Diabetes & Metabolism Journal

Volume 28(6); December 2004

Review

Clinical Pancreatic Islet Allotransplantation.: Sung Hee Ihm; Korean Diabetes J. 2004;28(6):459-467. Published online December 1, 2004

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Abstract PDF: No abstract available.

Original Articles

Hypothalamic AMPK Activity in Diabetic Rats.: Churl Namkoong, Min Seon Kim, Woo Je Lee, Pil Geum Jang, Seong Min Han, Eun Hee Koh, Joong Yeol Park, Ki Up Lee; Korean Diabetes J. 2004;28(6):468-477. Published online December 1, 2004

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Abstract PDF: BACKGROUND
AMP-activated protein kinase (AMPK) acts as a cellular energy sensor that is activated during states of low energy charge and it regulates the various metabolic pathways to reestablish the normal cellular energy balance. It has recently been demonstrated that AMPK activity is altered by the state of energy metabolism in the hypothalamic neurons and this mediates the feeding response. METHODS: Diabetes was induced by an intra-peritoneal injection of streptozotocin (STZ) in Sprague-Dawley rats. The diabetic rats were maintained for 3 weeks with or without insulin treatment. 3 weeks later, we collected hypothalamus and we then assayed the phosphorylation of AMPK and the activity of acetyl CoA carboxylase (ACC) and isoform-specfic AMPK. To determine the effect of hypothalamic AMPK inhibition on diabetic hyperphagia, we administered an AMPK inhibitor, compound C, into the third ventricle in the STZ-induced diabetic rats. RESULTS: Phosphorylation of AMPK, which is a marker of AMPK activation, increased in the hypothalamus of the STZ-induced diabetic rats (DR). Moreover, 2-AMPK activity, but not 1-AMPK activity, increased by 2-fold in hypothalamus of the DRs. Phosphorylation of hypothalamic acetyl CoA carboxylase (ACC), a key downstream enzyme of AMPK, also increased in the DRs and this caused a reduction in ACC activity. Insulin treatment completely reversed the diabetesinduced changes in the hypothalamic AMPK and ACC, suggesting that insulin deficiency was associated with the changes in hypothalamic AMPK and ACC. Inhibition of AMPK by an intracerebroventricular administration of AMPK inhibitor, compound C, attenuated the development of diabetic hyperphagia and reduced the blood glucose levels in DRs. CONCLUSION: We have demonstrated that hypothalamic AMPK activity increased in the DRs, and inhibition of hypothalamic AMPK activity attenuated the development of diabetic hyperphagia. These data indicate that the enhanced hypothalamic AMPK activity may contribute to the development of diabetic hyperphagia

Mitogenic Effects and Signaling Pathway of Insulin-Like Growth Factor-I (IGF-I) in the Rat Beta Cell Line (INS-1).: In Kyung Jeong, Ja Young Kim, Hyung Joon Yoo, Myung Shik Lee, Moon Kyu Lee, Kwang Won Kim; Korean Diabetes J. 2004;28(6):478-489. Published online December 1, 2004

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Abstract PDF: BACKGROUND
Nutrients and growth factors are known to stimulate pancreatic beta cell mitogenesis. IGF-I acts as a survival factor by limiting apoptosis and stimulating proliferation in many cell types. However, the appropriate mitogenic signaling pathways have not been defined. The aim of this study is to elucidate the mitogenic effect and signaling pathways of IGF-I in the rat beta cell line (INS-I). METHODS: The studies were performed using the rat pancreatic beta cell line, INS-1. INS-1 cells were cultured in RPMI 1640 containing serum-free, 0.2% BSA and 11.1 mmol/L glucose media for 24 hours, and the cells were then treated with IGF-I and different concentrations of glucose or tyrosine phosphorylation inhibitors, or insulin. The cell proliferation was measured by the [3H]thymidine uptake and MTT assay. The cell cycle was analyzed by a flow cytometer by using propidium iodide staining. Western blot analyses were performed using antibodies against PY20 and phospho-MAPK. RESULTS: 1) MTT assay and the [3H]thymidine uptake showed that IGF-I stimulated the INS-1 cell proliferation in a dose dependent manner. Glucose was noted to independently increase the INS-1 cell proliferation. A combination of IGF-I and glucose has a synergistic effect on the proliferation of INS-I cells. Insulin did not influence on the mitogenic effect of IGF-I. 2) The S fraction of INS-1 cells treated with IGF-I was increased in a dose dependent manner. IGF-I stimulated the exit from G1 into the S phase of the cell cycle. 3) Investigation of the role of the PI3K and MAPK, by using of the inhibitors LY294002, wortmannin, and PD98059, demonstrated that the activation of MAPK, but not PI3K, required to stimulate the proliferation of INS-1 cells. 4) IGF-I stimulated the phosphorylation activation of pp60 and phospho-MAPK in the INS-1 cells. IGF-I induced the beta cell proliferation, and this was mediated via a signaling mechanism that was facilitated by MAPK. CONCLUSION: The proliferative effect of IGF-I on pancreatic beta cell seems to be mediated through MAPK signaling pathway.

