Efficacies of Stem Cell Therapies for Functional Improvement of the β Cell in Patients with Diabetes: A Systematic Review of Controlled Clinical Trials

BACKGROUND AND OBJECTIVES: This study was performed to investigate whether stem cell therapy enhances β cell function by meta-analysis with proper consideration of variability of outcome measurements in controlled trial of type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM) patients. METHODS: A systematic search was performed from inception to January 2018 in PubMed, EMBASE, and Cochrane databases. β cell function was assessed by stimulated C-peptide, fasting C-peptide, normal glycosylated hemoglobin levels (HbA1C), and exogenous insulin dose patterns. The quality of the studies were assessed by both the Cochrane Collaboration's Risk of Bias (ROB) for Randomized controlled trials and the Risk of Bias in Non-randomized Studies of Interventions (ROBINS-I) for non-randomized controlled trials. RESULTS: From the selected final 15 articles, total of 16 trials were analyzed. There were 6 T1DM trials (total 153 cases) and 10 T2DM trials (total 457 cases). In T2DM patients, the changes in stimulated C-peptide, HbA1c, and exogenous insulin dose versus baseline showed a favorable pattern with a significant heterogeneity in stem cell therapy. In T1DM, there was no significant difference between control group and stem cell therapy group in three indicators except for HbA1c. Most of the studies were rated as having high risk of bias in the quality assessment. CONCLUSIONS: The stem cell therapy for DM patients is not effective in T1DM but seems to be effective in improving the β cell function in T2DM. However the observed effect should be interpreted with caution due to the significant heterogeneity and high risk of bias within the studies. Further verification through a rigorously designed study is warranted.

Acarbose Add-on Therapy in Patients with Type 2 Diabetes Mellitus with Metformin and Sitagliptin Failure: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study

BACKGROUND: We evaluated the efficacy and safety of acarbose add-on therapy in Korean patients with type 2 diabetes mellitus (T2DM) who are inadequately controlled with metformin and sitagliptin. METHODS: A total of 165 subjects were randomized to metformin and sitagliptin (Met+Sita, n=65), metformin, sitagliptin, and acarbose (Met+Sita+Acarb, n=66) and sitagliptin and acarbose (Sita+Acarb, exploratory assessment, n=34) therapy in five institutions in Korea. After 16 weeks of acarbose add-on or metformin-switch therapy, a triple combination therapy was maintained from week 16 to 24. RESULTS: The add-on of acarbose (Met+Sita+Acarb group) demonstrated a 0.44%±0.08% (P<0.001 vs. baseline) decrease in glycosylated hemoglobin (HbA1c) at week 16, while changes in HbA1c were insignificant in the Met+Sita group (−0.09%±0.10%, P=0.113). After 8 weeks of triple combination therapy, HbA1c levels were comparable between Met+Sita and Met+Sita+Acarb group (7.66%±0.13% vs. 7.47%±0.12%, P=0.321). Acarbose add-on therapy demonstrated suppressed glucagon secretion (area under the curve of glucagon, 4,726.17±415.80 ng·min/L vs. 3,314.38±191.63 ng·min/L, P=0.004) in the absence of excess insulin secretion during the meal tolerance tests at week 16 versus baseline. The incidence of adverse or serious adverse events was similar between two groups. CONCLUSION: In conclusion, a 16-week acarbose add-on therapy to metformin and sitagliptin, effectively lowered HbA1c without significant adverse events. Acarbose might be a good choice as a third-line therapy in addition to metformin and sitagliptin in Korean subjects with T2DM who have predominant postprandial hyperglycemia and a high carbohydrate intake.

