Chang-Soon Koh

Decreased mitochondrial DNA content in peripheral blood precedes the development of non-insulin-dependent diabetes mellitus

Qualitative changes in mitochondrial DNA (mtDNA), such as mutations and deletions, have been implicated in the pathogenesis of diabetes mellitus. In addition to the qualitative changes, mtDNA is subject to quantitative changes, and is vulnerable to oxidative stress, resulting in both qualitative and quantitative changes. This study was performed to investigate whether quantitative changes in mtDNA occur in non-insulin-dependent diabetes mellitus (NIDDM) patients and also in pre-diabetic subjects. MtDNA content from peripheral blood was measured by slot-blot analysis in 55 NIDDM patients and 29 age- and sex-matched control subjects. We have also analysed the mtDNA copies by quantitative polymerase chain reaction (PCR) method in 23 pre-diabetic subjects who converted to diabetic in 2 years and 22 age- and sex-matched control subjects who remained non-diabetic. Mean mtDNA quantity measured by slot blot method was 35% lower in patients with NIDDM than in control subjects (12.3+/-8.1 vs. 19.1+/-8.2 AU/microg DNA; P < 0.05). MtDNA quantities did not correlate with age, body mass index, duration of diabetes or HbA1c levels. We have also found that the mtDNA copies in subjects who converted to diabetes in 2 years were lower than in controls even before the development of diabetes (102.8+/-41.5 vs. 137.8+/-67.7 copies/pg template DNA P < 0.05). Inverse correlations were noted between mtDNA content and baseline waist hip circumference ratio (WHR) (r = -0.31, P < 0.05), and fasting glucose level (r = - 0.35, P < 0.05), diastolic blood pressure (r = -0.36, P < 0.05), and WHR (r = -0.40, P < 0.01) after development of diabetes. In conclusion, we demonstrate that the content of mtDNA decreases in peripheral blood of patients with NIDDM and the lower mtDNA levels precede the development of diabetes.

Changes in the Clinicopathological Characteristics and Outcomes of Thyroid Cancer in Korea over the Past Four Decades

BACKGROUND Thyroid cancer has increased globally, with a prominent increase in small, papillary thyroid cancers (PTC). The Korean population has a high iodine intake, high prevalence of BRAF V600E mutations, and family histories of thyroid cancer. We examined the clinicopathological characteristics and outcomes of thyroid cancers in Korean patients over four decades. METHODS The medical records of 4500 thyroid cancer patients, between 1962 and 2009 at a single center, including 3147 PTC patients, were reviewed. RESULTS The mean age of the patients was 46.8±13.2 years; women accounted for 82.9% of the patients, and the median follow-up duration was 4.8 years (mean 7.0±5.8 years, range 1-43 years). The number of patients visiting the clinic increased from 411 during 1962-1990 to 2900 during 2000-2009. Age at diagnosis increased from 39.6±12.9 to 48.6±12.4 years. The male to female ratio increased from 1:6 to 1:4.5. The proportion of small (<1 cm) tumors increased from 6.1% to 43.1%, and the proportion of cancers with lymph node (LN) involvement or extrathyroidal extension (ETE) decreased from 76.4% to 44.4% and from 65.5% to 54.8% respectively. Although there were decreases in the proportion of LN involvement and ETE, these decreasing rates were not proportional to the expected rates based on the decreased proportion of large tumors. The overall recurrence and mortality rates were 13.3% and 1.4%. The five-year recurrence rate significantly decreased (from 11% to 5.9%), and the five-year mortality also improved (from 1.5% to 0.2%). CONCLUSIONS The incidence of thyroid cancer has rapidly increased, with a decrease in tumors of large size, LN involvement, and ETE, although the decreasing rates of LN involvement and ETE were not as prominent as decreasing rates of large size tumors. The mortality and recurrence rates have also decreased. Future long-term follow-up of patients diagnosed in the most recent decade is needed to confirm the prognostic characteristics of Korean PTC patients.

Intra-abdominal fat is associated with decreased insulin sensitivity in healthy young men.

To distinguish the relative role of intra-abdominal and subcutaneous abdominal fat in metabolic aberrations in upper body fat localization, we measured the relationship between regional fat distribution and insulin sensitivity in nine young men (28.6 +/- 0.7 years; body mass index [BMI], 24.7 +/- 1.3 kg/m2). Regional fat distribution was measured by anthropometric measurement and computed tomography (CT). Insulin sensitivity was measured by euglycemic hyperinsulinemic glucose clamp. Insulin sensitivity, expressed as the ratio of rate of glucose utilization to the mean plasma insulin concentration during the second hour of glucose clamp (M/I) was negatively correlated with BMI (r = -.91, P less than .001), waist to hip girth ratio (WHR) (r = -.80, P less than .01), subcutaneous abdominal fat area (r = -.90, P less than .001), and intra-abdominal fat area (r = -.88, P less than .01). Stepwise forward regression analysis showed that in addition to BMI, intra-abdominal fat area was a significant correlate of decrease in insulin sensitivity. These findings suggest that intra-abdominal fat play an important role in decreasing insulin sensitivity, even in healthy young men.

