Diabetes & Metabolism Journal

Original Articles

Complications
The Association between Pancreatic Steatosis and Diabetic Retinopathy in Type 2 Diabetes Mellitus Patients: Jee Sun Jeong, Mee Kyung Kim, Kyung Do Han, Oak Kee Hong, Ki-Hyun Baek, Ki-Ho Song, Dong Jin Chung, Jung-Min Lee, Hyuk-Sang Kwon; Diabetes Metab J. 2018;42(5):425-432. Published online August 9, 2018; DOI: https://doi.org/10.4093/dmj.2017.0107

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Background

Whether pancreatic steatosis has a local or systemic effect, like ectopic fat of other major organs, remains unknown. Data on the influence of pancreatic steatosis on microvascular complication are rare. Therefore, we investigated the relationship between pancreatic steatosis and diabetic retinopathy (DR) in patients with type 2 diabetes mellitus (T2DM).

Methods

The attenuation of three pancreatic regions (head, body, and tail) and the spleen (S) in 186 patients with T2DM was measured using non-enhanced computed tomography imaging. We used three parameters for the assessment of pancreatic steatosis (‘P’ mean: mean attenuation of three pancreatic regions; P–S: difference between ‘P’ mean and ‘S’; P/S: the ‘P’ mean to ‘S’ ratio). The presence of DR was assessed by an expert ophthalmologist using dilated fundoscopy.

Results

The average P mean was 29.02 Hounsfield units (HU), P–S was −18.20 HU, and P/S was 0.61. The three pancreatic steatosis parameters were significantly associated with the prevalence of DR in non-obese T2DM patients. In the non-obese group, the odds ratios of P mean, P–S, and P/S for the prevalence of DR, after adjustment for age, sex, and glycosylated hemoglobin level, were 2.449 (P=0.07), 2.639 (P=0.04), and 2.043 (P=0.02), respectively.

Conclusion

In this study, pancreatic steatosis was significantly associated with DR in non-obese patients with T2DM. Further studies are necessary to clarify the causal relationship between pancreatic steatosis and the development of DR.

Citations

Citations to this article as recorded by

Intra‐pancreatic fat is associated with continuous glucose monitoring metrics
Yutong Liu, Wandia Kimita, Xiatiguli Shamaitijiang, Loren Skudder‐Hill, Ivana R. Sequeira‐Bisson, Maxim S. Petrov
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Association between Intrapancreatic Fat Deposition and Lower High-Density Lipoprotein Cholesterol in Individuals with Newly Diagnosed T2DM
Jianliang Wang, Qingyun Cai, Xiaojuan Wu, Jiaxuan Wang, Xiaona Chang, Xiaoyu Ding, Jia Liu, Guang Wang, Muhittin Yurekli
International Journal of Endocrinology.2023; 2023: 1. CrossRef
The comparison of pancreatic and hepatic steatosis in healthy liver donor candidates
Bedriye Koyuncu Sokmen, Tolga Sahin, Alihan Oral, Erdem Kocak, Nagihan Inan
Scientific Reports.2021;[Epub] CrossRef
Computed Tomography-Estimated Pancreatic Steatosis is Associated with Carotid Plaque in Type 2 Diabetes Mellitus Patients: A Cross-Sectional Study from China
Pengtao Sun, Chunzhi Fan, Rengui Wang, Tongwei Chu, Xiaoli Sun, Dongxue Zhang, Xuechao Du
Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy.2021; Volume 14: 1329. CrossRef

The effects of mixed chimerism conducted by natural killer cell depletion with non myeloablation on islet allograft rejection.: Heon Seok Park, Seok Goo Cho, Chung Gyu Park, Oak Kee Hong, Ji Won Kim, Bo Ryung Kim, Kun Ho Yoon; Korean Diabetes J. 2006;30(1):54-63. Published online January 1, 2006; DOI: https://doi.org/10.4093/jkda.2006.30.1.54

