Diabetes & Metabolism Journal

Volume 24(4); August 2000

Original Articles

Effect of Overexpression of Gi Proteins on Insulin Actions in 3T3-L1 Adipocytes.: Hyun Shik Son, Bong Yun Cha, Sung Dae Moon, Jung Min Lee, Ok Ki Hong, Sang Ah Chang, Yu Bae Ahn, Kun Ho Yoon, Kwang Woo Lee, Ho Young Son, Sung Koo Kang; Korean Diabetes J. 2000;24(4):404-412. Published online January 1, 2001

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Abstract PDF: BACKGROUND
It has been reported that G proteins are involved in biological actions of insulin. Especially, Gi protein is more associated with insulin actions than Gs proteins. Gi protein has at least three different subtypes of Gi 1, Gi 2 and Gi 3 protein. However, it is not certain which subtypes of Gi proteins are associated with biological actions of insulin. METHODS: To investigate which subtypes of Gi proteins are associated with insulin action, we overexpressed three different kinds of Gi protein, Gi 1, Gi 2 and Gi 3 protein, in 3T3-L1 adipocytes using DNA-polylysine-adenovirus complex transfection method. After incubating for 2 hours, 3T3-L1 adipocytes were treated with 100 nM insulin for the evaluation of biological actions of insulin. Moreover, to elucidate insulin stimulated insulin receptor autophosphorylation and IRS-1 phosphorylation, 3T3-L1 adipocytes were stimulated with 100 nM insulin for 10 minutes, homogenized and immunoprecipitated with anti-phosphotyrosine antibody. RESULTS: Transfection with Gi 2 gene resulted in increment in insulin-stimulated [3H]2-deoxyglucose (DOG) uptake without affecting basal 2-DOG uptake, but not with Gi 1 and Gi 3 gene transfection. There was unchanged glycogen synthesis rate in all three Gialphasubtypes. Insulin-induced increments of insulin receptor autophos phorylation and IRS-1 phosphorylation were found in Gi 2 protein overexpressed group, only. CONCLUSION: These results suggest that Gi 2 protein may be associated with regulation of biological actions of insulin.

Regulation of mFABP (fatty acid binding protein) Expression by PPAR in Cultured Human Skeletal Muscle Cell.: Hyeosn Jeong Jeon, Won Shik Shinn, Jeong Mi Kim, Hye Kyung Hong, Kyong Soo Park, Seong Yeon Kim, Hong Kyu Lee; Korean Diabetes J. 2000;24(4):413-420. Published online January 1, 2001

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Fatty acid binding protein (FABP), putative mammalian fatty acid transporter, plays a role in fatty acid transport, the modulation of cellular signal transduction pathways and the protection against detergent like effects of fatty acids. FABP found in liver, adipose tissue, heart, skeletal muscle and FABP in skeletal muscle accounts for 2% of total protein mass. FABP expression has shown to be up-regulated by PPAR in liver and adipocyte. Adipocyte and liver FABP genes have a functional PPRE (PPAR responsive element) in their promoter region. This evidence led us to investigate for a possible the regulation of mFABP expression by PPAR in cultured human skeletal muscle cell. METHODS: Myoblast were cultured in SkGM for 4weeks and were differentiated into myocyte in MEM for 4days. The myocytes were treated with PPAR ligand (troglitazone: 5 g/mL) or transduction with adenovirus-PPAR 1 (Ad-PPAR 1). mFABP expression was identified by northern blot. RESULTS: mFABP expression was up-regulated by 4.0+/-1.2 fold in the PPAR ligand (p<0.05). There was increased in mFABP expression with transduction with adenovirus-PPAR 1 while there was no change in mFABP expression which transducted with adenovirus - -galactosidase. CONCLUSION: These results demonstrates that mFABP expression is up-regulated by both PPAR ligand and by PPAR 1 over expression in cultured human skeletal muscle cells.

