Diabetes & Metabolism Journal

Volume 23(5); October 1999

Original Articles

Chronary Heart Disease and Homecysteine metabolism.: Hak Chul Jang; Korean Diabetes J. 1999;23(5):621-624. Published online January 1, 2001

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Abstract PDF: No abstract available.

Methylenetetrahydrofolate Reductase Polymorphism in Korean Type 2 Diabetic Patients with Macroangiopathy.: Ki Won Oh, Won Young Lee, Yoo Bae Ahn, Ki Ho Song, Soon Jib Yoo, Kun Ho Yoon, Moo Il Kang, Bong Yun Cha, Kwang Woo Lee, Ho Young Son, Sung Koo Kang; Korean Diabetes J. 1999;23(5):625-634. Published online January 1, 2001

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Abstract PDF: BACKGROUND
Hyperhomocysteinemia is an inde-pendent risk factor for cardiovascular disease. Recently, a mutation (677CT) was identified in the methylenetetrahydrofolate reductase (MTHFR) gene, leading to the substitution of valine (V) for alanine (A). This mutation causes a reduced folate-dependent enzyme activity which leads to increased homocysteine. In this study, we examined the association between the V allele of the methylenetetrahydrofolate reductase gene and macroangiopathy in Korean patients with type 2 diabetes mellitus. METHODS: In 54 type 2 diabetic patients with macroangiopathy and 198 normal subjects, the MTHFR genotypes were analyzed by polymerase chain reaction (PCR), followed by Hinfl digestion. To confirm the detection of the MTHFR polymorphism by the PCR-restriction fragment length polymorphism (RFLP) analysis, DNA Sequencing was performed on the PCR products. RESULT: The allele frequency of the V mutation was slightly higher in the patients than in the normal subjects, but that was statistically not significant. The crude ORs and 95% CIs for the allele frequency of the V mutation were 1.16 (0.76~1.79). Genotype frequencies were 35.9% for AA, 48.4% for AV, and 15.7% for VV in the normal subjects. And they were 31.5% for AA, 50.0 % for AU, and 18.5 % for VV in the patients. The crude ORs and 95% CIs for the VV genotype were 1.22 (0.56~2.67). In multiple regressian model, the VV genotype was not associated with diabetic macroangiopathy. CONCLUSION: Although, the frequencies of VV genotype in Korean normals (=16%) are higher than those of other thical populations (=12%), this mutation is not associated with macroangiopathy in type 2 diabetic patients. But, our sample size was too small and larger cohort studies will be needed to confirm the effect of MTHFR polymorphism on the development of macroangiopathy in diabetic patients.

Effect of Protein Kinase C Inhibitors on Expression of TGF-betamRNA in Cultured Mesangial Cells Under High Glucose Concentration.: Yoon Sang Choi, Dong Seop Choi; Korean Diabetes J. 1999;23(5):635-646. Published online January 1, 2001