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Abstract PDF: BACKGROUND
Because of the shortage of human pancreas and immunorejection, very small fraction of patients with type 1 diabetes can be treated with islet transplantation. The immune tolerance induction for overcoming the immume rejectin of trausplamted islets could be conducted by hematopoietic mixed chimerims with various invasive methods. The purpose of this study is to investigate the effect of mixed chimerims conducted by newly developed minimally invasive methods on islet allografts rejection in streptozotocin induced diabetic mice. METHODS: Recipient, Balb/c(H-2Kd) mice were injected intraperitoneally with anti- asialoGM1 antibody at one day before bone marrow transplantation. There were received total body irradiation at a dose of 500 cGy and followed by tail vein injection of the 2 x 10(7) T-cell depleted bone marrow cells from C57BL/6(H-2Kb). Mixed chimerism mice were determined by gDNA PCR of lymphocyte MHC class I gene (H-2K) on 21st day. Streptozotocin induced diabetic mixed chimera mice were received islet transplantation from bone marrow donors. Grafts, spleen and peripheral blood were obtained from the mixed chimera mice, and there were used by Immunohistochimeical staining, flow cytometric analysis and gDNA PCR on 21st day. RESULTS: The blood glucose levels of streptozotocin induced diabetic mice were normalized by transplantation of bone marrow donor islets and maintained during 30 days. After removal of first islet allografts, hyperglycemia was re-established. We could re-confirmed donor specific tolerance of transplanted islets by second transplantation of bone marrow donor islets. Normoglycemia was maintained during 21 days after second islet transplantation. Furthermore islet grafts from MHC-mismatched third party mice were immediately rejected. Flow cytometric analysis results suggest that the mixed chimerism mice were maintain during the whole study period. CONCLUSION: The mixed chimerism model conducted by newly developed and minimally invasive method effectively prevents the islet allo grafts rejection in STZ-induced mixed chimerism mice.

Characterization of Preadipocyte factor-1 (Pref-1) Expressing Pancreatic Cells.: Marie Rhee, Sun Hee Suh, Youn Joo Yang, Ji Won Kim, Sung Yoon Jeon, Oak Kee Hong, Seung Hyun Ko, Yoon Hee Choi, Bong Yun Cha, Ho Yong Son, Kun Ho Yoon; Korean Diabetes J. 2005;29(6):507-516. Published online November 1, 2005

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Abstract PDF: BACKGROUND
Preadipocyte factor-1/Delta-like 1(Pref-1/Dlk1) is a type I membrane protein that has six epidermal growth factor (EGF)-like repeats in its extracellular and a short cytoplasmic domain. It is widely expressed in embryonic tissues, whereas its expressions were limited in adult and postnatal stage. To characterize the Pref-1 expressing cells during pancreas development and regeneration after birth, we analyzed Pref-1 expression in embryonic and adult partial pancreatectomized rat pancreas, and primary cultured neonatal pig pancreatic cells. METHODS: Whole fetuses or pieces of rat pancreas were obtained at E20. 90% partial pancreatectomy (Px) and sham operation were done using 5 week-old Sprague-Dawley rats. Experimental animals were divided into 11 groups by time of killing after surgery; 0, 1, 3, 6 and 12 hours, 1, 2, 3, 5, 7, and 14 days. All tissues were immunostained with Pref-1 and analysed by reverse transcriptase (RT)-PCR. Porcine neonatal pancreas cell clusters (NPCCs) were prepared from neonatal pigs aged 1-2 days. Cells were harvested on day 0, 3, 4, 5, 6, and 7 after dispersion. All cells were immunostained with Pref-1 and other specific cell markers such as Pan-cytokeratin (Pan-CK), vimentin (VT) and islet hormones, and confirmed by Western blot, RT-PCR and fluorescence activated cell sorting (FACS) analysis. RESULTS: In the rat embryonic pancreas at E20, Pref-1 expression was restricted only in the small branching ductules. In adult rat pancreas, Pref-1 was not expressed at all. Whereas, Pref-1 transiently expressed in the small regenerating duct cells located in foci of regeneration in Px model, then completely disappeared at day 7. The Pref-1 mRNA measured by RT-PCR was peaked at day 3 after Px and then gradually disappeared. Pref-1 expression pattern was also reproduced in monolayer cultured NPCCs. In NPCCs, protein levels of Pref-1 were peaked at day 0 to day 4 then gradually disappeared until day 7 by western blot. Most of Pref-1 expressing cells were co-stained with cytokeratin. The proportion of Pref-1 expressing cells in dispersed NPCCs were counted and isolated by FACS at 3 days after culture were 25% and then decreased over time during 7 days culture period. CONCLUSIONS: Pref-1 expression was regained in adult pancreatic cells during regeneration in vivo and in vitro and Pref-1 might be a useful marker for the pancreatic protodifferentiated cells.