DNA Methylation Profiles of Blood Cells Are Distinct between Early-Onset Obese and Control Individuals

Obesity is a highly prevalent, chronic disorder that has been increasing in incidence in young patients. Both epigenetic and genetic aberrations may play a role in the pathogenesis of obesity. Therefore, in-depth epigenomic and genomic analyses will advance our understanding of the detailed molecular mechanisms underlying obesity and aid in the selection of potential biomarkers for obesity in youth. Here, we performed microarray-based DNA methylation and gene expression profiling of peripheral white blood cells obtained from six young, obese individuals and six healthy controls. We observed that the hierarchical clustering of DNA methylation, but not gene expression, clearly segregates the obese individuals from the controls, suggesting that the metabolic disturbance that occurs as a result of obesity at a young age may affect the DNA methylation of peripheral blood cells without accompanying transcriptional changes. To examine the genome-wide differences in the DNA methylation profiles of young obese and control individuals, we identified differentially methylated CpG sites and investigated their genomic and epigenomic contexts. The aberrant DNA methylation patterns in obese individuals can be summarized as relative gains and losses of DNA methylation in gene promoters and gene bodies, respectively. We also observed that the CpG islands of obese individuals are more susceptible to DNA methylation compared to controls. Our pilot study suggests that the genome-wide aberrant DNA methylation patterns of obese individuals may advance not only our understanding of the epigenomic pathogenesis but also early screening of obesity in youth.

Reliability and Validity of the Korean Version of the General-Food Craving Questionnaire-Trait for Children

OBJECTIVE: The General-Food Craving Questionnaire-Trait (G-FCQ-T) is a validated, assessment scale for food craving. The aim of this study was to measure its reliability and validity for Korean children. METHODS: A total of 172 children (94 boys and 78 girls) were selected to fill out a set of questionnaires, including the G-FCQ-T, the Children's version of the Dutch Eating Behavior Questionnaire (DEBQ-C), and the Three-Factor Eating Questionnaire (TFEQ) in the Korean language. RESULTS: The internal consistency (Cronbach's alpha=0.933) and test-retest reliability (r=0.653) were satisfactory. The G-FCQ-T showed a significantly positive correlation with the DEBQ-C (r=0.560) and the TFEQ (r=0.397). The optimum cutoff score of the G-FCQ-T set by Receiver Operating Characteristics analysis was 51, with sensitivity and specificity of 0.833 and 0.825, respectively, for children. CONCLUSION: The G-FCQ-T showed good reliability and validity for assessing food craving for children and could become a practial instrument in clinical and research settings.

Physician-Directed Diabetes Education without a Medication Change and Associated Patient Outcomes

BACKGROUND: When patients with diabetes mellitus (DM) are first referred to a hospital from primary health care clinics, physicians have to decide whether to administer an oral hypoglycemic agent (OHA) immediately or postpone a medication change in favor of diabetes education regarding diet or exercise. The aim of this study was to determine the effect of diabetes education alone (without alterations in diabetes medication) on blood glucose levels. METHODS: The study was conducted between January 2009 and December 2013 and included patients with DM. The glycosylated hemoglobin (HbA1c) levels were evaluated at the first visit and after 3 months. During the first medical examination, a designated doctor also conducted a diabetes education session that mainly covered dietary management. RESULTS: Patients were divided into those who received no diabetic medications (n=66) and those who received an OHA (n=124). Education resulted in a marked decrease in HbA1c levels in the OHA group among patients who had DM for 10 years showed a slightly lower HbA1c target achievement rate of <6.5% (odds ratio, 0.089; P=0.0024). CONCLUSION: For patients who had DM for more than 5 years, higher doses or changes in medication were more effective than intensive active education. Therefore, individualized and customized education are needed for these patients. For patients with a shorter duration of DM, it may be more effective to provide initial intensive education for diabetes before prescribing medicines, such as OHAs.

Reduction of Sulfonylurea with the Initiation of Basal Insulin in Patients with Inadequately Controlled Type 2 Diabetes Mellitus Undergoing Long-Term Sulfonylurea-Based Treatment