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Abstract PDF: BACKGROUND
Diabetic nephropathy is characterized by hypertrophy of both glomerular and tubular elements, thickening of the glomerular and tubular basement membranes, progressive accumulation of extracellular matrix components in mesangium, and tubulointerstitial fibrosis. Hyperglycemia increases the level of diacylglycerol (DAG) and activates protein kinase C (PKC) in mesangial cells and other vascular tissues. PKC activation regulates a number of vascular functions such as vascular permeability, contractility, cellular proliferation, basement membrane synthesis, signal transduction mechanisms for hormones and growth factors, In addition, glomerular mesangial cells play an important role in the development of diabetic nephropathy. Mesangial cells have many functions such as contractile properties, phagocytosis of macromolecules, synthesis of matrix proteins, and production of and response to growth factors (e.g., PDGF, TGF beta). Also, these growth factors play important roles for mesangial cell proliferation and in pathophysiology of diabetic nephropathy. Specifically, TGF beta is a key mediator in development of diabetic nephropathy. This study was performed to evaluate the relationship between PKC activation and TGF f3 production in mesangial cells under high glucose condition. METHODS: The expression of the TGF beta mRNA was evaluated in cultured human mesangial cells by semiquantitive RT-PCR, under varying degree of glucose concentrations (5 mM, 10 mM, 30 mM) with and without treatment of PKC inhibitors (calphostin C, Vitamin-E). RESULT: In control group (no treatment), ratio of TGF beta/beta-aetin mRNA in 5mM, 10mM, 30mM glucose were 1.694+/-0.223, 3.383+/-2.089, 5,474+/-1.74S, respectively. In calphostin C treated group, ratio of TGF beta/beta-actin mRNA in 5mM, 10mM, 30mM glucose were 1.457+/-0,322, 1.379+/-0.138, 1.205+/-0.050, respectively. In vitamin E treated group, ratio of TGF beta/beta-actin mRNA in 5mM, 10rnM, 30mM glucose were 1.198+/-0.081, 1.995+/-1.625, O.S04+/-0.570, respectively. In 10mM glucose concentration, ratios of TGF beta/beta-actin mRNA were reduced in calphostin C and vitamin E treated groups, compared with those in control group. But, there were no statistical significancies (p=0.191, 0.208). In high glucose concentration (30mM), ratios of TGF /3/f3-actin mRNA were significantly reduced in calphostin C and vitamin E treated groups compared with those in control group (p<0.05), respectively. CONCLUSIONS: These results indicate that high glucose concentration induce TGF beta expression in eultured mesangial cells through PKC activation. This suggests that selective PKC beta isoform inhibitors may be useful for treatment and prevention of diabetie nephropathy.

Insulin Secretion, Insulin Sensitivity and Body Fat Distribution Patterns in Patients with Impaired Glucose Tolerance.: Jin Hwa Lee, Yeon Ah Sung, Nan Ho Kyung, Yeon Jin Jang; Korean Diabetes J. 1999;23(5):647-660. Published online January 1, 2001

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Abstract PDF: BACKGROUND
Type 2 diabetes mellitus(DM) is characterized by impaired insulin secretion and decreased insulin sensitivity, and often preceded by impaired glucose tolerance (IGT). To determine the relative importance of impaired insulin secretion and insulin resistance in development of type 2 DM, we evaluated body fat distribution patterns, insulin secretion and sensitivity in patients with IGT. METHODS: Thirty-six patients with IGT and age and weight matched twenty-four control subjects, were recruited from urban diabetes incidence cohort. Fasting serum glucose and insulin were measured. Body fat distribution pattern was assessed by waist to hip ratio (WHR), percent body fat and fat mass measured by bioelectrical impedence analyzer, and visceral to subcutaneous fat ratio (VSR) at the level of umbilicus using the computed tomography. Using insulin modified intravenous glucose tolerance test, insulin sensitivity was measured as minimal model derived sensitivity index (S(I)), and insulin secretion was measured as acute insulin response to glucose (AIR(g)) and beta-cell disposition index (AlR(g) X Sr). RESULT: l) In the patients with IGT, AIR(g)X S(I)(p<0.01) and area under the curve of insulin (AUC(I))(p<0.01) were significantly decreased compared with control subjects and age was greater than control subjects without statistical significance (p=0.17). 2) In the patients with IGT, body fat distribution patterns, indices of insulin secretion and sensitivity were not different according to the presence of family history of DM. AIR, and S(I) were negatively correlated in control subjects (r=-0.38, p=0.08) and the patients with IGT without family history of DM (r=-0.37, p=0.10), but not in the patients with IGT with family history of DM. 3) In the patients with IGT, indices of insulin secretion and sensitivity were not different according to body mass index (BMI). In both obese (BMI>=25 kg/m ) and non-obese (BMI<25 kg/m) patients with IGT, AIR(g)(p<0.05) and AIR(g) X S(I) were significantly decreased compared with control subjects (p<0.01). 4) In control subjects, age (p<0.05) and body fat mass (p<0.05) were significantly associated with AIR(g) X S(I) by multiple regression analysis. In the patients with IGT, body fat mass was significantly associated with AIR(g)(p<0.01) and AUC(I)(p<0.01), and BMI(p<0.01) was significantly associated with S(I). CONCLUSION: In patients with IGT, impaired insulin secretion was more prominent than decreased insulin sensitivity as compared with control subjects regardless of obesity and the presence of family history.

