ; Hyperglycemia ; Mandible ; Osteoblasts ; Rats ; Sulfonylurea Compounds

AIMTo establish a polarographic method of parallel catalytic hydrogen wave for determination of glimepiride.

METHODSThe catalytic wave of glimepiride in the presence of K2S2O8 was used to improve the analytical sensitivity. The rapid determination of glimepiride was done by linear single sweep polarography.

RESULTSThe catalytic hydrogen wave of glimepiride was measured at ca. -1.36 (vs SCE) in 0.09 mol x L(-1) Na2B4O7-KH2PO4 (pH 6.24 +/- 0.1) supporting electrolyte. When 1.0 x 10(-2) mol x L(-1) K2S2O8 was present, the current increased by 25 times, and the peak potentioal was unchanged, producing a more sensitive parallel catalytic hydrogen wave. The peak current of the parallel catalytic hydrogen wave was rectilinear to the glimepiride concentration in the range 1.0 x 10(-7) - 4.2 x 10(-5) mol x L(-1) (r = 0.9990, n = 9). The detection limit was 5.0 x 10(-8) mol x L(-1).

CONCLUSIONThe proposed method could be applied to the determination of glimepiride in pharmaceuticals without preliminary separation.

Catalysis ; Humans ; Hypoglycemic Agents ; analysis ; urine ; Male ; Polarography ; methods ; Potassium Compounds ; analysis ; Sulfates ; analysis ; Sulfonylurea Compounds ; analysis ; urine

BACKGROUND: Although many anti-diabetic drugs have been used to control hyperglycemia for decades, the efficacy of commonly-used oral glucose-lowering agents in Korean type 2 diabetic patients has yet to be clearly demonstrated. METHODS: We evaluated the efficacy of glimepiride, metformin, and rosiglitazone as initial treatment for drug-naive type 2 diabetes mellitus patients in a 48-week, double-blind, randomized controlled study that included 349 Korean patients. Our primary goal was to determine the change in HbA1c levels from baseline to end point. Our secondary goal was to evaluate changes in fasting plasma glucose (FPG) levels, body weight, frequency of adverse events, and the proportion of participants achieving target HbA1c levels. RESULTS: HbA1c levels decreased from 7.8% to 6.9% in the glimepiride group (P<0.001), from 7.9% to 7.0% in the metformin group (P<0.001), and from 7.8% to 7.0% (P<0.001) in the rosiglitazone group. Glimepiride and rosiglitazone significantly increased body weight and metformin reduced body weight during the study period. Symptomatic hypoglycemia was more frequent in the glimepiride group and diarrhea was more frequent in the metformin group. CONCLUSION: The efficacy of glimepiride, metformin, and rosiglitazone as antidiabetic monotherapies in drug-naive Korean type 2 diabetic patients was similar in the three groups, with no statistical difference. This study is the first randomized controlled trial to evaluate the efficacy of commonly-used oral hypoglycemic agents in Korean type 2 diabetic patients. An additional subgroup analysis is recommended to obtain more detailed information.
Body Weight ; Diabetes Mellitus, Type 2 ; Diarrhea ; Fasting ; Glucose ; Humans ; Hyperglycemia ; Hypoglycemia ; Hypoglycemic Agents ; Metformin ; Plasma ; Sulfonylurea Compounds ; Thiazolidinediones