The Effect of cAMP-Elevating Agents on High Glucose-Induced Apoptosis of Isolated Islets of Rat Pancreas.: Gwan Pyo Koh, Kwang Sik Suh, Suk Chon, Seung Joon Oh, Jeong Taek Woo, Sung Woon Kim, Jin Woo Kim, Young Seol Kim, Sun Hee Kwon; Korean Diabetes J. 2004;28(6):490-500. Published online December 1, 2004

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Abstract PDF: BACKGROUND
High glucose-induced apoptosis has been implicated in the loss of beta-cells of the pancreatic islets in animal models of type 2 diabetes. GLP-1 has been shown to reduce apoptosis by the cAMP-dependent mechanism in beta-cells. Other studies have also shown that elevated levels of intracellular cyclic AMP delayed apoptosis in other types of cells. We investigated whether cAMP-elevating agents could suppress the high glucose-induced apoptosis of isolated rat islets. METHODS: Pancreatic islets were isolated from Sprague-Dawley (SD) rats. The expression of phosphodiesterase (PDE) 3 subtypes was investigated by using extracts of freshly isolated islets and analyzing them by RT-PCR. After 2 days of isolation, the islets were cultured in RPMI-1640 media containing 5% FBS with various glucose concentrations (11.1, 16.7 and 27.8 mM), 5x10-6 M forskolin, 2x10-4 M 3-isobutyl-1-methylxanthine (IBMX), 10-5 M cilostazol, and 10-6, 5x10-6 and 10-5 M H-89 for 5 days. The islet apoptosis was measured by a sandwich enzyme-immunoassay using antihistone antibody. RESULTS: Apoptosis was lowest at 11.1 mM glucose concentration, and increased at higher glucose concentrations (1.00 +/- 0.04 A.U. (arbitrary unit) at 11.1 mM, 1.17 +/- 0.12 A.U. at 16.7 mM, and 1.65 +/-0.13 A.U. at 27.8 mM (P <0.05 for 11.1 mM). Both PDE 3A and 3B mRNA were expressed in the islet extracts. In 16.7 and 27.8 mM glucose concentrations, forskolin (P <0.01), IBMX (P <0.05) and cilostazol (P < 0.05) suppressed apoptosis of the islet cells. Protein kinase A (PKA) nhibitor, H-89, did not prevent the inhibition of apoptosis by forskolin. CONCLUSION: These results show that high glucose-induced apoptosis of the cells in rat islet is attenuated by such cAMP-elevating agents as cilostazol. However, cyclic AMP regulation of islet apoptosis may occur via a PKA-independent signaling pathway.