Metabolic Factors Influencing Serum Potassium Levels in Diabetic Ketoacidosis.: Sung Jin Kim, Seung Oh Suh, Sung Hee Ihm, Hyun Kyu Kim, Doo Man Kim, Jae Myung Yoo, Moon Gi Choi, Hyung Joon Yoo; Korean Diabetes J. 1999;23(5):661-668. Published online January 1, 2001

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Abstract PDF: BACKGROUND
The serum K level is normal or high in the majority of patients with diabetic ketoacidosis (DKA) despite significant total body K+ deficits. This might be due to the combined effects of severe acidosis, insulin deficiency, volume contraction, hyperglycemia and hypertonicity that usually accompany DKA. The aim of this study was to investigate the most likely determinants of the serum K+ levels among metabolic derangements observed in DKA patients. METHODS: The subjects were 88 DKA patients who had normal or high initial serum K+ levels. We anaylzed the correlation between initial serum K' levels and metabolic parameters (arterial pH, arterial HCO(3-) level, anion gap, serum glucose level, osmolality, BUN and fasting C-peptide levels), by simple linear regression analysis and stepwise multiple regression analysis. RESULT: Serum K+ levels correlated significantly with initial arterial pH(r=-0.38, p<0.001), HCO(3-) (r=-0.35, p<0.001), anion gap(r=0.21, p<0.05), serum glucose (r=0.22, p<0.05) and fasting C-peptide (r=-0.33, p<0.05) levels. Among these, arterial HCO(3-), serum glueose and fasting C-peptide levels had significant and independent effects on serum K+ levels. These levels could account for about 33% of the observed variance in serum K+ levels. CONCLUSION: These results suggest that metabolic acidosis and hyperglycemia in DKA, which result primarily from insulin deficit, are the main determinants of increased serum K+ levels.

Reduced Erythropoietin Responsiveness to Anemia in Diabetic Patients before Advanced Diabetic Nephropathy.: Yong Seok Yun, Sung Cheol Kim, Nae Chun Yoo, Young Duk Song, Sung Kil Lim, Kyung Rae Kim, Hyun Chul Lee, Jee Sook Hahn, Kap Bum Huh; Korean Diabetes J. 1999;23(5):669-677. Published online January 1, 2001

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Abstract PDF: BACKGROUND
We have often encountered some diabetie patients, in whom the causes of anemia were not clearly identified, despite differential hematologic studies. We, therefore, studied the clinical and biochemical characteristics of diabetic patients with anemia of uncertain cause. The study measured erythropoietin levels in diabetic subjects without significant diabetic renal disease. METHODS: Among 62 medical records of diabetic patients with anemia, showing no evidence of advanced diabetic nephropathy (creatinine clearance > 30 mL/min/1.73m2), the causes of the anemia were evaluated. In addition, we recruited 35 diabetic patients with uncertain causes of anemia, in order to evaluate the serum erythropoietin(Epo) responsiveness. Also, we compared their Epo levels to a group of non-diabetie subjects with similar degree of anemia. RESULT: The causes of anemia were not able to be identified in 28 (45.2 %) of 62 patients. The serum Epo levels of diabetic patients with anemia of uncertain cause (17.6+/-8.1), were significantly lower than those of non-diabetic patients with the same degree of decrease in hemoglobin levels (144.9+/-108.0 mIU/mL, p<0.001). The hemoglobin levels of diabetic patients were correlated with creatinine clearance (r=0.34, p=0.03), serum creatinine levels (r=-0.49, p=0.003), and albumin excretion rate (r=-0.44, p=0.009). But, showed no relation with age, duration of diabetes, glycated hemoglobin, presence of retinopathy or neuropathy. CONCLUSION: We concluded that reduced Epo responsiveness to anemia could explain the anemia present in diabetic patient but without advanced diabetic nephropathy. This may reflect early renal interstitial damage.