Pancreatic Stellate Cell Activation by High Glucose and Its Effect on Angiotensin II.: Seung Hyun Ko, Oak Kee Hong, Min Kyung Lee, Eun He Park, Sung Soo Lee, Yu Bai Ahn, Ki Ho Song, Bong Yun Cha, Ho Young Son, Myung Jun Kim, In Kyung Jung, Kun Ho Yoon; Korean Diabetes J. 2005;29(4):304-314. Published online July 1, 2005

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Abstract PDF: BACKGROUND
Pancreatic stellate cells (PSCs) are known to be related to pancreatic inflammation and fibrosis, and are the result of extracellular matrix(ECM) protein synthesis. Recent studies have shown that blockade of the renin-angiotensin system (RAS) attenuated pancreatic inflammation and fibrosis. However, there is little data relating to high glucose (HG) and its effects on PSCs. We investigated the effects of HG on ECM protein and angiotensin II(AT II) in PSCs. METHODS: Isolated PSCs were cultured in HG(D-glucose 5.5(LG), 27.8 mM(HG)) medium. The levels of AT II and TGF-beta were measured using radioimmunoassay, and the AT II-stained cells counted. RT-PCR for the AT II receptor subtypes and Western blot analyses for the expressions of ECM proteins, such as connective tissue growth factor(CTGF) and collagen type IV, were performed. The AT II receptor antagonist, candesartan(10micrometer), and angiotensin converting enzyme inhibitor, ramiprilat(100nM) treatedments were also used. RESULTS: The thymidine uptake of the PSCs increased 4 times in the HG culture. The AT II levels(LG vs. HG, 17.1+/-4.9 vs. 36.0+/-.2pg/mL, P<0.05) and AT II-stained PSCs (LG vs. HG, 22.5+/-2.0 vs. 39.3+/-11.0%, P<0.05) were significantly increased after 6 hrs under HG conditions. The TGF-beta concentration was also significantly higher under HG conditions(LG vs. HG, 436.3+/-69.0 vs. 1115.1+/-434.0pg/mL, P<0.05) after 72 hrs. After 72 hrs, the protein expressions of CTGF and collagen type IV under HG conditions were significantly increased and effectively attenuated by the candesartan and ramiprilat treatments. CONCLUSION: A high glucose concentration could significantly increased PSCs proliferation, which also correlated with the AT II production. Consequently, PSCs proliferation was caused by HG induced ECM protein synthesis, and was attenuated by the AT II receptor antagonist. Therefore, pancreatic inflammation and fibrosis could be aggravated by hyperglycemia, and AT II might play an important role in the pathogenesis.

Induction of Immune Tolerance by Macrochimerism: Preliminary Study for Overcome of Islet Allograft Rejection.: Oak Kee Hong, Sung Joo Kim, Chung Gyu Park, Chul Woo Chung, Hyuk Sang Kwon, Yoon Hee Choi, Bong Yun Cha, Ho Yong Son, Kun Ho Yoon; Korean Diabetes J. 2005;29(2):112-121. Published online March 1, 2005

