Diabetes & Metabolism Journal

Volume 26(1); February 2002

Review

Paradoxical Roles of Pancreatic Beta Cell Stimulators with Respect to Insulin Secretion and Its Morphological Changes in the Beta Cell.: In Kyung Jeong, Kwang Won Kim; Korean Diabetes J. 2002;26(1):1-15. Published online February 1, 2002

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Editorial

Protein Deficiency and Type 2 Diabetes Mellitus.: Bong Soo Cha, Soo Kyung Kim; Korean Diabetes J. 2002;26(1):16-20. Published online February 1, 2002

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Original Articles

Pancreatic beta-cell Function and Development in Male Offspring of Protein-Malnourished Rats.: Hyeong Kyu Park, Cheng Ji Jin, Do Joon Park, Chan Soo Shin, Kyong Soo Park, Seong Yeon Kim, Hong Kyu Lee; Korean Diabetes J. 2002;26(1):21-30. Published online February 1, 2002

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Abstract PDF: BACKGROUND
Nutritional deprivation of the fetus and infant may be associated with susceptibility to impaired glucose tolerance or type 2 diabetes in adult life. This association has been interpreted as a long-term effects of nutritional factors that reduce fetal growth and impair the development of tissues that regulate glucose metabolism. This study aimed to investigate the effect of protein malnutrition in a fetus and early life on the pancreatic beta-cell function and development. METHODS: Sprague-Dawley rats were fed a low-protein (8% casein) diet during pregnancy and lactation. Their male offspring were weaned onto either a control (18% casein) diet (recuperated group, R) or a low-protein diet (low-protein group, LP). The offspring of the rats fed control diet were weaned onto control diet (control group, C). Glucose tolerance tests and morphometry of the pancreas were performed to evaluate the pancreatic beta-cell function and development at the 25th week of age. RESULTS: Offspring of the protein-malnourished rats had a significantly lower body weights than the controls. The R and LP showed no major impairment in glucose tolerance, but the plasma insulin concentrations in the R (0.24+/-.03 nmol/L) and LP (0.28+/-.02 nmol/L) groups were lower at 20 min during IVGTT than the C (0.43+/-.05 nmol/L) groups. The areas under the curve for insulin (AUC insulin) during IVGTT were significantly lower in R and LP (0.39+/-.03 nmol/L/min, 0.43+/-.02 nmol/L/min) groups than the C (0.54+/-.03 nmol/L/min) group. In particular, the rats with fetal protein malnutrition showed severe impairment in late-phase insulin secretion to a glucose load. Both the pancreas weight and the proportion of the pancreas weight to the body weight were significantly lower in the R and LP groups than the C group. The proportion of beta-cells to pancreatic cells was lower in the LP (0.91+/-.14%) group than the C (2.19+/-.23%) and R (1.79+/-.25%) group. The relative beta-cell mass was significantly lower in the LP (by 62%) group that the C group. CONCLUSION: Rats with fetal protein malnutrition showed persistently impaired pancreatic beta-cell development and reduced insulin secretion capacity. These findings suggest that in utero protein malnutrition can contribute to the development of type 2 diabetes in adult life along with other deleterious environmental or genetic conditions.

Insulin Gene Therapy using Vascular Smooth Muscle Cells in Diabetic Rats.: Tae Geun Oh, Mi Ja Lee, Young Ku Kim, Seung Tak Kim; Korean Diabetes J. 2002;26(1):32-46. Published online February 1, 2002

