Diabetes & Metabolism Journal

Volume 23(2); April 1999

Original Articles

Regulation of Guanine Nucleotide Binding Protein Activity in Normal Rat Pancreatic Islet Secretory Granule by Arachidonic Acid and its Metabolites.: Yeon Ah Sung; Korean Diabetes J. 1999;23(2):120-130. Published online January 1, 2001

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Abstract PDF: BACKGROUND
Arachidonic acid (AA) generated by the activation of phospholipase A2. and 12hydroxyeicasateraenoic acid (12-HEIE), a lipoxygenase metabolite of AA stimulates glucose induced insulin secretion in pancreatic islets, whereas prostaglandin E. (PGE2), a cyclooxygenase metabolite of AA, inhibits it. This effect of PGE2 is largely reversible by pertussis toxin, suggesting a possible involvement of Gi or Go-like proteins. The purpose of this study was to investigate the regulation of guanine nucleotide binding protein (G-protein) activity by AA and its metabolites (12-HETE and PGE2) in the secretory granule of normal rat pancreatic islets. METHODS: After isolation and subcellular fractionation of pancreatic islets from male Sprague Dawley rats, measurements of GTPase activity using [y-P32]GTP hydrolysis and GTP binding by [y-S35] GTPvS in secretory granules were performed. RESULTS: l. AA inhibited a high affinity low Km and a low affinity high Km GTPase activity in the normal rat islet secretory granule in a concentration dependent manner. Half maximal inhibition was demonstrable at 90 pM AA concentration known to stimulate both phases of glucose-induced insulin secretion. 2. PGE2 stimulated a high affinity low Km and a low affinity high Km GTPase activity in the normal rat islet secretory granule in a concentration dependent manner and this effect was more prominent in the high affinity low Km GTPase. Half maximal stimulation was demonstrable at 0.8uM PGE2, a concentration known to inhibit both phases of glucose-induced insulin secretion from pure beta cell lines and pancreatic islets. 3. PGE2 as well as other inhibitors of insulin secretion (such as epinephrine or clonidine) also stimulated high and low Km GTPase activity and these effects on low Km GTPase were recovered by pertussis pretreatment. Of the five prostaglandins (PGF2, PGA2, PGD2, and PGB2), only PGE2. stiniulated GTPase activity significantly (p<0.05). 4. 12-HETE had no effecl on GTPase activity. 5. AA increased GTP binding significantly(p< 0.05), but 12-HETE and PGE, had no measurable effects on GTP binding. CONCLUSION: In secretory granules of normal rat pancreatic islet cells, AA might have their stimulatory effect on insulin secretion via inhibition of GTPase activity and increased GTP binding, whereas PGE might represent their action via stimulation of low Km GTPase activity.

Effect of Hyperglycemia on Internalization of Insulin-receptor Complexes in Human Umbilical Vein Endothelial Cells.: Ki Ho Song, Yu Bae Ahn, Je Ho Han, Soon Jip Yoo, Kun Ho Yoon, Moo Il Kang, Bong Yun Cha, Kwang Woo Lee, Ho Young Son, Sung Koo Kang; Korean Diabetes J. 1999;23(2):131-141. Published online January 1, 2001