The Relation of Carotid Arterial Plaque to Apolipoprotein E Polymorphism in Subjects with Type 2 Diabetes Mellitus.: Seung Hyun Lee, Chi Young Moon, Jeong Ki Choi, Kyoung Deok Shin, Hyun Kag Kim, Wan Hee Yoo, Tae Sun Park, Hong Sun Baek, Dal Sik Kim; Korean Diabetes J. 1999;23(5):678-685. Published online January 1, 2001

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Abstract PDF: BACKGROUND
Apolipoproiein (Apo E) is one of the major proteins involved in catabolism of triglyceride (TG)-rich lipoproteins. Apo E poly-morphism contributes to the variation in plasma cholesterol levels and may influence the risk of atherosclerosis. This study was undertaken to know whether apo E polymorphism is associated with carotid artery intima, media thickness and plaque formation in type 2 diabetic patients. METHODS: We determined the apo E genotypes of 130 type 2 diabetic patients by modified Amplification Refractory Mutation System (ARMS) and classified all patients into E2, E3, E4 subgroups. The carotid artery IMT and plaque formation were determined with B-mode ultrasonography. RESULT: The apo E allele frequency of patients were E2 11.5%, E3 76.2%, FA 12.3% (p=0.0001). LDL-cholesterol levels were higher in patients with E4 allele, and HDL-cholesterol levels were lower in patients with FA allele than in patients with E2, E3 subgroups. The patients with carotid artery plaque have more E4 alleles in comparison to the patients without it(p=0.0001). FA allele group has higher carotid IMT than E2 and E3 allele groups (p=0.013). CONCLUSIONS: Apo E polymorphism is associated with carotid artery IMT and plaque formation in type 2 diabetic patients. Patients with E4 isoform is more likely to develop the atherosclerosis, carotid and coronary artery diseases than other apo E isoforms.

The Comparison between Doppler Ultrasonography and Digital Infrared Thermographic Imaging (DITI) in Detecting the Diabetic Peripheral Angiopathy.: Yoon Sang Choi, Hyun Ju Um, Seung Oh Song, Si Yong Kim, Byong Ik Kim, Young Uk Lee, Seok Won Park, Yoo Lee Kim, Hwa Young Lee, Yong Wook Cho, Sang Jong Lee; Korean Diabetes J. 1999;23(5):686-694. Published online January 1, 2001

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Abstract PDF: BACKGROUND
The frequency of nontraumatic lower extremities amputation has significantly increased in patients with type 2 diabetes (DM). Digital Infrared Thermographic (DITI) has been used to demonstrate the skin temperature and its change. mellitus Imaging regional Doppler ultrasonography was developed to show excellent images of superficial arteries. In this study, we observed the relationship between DITI and doppler ultrasonography for detection or evaluation of diabetic peripheral angiopathy. METHODS: 71 patients with type 2 DM were divided to groups with and without peripheral arterial obliteration (PAO) by ankle pressure index (API). For all patients, doppler ultrasonography of lower extremities was performed in measuring inner diameter, wall thickness and calcification of femoral, popliteal and dorsalis pedis artery. DITI was done also. We analized the result of doppler ultrasono-graphy and DITI findings. RESULT: 1) In clinical characteristics of patients between nonperipheral arterial obliteration (NPAO) and PAO : there was no significant differences between two groups with respect to age, sex, smoking, BMI (body mass index), FPG (fasting plasma glucose)/2HPG (2 hour plasma glucose), HbA(1C), serum lipid profile and/or the frequency of NPDR (nonproliferative diabetic retinopathy). However, the number of patients with hypertension and 24hr urine total protein amount were significantly increased in PAO group. 2) The results of doppler ultrasonographic imaging of lower extremities: In PAO group, inner diameters of common femoral artery and dorsalis pedis artery were significantly narrower than in those of NPAO group. However, no difference was detected in respect to vessel wall thickness. The numbers of calcified vessel wall have significantly increased in all vessels in PAO group 3) The results of DITI patterns of big toes after cold stimulus: (1) In 49 patients with NPAO: 11 showed as normal, 14 an increased, 15 a decreased, and 9 flat patterns, respectively. (2) All of 22 patients with PAO showed abnormal patterns. Among them, 2 showed a decreased, but 20 a flat pattern. 4) The comparison between the results of doppler ultrasonography and DITI: In all groups, inner diameter of common femoral artery, which was measured by doppler ultrasonography, were narrow in the flat pattern. Also, the number of calcified vessel walls in common femoral artery and dorsalis pedis artery increased more in the same patterns. No significant difference of vessel wall thickness was found between both groups. CONCLUSION : Vasoreaction of lower extremities after cold stimulus was mainly related to PAO of the common femoral artery and dorsalis pedis artery. DITI is a useful method used in detecting the early state of artherosclerosis. As a result, it can be employed in early prevention and treatment of diabetic angiopathy. If DITI is combined with doppler ultrasonography, we can practice more precise diagnosis and follow-up in diabetic peripheral angiopathy.

