Diabetes & Metabolism Journal

Original Articles

The Relation of Serum Adipokines with Metabolic Risk Factors in Type 2 Diabetic Subjects.: Tae Seo Sohn, Jung Min Lee, Sang Ah Chang, Hyun Shik Son, Young Mi Ku, Bong Yun Cha, Kwang Woo Lee, Ho Young Son, Sung Ku Kang; Korean Diabetes J. 2004;28(6):521-529. Published online December 1, 2004

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Abstract PDF: BACKGROUND
Accumulation of fat, especially in the visceral space, has been claimed to have a causative role in the development of macroangiopathies, because of the secretion of adipokine from the fat tissue. Indeed, the adipocyte secretes chemical messengers (e.g., adipokines) that include leptin, TNF-alpha , IL-6, adiponectin, and resistin. Since adipokines have biologic activities within the vascular system, they might be involved in the development of diabetic angiopathies. The aim of this study is to investigate the relation of adipokine with adiposity, metabolic risk factors, diabetic micro-, and macroangiopathies in type 2 diabetic patients. METHODS: The subjects of this study were 57 type 2 diabetic patients. Anthropometric parameters (height, body weight, waist circumference and body fat composition), cardiovascular risk factors (BP, Lp (a), lipid profile, hs-CRP, fibrinogen), status of glucose metabolism (HbA1c, fasting glucose), diabetic microvascular complication, intima-media thickness (IMT) at both common carotid artery and adipokine (leptin, adiponectin, resistin) were measured. RESULTS: The correlation between the serum adipokine level and duration of diabetes was statistically significant (P <0.01). The leptin was correlated with body mass index (r=0.446, P <0.01), waist circumference (r=0.553, P <0.01) and body fat content (r=0.573, P <0.01). The adiponectin was negatively correlated with plasmatotal cholesterol (r=-0.366, P <0.01) and triglyceride (r=-0.276, P <0.05). The resistin was correlated with Lp (a) (r=0.386, P <0.01), hs-CRP (r=0.413, P <0.01), fibrinogen (r=0.562, P <0.01) and 24hr microalbuminuria (r=0.353, P <0.05). The adiponectin was increased in patients with microalbuminuria than with normo- and macroalbuminuria (P <0.05). The resistin was increased in patients with micro- or macroalbuminuria than normoalbuminuria (P <0.05). The adiponectin was increased in patients with retinopathy (P <0.05). The serum adipokine level was not correlated with IMT of common carotid artery. CONCLUSION: This study reveals that serum adipokine was related with metabolic risk factor in type 2 diabetic patients. Among adipokines, adiponectin and resistin might be involved in diabetic angiopathy. The underlying mechanisms remained to be elucidated in the role of adipokine to the development of diabetic angiopathy.

Apolipoprotein E Genetic Polymorphism and Diabetic Microangiopathy in Type 2 Diabetic Patients.: Jong Suk Park, Joo Young Nam, Chul Sik Kim, Dol Mi Kim, Min Ho Cho, Jina Park, Chul Woo Ahn, Bong Soo Cha, Sung Kil Lim, Kyung Rae Kim, Hyun Chul Lee; Korean Diabetes J. 2004;28(6):511-520. Published online December 1, 2004

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Abstract PDF: BACKGROUND
The pathophysiological causes for the development and progression of diabetic microangiopathy are not well known, but the apo E genetic polymorphism has been proposed to be involved in the disease's development and progression. The aim of this study was to investigate the association between the apo E genetic polymorphism and diabetic microangiopathy in Korean type 2 diabetic patients. METHODS: One hundred eighteen patients with type 2 diabetes who had a duration of diabetes longer than 8 years were divided into the three apo E groups (the E2, E3 and E4 groups). The plasma levels of lipids were measured. The frequency of diabetic nephropathy, retinopathy and neuropathy were compared among the three apo E genotype groups. RESULTS: The frequency of overt nephropathy was significantly greater for the apo E2 patients with diabetes (46.7%) than for the apo E3 (16.7%) or apo E4 patients (10.5%). Logistical regression analysis showed that the odds ratio of the apo E2 and apo E4 genotypes for the presence of overt nephropathy were 4.779 (P < 0.01) and 0.643 (P = 0.583), respectively. Plasma TG levels were significantly greater for the apo E2 patients. This study did not find any association between diabetic retinopathy, neuropathy and apo E polymorphism. CONCLUSION: Apo E2 is a positive risk factor for diabetic nephropathy in Korean type 2 diabetic patients. TG may have an important role in diabetic nephropathy.