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Abstract PDF: BACKGROUND
Type 1 diabetes mellitus is caused by a lack of insulin. The purpose of this study was to test whether blood glucose control in severe diabetic animals can be achieved by transplanting of rat vascular smooth muscle cells which are transduced with the insulin gene using a retroviral vector system. METHODS: After cloning the recombinant retroviral plasmid including human mutated proinsulin cDNA which contains furin endopeptidase cleavage site, the resulting plasmid, LInABCSN, was transfected into the retroviral packaging cell line (PA317/LhInABCSN). The resulting retrovirus in the supernatant of PA317/ LhInABCSN infected the F344 rat vascular smooth muscle cell (SMC) and produced the SMC/LhInABCSN cells. After transplanting SMC/LInABCSN cells into the internal carotid artery of the rat, diabetes was induced by an intraperitoneal streptozotocin (STZ) injection (50 mg/kg) 2 week later. The blood glucose and insulin levels, percent weight change and the survival rates between the control group (SMC/LNFZ) and the treatment group (SMC/LInABCSN) were compared. RESULTS: The insulin concentrations in the supernatant of the SMC/LhInABCSN mice were 160.2 IU/mL in 24 hours, 243.6 IU/mL in 48 hours and 350.2 IU/mL in 72 hours, but the proinsulin concentrations in 24, 48 and 72 hours were all lower than 1 pmol/L. After 1 day and 3 days of the STZ injection, there were no differences in glucose concentrations between treatment group (n=10) and control group (n=10). There were no statistical differences in the percent weight change between the control and treatment group but the treated rats showed bad a lower weight loss than control rats. After 3 days of the STZ injection, serum insulin concentration of treatment group showed slightly higher levels than the control group (2.7+/-.5 IU/mL vs. 1.6+/-.1 IU/mL, p=0.077). The survival showed a significant increase in treatment group (median survival: 29 days, 9-104 days) compared to the control group (median survival: 6 days, 3-49 days, p < 0.05). CONCLUSION: Although this study did not show a normal glucose concentration in treated rats, it did show significantly higher survival compared to control rats. It is believed that gene therapy using rat vascular smooth muscle cells which transduced the insulin gene may be a new insulin delivery method.

Mechanism of Impaired Endothelium-dependent Vasodilation in Otsuka Long-Evans Tokushima Fatty (OLETF) Rats .: Kook Jin Chun, Seok Man Son, In Ju Kim, Chi Dae Kim, Seok Dong Yoo, Yong Ki Kim; Korean Diabetes J. 2002;26(1):47-57. Published online February 1, 2002

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Abstract PDF: BACKGROUND
Impaired vascular endothelium-dependent relaxation and augmented contractile responses have been reported in several long-term animals hyperglycemia models and human diabetic patients. Since oxidative stress has been implicated as a contributor to impaired vascular function, the mechanism of an impaired endothelium-dependent vasodilation in Otsuka Long-Evans Tokushima Fatty (OLETF) rats was investigated. METHODS: This present study was undertaken to characterize both the vascular production and the enzymatic source of the superoxide anion in the type 2 diabetic rats. RESULTS: In the thoracic aortas of OLETF rats, endothelium-dependent relaxation was markedly attenuated compared to that of the control rats (LETO, Long-Evans Tokushima Otsuka) in association with a significant increase in superoxide production (2421.39+/-07.01 nmol/min/mg). There was no difference in eNOS expression between the OLETF rats and LETO rats. The increased production of superoxide anion was significantly attenuated by diphenyleneiodonium (DPI, 10 mol/L), NAD (P)H oxidase inhibitor. In line with these results, studies using various enzyme inhibitors such as DPI, allopurinol, rotenone and L-NMMA suggest that the main source of superoxide anions in the aorta is NAD (P)H oxidase. CONCLUSION: These results suggest that enhanced NAD(P)H oxidase activity and reduced nitric oxide (NO) availability through an interaction between NO and superoxide anion contribute to the impaired endothelium-dependent vasodilation in OLETF rats.