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It is well known that hyperglycemia activates protein kinase C (PKC) in vascular endothelial cells. However, the effect of hyperglycemia on internalization and recycling of insulin receptors by insulin in endothelial cells has not been examined thus far. METHODS: Human umbilical vein endothelial cells (HUVECs) were isolated from healthy, pregnant women. Confluent HUVECs were incubated in a culture media containing either 5 (NG group) or 25 mM glucose (HG group) for 4 days. Then, we measured the insulin binding, internalization and recycling of the insulin receptor and release of internalized insulin into the media. RESULTS: There was no difference in binding of 0.17 nM 125I-insulin between the two groups. However, the amount of internalized 125I-insulin, determined by the aeid washing method, was significantly greater in the HG group compared to the NG group. The addition of 10 pM 1-(5-isoquino-linesulfonyl)-2-methyl-piperazine (H7), a PKC inhibitor, to the HG group prevented the increase of internalization in 125I-insulin. In addition, preincubation with unlabeled insulin resulted in a decrease of 125I-insulin binding to a greater extent in the HG group compared with the NG group, indicating that high glucose levels increased internalizntion of insulin receptors. The high glucose-induced increase in internalization of insulin receptors was prevented by an addition of H7. Recycling of insulin receptors to the cell surface was not affected by high glucose. Internalized 125I-insulin released into media with time. The released amount of I-insulin in the HC group tended to be greater compared to the NG group. CONCLUSION: These results suggest that hyperglycemia may increase internalization of the insulin-receptor complexes in vascular endothelial cells through PKC activation.

The Effect of Cyclosporine on Insulin Sensitivity in Streptozotocin Induced Diabetic Rats.: Ju Seop Kang, Dong Sun Kim, Chang Beom Lee, Yong Soo Park, Woong Hwan Choi, Tae Wha Kim, Mok Hyun Kim; Korean Diabetes J. 1999;23(2):142-146. Published online January 1, 2001

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Cyclosporine (CsA), being used as a immunosuppressant is known to have deleterious effects on the liver and kidney, but the harmful effect on glucose tolerance has not been clearly elucidated. This study was undertaken to determine whether the CsA affected peripheral insulin sensitivity in streptozotocin (STZ)-induced diabetic Sprague-Dawley rats. METHODS: After the daily treatment of CsA (10mg/kg, i.p.) for 2 weeks, glucose tolerance tests were carried out by the intraperitoneal administration of glucose alone or in conjunction with insulin (5 U/kg, s.c.). The glucose tolerance and peripheral insulin sensitivity were determined by measuring the deremental area under the time-lasma glucose concentration curve (AUC; mg-min/mL) according to the trapezoidal rule. The plasma glucose levels (mg/dL) were measured by a glucose analyzer at 0, 10, 30, 60, 90 and 120min after glucose load (2 g/kg). The STZ-diabetic rats were divided into thre groups (GLU- as control, INS+GLU- and CsA+INS+GLU-treated group, n 7 in each groups). RESULTS: In STZ-diabetic rats, the AUC 0-120 of the CsA+INS+GLU-treated group was significantly (p<0.01) lower than those of the control group (48.6% of control), but significantly (p<0.03) higher thain those of the INS+GLUtreated group (28.1% of control). CONCLUSIONS: These results suggest that intraperitoneal injection of CsA gives rise to a deterioration of glucose etabolism which is probably due to a decrease of insulin sensitivity of peripheral tissue in STZ-diabetic rats.

Plasma Proinsulin Levels among the Control, Impaired Glucose Tolerance and Type 2 Diabetes Mellitus during Oral Glucose Tolerance Test.: Mi Deok Lee, Young Uck Kim, Hong Seung Kim, Young Goo Shin, Choon Hee Chung; Korean Diabetes J. 1999;23(2):147-154. Published online January 1, 2001

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Increased secretion of proinsulin has been associated with beta-cell dysfunction. Hyper-proinsulinemia is suggested to be a predictor for the progression of IGT to type 2 DM. In this study, we compared the concentration of insulin, C-peptide and proinsulin levels among the control group, IGT and type 2 DM group during the oral glucose tolerance test. We investigated whether hyperproinsulinemia was an effective predictor of beta-cell impairment befre the clinical onset of type 2 diabetic subjects. METHODS: We studied proinsulin, insulin(using an assay that display appreciable cross-reactivity with proinsulin) and proinsulin:insulin ratio during the oral glucose tolerance test in 14 controls, 20 IGT and 20 type 2 DM. We also compared proinsulin, proinsulin response areas and proinsulin:insulin ratio among the three groups. RESULTS: There were no significant differences in the baseline and 30min proinsulin levels among three groups. However, proinsulin response areas in IGT were higher than those in other groups. Baseline proinsulin/insulin ratio and post-load proinsulin/ insulin ratio were not significantly different among the three groups. In IGT group, the proinsulin response after glucose loading was rapidly increased, but was blunted in diabetic patients. CONCLUSION: We suggest that pancreatic beta cell dysfunction was ongoing before the clinical onset of DM and hyperproinsulinemia, especially the proinsulin response areas during oral GTT may be a predictor for the development of type 2 DM.