Mitochondrial DNA 5178 C>A Polymorphism is Associated with Serum Lipid Levels.: Hyeon Jae Kim, Min Young Cho, Min Kim, Ku Cheol Park, Goo Jun Kang, Cheol Hak Jang, Yeon Seong Kim, Kyu Hong Lee, Soo Kyong Park; Korean Diabetes J. 2004;28(6):501-510. Published online December 1, 2004

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Abstract PDF: BACKGROUND
The mitochondrial DNA 5178 C>A polymorphism (Mt5178A) has been reported to the be associated with longevity, serum lipid levels and acute myocardial infarction in Japanese population. However, most of the studies on this subject have been confined to the Japanese population, and there have been fewer studies that tried to prove the association between Mt5178A polymorphism and type 2 diabetes or diabetic macrovascular complication. METHODS: The mt5178A polymorphism was genotyped in 658 type 2 diabetic patients and 334 non-diabetic controls subjects, and information on all the subjects' coronary heart disease and cerebrovascular disease was obtained from chart records. The anthropometric parameters, fasting blood glucose, insulin and lipid profiles were then measured. RESULTS: The frequency of the Mt5178A genotype in the control group (109/334; 32.6%) was not different from that found in the type 2 diabetic patients (223/658; 33.9%). The prevalence of cerebrovascular disease and coronary heart disease in the type 2 diabetic patients was not different between the Mt5178A genotype and the Mt5178C genotype. However, after adjustments for age and the body mass index, the HDL cholesterol concentration in men carrying the Mt5178A genotype was significantly higher than the HDL cholesterol concentration in men carrying the Mt5178C genotype (P = 0.007). The triglyceride concentration in women carrying the Mt5178A genotype was significantly lower than that in women carrying the Mt5178C genotype (P = 0.007). In addition, the frequency of the Mt5178A genotype in the control group increased with advanced age (P = 0.002). CONCLUSION: We could not find the association between Mt5178A and type 2 diabetes or diabetic macrovascular complication. However, the Mt5178 C>A polymorphism is associated with serum lipid levels and its frequency is increased with advanced age

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.

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.

Fetal Organogenesis in a Pregestational Diabetic Mother Who has Taking an Oral Hypoglycemic Agent in Early Pregnancy.: Chang Beom Lee, Seung Yong Kim; Korean Diabetes J. 2004;28(6):530-537. Published online December 1, 2004

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Abstract PDF: BACKGROUND
Women with diabetes mellitus are not treated with oral hypoglycemic agents because of the concerns about teratogenicity and neonate complication. There is not enough information about the safety of these drugs and especially during the first trimester of pregnancy. METHODS: Eight type 2 diabetic pregnant women with accidental exposure to an oral hypoglycemic agent during embryogenesis and twenty type 2 diabetic pregnant women who were matched for age, weight, and glycemic control, but they were not exposed to an oral hypoglycemic agent, were compared retrospectively. RESULTS: 1) Three out of the eight neonates (38%) in the oral hypoglycemic agent group had congenital malformations and stillbirth compared with five out of twenty (25%) in the control group (Odds ratio 1.8; range: 0.2~13.8, P >0.05). 2) In the control group, the mean HbA1c of the 5 mothers with anomalistic neonates and stillbirths was higher than that of 15 mothers with normal neonates (8.8% vs. 6.2 %, P = 0.1). The anomalies included three congenital heart diseases (1 ventricular septal defect, 2 patent ductus arteriosus) and one renal agenesis. 3) In the oral hypoglycemic agent group, the mean HbA1c of the 3 mothers with anomalistic neonates and stillbirth was higher than that of the 5 mothers with normal neonates (9.0% vs. 6.3%, P = 0.4). The anomalies included one urachal sinus and one facial palsy that have not been commonly described for diabetic embryopathy. 4) In both groups, the mean HbA1c of 8 mothers with complicated neonates and the 20 mothers with normal neonates was 8.1% and 6.8%, respectively, (P =0.09). CONCLUSION: We found no obvious indication for therapeutic abortions in patients who have accidentally been treated with an oral hypoglycemic agent during embryogenesis. On the contrary, it seems reasonable to reassure these women with respect to their risk of having a malformed baby, and then to stop treatment with an oral hypoglycemic agent and initiate insulin treatment.