Artificial induction of intravascular lipolysis by lipid-heparin infusion leads to insulin resistance in man

SummaryAlthough extensive evidence indicates that free fatty acids can decrease glucose utilization in vitro, it is still controversial how an increase in lipolysis affects glucose metabolism in man. To test the hypothesis that an increase in lipolysis is related to insulin resistance, we examined the effect of lipid-heparin infusion on glucose metabolism in ten normal subjects by the euglycaemic glucose clamp technique and isotopic determination of glucose turnover. In the control euglycaemic clamp studies with insulin infusion at 0.2 and 1.0 mU·kg−1·min−1, endogenous glucose production was suppressed from the basal rate of 2.0±0.3 mg· kg−1min−1 to 1.1±0.7 mg·kg−1·min−1 and -0.4±0.7mg· kg−1min−1 respectively. Glucose utilization increased from the basal rate of 2.0±0.3 mg·kg−1min−1 to 2.3±0.5mg· kg−1min−1 and 5.9±1.8 mg·kg−1min−1 respectively. When the euglycaemic clamp studies were coupled with lipid-heparin infusion at comparable low and high rates of insulin infusion, endogenous glucose production increased (1.8± 0.7 mg·kg−1·min−1, p<0.001, and 0.3±0.6 mg·kg−1· min−1, p<0.05, respectively), and glucose utilization decreased (2.1±0.3 mg·kg−1·min−1, not significant, and 3.2±0.7 mg·kg−1·min−1, p<0.001 respectively). These data suggest that the artificial induction of intravascular lipolysis by lipid-heparin infusion leads to a state of insulin resistance in man.

Prevalence of Diabetes and IGT in Yonchon County, South Korea

OBJECTIVE To determine the prevalence of diabetes and impaired glucose tolerance (IGT) in Yonchon County of South Korea and to investigate their associated factors. RESEARCH DESIGN AND METHODS We performed a population-based cross-sectional study with random cluster sampling of residents ≥30 years of age. Among the 3,804 residents sampled, a total of 2,520 participants had a standard 75-g oral glucose tolerance test and answered a detailed questionnaire. We also collected standard anthropometric data. RESULTS If the data for participants in the age range of 30–64 years were adjusted to the standard world population, the prevalence of diabetes was 7.2% and the prevalence of IGT was 8.9%. It was observed that the significant factors associated with diabetes were waist-to-hip circumference ratio, serum triglyceride levels, age, systolic blood pressure, family history of diabetes, and locality. CONCLUSIONS The prevalence of diabetes in Yonchon County was substantially higher than was previously suggested. The risk of diabetes increased with the increased central obesity and metabolic disturbances associated with insulin resistance.

Risk factors for the development of NIDDM in Yonchon County, Korea

OBJECTIVE To determine the risk factors for the development of NIDDM in Yonchon County of Korea. RESEARCH DESIGN AND METHODS We studied 1,193 Korean nondiabetic subjects at baseline who participated in a 2-year follow-up study on diabetes in Yonchon County. A 75-g oral glucose tolerance test was performed 2 years after the baseline examination. Age, sex, and anthropometric and metabolic characteristics at baseline were analyzed simultaneously as potential predictors of conversion to NIDDM. We also designed a nested case-control study to determine the role of hyperinsulinemia and/or hyperproinsulinemia in the conversion to NIDDM in patients with newly developed diabetes and control subjects matched for age, sex, BMI, and waist-to-hip-ratio. RESULTS At 2 years, 67 subjects developed diabetes, as defined by World Health Organization criteria. The age-adjusted incidence was significantly higher in men (6.4%) than in women (3.0%), and the incidence increased as age increased in both sexes. Multiple logistic regression analysis revealed age, male sex, and fasting and 2-h glucose levels to be significant risk factors for the development of NIDDM, whereas waist-to-hip ratio and BMI were not. In a nested case-control study, baseline proinsulin but not insulin levels were significantly higher in subjects who progressed to NIDDM than in those who did not. CONCLUSIONS In the Korean population, β-cell dysfunction, as measured by high proinsulin levels, seems to be associated with subsequent development of NIDDM, whereas regional and general obesity and fasting insulin levels, which may be a surrogate for insulin resistance, were not.