Lack of Effectiveness of Glomerular Hyperfiltration on Development of Microalbuminuria in Type 2 Diabetic Patients: five Year Follow-up Study.: Eun Sook Kim, Sang Wook Kim, Jin Yub Kim, Joong Yeol Park, Sung Kwan Hong, Ki Up Lee; Korean Diabetes J. 1999;23(2):155-161. Published online January 1, 2001

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Glomerular hyperfiltration (GHF) is found in 30-40% of patients with type 1 diabetes at the onset of the disease. Several lines of evidence suggest that this might be responsible for the development of diabetic nephropathy. However, it is still controversial whether GHF is a risk factor in patients with type 2 diabetes. This led us to perform a five-year-prospective study in normoalbuminuric type 2 diabetic patients. METHODS: A total of 68 patients with type 2 diabetes were studied prospectively, They were all normoalbuminuric initially. Glomerular filtration rate was determined by the 51Cr-EDTA single injection method and urinary albumin excretion rate by the radioimtnunoassay method. RESULTS: GHF was present in 19 out of 68 patients. At follow-up, l7 out of 49 patients of the normofiltration group and 3 out of 19 patients of GHF group progressed to microalbuminuria (p>0.05). Multiple logistic regression analysis revealed that the known duration of diabetes, systolic hypertension, and the presence of retinopathy were independently associated with the development of microalbuminuria. CONCLUSION: Our study suggests that GHF does not predict the subsequent development of diabetic nephropathy as indicated by the elevation of the urinary albumin excretion rate during the five year interval.

The Risk Factors of Diabetic Retinopathy in NIDDM Patients.: Won Tae Seo, Seung O Song, Sy Young Kim, Yoon Sang Choi, Hye Ran Jang, Sang Jong Lee; Korean Diabetes J. 1999;23(2):162-171. Published online January 1, 2001

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Diabetic retinopathy, which is one of the microvascular complications, has been shown to be related to visual disturbance and blindness. In this report we examined the risk factors for diabetic retinopathy in NIDDM patients and investigate the relationship between the prevalence of diabetic retinopathy and other risk factors. METHODS: Clinical characteristics and laboratory findings such as HbAlc, fasting plasma glucose, hemoglobin, BUN, creatinine and lipid profile and treatment modality were evaluated and their relation with diabetic retinopathv were analyzed. Fundoscopic examinations of the retina were performed using direct/indirect opthalmoscopy and fundus photograph. The grade of retinopathy was judged from the results of opthalmological examinations and were elassified into non-proliferative retinopathy and proliferative retinopathy. RESULTS: A total of 163 patients with NIDDM (M/F=59:104) were evaluated. Of these patients, 80 of them developed diabetic retinopathy. 71 patients were detected to have non-proliferatie and 9 patients to have proliferative retinopathy. The presence of proteinuria, the long diabetic duration, hypertension, anemia, the high plasma glucose levels, the high level of HbA1c, old age were all associated with the development of diabetic retinopathy. I-lowever, sex, body mass index, type of therapy, lipid profile, C-peptide levels, insulin levels had little impact on the development of retinopathy. CONCLUSIONS: The presence of proteinuria, the long diabetic duration, hypertension, anemia, high plasma glucose levels, high HbA., and old age are important risk factors for the development of rc;tinopathy in patients with NIDDM.

