Hae Kyung Yang

Predicting the Development of Diabetes Using the Product of Triglycerides and Glucose: The Chungju Metabolic Disease Cohort (CMC) Study

Background To determine whether the TyG index, a product of the levels of triglycerides and fasting plasma glucose (FPG) might be a valuable marker for predicting future diabetes. Methods A total of 5,354 nondiabetic subjects who had completed their follow-up visit for evaluating diabetes status were selected from a large cohort of middle-aged Koreans in the Chungju Metabolic Disease Cohort study. The risk of diabetes was assessed according to the baseline TyG index, calculated as ln[fasting triglycerides (mg/dL) × FPG (mg/dL)/2]. The median follow-up period was 4.6 years. Results During the follow-up period, 420 subjects (7.8%) developed diabetes. The baseline values of the TyG index were significantly higher in these subjects compared with nondiabetic subjects (8.9±0.6 vs. 8.6±0.6; P<0.0001) and the incidence of diabetes increased in proportion to TyG index quartiles. After adjusting for age, gender, body mass index, waist circumference, systolic blood pressure, high-density lipoprotein (HDL)-cholesterol level, a family history of diabetes, smoking, alcohol drinking, education level and serum insulin level, the risk of diabetes onset was more than fourfold higher in the highest vs. the lowest quartile of the TyG index (relative risk, 4.095; 95% CI, 2.701–6.207). The predictive power of the TyG index was better than the triglyceride/HDL-cholesterol ratio or the homeostasis model assessment of insulin resistance. Conclusions The TyG index, a simple measure reflecting insulin resistance, might be useful in identifying individuals at high risk of developing diabetes.

Identifying subgroups of obesity using the product of triglycerides and glucose: the Korea National Health and Nutrition Examination Survey, 2008–2010

To determine whether the TyG index, a product of the levels of triglycerides and glucose, may be a valuable marker for identifying metabolically obese but normal weight (MONW) or metabolically healthy but obese (MHO) individuals.

Current status of encapsulated islet transplantation

Islet transplantation is a treatment modality for diabetes mellitus that can maintain insulin levels within a physiologically appropriate range. However, wider clinical application is limited by insufficient donor numbers and a need for lifelong immunosuppression. Despite various clinical and preclinical trials, there is no single standard immunosuppressive regimen that can suppress acute and chronic immune reactions with lower toxicity to grafted islets. One of the strategies for overcoming lifelong immunosuppression is the incorporation of encapsulation technology, which can provide a physical immune barrier by keeping out high molecular weight immune system components, while still allowing low molecular weight oxygen, insulin and nutrients to pass through. Encapsulated islet transplantation approaches that have been studied so far include macroencapsulation, microencapsulation, conformal coating and nanoencapsulation. Herein we will review the basic concepts of islet encapsulation technique, earlier works to recent progress related to clinical studies and corporate investigations on encapsulated islet transplantation.

Changes in Metabolic Health Status Over Time and Risk of Developing Type 2 Diabetes: A Prospective Cohort Study.

AbstractMetabolic health and obesity are not stable conditions, and changes in the status of these conditions might lead to different clinical outcomes. We aimed to determine whether changes in metabolic health status or obesity over time have any effect on the risk of future diabetes.Nondiabetic individuals (n = 2692) from a population-based prospective cohort study with baseline and 2 follow-up examinations at 4-year intervals were included. Being “metabolically obese” (MO) was defined as being in the highest quartile of the TyG index (ln [fasting triglycerides (mg/dL) × fasting glucose (mg/dL)/2]), whereas falling into the lower 3 quartiles was regarded as being “metabolically healthy” (MH). Individuals were classified as “obese” (O) or “nonobese” (NO) using a body mass index of 25 kg/m2 as a cut-off. The risk of diabetes at year 8 was assessed according to changes of metabolic health status between year 0 and 4.Multivariate-adjusted relative risks (RRs) (95% confidence interval [CI]) of diabetes were significantly higher in individuals who retained the MONO phenotype (RR 3.72, 95% CI 2.10, 6.60) or who had progressed to MONO from the MHNO phenotype (RR 1.96, 95% CI 1.06, 3.61), whereas it was not significant in individuals who had improved to MHNO from the MONO phenotype (RR 0.67, 95% CI 0.26, 1.74) compared with individuals who retained the MHNO phenotype. In contrast, obese individuals had significantly higher RRs for diabetes, independent of changes in metabolic health status, whereas weight reduction resulted in a decreased risk of diabetes. Sensitivity analysis using the presence or absence of the metabolic syndrome as a definition of metabolic health revealed similar results.Changes in metabolic health status were an independent risk factor for future diabetes in nonobese individuals, whereas general obesity had a greater contribution to the risk of obese individuals developing diabetes. These observations might imply a different intervention strategy for diabetes prevention according to obesity status.