Insulin Requirement for Korean Type 1 Diabetics using Continuous Insulin Infusion with Portable External Pumps.: Hye Jin Lee, Kwon Beom Kim, Kyung Ah Han, Kyung Wan Min, Eung Jin Kim; Korean Diabetes J. 2004;28(6):538-546. Published online December 1, 2004

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Abstract PDF: BACKGROUND
Insulin pumps can be extremely effective in achieving a normal or near-normal blood glucose level in type 1 diabetic patients. For designing a pump program in western countries, it has been recommended that approximately half of the daily insulin dose should given in the basal infusion, and the other half make up the meal-related bolus dose. However, peoples' diet composition is quite different among the many countries. The carbohydrate composition in the Korean diet is higher (60~65%) than that in the western diet (45~50%). Carbohydrate is much more glycemic than protein or fat. Therefore, we evaluated the basal and meal-related insulin requirements for Korean type 1 diabetics by using continuous insulin infusion with portable external pumps. METHODS: Twenty three type 1 diabetic patients were admitted for continuous subcutaneous insulin infusion (CSII), and they were given a calculated diet (60% carbohydrate, 20% protein, and 20% fat). The Basal rates were set for the blood glucose levels to remain in the target range during 12 hour fasting state. The meal related bolus dose was set to remain in the target range at the premeal state. RESULTS: The daily total insulin requirement was 99.7 +/-0.3% of prepump insulin dose, and 0.57 +/-0.21 unit per kilogram of body weight. The basal and mealrelated insulin dose among the daily total insulin requirements were 33.7 +/-8.6 and 66.3 +/-8.6%, respectively. The daily total, basal and meal-related insulin requirements were not significantly related with body weight, but the glucose disposal rate per 1unit of insulin was significantly related with body weight (r=-0.424, P <0.05). CONCLUSION: Although the daily total insulin requirement per kilogram of body weight in Korean type 1 diabetics was similar to that in western diabetics, the basal insulin requirements were less and the meal-related insulin requirements were more than that in western diabetics.

Case Reports

A Case of Failure in Insulin Pump Treatment due to Abdominal Subcutaneous Fat Atrophy and Lipohypertrophied Nodules.: Sang Youl Rhee, Suk Chon, Gwanpyo Koh, Seungjoon Oh, Jeong taek Woo, Sung Woon Kim, Jin Woo Kim, Young Seol Kim; Korean Diabetes J. 2004;28(6):547-553. Published online December 1, 2004

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Abstract PDF: The insulin pump is an effective glycemic control device those function is analogous to the physiologic regulation of insulin in vivo. When sufficient patient education and proper selection of patients is done, the insulin pump is one of the most effective treatment modalities for diabetic patients. However, various side effects and complications might occur during its application. We report here on an unusual case of diabetic ketoacidosis that was caused by acute inflammatory colitis and insulin pump malfunction. Peculiarly, the cause of pump malfunction was far removed from its mechanical problem. We concluded that the cause of the insulin pump malfunction was due to abdominal subcutaneous fat atrophy and the lipohypertrophied nodules of the patient that developed due to the prolonged usage of the insulin pump.

A Case of Severe Prolonged Hypoglycemia Caused by Combined Ramipril and Amiloride Treatment in a Nondiabetic Woman.: Min Ho Cho, Dol Mi Kim, Chul Sik Kim, Joug Suk Park, Joo Young Nam, Jin Hyuck Chang, Jina Park, Chul Woo Ahn, Bong Soo Cha, Sung Kil Lim, Kyung Rae Kim, Hyun Chul Lee; Korean Diabetes J. 2004;28(6):554-557. Published online December 1, 2004

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Abstract PDF: The relationship between angiotensin converting enzyme inhibition and hypoglycemia remains controversial. An 82-year-old, nondiabetic woman who had taken ramipril 5 mg with amiloride 5 mg for two months was admitted to the hospital because of her altered mentality. Her plasma glucose was 1.5 mmol/L and she regained her consciousness after normalization of the plasma glucose. The recurrent attacks of hypoglycemia ended when she stopped taking ramipril. Her hypoglycemia was thought to result from the combined deficiency of catecholamines and cortisol that was induced by a deficiency of angiotensin II. The glucagoninsensitivity was thought to result from a chronic elevation of bradykinin due to the ACE inhibitor, and the relative hyperinsulinemia was though to be cased by the amiloride.

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