Alterations of Plasma Atrial Natriuretic Peptide and its mRNA in Non-insulin Dependent Diabetic Model of Rats.: Byeong Dae Yoo, Won Kyun Park, Young Su Hong, Dae Kyu Song, Jae Hoon Bae; Korean Diabetes J. 2000;24(4):421-430. Published online January 1, 2001

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Abstract PDF: BACKGROUND
Diabetes mellitus has led to change in fluid and electrolyte balance and consequently affected blood volume and blood pressure. These changes can trigger the secretion and synthesis of atrial natriuretic peptide (ANP) from both atrial and extra-atrial tissues. ANP plays an important role in the regulations of body fluid balance and blood pressure. Therefore, this study was carried out to elucidate whether or not atrial and extra-atrial synthesis of ANP is influenced in experimental non-insulin dependent diabetes mellitus (NIDDM) rats. METHODS: Neonatal rats were induced into NIDDM rats by single injection of streptozotocin (80 mg/kg). Plasma ANP level was measured by the use of radioimmunoassay method and the ANP mRNA expressions from the right atrium, left ventricle, hypothalamus and kidney were analyzed by reverse transcription- polymerase chain reaction with [32P]-dCTP at 8 weeks after injection of streptozotocin or citrate buffer. RESULTS: Blood glucose was more significantly increased at 2 hours after glucose loading in NIDDM rats than control rats. Plasma concentration of ANP tended to significantly increase in NIDDM rats compared with control rats. The expressions of ANP mRNA from each tissue were observed in different patterns. Right atrial ANP mRNA expression revealed non-significant increasing trend in NIDDM rats, whereas left ventricular ANP mRNA did not have difference. However, both hypothalamic and renal ANP mRNA expressions in NIDDM rats were significantly increased. CONCLUSION: These results indicate that the enhanced expressions of hypothalamic and renal ANP mRNA act as an important regulator of electrolytes and body fluid volume in neonatally streptozotocin-induced NIDDM rats.

The Stimulatory Effect of IL-1on The Insulin Secretion and Its Relating Factors.: In Kyung Jeong, Seung Hoon Oh, Tong Mook Kang, Jae Hoon Jeong, Yong Ki Min, Myung Shik Lee, Moon Kyu Lee, Kwang Won Kim; Korean Diabetes J. 2000;24(4):431-443. Published online January 1, 2001

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Abstract PDF: BACKGROUND
The inhibitory effect of IL-1 on the insulin secretion has been validated in pathogenesis of type 1 diabetes, but complex results about the stimulatory effect of IL-1 have been reported. The aims of this study are to clarify the effects of IL-1 on insulin secretion of pancreatic islets and to investigate the mechanisms in terms of preproinsulin synthesis, inducible NOS expression, and calcium channel activity. METHODS: Islets were isolated from male Sprague-Dawley (SD) rat by modified Lacy-Kostianovsky's method. After islets were treated with different concentrations (0, 0.5, 5, 50, 500 pmol/L) and exposure time (2, 6, 24 hours) of IL-1 , morphology, viability, static stimulation of insulin to glucose, insulin content, preproinsulin mRNA expression, iNOS mRNA expression and calcium channel activity were measured. RESULTS: 1) Viability of islets was reduced in high concentrations of long term exposure of IL-1 . 2) Insulin secretion was stimulated in islets treated with 5, 50, and 500 pmol/L of IL-1 for 2 hours and 0.5 pmol/L for 6 hours. It was inhibited in 5, 50, and 500 pmol/L for 6 and 24 hours. 3) Insulin content was not significantly different regardless of concentration and exposure time of IL-1 . 4) Preproinsulin mRNA expression increased in islets treated with 50, 500 pmol/L of IL-1 for 2 hours. After 24 hours, it decreased in dose dependent manner. 5) iNOS mRNA expression was detectable after 2 hours in the presence of IL-1 , peaks at 6 hour and decreased after 24hours. It was increased above 5 pmol/L of IL-1 in dose dependent manner. 6) Activities of the voltage-dependent Ca2+ channels were not different among groups. CONCLUSION: IL-1 plays a positive role in terms of insulin secretion and insulin synthesis in high concentration of short term or low concentration of long term. These effects of IL-1 might be neither dependent of iNOS pathway nor Ca2+ channel activity.