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Abstract PDF: BACKGROUND
Recently islet transplantation(TPx) has achieved remarkable results while it is not the ultimate solution yet because of a serious shortage of human pancreases, immune rejection and recurrence of autoimmunity. Immune tolerance induction is one of the ideal way for overcome the immune rejection and recurrence of autoimmunity after islet TPx. In this study, we tested the efficacy of the mixed chimerism conducted by minimally invasive regimens on induction of immune tolerance in allogenic skin transplantation model. METHODS: Busulfan(600microgram/mouse) was administered on day -1, and 0.1 mg monoclonal antibody against CD45RB and 0.5 mg monoclonal antibody against CD154 were administered intraperitoneally on days 0, 2, 4, and 6. We gave the C57BL/6 recipients either a standard-dose(2x107 bone marrow cells/mouse; SBMT-Ig) or a high-dose(20x107 bone marrow cells/mouse; HBMT-Ig) of bone marrow from BALB/c donors. After transplantation the, C57BL/ 6 recipients received BALB/c donor skin grafting on day 0. Untreated control animals in each group, both the SBMT and HBMT mice(without busulfan) were treated with marrow cells only, and they received transplanted skin grafts from the BALB/c donor on day 0. We monitored chimerism by flow cytometry and we monitored tolerance by skin grafting. RESULTS: Chimerism was significantly increased in all the groups and it peaked on day 56 after bone marrow transplantation. On day 56, chimerism in the peripheral blood did not significantly differ between the SBMT(15.0+/-3.6%) mice and the HBMT+Ig(15.3+/-6.5%) mice. Allogenic skin transplanted on the untreated mice was invariably lost within 20 days, with a mean survival time of 10.0+/-2.5 days for the SBMT mice and 13.3+/-4.9 days for HBMT mice. The skin survival rates were significantly greater for the SBMT+Ig mice(39.0+/-36.6days) and for the HBMT+Ig mice(79.9+/-43.6 days)(HBMT+Ig vs. SBMT P=0.006: HBMT+Ig vs. SBMT+Ig P=0.0087: HBMT+Ig vs. HBMT P=0.0093). Although three of the eight(37.5%) HBMT+Ig mice showed a high skin graft survival rate >120 days, the chimerism was 3.4+/-1.3% in the peripheral blood. In the HBMT+Ig mice, chimerism was higher in the thymus(8.05+/-9.7%) than in the peripheral blood and it was significantly higher than in the thymus of the HBMT mice(0.36+/-0.5%)(P< 0.05). CONCLUSIONS: These data shows that chimerism created by minimally invasive method with high-dose bone marrow and anti-CD45RB/CD154 antibody seems promissing way for prolongation of islet allograft survival

The Effects of Dexamethasone on the Expansion and Transdifferentiation of Transplanted Porcine Neonatal Pancreas Cell Clusters into beta-cells in Normal Nude Mice.: Ji Hun Yang, Sun Hee Suh, Sung Yoon Jeon, Oak Kee Hong, Kun Ho Yoon; Korean Diabetes J. 2004;28(5):356-366. Published online October 1, 2004

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Several studies have suggested that glucocorticoid has an influence on the development and function of the -cells. Thus, we undertook this study to determine whether exposure to dexamethasone (Dx) has an influence on the expansion or transdifferentiation of transplanted porcine NPCCs. METHODS: After transplantation (Tx) of 4,000 islet equivalents (IEQs) of porcine NPCCs into normal nude mice, Dx (1mg/kg) or the control vehicle were injected daily for 10 weeks. To clarify the effects of timing and duration of the Dx, one group was treated by Dx at the first 2 weeks (n=10) and the other group was treated later 8 weeks (n=10) during the 10 weeks treatment period. Thr total graft and beta-cell masses were determined by morphometric analysis. We preformed semi-quantitative RT-PCR for evaluating the pancreas transcription factors. RESULTS: The relative volume and absolute mass of the beta-cells and the total graft were significantly decreased by 10 weeks Dx treatment. Moreover, Dx treatment at thr first 2 weeks (n=10) also significantly decreased the total graft mass and absolute mass of the beta-cells. The relative volume of the beta-cells was negatively correlated and the area of the duct cysts was positively correlated with the duration of the Dx treatment. Pancreas transcription factors including PDX1, Ngn 3, ISL1 and NKx6.1 were decreased in the graft by 2 days treatment of Dx. CONCLUSION: These results suggest that Dx treatment suppresses the expansion and transdifferentiation of transplanted pancreas precursor cells into beta-cell.