Risk Factors for Peripheral Arterial Disease as Screened by Plethysmography in Patients with NIDDM.: Hyuk Jae Chang, Dae Jung Kim, Byoung Joo Choi, Young Guk Ko, Churl Woo Ahn, Dong Ryeol Ryu, Yong Seok Yun, Seol Hye Han, Jae Hyun Nam, Seok Won Park, Young Duk Song, Sung Kil Lim, Kyung Rae Kim, Won Heum Shim, Hyun Chul Lee, Kap Bum Huh; Korean Diabetes J. 1999;23(2):172-181. Published online January 1, 2001

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Peripheral arterial disease (PAD) is one of the clinical manifestations of the atherosclerotic disease process. Early onset and rapid progression of PAD in diabetic patients has been well documented. PAD in diabetic patients has also been associated with an increased risk for total and cardiovascular mortality. Plethysmography is a noninvasive test to screen for the presence of PAD. Thus the aim of this study is to assess the risk factors for PAD screened by plethysmography in NII)DM patients. METHODS: A total of 289 NIDDM patients who undlerwent plethysmography were entered into our annlysis. Clinical characteristics of 38 patients with an ankle-brachial index of <0.9 (group B) were conapared with those of 231 patients with an ankle-brachial index of >1.0 (group A). RESULTS: Abnormalities in plethysmographic findings were found in 45.7% of diabetic patients. Age, duration of diabetes, hypertension, smoking, previous history of vascular diseases, HDL cholesterol, TC/HDL, and LDL/HDL appeared to be factors significantly related to PAD. Fasting sugar, HbAlc, total cholesterol, LDL cholestero1, trigly ceride, fibrinogen, lipoprotein(a), and waist-hip ratio were not significantly different between the two groups. The multiple logistic regression analysis showed the signficant contribution of the previous history of vascular disease (p=0.0028) and age (p-0.0115) to PAD in diabetic patients. CONCLUSION: The prevalence of PAD defined by plethysmography in our subjects was 45.7% higher than expected, suggests that efforts for early detection and prevention of PAD should be emphasized in diabetic patients.

The Relationship between Apolipoprotein E Phenotypes, Serum Lipid Metabolism, and Oxidative Stress in Korean Type 2 Diabetic Patients.: Soo Bong Choi, Sun Min Park; Korean Diabetes J. 1999;23(2):182-192. Published online January 1, 2001

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The cause of type 2 diabetes mellitus (DM) is not known, but one of the causes may be the reduction of insulin secretion through the fibrosis formed with amyloid deposits in pancreatic beta cells. Amyloidogenesis in hippocampus is a characteristic feature in Alzheimers disease. Possession of the Apolipoprotein (Apo) E 4 allele (E4/2, FA/3 or E4/4) is a risk factor for the development of Alzheimers disease. However, it is controversial that Apo E polymophsim is associated with the etiopathology of type 2 DM. Both Alzheimers disease and type 2 DM has increased oxidative stress, which may be related to the formation of fibrosis. The purpose of this study was to investigate the distribution of Apo E phenotypes in type 2 diabetic subjects and healthy subjects, and to determine whether Apo E phenotypes influenced serum lipid profiles and glutathione peroxidase and superoxide dismutase activities of red blood cells in type 2 DM and healthy subjects. METHODS: Overnight fasting blood was collected from 84 type 2 diabetic patients and 85 healthy subjects. Apo E phenotypes was determined by the isoelectrofocusing method. Serum lipid profiles and supetoxide dismutase and glutathione peroxidase activ'ities of red blood cells (RBC) were measured. RESULTS: The frequency of Apo E 4 in the type 2 DM was higher than that in the control group (p<0,05). The serum total cholesterol and triglyceride levels of the type 2 DM were overall higher than in healthy subjects. Serum lipid profiles were not affected by Apo E phenotypes in healthy subjects. However, semm total cholesterol levels of type 2 diab diabetic patients with Apo E3/3 were signifcantly lower than those with Apo FA/3 (p<0.05), but serum HDL, cholesterol levels had an opposite tendency. Serum triglyceride levels of type 2 diabetic patients with Apo E3/2 were higher than those with Apo E4/3 (p<0.05), RBC superoxide dismutase and gluta,thione peroxidase activities in type 2 diabetic patients tended to be lower than those in the control group. These enzyme activities of type 2 diabetic patieints with Apo E3 were lowest among the Apo E phenotype groups (p<0.05). CONCLUSION: This result suggests that type 2 diabctic patients had more Apo E 4 allele than in healthy people. Antioxidant enzyme activities decrqased in type 2 diabetic patients with Apo E 4 allele. Serum lipid profiles of type 2 diabetic patients with Apo E 4 allele was an increased risk factor for cardiovascular disease.