BACKGROUND: There were a limited number of studies about β-cell function after insulin initiation in patients exposed to long durations of sulfonylurea treatment. In this study, we aimed to evaluate the recovery of β-cell function and the efficacy of concurrent sulfonylurea use after the start of long-acting insulin. METHODS: In this randomized controlled study, patients with type 2 diabetes mellitus (T2DM), receiving sulfonylurea for at least 2 years with glycosylated hemoglobin (HbA1c) >7%, were randomly assigned to two groups: sulfonylurea maintenance (SM) and sulfonylurea reduction (SR). Following a 75-g oral glucose tolerance test (OGTT), we administered long-acting basal insulin to the two groups. After a 6-month follow-up, we repeated the OGTT. RESULTS: Among 69 enrolled patients, 57 completed the study and were analyzed: 31 in the SM and 26 in the SR group. At baseline, there was no significant difference except for the longer duration of diabetes and lower triglycerides in the SR group. After 6 months, the HbA1c was similarly reduced in both groups, but there was little difference in the insulin dose. In addition, insulin secretion during OGTT was significantly increased by 20% to 30% in both groups. A significant weight gain was observed in the SM group only. The insulinogenic index was more significantly improved in the SR group. CONCLUSION: Long-acting basal insulin replacement could improve the glycemic status and restore β-cell function in the T2DM patients undergoing sulfonylurea-based treatment, irrespective of the sulfonylurea dose reduction. The dose reduction of the concurrent sulfonylurea might be beneficial with regard to weight grain.

Diabetic Neuropathic Cachexia in a 50-Year-Old Woman with Type 2 Diabetes: First Case Report in Korea / 임상당뇨병

Diabetic neuropathic cachexia (DNC) is one of the rarest presentations of diabetic neuropathy associated with profound weight loss. A 50-year-old Korean woman with poorly controlled type 2 diabetes complained of intractable pain in the trunk and lower extremities, and total body weight loss of 17% over a 6 month period. The patient's symptoms persisted after glucose control and various medications for neuropathic pain. A diagnosis of DNC was made based on the rapid onset of severe pain, polyneuropathy, and marked weight loss without evidence of end organ disease other than mild retinopathy, and the exclusion of other possible causes. Spontaneous improvement of the patient's neuropathic pain and gradual weight gain occurred after 6 months of supportive care. Since the original report of DNC, 31 cases have been published in the English-language literature; however, ours is the first reported case in Korea. Clinicians must be aware of this debilitating complication of diabetes because of its severity and rapid progression.

Reversal of Hypoglycemia Unawareness with a Single-donor, Marginal Dose Allogeneic Islet Transplantation in Korea: A Case Report

Pancreatic islet transplantation is a physiologically advantageous and minimally invasive procedure for the treatment of type 1 diabetes mellitus. Here, we describe the first reported case of successful allogeneic islet transplantation alone, using single-donor, marginal-dose islets in a Korean patient. A 59-yr-old patient with type 1 diabetes mellitus, who suffered from recurrent severe hypoglycemia, received 4,163 islet equivalents/kg from a single brain-death donor. Isolated islets were infused intraportally without any complications. The immunosuppressive regimen was based on the Edmonton protocol, but the maintenance dosage was reduced because of mucositis and leukopenia. Although insulin independence was not achieved, the patient showed stabilized blood glucose concentration, reduced insulin dosage and reversal of hypoglycemic unawareness, even with marginal dose of islets and reduced immunosuppressant. Islet transplantation may successfully improve endogenous insulin production and glycemic stability in subjects with type 1 diabetes mellitus.

The Insulin Resistance but Not the Insulin Secretion Parameters Have Changed in the Korean Population during the Last Decade

BACKGROUND: This study aimed to compare the patterns of insulin secretion and resistance between Korean subjects in the 1990s and 2000s. METHODS: Insulin secretion and resistance indices were calculated from subjects who underwent 75-g oral glucose tolerance tests in the year 1997 to 1999 and 2007 to 2011 at the Seoul St. Mary's Hospital, Korea. RESULTS: A total of 578 subjects from the 1990s (mean age, 48.5 years) and 504 subjects from the 2000s (mean age, 50.2 years) were enrolled. Compared with the subjects from the 1990s, those from the 2000s exhibited increased insulin resistance (increased homeostatic model assessment for insulin resistance), and reduced insulin sensitivity (reduced Matsuda index and quantitative insulin sensitivity check index), regardless of their glucose tolerance status. However, insulinogenic index did not reveal significant differences between the 2 decades in subjects with or without diabetes. A distinct relationship was confirmed between Matsuda index and total area under the curve (insulin/glucose) in each glucose tolerance group. The mean product of the Matsuda index and the total area under the curve (insulin/glucose) as well as the oral disposition index, was lower in subjects with normal glucose tolerance from the 2000s than in those from the 1990s. CONCLUSION: After rapid economic growth and changes in lifestyle patterns, insulin resistance has worsened across the glucose tolerance status; however, the insulin secretory function remained unchanged, which resulted in an increase in the susceptibility to the development of type 2 diabetes mellitus among Korean subjects without diabetes. We could not rule out the potential selection bias and therefore, further studies in general Korean population are needed.