Clinical Application of Electrogastrography in Type 2 Diabetic Gastroparesis.: Seong Bin Hong, Moon Suk Nam, Yoon Juo Oh, Sung Ki Kim, Yoe Joo Kim, Pum Soo Kim, Mi Rim Kim, Yong Seong Kim, Young Soo Kim; Korean Diabetes J. 1999;23(5):695-701. Published online January 1, 2001

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Abstract PDF: BACKGROUND
Electrogastrography (EGG) enables the cutaneous measurement of gastric electric activity. Abnormal gastric slow wave frequencies have been observed in diabetic gastroparesis. The aim of this study was to know the clinical application of EGG, and to determine the relationship between gastric myoelectrical activity and gastric emptying time (GET) in patients with type 2 diabetes mellitus. METHODS: This study included 26 type 2 diabetic patients (11 men, 15 women, mean age 53+/-10 years, disease duration 10.5+/-6.5 years). They were given solid and liquid diet with 1 mCi (99m)Tc DTPA for measuring GET (Tl/2). They were divided into normal GET group (Tl(2 < 60 minutes) and delayed GET group (Tl/2 > 60 minutes). Gastric myoelec-trical activity was recorded by cutaneous EGG. EGG was recorded for 30 minutes in fasting state and 30 minutes in post-prandial state with same test meal. Several EGG variables including percentages of dominant frequency in the normal range (2 cycle per minute, cpm), bradygastria (0.5~2 cpm), tachygastria (4~9cpm), postprandial to preprandial power ratio, and dominant frequency instability coefficient (DFIC) were calculated by fast Fourier transformation. Result: Autonomic nerve function test showed no difference between normal GET group and delayed GET group. EGG values in delayed group did not differ from data in normal group. There were no correlation between b1ood glucose level and GET. In fasting, normal slow wave (r=-0.50, p<0,05) and bradygastria (r=0.50, p<0.05) were correlated with fasting blood glucose. And in postprandial state, normal slow wave (r=0.47, p<0.05) and bradygastria (r=0.84, p<0.05) were correlated significantly with fasting blood glucose. EGG parameters did not correlated with GET CONCLUSION : EGG may be influenced by blood glucose level, but seems to be less valuable for assessment of gastroparesis in Korean type 2 diabetes mellitus, according to our investigation.

The Prevalence of Chronic Complications in Non-Insulin Dependent Diabetic Patients.: Jick Hwa Nam, Soon Hee Lee, Hyun Jeong Lee, Jeung Hun Han, Jung Guk Kim, Sung Woo Ha, Bo Wan Kim; Korean Diabetes J. 1999;23(5):702-714. Published online January 1, 2001