Humoral Immunological Marks in Patients with Child-onset and Adult-onset Type 1 Diabetes.: Hyun Dae Yoon, Jae Hong Kim, Jung Hyun Oh, Jin Chul Park, Sang Yub Nam, Ji Soon Yoon, Kyu Chang Won, In Ho Cho, Choong Ki Lee, Joong Yeol Park, Sung Kwan Hong, Ki Up Lee, Hyoung Woo Lee; Korean Diabetes J. 2000;24(4):444-456. Published online January 1, 2001

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Type 1 diabetes mellitus is an autoimmune disease in which serum antibodies against islet antigens have been recognized. These antibodies include cytoplasmic islet cell antibodies (ICA), and glutamic acid decarboxylase (GAD)65 antibodies and IA2 antibodies. It has been reported that the prevalence of these autoantibodies is different among Caucacian and Asian and Korean type 1 diabetes patients. And the natural course of type 1 diabetes can differ according to the age of onset. But, in contrast to the classic juvenile onset type 1 diabetes, the adult onset type 1 diabetes is poorly characterized about clinical and autoimmune differences at presentation. Thus, this study was perfomed to evaluate clinical and autoimmune characteristics at presentation in subjects with either child onset or adult onset type 1 diabetes and to establish an autoimmune pathogenesis in Korean type 1 diabetes. METHOD: We examined the clinical characteristics of child onset type 1 diabetes (n=32) and adult onset type 1 diabetes (n=40) retrospectively. At the same time, ICA from these patients was measured by standard indirect immunofluorescence, GADA and IA2A from these patients were measured by radioimmunoassay. RESULTS: The mean duration of disease was longer in the adult onset and their serum fasting C-peptide concentration at diagnosis were higer. The prevalence of ICA, GADA, IA2A in sera from 32 patients with child onset type 1 diabetes was 50%, 38% and 31% respectively. And, the prevalence of ICA, GADA and IA2A in sera from 40 patients with adult onset type 1 diabetes was 30%, 25% and 18% respectively.The prevalence of ICA, GADA and IA2A in sera from 39 patients with typical type 1 diabetes was 46%, 30% and 16% respectively. And, the prevalence of ICA, GADA and IA2A in sera from 33 patients with atypical type 1 diabetes was 30%, 30% and 25% respectively. The concordance rate of ICA and GADA in child onset and adult onset diabetes was 81% (26/32), 80% (32/40) respectively. In a subset of these patients with recent onset type 1 diabetes (duration of diabetes < or = 1 year), the prevalence of ICA, GADA and IA2A was 75% (3/4), 75% (3/4), 100% (1/1) respectively, in the child onset type 1 diabetes. CONCLUSION: These observations show that autoantibodies in Korean patients with child onset type 1 diabetes is similar compaired with other Asian groups but is lower than Caucasian patients with type 1 diabetes and the prevalence of humoral immunologic makers in child onset type 1 diabetes was higher than that of adult onset diabetes. These results suggest that autoimmune response is a significant cause of Korean type 1 diabetes but other factors except autoimmunity may play an important role in the pathogenesis of Korean type 1 diabetes.

Re-transplantation of Pancreatic Islets in Insulin Dependent Diabetes Mellitus.: Tae Young Yang, Seung Hoon Oh, In Kyung Jeong, In Ah Seo, Eun Young Oh, Gun Young Cho, Sung Joo Kim, Jae Hoon Chung, Yong Ki Min, Myung Shik Lee, Moon Kyu Lee, Kwang Won Kim, Young Soo Do, Sung Wook Choo; Korean Diabetes J. 2000;24(4):457-466. Published online January 1, 2001