Effects of 6-Month Sitagliptin Treatment on Insulin and Glucagon Responses in Korean Patients with Type 2 Diabetes Mellitus

BACKGROUND: This study aimed to evaluate the effect of sitagliptin, an oral dipeptidyl peptidase-4 inhibitor, on insulin secretion and glucagon suppression in Korean subjects with type 2 diabetes mellitus. METHODS: Twenty-four subjects underwent a 75-g oral glucose tolerance test (OGTT) before and after 6 months of sitagliptin treatment. Sitagliptin, insulin, and sulfonylurea were withdrawn for 3 days before OGTT to eliminate any acute effects on beta-cell insulin or alpha-cell glucagon secretion. Venous samples were drawn five times during each OGTT to measure plasma glucose, insulin, and glucagon. Indices on insulin secretion and resistance were calculated. RESULTS: Early phase insulin secretion, measured by the insulinogenic index significantly increased after 6 months of sitagliptin treatment, especially in the higher baseline body mass index group and higher baseline glycosylated hemoglobin (HbA1c) group. There were no significant differences in the insulin resistance indices before and after sitagliptin treatment. Although no significant differences were observed in the absolute levels of glucagon and the glucagon-to-insulin ratio, there was a significant reduction in the percentile change of glucagon-to-insulin ratio at 30- and 120-minute during the OGTT. CONCLUSION: Although the HbA1c level did not decrease significantly after 6 months of sitagliptin treatment, an increase in insulin secretion and reduction in early phase postprandial plasma glucagon-to-insulin ratio excursion was confirmed in Korean subjects with type 2 diabetes.

HbA1c Variability and Micro- and Macrovascular Complications of Diabetes / 임상당뇨병

Glycemic variability comprises 'glucose variability' and 'hemoglobin A1c (HbA1c) variability.' Glucose variability relates to the within-day fluctuation of glucose level and may eventually reflect an increase in HbA1c level. Long-term glycemic variability, which is assessed by HbA1c fluctuation, reflects changes in glycemia over longer periods of time. Previous reports from several cohort studies have demonstrated that HbA1c variability is associated with the development or progression of microvascular complication in type 1 and 2 diabetes mellitus. However, data on the impact of HbA1c variability on macrovascular complications are controversial, and little is known about its impact on mortality. Further studies with a larger population including various ethnic groups are required to verify the impact of HbA1c variability on micro- and macrovascular complications of diabetes. Also, stabilized control of long-term glucose level should be emphasized based on these study results.

Two Cases of Diabetic Ketoacidosis Associated with Paliperidone Treatment in Schizophrenia / 임상당뇨병

Atypical antipsychotics, which have better efficacy and fewer side effects compared to first-generation antipsychotics, are being used increasingly for the treatment of schizophrenia. However, adverse events such as weight gain, diabetes mellitus and abnormal lipid profile have been reported in patients treated with these agents. Diabetic ketoacidosis (DKA) is a rare side effect of atypical antipsychotics, but deserves attention due to its severity. Although various atypical antipsychotics have been reported as causing DKA, there have been no reports showing an association with DKA and paliperidone, which is a recently developed antipsychotic agent. Here, we report two cases of DKA in patients with paliperidone therapy. Both cases had no history of diabetes before use of paliperidone, and DKA was manifested within 2 years of starting paliperidone therapy. Like other atypical antipsychotics, use of paliperidone warrants monitoring for metabolic derangements including DKA.

The Definition of Metabolically Healthy Obesity / 임상당뇨병

Metabolically healthy obesity (MHO) is a term indicating a subgroup of obese individuals who demonstrate normal to high levels of insulin sensitivity, a lower level of visceral adiposity and more favorable cardiovascular risk profiles. Although identifying MHO might have clinical significance in terms of management strategies, there is no consensus regardingthe criteria used for defining this subgroup. Several different definitions have been used for MHO, and this has resulted in a wide range of prevalence and low agreement between classifications. The analyses of clinical characteristics and the metabolic outcomes also showed controversial findings because of the different definitions used. Developing a standardized criteria that is easily applicable and that accurately accounts for risk factors for predicting the development of type 2 diabetes or cardiovascular outcomes is of clinical value and will broaden our understanding regarding the clinical importance of MHO.