Obesity, metabolic health, and mortality in adults: a nationwide population-based study in Korea

BMI, metabolic health status, and their interactions should be considered for estimating mortality risk; however, the data are controversial and unknown in Asians. We aimed to investigate this issue in Korean population. Total 323175 adults were followed-up for 96 (60–120) (median [5–95%]) months in a nationwide population-based cohort study. Participants were classified as “obese” (O) or “non-obese” (NO) using a BMI cut-off of 25 kg/m2. People who developed ≥1 metabolic disease component (hypertension, diabetes, dyslipidaemia) in the index year were considered “metabolically unhealthy” (MU), while those with none were considered “metabolically healthy” (MH). The MUNO group had a significantly higher risk of all-cause (hazard ratio, 1.28 [95% CI, 1.21–1.35]) and cardiovascular (1.88 [1.63–2.16]) mortality, whereas the MHO group had a lower mortality risk (all-cause: 0.81 [0.74–0.88]), cardiovascular: 0.73 [0.57–0.95]), compared to the MHNO group. A similar pattern was noted for cancer and other-cause mortality. Metabolically unhealthy status was associated with higher risk of all-cause and cardiovascular mortality regardless of BMI levels, and there was a dose-response relationship between the number of incident metabolic diseases and mortality risk. In conclusion, poor metabolic health status contributed more to mortality than high BMI did, in Korean adults.

Long-term Efficacy and Biocompatibility of Encapsulated Islet Transplantation With Chitosan-Coated Alginate Capsules in Mice and Canine Models of Diabetes.

Background Clinical application of encapsulated islet transplantation is hindered by low biocompatibility of capsules leading to pericapsular fibrosis and decreased islet viability. To improve biocompatibility, we designed a novel chitosan-coated alginate capsules and compared them to uncoated alginate capsules. Methods Alginate capsules were formed by crosslinking with BaCl2, then they were suspended in chitosan solution for 10 minutes at pH 4.5. Xenogeneic islet transplantation, using encapsulated porcine islets in 1,3-galactosyltransferase knockout mice, and allogeneic islet transplantation, using encapsulated canine islets in beagles, were performed without immunosuppressants. Results The chitosan-alginate capsules showed similar pore size, islet viability, and insulin secretory function compared to alginate capsules, in vitro. Xenogeneic transplantation of chitosan-alginate capsules demonstrated a trend toward superior graft survival (P = 0.07) with significantly less pericapsular fibrosis (cell adhesion score: 3.77 ± 0.41 vs 8.08 ± 0.05; P < 0.001) compared to that of alginate capsules up to 1 year after transplantation. Allogeneic transplantation of chitosan-alginate capsules normalized the blood glucose level up to 1 year with little evidence of pericapsular fibrotic overgrowth on graft explantation. Conclusions The efficacy and biocompatibility of chitosan-alginate capsules were demonstrated in xenogeneic and allogeneic islet transplantations using small and large animal models of diabetes. This capsule might be a potential candidate applicable in the treatment of type 1 diabetes mellitus patients, and further studies in nonhuman primates are required.