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Over the past 20 years, significant advances have been made in human islet transplantaiton. However, cases of prolonged insulin independence after islet allotransplantation have rarely been reported and over time, a slight, gradual decrease in insulin secretion appears to occur, as suggested by the lower C-peptide. Although preliminary clinical success achieved over the past few years has been considerably higher with whole pancreatic transplant than with isolated islet grafts, both approaches remain experimental. Islet grafts might gain, over time, increasing credibility and might eventually provide an easier alternative in terms of grafting procedures and patient management, as compared with the more "traumatizing" whole-pancreas transplantation. Also, using islet, re-tran- splantation is possible. But it is not known whether re-transplantation of islet could be suitable for those patients who lost grafted islet function. The aim of the present study was to investigate the benefits of re-transplantation of islet in previously simultaneous islets-kidney transplant(SIK) patient who have lost graft function. METHODS: The recipient was a 32 year old male. First islet transplantation was underwent at December 25, 1999. However, the grafted islets lost function after 70 days. So we performed re-transplantation of islets. The isolation of islet was conducted sterilely on a laminar flow hood and isolated by a modified Recordi method. The islet was injected slowly into the liver via a cannular placed in the potal vein for 20 minutes. RESULTS: Transplanted islets were 90,000 IEq at first islet transplantation, 370,000 IEq at second islet transplantation. The insulin requirement was reduced from 75-85 to 35-40 U/day, the basal C-peptide level was 1.5 ng/mL at 7 days posttransplant Unfortunately, the grafted islets lost function after 70 days. After second transplantation, the insulin requirement was reduced to 26 U/day. CONCLUSIONS: Despite the continuous need for exogenous insulin therapy, islet transplantation can prevent wide glucose fluctuations, thus resulting in norma lization of glycemic control and improvement in HbA1c, and also, show that islets can be successfully and safely re-transplanted intraportally in patients who have lost previously grafted islet function (J Kor Diabetes Asso 457~466, 2000).

Plasma Proinsulin Secretion in Impaired Glucose Tolerance and Newly Diagnosed Type 2 Diabetes Mellitus.: Byoung Ho Kong, Seung Jin Choi, Jae Tack Kim, Yeon Shang Oh, Soon Hyun Shinn; Korean Diabetes J. 2000;24(4):467-475. Published online January 1, 2001

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Type 2 diabetes mellitus is characterized beta cell dysfunction and insulin resistance but the relative roles of the two factors are different in various ethnic groups. The changes in plasma proinsulin levels is thought to be a marker for the beta-cell dysfunction. To study the role of beta cell dysfunction in the pathogenesis of type 2 diabetes mellitus we compared the concentrations of plasma insulin, C-peptide and proinsulin among the control group, impaired glucose tolerance (IGT) group and newly diagnosed Type 2 Diabetes Mellitus (DM) group during the oral glucose tolerance test. METHODS: In 47 newly diagnosed patients with type 2 DM, 9 IGT and 13 controls the 75g oral glucose tolerance test (OGTT) were performed and samples were analyzed for glucose, insulin, C-peptide and proinsulin. RESULTS: 1) In IGT group plasma insulin, C-peptide and proinsulin concentrations were increased markedly during OGTT but were blunted in type 2 diabetes group. 2) The basal plasma proinsulin level was 7.7+/-4.4 pmol/L in control group, 15.2+/-6.9 pmol/L (p<0.005) in IGT group, and 16.9+/-8.3 pmol/L (p<0.005) in type 2 DM group, and the proinsulin levels at 60 min, 90 min, 120 min during OGTT were significantly elevated in IGT group than those of control group. 3) The plasma proinsulin/insulin ratio were significantly increased in IGT group and type 2 DM group at basal and 30 min during OGTT. 4) The proinsulin response areas were significantly increased in IGT group (110.7+/- 13.1 pmol/L/hr, p=0.048) than those of control group (73.6+/-5.1 pmo l/L/hr) and type 2 DM group (80.5+/-5.9 pmol/L/hr). CONCLUSION: Beta cell secretory defects such as proinsulin secretion were present in impaired glucose tolerance and the changes of insulin secretory function might have a role in the pathogenesis of type 2 DM.