Erythropoietin Antibody-Positive Pure Red Cell Aplasia Diagnosed after Surgical Intervention for Malignant Gastric Ulcer Bleeding / 대한내과학회지

Rarely, patients on erythropoietin stimulating agent (ESA) therapy develop antibodies that neutralize both ESA and endogenous erythropoietin, resulting in antibody-mediated pure red cell aplasia (PRCA). The sudden development of severe transfusion-dependent anemia requires rapid recognition, the evaluation of PRCA, and prompt intervention after differentiating other causes of anemia, such as iron deficiency, occult bleeding, and infection. Here, we report the case of a 67-year-old male undergoing hemodialysis who presented with the anemia of chronic blood loss from a malignant gastric ulcer. Even after surgical intervention for stomach cancer and increasing the erythropoietin dosage, the anemia was not correctable and required monthly packed red blood cell transfusions. Further evaluation revealed positive erythropoietin antibody, and a bone marrow biopsy showed no red blood cell precursors, supporting the diagnosis of PRCA.

No-Reflow Phenomenon During Treatment of Coronary In-Stent Restenosis With a Paclitaxel-Coated Balloon Catheter

Drug-eluting balloon (DEB) with angioplasty a paclitaxel-coated balloon catheter is an effective treatment option in patients with in-stent restenosis (ISR) after a drug-eluting stent (DES). We describe a case in which 'no-reflow' phenomenon developed after DEB angioplasty of a DES ISR lesion. Coronary flow was restored after intracoronary administration of nicorandil.

A Case of Spontaneous Bladder Rupture Mimicking Diabetic Nephropathy in a Patient with Type 2 Diabetes Mellitus / 고신대학교의과대학학술지

Spontaneous rupture of the urinary bladder is a rare clinical entity, with the incidence reported as 1 in 126,000 hospital admissions. It is often associated with malignancy, inflammatory lesions, irradiation, calculus, diverticulum, binge alcohol drinking, continuous bladder irrigation, and neurogenic bladder. In rare instances, bladder rupture occurs without obvious causes. This rare clinical condition is difficult to diagnose because of vague symptoms. High index of suspicion is needed as the mortality rate is high if untreated. A 37-year-old woman with uncontrolled type 2 diabetes, was admitted to the emergency room complaining of progressive abdominal distension and discomfort. She had a past history of tubo-ovarian and bladder abscess, and had undergone multiple surgical operations. From ascites fluid study, she was diagnosed as spontaneous bladder rupture. A transurethral catheter was inserted and the symptoms and signs resolved. Bladder rupture, mimicking acute kidney injury of diabetic nephropathy was disclosed without surgery.

Expansile Mass of the Rib / 이화의대지

A 60-year-old man visited our hospital because of the incidentally found mass of the rib on chest radiography. Chest X-ray showed expansile bony hypertrophy on left 5th rib and bone setting of the computed tomography scan of chest revealed 4.2x2.5 cm sized, elongated bony expansion with geographic radiolucent lesion in the medullary cavity and cortical thinning. Technetium-99m bone scintigraphy showed diffusely increased radioactivity along the left 5th rib. We present this case to discuss about a possible differential diagnosis in this type of lesion.

A Case of Left Ventricular Pseudoaneurysm in the Left Atrioventricular Groove after Mitral Valve Replacement

Left ventricle-coronary sinus fistula and left ventricular pseudoaneurysm are unusual and frightening complications after mitral valve replacement. A 27-year-old female patient underwent mitral valve replacement 5 years previously and trans-thoracic echocardiography showed an outpouching lesion at the atrioventricular groove. It was difficult to differentiate whether the lesion was a left ventricle-coronary sinus fistula or a left ventricular pseudoaneurysm by two-dimensional echocardiography. Cardiac computed tomography confirmed a left ventricular pseudoaneurysm compressing the coronary sinus.