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Abstract PDF: BACKGROUND
The chronic complications of diabetes mellitus are important prognostic factors of diabetics. The pathogenic mechanisms have not been known exactly and the prevalence is different according to the race and the reporter. In general, the development of diabetic microangiopathy depends on the duration and the severity of disease, while that of macroangiopathy does not. This study was undertaken to investigate the prevalence of diabetic chronic complications according to age and duration of diabetes and to elucidate associated factors and correlation of chronic complications. METHODS: We studied 1,270 patients with non- insulin dependent diabetes mellitus (NIDDM) who visited the Endocrine-metabolism clinic at Kyungpook National University during the period from February 1992 to September 1996. We investigated prevalence, severity, associated factors and correlation of chronic vascular complications, including micro- and macroangiopathy. RESULT: 1) The ratio of male to female was similar and the average duration was 7.8 years. Diabetes mellitus was most prevalent in the 6th decade and the 1-5 years of diabetes duration. 2) The prevalences of retinopathy, nephropathy and peripheral polyneuropathy were 47.8%, 31.9% and 41.0%, respectively. Macrovascular complications were found in 6.2% of patients and the prevalences of coronary artery disease, cerebrovas-cular disease and peripheral artery disease were 2.4%, 3.4%, 0.4%, respectively. Prevalence of diabetic foot was 4.4%. 3) The prevalence and severity of microvascular complications increased as the age and diabetic duration of patients increased. In the group of same age, the prevalence of microvascular complications increased as the duration of diabetes increased. However, prevalence of macrovascular complica-tions especially coronary artery disease depended on the age, but not the duration of diabetes (p<0.05). 4) In the group over 10 years of diabetes, the fasting blood glucose, age and serum creatinine levels were increased, while hemoglobin and total protein levels were decreased than other groups (p<0.05). 5) The development of diabetic retinopathy was related to the duration, fasting blood glucose, albumine excretion rate and serum creatinine. The nephropathy was related to the duration and systolic blood pressure. The peripheral polyneuropathy was related to the duration, fasting blood glucose and body mass index. Macrovascular complications-particularly, coronary artery disease-were related to the age of diabeties (p<0.05). 6) There was significant relation between development of retinopathy, nephropathy and neuropathy but no relation between development of micro and macrovascular complications (p<0.05). CONCLUSION : The prevalence of microvascular complications in non-insulin dependent diabetics increased as the duration and the age of diabetics increased. The development of microvascular complications was related to the duration of disease and the glycemic control. There was relation between development of retinopathy, nephropathy and neuropathy. The development of macrovascular complications, however, was related to the age of diabetics but not to the microvascular complications. Our results suggest that different pathogenic mechanisms may be involved in the development of micro- and macrovaseular complications of diabetes mellitus.

Case Report

A Case of Severe Hypertriglyceridemia with Diabetic Ketoacidosis.: Dong Seop Choi, Jeong Heon Oh, Ie Byung Park, Jin Won Kim, Kyung Mook Choi, Yong Hyun Kim, Nan Hee Kim, Sang Jin Kim, Sei Hyun Baik; Korean Diabetes J. 1999;23(5):715-721. Published online January 1, 2001

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Abstract PDF: Severe hypertriglyceridemia exceeding 5.6 mmol/L in diabetic ketoacidosis occasionally occur in patients with type 1 diabetes mellitus. The pattern of dyslipidemia is usually Fredrickson classification type lV. But it also exists in type III and type V. However, extreme triglyceridemia, triglyceride level exceeds 22.6 mmol/L, occur rarely in the modern era of insulin therapy. And the pattern is usually Fredrickson type I. The severe hypertriglyceridemia in diabetic ketoacidosis is mainly due to lipoprotein lipase deficiency, and secondly to insulin deficiency. The severity usually improves with insulin replacement. In patients with extreme hypertriglyceri-demia, serum electrolyte values of the patients are fallaciously low, and it leads to the misinterpretation of biochemical results and to the inappropriate treatment. We reported a case of a 25 years old female patient with diabetic ketoacidosis and extreme hypertriglyceridemia. At admission, the color of her serum was milky, her plasma triglyceride concentration was 144.7 mmol/L (12864 mg/dL), cholesterol was 25.5 mmol/L (982 mg/dl), and HDL-cholesterol was 0.77 mmol/L (40 mg/dL). The biochemical values at admission could not be measured. Empirical therapy was administered with the use of insulin and fluid. After the initial treatment with insulin and fluid, plasma triglyceride declined rapidly and was nearly normal after 72 hours. We also measured fasting blood glucose concentration and lipid profiles from her father and two sisters. Their plasma glucose and lipid profiles were normal.

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