Comparison of the Antiproteinuric Effect to ACE Inhibitors in NIDDM Patients with Nephropathy According to Genotypes of ACE Gene.: Yong Mo Yang, Jeong Chul Seo, Kyoung Soo Lee, Won Joong Jeon, Hyun Hee Lee, Ji Bong Jeong, Seong Su Koong, Tae Geun Oh; Korean Diabetes J. 2000;24(4):476-484. Published online January 1, 2001

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Albuminuria is a risk factor for progression of diabetic nephropathy. Antihypertensive treatment, especially angiotensin converting enzyme (ACE) inhibition, has been shown to reduce albuminuria and to ameliorate progression of diabetic nephropathy in IDDM patients. Recently, an insertion (I)/deletion (D) polymorphism of the ACE gene (ACE/ID) has been shown to influence the antiproteinuric efficacy of ACE inhibition in non-diabetic renal disease and the deterioration in kidney function in both non-diabetic and diabetic kidney disease. We evaluated the potential role of the ACE/ID polymorphism on the antiproteinuric responsiveness to ACE inhibition in NIDDM patients with nephropathy. METHODS: 35 NIDDM patients with overt proteinuria were included in this study. DNA amplified by PCR techniques was used to detect the two alleles of the ID polymorphism. Subjects were classified as II+ID group and DD group according to the presence (I) or absence (D) of a 270 base pair insertion. Ramipril was used for ACE inhibition. At a baseline and an end of the study(6 months later from baseline), arterial blood pressure, HbA1c, serum creatinine, creatinine clearance, and 24 hour urine protein amount were measured. The significant response to ACE inhibition was defined as a decline in proteinuria > or =30% of baseline. RESULTS: The MABP was decreased significantly in each groups, but the degree of BP reduction was not different between the groups. Twenty-four hour urine protein amount and creatinine clearance was not different in each groups and between CONCLUSION: Antiproteinuric effect of ACE inhibition was not associated with ACE/ID polymorphism in diabetic patients with nephropathy.

The Role of beta-cell Dysfunction and Insulin Resistance in the Development of Post-renal Transplantation Diabetes Mellitus.: Jae Hyun Nam, Hyun Chul Lee, Churl Woo Ahn, Jang Il Mun, Soon Il Kim, Kiil Park, Young Duk Song, Sung Kil Lim, Kyung Rae Kim, Kap Bum Huh; Korean Diabetes J. 2000;24(4):485-514. Published online January 1, 2001

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Our study was undertaken to investigate the pathogenesis and possible risk factors for post-renal transplantation diabetes mellitus (PTDM). METHODS: we recruited 114 patients with normal glucose tolerance, and performed the 75 g oral glucose tolerance tests (OGTT) and the short insulin tolerance tests 1 week before and 9~12 months after transplantation, respectively. RESULTS: The subjects were classified into three groups on the basis of OGTT after transplantation by WHO criteria: 1) 36 (31.6%) subjects with normal glucose tolerance; 2) 51 (45.7%) subjects with impaired glucose tolerance; and 3) 27 (23.7%) subjects with post-renal transplantation diabetes mellitus. Dosages of steroid and cyclosporin-A (CsA) were equivalent among the 3 groups. Before transplantation, the fasting and 2-h plasma glucose, and proinsulin/insulin (PI/I) ratios were significantly higher in the IGT and PTDM groups than in the NGT group, but insulin sensitivity index (ISI) was not different among 3 groups. In addition, the area under the curve (AUC)-insulin on OGTT was significantly lower in the PTDM group than in the NGT group. After transplantation, however, ISI was increased in all groups. Furthermore, the ISI and PI/I ratios revealed significantly higher values in the PTDM group than in the NGT group after transplantation. CONCLUSION: These results revealed that fasting and 2-h plasma glucose levels, as well as proinsulin/insulin ratio before transplantation, which may all be indicators of beta-cell dysfunction, could be the predictors for the development of PTDM and beta-cell dysfunction rather than insulin resistance was proved to be the main factor for the pathogenesis of PTDM.

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