Effect and Mechanism of High Glucose Level on the Expression of an Adhesion Protein, beta ig-h3, and Cellular Function in Endothelial Cells.: Sung Woo Ha, Hye Jin Yeo, Jong Sup Bae, Sung Chang Chung, Jung Guk Kim, In San Kim, In Kyu Lee, Bo Wan Kim; Korean Diabetes J. 2003;27(4):323-331. Published online August 1, 2003

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Abstract PDF: BACKGROUND
Diabetes mellitus is a high risk condition for the development of atherosclerotic and thromboembolic macroangiopathy. There are many factors which are involved in development of these processes. Given the central pathogenic role of endotheliopathy in atherosclerosis, it is likely that this vascular monolayer is the ultimate target of injury in response to many cytokines and growth factors. A dysfunctional endothelium may contribute to the proatherogenic environment. Transforming growth factor (TGF-beta) is a key factor in the development of diabetic angiopathy and atherosclerosis because of its effect on the accumulation of extracellular matrix proteins and endothelial function. The adhesive molecule betaig-h3 is an extracellular matrix protein whose expression is induced by TGF-beta. Considering that TGF-beta plays an important role in diabetic complications and that betaig-h3 is a downstream target gene of TGF-beta, we hypothesized that betaig-h3 may also play a role in the development of diabetic angiopathy through its effect on the endothelial function. Therefore, we examined the effects of high glucose level on the expression of betaig-h3 and endothelial function in human umbilical vein endothelial cells (HUVECs). We also studied the mechanisms of this high glucose-induced betaig-h3 expression. METHODS: Endothelial cells were isolated from human umbilical cord and conditioned with different concentrations of TGF-beta or glucose. We measured TGF-beta and betaig-h3 protein presence/concentration/expression in cell supernatant by ELISA and examined whether TGF-beta is involved in high glucose-induced betaig-h3 expression. Finally, we investigated the biologic function of betaig-h3 in endothelial cells by using adhesion assay. RESULTS: Our study demonstrated that both high glucose level and TGF-beta induced betaig-h3 protein expression in HUVECs. High glucose level also induced TGF-beta protein expression in cells. Anti-TGF-beta antibody almost completely blocked high glucose-induced betaig-h3 expression. betaig-h3 was found to support the adhesion of endothelial cells. CONCLUSION: These results suggest that high glucose level upregulates betaig-h3 protein levels through the induction of TGF-beta and that betaig-h3 may play an important role in diabetic angiopathy by regulating adhesive function of endothelial cells.

Effect and Mechanism of Vascular Endothelial Growth Factor on Endothelial Nitric Oxide Synthase Expression in Aortic Endothelial Cells.: Soon Hee Lee, Jung Guk Kim, Joong Yeol Park, Sung Woo Ha, Bo Wan Kim; Korean Diabetes J. 2002;26(5):396-404. Published online October 1, 2002

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Abstract PDF: BACKGROUND
Vascular endothelial growth factor (VEGF), a soluble angiogenic factor produced by many tumor and normal cells, is a potent angiogenic and vascular permeability factor. VEGF plays a key role in both pathological and physiological angiogenesis. There are many recent findings regarding the role of VEGF in diabetic microvascular and macrovascular diseases. Many approaches with VEGF-related therapies begin to treat and prevent these complications and have been used for the treatment of microvascular complications such as diabetic retinopathy, whereas VEGF agonists have been used to treat macrovascular complications such as myocardial infarction and peripheral limb ischemia. Nitric oxide (NO) is known to mediate many physiological and pathological functions, including modulation of vascular tone, permeability, and capillary growth. Recent reports indicate that NO may play an intimate role in VEGF signaling. Therefore, we hypothesized that the expression of eNOS may be regulated by VEGF. The objectives of the present study were to determine whether VEGF up-regulates the expression of endothelial NO synthase (eNOS) in endothelial cells and to elucidate the mechanism that mediate this response. METHODS: Endothelial cells were isolated from bovine aortae. The expression of eNOS was assessed by Northern blotting analysis. To evaluate the mechanism of VEGF-induced eNOS expression, endothelial cells were conditioned with VEGF and pretreated with phorbol-12-myristate acetate (PMA), a protein kinase C (PKC) activator, or GF109203X (GFX), a PKC inhibitor. The changes of eNOS gene expression. RESULTS: VEGF significantly increased the expression of eNOS mRNA in bovine aortic endothelial cells (BAEC) in time and dose dependent manners. PMA increased the expression of eNOS mRNA, as well as the VEGF-induced expression of eNOS mRNA in endothelial cells, while inhibition of the PKC activity, with the GFX blocked the upregulation of the VEGF-induced eNOS mRNA. CONCLUSION: The results suggest that VEGF upregulates eNOS gene expression in aortic endothelial cells, by a PKC dependent pathway and, eNOS may be important in the development of VEGF-induced angiopathy.