Evaluation of serum basal thyrotrophin levels and thyrotrophin receptor antibody activities as prognostic markers for discontinuation of antithyroid drug treatment in patients with Graves' disease

OBJECTIVE We evaluated whelther antithyroid drug treatment could be terminated more appropriately when both the serum basal thyrotrophin (TSH) level and TSH receptor antibody activity have become normal.

The Low Prevalence of Immunogenetic Markers in Korean Adult-Onset IDDM Patients

OBJECTIVE IDDM is an autoimmune disease that occurs among genetically susceptible individuals. In Asian populations, it is not uncommon for adult patients with NIDDM to eventually lose β-cell function and develop IDDM. These individuals may be characterized by autoantibodies to GAD and high-risk HLA-DQ alleles, which are unlikely to be prevalent among patients with true NIDDM or in the general population. The objective of the present study was to evaluate and compare the prevalence of these immunogenetic markers in NIDDM patients and healthy nondiabetic individuals from Korea. RESEARCH DESIGN AND METHODS The prevalences of anti-GAD antibodies and HLA-DQA1 and DQB1 alleles among 121 patients with newly diagnosed NIDDM identified from a population-based study in Yonchon, Korea, and 100 matched healthy control subjects were evaluated and compared. RESULTS The overall prevalence of anti-GAD antibodies was 1.7% (2 of 121) in patients with previously undiagnosed NIDDM, whereas 1 of 100 control subjects had a positive test for antibodies. Among those who tested positive, titers of antibodies to GAD were not high. No statistically significant differences in the distributions of either mean levels of anti-GAD antibodies or DQA1 and DQB1 alleles were found comparing NIDDM patients with control subjects. Interestingly, the frequency of DQB1*non-Asp-57 and DQA1*Arg-52 alleles in the Korean adult control population was similar to that in the U.S. white population (DQB1*non-Asp-57: 0.431 vs. 0.475; DQA1*Arg-52: 0.492 vs. 0.463). CONCLUSIONS The low prevalence of anti-GAD antibodies and HLA-DQA1 and DQB1 susceptibility alleles among recent-onset NIDDM patients, which was similar to observations in control subjects, suggests that diabetes in Korean adults is unlikely to have an autoimmune component to its pathogenesis.

Insulin restores fatty acid composition earlier in liver microsomes than erythrocyte membranes in streptozotocin-induced diabetic rats

Alterations of fatty acid composition have been observed in a number of tissues in both experimental and human diabetes. Suppression of delta 6 desaturase in the liver, a key enzyme of fatty acid desaturation, has been reported to be responsible for these phenomena. We measured the fatty acid composition of the liver and the erythrocytes, and examined delta 6 desaturase activities to compare the effect of short-term insulin therapy on the tissues with and without delta 6 desaturase, ie., the liver and the erythrocytes using streptozotocin (STZ)-induced diabetic rats. Linoleic (P < 0.05), palmitic (P < 0.01) and docosahexaenoic (DHA) acid (P < 0.01) were higher and arachidonic (P < 0.01) and oleic acid (P < 0.01) were lower in the liver microsomes of diabetic rats when compared to those in control rats. These alterations were partly reversed with insulin treatment. In the erythrocyte membrane, linoleic (P < 0.01) and stearic acid (P < 0.05) were higher, and palmitic (P < 0.05), palmitoleic (P < 0.01), and arachidonic acid (P < 0.01) were lower in diabetic rats. In contrast to the case of the liver microsomes, however, these alterations were persistently observed after 48 h of insulin treatment. The activities of delta 6 desaturase in diabetic rats were 68% of those of controls (P < 0.05), and increased to 119% of controls after insulin treatment. These results show that insulin restores the fatty acid composition earlier in the liver microsome than in the erythrocyte membrane in STZ-induced diabetic rats. The erythrocyte membrane would not be suitable for the investigation dealing with rapid changes of fatty acid composition.

Evaluation of Bone Metastases by Tc-99m MDP Imaging in Patients With Stomach Cancer

The authors conducted a retrospective review of 234 bone scans of stomach cancer patients who had been diagnosed at the Seoul National University Hospital. In 106 of the 234 cases (45.3%), there were abnormal bone scan results, suggestive of bone metastases. The most common site of bone metastases was the spine, followed by the ribs, pelvis, femur, and skull. These sites were similar to those known for other malignant diseases. The incidence of bone metastases increased according to the duration of disease, especially within 12 months after diagnosis in patients with stage III gastric cancer. The incidence of bone metastases increased as the clinical stage increased. However, the incidence of metastases did not relate to gastric cancer pathologic type. The authors found 6 cases of “superscan” In the 234 bone scans (2.6%). The bone scan findings correlated positively with the level of serum alkaline phosphatase.