Effects of Gutathione on Cyclosporine A-induced Cyotoxicity in Cultured Rat Insulinoma (RIN5mF) Cells.: Dong Hyun Choi, Byoung Rai Lee, Dai Yong Jang, Jong O Kim, Byung Soo Kim, Ki Young Chung, Tae Young Lim, Byung Chul Shin, Hak Yeon Bae; Korean Diabetes J. 2002;26(1):58-64. Published online February 1, 2002

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Abstract PDF: BACKGROUND
Cyclosporin A (CsA) is a immunosuppressive agent that is most widely used in organ transplanted patients to prevent immunorejection, However, it has some side effects, including diabetes mellitus, nephrotoxicity and hypertension. The mechanism of CsA cytotoxicity is unclear but it has been suggested that reactive oxygen species are involved in the cytotoxic reactions. The purpose of this study was to determine the effects of glutathione, as a physiological antioxidant on CsA induced beta-cell toxicity. METHODS: Rat insulinoma (RINm5F) cells were incubated with culture media (RPMI1640) in the presence of CsA and/or buthionine sulfoximine (BSO), which is an inhibitor of r-glutamyl cysteine synthetase, and reduced glutathione. The viable cells were examined using 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide (MTT) and was determined by a spectrophotometer at a wavelength of 570 nm. RESULTS: Incubating the RINm5F cells with CsA resulted in a decrease in cell viability with increasing dose. This deceased cells viability, induced by CsA was potentiated by BSO treatment. The CsA and BSO induced cells toxicity was reduced significantly by the reduced glutathione. CONCLUSION: The results suggest that pancreatic beta-cell may be injured by CsA and glutathione may have some role in cytotoxicity.

The Effect of Step-wised, Controlled Cooling Method for Islet Cryopreservation on the in vivo and in vitro Islet Function.: In Kyung Jeong, Seung Hoon Oh, Byung Joon Kim, Tae Young Yang, Byung Wan Lee, Chang Young Ha, Jung Hyung Noh, Jae Hoon Chung, Young Ki Min, Myung Shik Lee, Moon Kyu Lee, Kwang Won Kim; Korean Diabetes J. 2002;26(1):65-74. Published online February 1, 2002

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Abstract PDF: BACKGROUND
Although islet transplantation has been attempted to reverse the state of diabetes, achieving a critical number of islets and modulating the immune response limit the success ofl islet transplantation. Cryo-preservation of islets offers many important benefits for islet transplantation by collecting islets with a wide variety of HLA phenotypes and islet MHC expression. The aims of this study was to determine the optimal conditions for cryo-preservation by using a controlled cooling method and to evaluate in vitro and in vivo functional properties of the cryo-preserved islets. METHODS: Collagenase-isolated, Ficoll-purified islets were cultured for 48 hours. They were aliquoted into freezing tubes (1000 islets per tube), equilibrated with 2 M dimethyl sulfoxide (DMSO) in three steps, supercooled, nucleated, and controll- cooled at rate of 0.25 degrees C/min to - 40 degrees C prior to storage at - 196 degrees C. Rapid thawing and removal of DMSO with 0.75 M sucrose preceded 48 hour of culture and the morphology, viability, glucose-induced insulin secretion, and in vivo function of rats transplanted with cryopreserved islets was reexamined. RESULTS: 1) Recovery was 90.2+/-0.2%, 85.7+/-0.1% and 81.7+/-0.1% immediately after, 24 hours and 72 hours after thawing respectively. The viability was 60+/-5%, 80+/-5%, 90+/-5% immediately after, 24 hours and 72 hours after thawing respectively. 2) The glucose-stimulated-insulin secretion (GSIS) tended to decrease immediately after thawing, but GSIS increased to the level of pre-cryopreservation 72 hours after thawing. 3) The in dynamic GSIS, the first and the second phase of insulin secretion were well preserved in islets cultured for 72 hours after thawing. 4) The cryopreserved islets were cultured for 3 days and transplanted into renal sub-capsular space of streptozotocin (STZ) induced diabetic rats. The duration of normoglycemia in the STZ-induced diabetic rats transplanted with cryopreserved islets was significantly longer than that of the fresh islets. CONCLUSION: The optimal condition of cryopreservation using the controlled cooling method was established in rat pancreatic islets. This cryopreservation method can be a feasible approach for human islet transplantation.

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