BACKGROUND: Metformin, sulfonylurea, and dietary fiber are known to affect gut microbiota in patients with type 2 diabetes mellitus (T2DM). This open and single-arm pilot trial investigated the effects of the additional use of fiber on glycemic parameters, insulin, incretins, and microbiota in patients with T2DM who had been treated with metformin and sulfonylurea. METHODS: Participants took fiber for 4 weeks and stopped for the next 4 weeks. Glycemic parameters, insulin, incretins during mixed-meal tolerance test (MMTT), lipopolysaccharide (LPS) level, and fecal microbiota were analyzed at weeks 0, 4, and 8. The first tertile of difference in glucose area under the curve during MMTT between weeks 0 and 4 was defined as ‘responders’ and the third as ‘nonresponders,’ respectively. RESULTS: In all 10 participants, the peak incretin levels during MMTT were higher and LPS were lower at week 4 as compared with at baseline. While the insulin sensitivity of the ‘responders’ increased at week 4, that of the ‘nonresponders’ showed opposite results. However, the results were not statistically significant. In all participants, metabolically unfavorable microbiota decreased at week 4 and were restored at week 8. At baseline, metabolically hostile bacteria were more abundant in the ‘nonresponders.’ In ‘responders,’ Roseburia intestinalis increased at week 4. CONCLUSION: While dietary fiber did not induce additional changes in glycemic parameters, it showed a trend of improvement in insulin sensitivity in ‘responders.’ Even if patients are already receiving diabetes treatment, the additional administration of fiber can lead to additional benefits in the treatment of diabetes.
Bacteria ; Diabetes Mellitus, Type 2 ; Dietary Fiber ; Gastrointestinal Microbiome ; Glucose ; Humans ; Incretins ; Insulin ; Insulin Resistance ; Metformin ; Microbiota ; Sulfonylurea Compounds

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

AIMTo study the protein binding of glimepiride.

METHODSAn HPLC-FA method is performed by using Pinkerton GFF II-S5-80 internal-surface reversed-phase silica support (150 mm x 4.6 mm ID, 5 microm) at pH 7.4 in a 67 mmol x L(-1) isotonic sodium phosphate buffer at 37 degree C. Other conditions included flow rate of 0.2 mL x min(-1), UV detection at wavelength 230 nm and injection volume 900 microL.

RESULTSNonlinear regression parameter estimation was used for the association constant measurement of glimepiride to both primary and secondary sites, which were 5.1 (micromol x L(-1)-1 and 1 for K1 and n1, and 0.017 (micromol x L(-1))-1 and 7 for K2 and n2, respectively.

CONCLUSIONThe method is shown to be suitable for investigation of protein binding of glimepiride.

Chromatography, High Pressure Liquid ; methods ; Humans ; Hypoglycemic Agents ; metabolism ; Protein Binding ; Serum Albumin ; metabolism ; Sulfonylurea Compounds ; metabolism

BACKGROUND/AIMS: Calcium channel blockers (CCBs) are anti-hypertensive medications that are used worldwide. CCB overdose has increased in proportion to the use of these drugs. Although amlodipine is the most widely used CCB, many physicians are not familiar with amlodipine overdose. We report the clinical outcome in patients with an intentional amlodipine overdose. METHODS: We retrospectively reviewed the medical records of the patients who visited Soonchunhyang University Cheonan Hospital with an amlodipine overdose from January 2002 through December 2010. We recorded the initial vital signs, blood chemistry, electrocardiography, and estimated amount of amlodipine ingested. RESULTS: Nine patients were enrolled, of whom two patients died. Both patients who died had ingested more than 200 mg/m2 of amlodipine, while all of the patients who ingested less than 200 mg/m2 of amlodipine survived. Three patients had blood sugar levels exceeding 200 mg/dL and two of these died despite high-dose insulin therapy in combination with glucose infusion (hyperinsulinemia/euglycemia therapy). Although three patients also took a glimepiride overdose, none had hypoglycemia. The amount of amlodipine ingested relative to the body surfaced area (BSA) was 197.1 +/- 92.3 mg/m2 in patients with an abnormal ECG and 58.5 +/- 27.1 mg/m2 in patients with a normal ECG. CONCLUSIONS: Amlodipine overdose can induce hyperglycemia, resulting in lethal cardiogenic shock owing to the decreased calcium influx, inappropriate energy production, and weakened inotropic effect. Therefore, amlodipine-induced hyperglycemia indicates a poor prognosis.
Amlodipine ; Blood Glucose ; Calcium ; Calcium Channel Blockers ; Electrocardiography ; Glucose ; Humans ; Hyperglycemia ; Hypoglycemia ; Insulin ; Medical Records ; Prognosis ; Retrospective Studies ; Shock, Cardiogenic ; Sulfonylurea Compounds ; Vital Signs