Effect of Transforming Growth Factor-Induced Gene Product, beta ig-h3 on Proliferation, Migration, and Adhesion of Aortic Smooth Muscle Cells Cultured in High Glucose.: Sung Woo Ha, Gui Hwa Jung, He Jin Yeo, Jong Sup Bae, Soon Hee Lee, Jung Guk Kim, Rang Woon Park, In San Kim, Bo Wan Kim; Korean Diabetes J. 2002;26(4):286-295. Published online August 1, 2002

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Abstract PDF: BACKGROUND
Diabetes mellitus is associated with a substantial increase in the prevalence of atherosclerotic disease. There are many factors which are involved in development of these processes. Transforming growth factor (TGF-beta) is known to be an important factor in the pathogenesis of diabetic vascular complications. TGF-beta-induced gene-h3 (beta ig-h3) is an adhesive molecule whose expression is induced by TGF-beta. Considering that TGF-beta plays an important role in diabetic complications and that beta ig-h3 is induced by TGF-beta, we hypothesized that beta ig-h3 may also play a role in the development of diabetic angiopathy. Then, we examined the effects of beta ig-h3 on biologic function of vascular smooth muscle cells (VSMCs) and potential roles of beta ig-h3 in the pathognesis of diabetic angiopathy. METHODS: VSMCs were isolated from rat thoracic aorta. We conditioned cells with different concentration of TGF-beta or glucose. We measured TGF-beta and beta ig-h3 protein in cell supernatant by ELISA. We also examined whether TGF-beta involves in high glucose-induced beta ig-h3 expression. Finally, we did proliferation, migration, and adhesion assay to investigate biologic function of beta ig-h3 in VSMCs. RESULTS: Our results demonstrated that TGF-beta induced beta ig-h3 expression in VSMCs in dose dependent manners. High glucose induced TGF expression as well as beta ig-h3 protein. Finally, beta ig-h3 was found to support the proliferation, migration, and adhesion of rat VSMCs. CONCLUSION: These results suggest that high glucose-and TGF-beta-induced beta ig-h3 may play an important role in diabetic angiopathy by regulating proliferation, migration, and adhesion of VSMCs.

Dissociation of Microangiopathy and Macroangiopathy in Patients with Type 2 Diabetes.: C J Seo, K Y Lee, K S Song, Y S Jung, Hong Kyu Kim, H Y Park, W G Lee, M H Kang; Korean Diabetes J. 2001;25(2):133-141. Published online April 1, 2001

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Abstract PDF: BACKGROUND
Type 2 diabetes is a heterogeneous disease. As to its complications, microangiopathy predominantly develop in some patients while macroangiopathy is more predominant in others. Therefore, this study was performed to identify the factors associated with such dissociation. METHODS: Type 2 diabetic patients were classified into the macro and microangiopathy groups by carotid intima-medial thickness (IMT) and the presence of severe diabetic retinopathy. Patients with IMT

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.

Soluble P-selectin, E-selectin, and VCAM-1 as Markers of Vascular Endothelial Damage in Diabetic Patients with Microangiopathy.: Young Sun Kim, Dong Won Byun, Kyo Il Seo, Myung Hi Yoo, Guk Bae Kim, Seong Soo Koong; Korean Diabetes J. 1998;22(1):35-46. Published online January 1, 2001

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Abstract PDF: BACKGROUND
Vascular complications of diabetic patients are common and are known as the major cause of death. Hyperglycemia has been supposed to be the leading cause of vascular complications by unknown mechanisms. In recent reports, hyperglycemia stimulated the expression of leukocyte-endothelial adhesion molecules in the endothelial cells, and increased plasma concentrations of their soluble forms. The aim of this study was to evaluate the role of plasma concentrations of soluble P-selectin(sP-selectin), soluble E-selectin(sE-selectin), and soluble VCAM-1(sVCAM-1) in diabetic patients with microvascular complications as markers of vascular endothelial damage. METHODS: In this study, plasma levels of sP-selection, sE-selectin and sVCAM-1 were determined by ELISA in 39 diabetic patients and 25 normal conirols. RESULTS: The concentrations of sP-selectin, sE-selectin, and sVCAM-1 in diabetic group were significantly higher than those in control group. The concentrations of sP-selectin and sE-selectin decreased sigruficantly after contol of hyperglycemia in diabetic group, but sVCAM-1 level was not altered by treatment. In diabetic group with microvascular complications, the concentrations of sP-selectin and sE-selectin significantly were elevated as compared with the diabetic group without microvascular complication, but the concentration of sVCAM-l was not different between the two groups. In diabetic group, the levels of sP-selectin, sE-selcctin, and sVCAM-1 were not correlated with the concentration of C-peptide, HbA1, triglyceride, total cholesterol, HDL-cholesterol and LDL-cholesterol. There was no difference between control group and diabetic group in terms of age and sex. There were not any differences of sP-selectin, sE-selectin, and sVCAM-1 concentration according to the duration of diabetes and the presence of hypertension. CONCLUSION: Hyperglycemia might stimulated the expression of P-selectin, E-selectin, and VCAM-1 in the endothelial cells and increased the plasma levels of their soluble forms. sP-selectin and sE-selectin could be used as indicators of ongoing vascular dysfunction in diabetes as well as a dynamic surrogate marker for the effectiveness of therapeutic interventions.

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