Self-Care and Related Factors in Patients with Diabetes.: Jin Ho Chun, Soo Boon Jung, Hae Sook Sohn; Korean Diabetes J. 1999;23(2):193-206. Published online January 1, 2001

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Abstract PDF: BACKGROUND
In patients with diabetes, self-care might be important for the prevention of complications and the improvement of quality of life. METHODS: To investigate the factors related to self-care in patients with diabetes, a questionnaire study of 128 diabetic patients at three hospitals in Pusan was done from November 1997 to March 1998. The questionnaire included the level of self-care, the knowledge of diabetes, health belief, the support of the family, stresses relating to the disease, personal characteri.;tics, medical history, relationship with medical personnel. The data was analyzed by PC SAS program (version 6.12) with the level of significance (a=0.05). RESULTS: In univariate analysis, the level of self-care was higher in the group with a greater level of knowledge, health belief, the support of family, and it was lower in the group with a greater level of stress (p<0.05). In the multiple regression analysis with the level of self-care as the dependent variable and each characteristic as independent variables, knowledge (9=0.132), health belief (g=0.469), stresses (B=-0.105), body mass index (9=-0.898), regular hospital visit (g=2.318), relationship with the physician (B=3.987) and current smoking habits (B=-5.205) were detected as significant factors (p<0.05), and current drinking factors (B=-3.742) were not significant (p>0.05). The value of R-square was 61%. CONCLUSIONS: To enhance the effectiveness for diabetes control through the enhancement of the patients self-care level, it suggested that self control of weight, smoking and stress would be necessary, and the level of knowledge and health belief should be increased with a good relationship with his physician. And thought it necessary to let them visit a physician regularly through efforts from family members and medical personnel.

A Case of Insulin Dependent Diabetes Mellitus with MELAS Syndrome Associated with a Mutation of Mitochondrial DNA.: Min Ho Choi, Hyun Mi Rhim, Ki Won Oh, Moo Il Kang, Bong Yun Cha, Kwang Woo Lee, Ho Young Son, Sung Koo Kang, Hyun Chul Lee, Kap Bum Huh; Korean Diabetes J. 1999;23(2):207-214. Published online January 1, 2001

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Abstract PDF: Mitochondrial mutations are associated with a wide range of disorders (Kearns-Sayre and chronic progressive external ophthalmoplegia syndromes, Myoclonic epilepsy and ragged-red fibre disease, Mitoehondrial encephalomyopathy, lactic acidosis, and stroke-like episodes, Leighs disease ancl cerebellar ataxia plus pigmentary retinopathy syndromes), which is inherited maternally. A-to-G mutation at nuclcotide position 3243 was originally identified in MEI.AS syndrome (mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes) and accounted for about 80% of the MELAS cases, Recently, this mutation was reported in maternally inherited NIDDM patients. It was also repoded that approximatedly 1% of diabetic patients have this mutation. We performed the molecular genetic analysis of mtDNA in one female insulin dependent diabetic patient with MELAS syndrome and her family members, and also confirmed the A-to-G mutation at nucleotide 3243 of the mtRNA Leu(UUR) gene in their family members.

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