Association between hemoglobin A1c variability and subclinical coronary atherosclerosis in subjects with type 2 diabetes

AIMS We examined the association between hemoglobin A1c (HbA1c) variability and subclinical coronary atherosclerosis in subjects with type 2 diabetes. METHODS We used the multidetector coronary computed tomography data collected from subjects with type 2 diabetes who did not have a history of cardiovascular disease or angina symptoms. HbA1c measurements preceding the date of cardiac imaging were retrospectively collected, and intraindividual SD (HbA1c-SD), CV and adjusted SD of HbA1c measurements were calculated. Subclinical coronary atherosclerosis was defined as calcium score >400 without any cardiac symptoms. RESULTS A total of 595 subjects were categorized according to the median value of each HbA1c variability indicators. The prevalence of subclinical coronary atherosclerosis was higher in higher HbA1c variability group compared with lower HbA1c variability group. Multivariable logistic regression analysis showed that higher HbA1c-SD and -CV were associated with the presence of subclinical coronary atherosclerosis, independent of mean HbA1c level in subjects with diabetes duration ≤10 years (OR [95% CI]; HbA1c-SD, 2.894 [1.105-7.584]; HbA1c-CV, 2.540 [1.022-6.316]). CONCLUSIONS Long-term stabilization of blood glucose level might be important in preventing subclinical coronary atherosclerosis in subjects with earlier period of type 2 diabetes.

Antifibrotic effect of rapamycin containing polyethylene glycol-coated alginate microcapsule in islet xenotransplantation

Islet microencapsulation is an attractive strategy for the minimization or avoidance of life‐long immunosuppression after transplantation. However, the clinical implementation of this technique is currently limited by incomplete biocompatibility. Thus, the aim of the present study was to demonstrate the improved biocompatibility of rapamycin‐containing polyethylene glycol (Rapa–PEG)‐coating on alginate microcapsules containing xenogeneic islets. The Rapa–PEG‐coating on the alginate layer was observed using scanning electron microscopy (SEM) and the molecular cut‐off weight of the microcapsules was approximately 70 kDa. The viabilities of the alginate‐encapsulated and Rapa–PEG‐coated alginate‐encapsulated islets were lower than the viability of the naked islets just after encapsulation, but these the differences diminished over time in culture dishes. Rapa–PEG‐coating on the alginate capsules effectively decreased the proliferation of macrophage cells compared to the non‐coating and alginate coating of xenogeneic pancreas tissues. Glucose‐stimulated insulin secretion did not significantly differ among the groups prior to transplantation. The random blood glucose levels of diabetic mice significantly improved following the transplantation of alginate‐encapsulated and Rapa–PEG‐coated alginate‐encapsulated islets, but there were no significant differences between these two groups. However, there was a significant decrease in the number of microcapsules with fibrotic cell infiltration in the Rapa–PEG‐coated alginate microcapsule group compared to the alginate microcapsule group. In conclusion, Rapa–PEG‐coating might be an effective technique with which to improve the biocompatibility of microcapsules containing xenogeneic islets. Copyright

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. Marys 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.

The Paradoxical Effects of AMPK on Insulin Gene Expression and Glucose‐Induced Insulin Secretion

The activation of AMP‐activated protein kinase (AMPK) is known to repress the expression of the insulin gene and glucose‐stimulated insulin secretion (GSIS). However, the mechanisms by which this occurs, as well as the effects of AMPK activation on glucolipotoxicity‐induced β‐cell dysfunction, have not been elucidated. To investigate the effects of 5‐amino‐4‐imidazolecarboxamide ribonucleotide (AICAR) and peroxisome proliferator‐activated receptorγ‐coactivator‐1α (PGC‐1α) on β‐cell‐specific genes under glucolipotoxic conditions, we performed real‐time PCR and measured insulin secretion by primary islets. To study these effects in vivo, we administered AICAR for 10 days (1 mg/g body weight) to 90% pancreatectomized hyperglycemic mice. The exposure of isolated rat and human islets to glucolipotoxic conditions and the overexpression of PGC‐1α suppressed insulin and NEUROD1 mRNA expression. However, the expression of these genes was preserved by AICAR treatment and by PGC‐1α inhibition. Exposure of isolated islets to glucolipotoxic conditions for 3 days decreased GSIS, which was also well maintained by AICAR treatment and by PGC‐1α inhibition. The administration of AICAR to 90% pancreatectomized hyperglycemic mice improved glucose tolerance and insulin secretion. These results indicate that treatment of islets with an AMPK agonist under glucolipotoxic conditions protects against glucolipotoxicity‐induced β‐cell dysfunction. A better understanding of the functions of molecules such as PGC‐1α and AMPK, which play key roles in intracellular fuel regulation, could herald a new era for the treatment of patients with type 2 diabetes mellitus by providing protection against glucolipotoxicity. J. Cell. Biochem. 117: 239–246, 2016.