The Effects of High Glucose, Insulin and TGF-beta 1 on Proliferation and Differentiation of the Pancreatic Stellate Cells.: Oak Kee Hong, Hyuk Sang Kwon, Kyu Hyun Yeom, Marie Lee, Ji Hun Yang, Seung Hyeon Ko, Soon Jib Yoo, Hyun Sik Son, Kun Ho Yoon, Bong Yeon Cha, Kwang Woo Lee, Ho Yong Son, Sung Koo Kang; Korean Diabetes J. 2003;27(3):228-240. Published online June 1, 2003

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Abstract PDF: BACKGROUND
Although chronic pancreatitis gives rise to fibrosis of pancreatic exocrine tissue, and type 2 diabetes is accompanied by pancreatic fibrosis, the mechanisms of fibrogenesis in the pancreas have been insufficiently studied. The activated Pancreatic stellate cells (PSC) have recently been identified in human and experimental fibrotic areas from chronic panceatitis tissues. As PSC are similar in their morphology and biochemistry to hepatic stellate cells, they are suspected to play the same role in pancreatic fibrogenesis as the hepatic stellate cells in liver fibrosis. The PSC were isolated from the rat pancreata, and mediators stimulating the proliferation and differentiation identified. METHODS: The pancreatic stellate shaped cells were isolated by a minor modification to the method described by Apte et al (ref), using a Nycodenz gradient. The isolated PSCs were confirmed by phase-contrast and by the immunofluorescence of vimentin, desmin and smooth muscle a-actin (a-SMA). The level of alpha-SMA was quantified by Western blot in the PSCs in the culture, over time, and the cell proliferation was measured by 3[H]-Thymidine incorporation. The effect of the proliferation and differentiation of the PSC were assessed in relation to D-glucose (500 mg/dL), Insulin (10 IU/mL) and TGF-beta (10 ng/mL) treatment of the culture medium. RESULTS: The stellate shaped cells from the rat pancreata grew readily in the culture. Unactivated PSCs, cultured for 3 days, had an angular appearance, contained lipid droplets, manifesting positive vitamin A autofliuorescence, and stained positively for vimentin and desmin, but negatively for alpha-SMA. Within 4~8 days of primary culturing, the PSCs were activated, the sizes and numbers of the fat droplets decreased, the cells flattened, developed long cytoplasmic extensions and expressed alpha-SMA. After 3 passages, almost 100% of the cells were positive for alpha-SMA expression, indicating a myofibroblast type of differentiation in vitro. The addition of high-glucose concentrations and insulin to the activated PSCs significantly stimulated cell proliferation (194.4+/-8.3, 175.0+/-31.0 vs. control), and when the combination of high- glucose and insulin was applied, the cell proliferation was increased to an even greater extent (247.0+/-21.8 vs. control). CONCLUSIONS: Pancreata stellate cells can be isolated, and cultured in vitro, from normal SD rats. High concentrations of glucose and insulin in culture medium activated the PSC proliferation.

The Effect of Nitric Oxide on Insulin Binding and Insulin Receptor Recycling in Bovine Aortic Endothelial Cells.: Hyuk Sang Kwon, Oak Kee Hong, Hee Soo Kim, Jung Min Lee, Sung Rae Kim, Sung Dae Moon, Sang Ah Jang, Hyun Shik Son, Kun Ho Yoon, Moo Il Kang, Bong Yun Cha, Kwang Woo Lee, Ho Young Son, Sung Koo Kang; Korean Diabetes J. 2003;27(3):213-227. Published online June 1, 2003

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The coexistence of insulin resistance and endothelial dysfunction is commonly observed in a variety of metabolic and cardiovascular disorders, including athero-sclerosis and type 2 diabetes mellitus. Because nitric oxide (NO), or nitric oxide synthase (NOS), has been suggested as a significant contributing factor in the development of endothelial dysfunction and insulin resistance, reactive NO or NOS were investigated to see if they contribute to the insulin internalization pathway. METHODS: The production of NO (Nitrite), the expression of eNOS (endothelial NOS), insulin binding and the insulin receptor internalization and recycling, following 48 hours of incubation with bradykinin (BK), acetylcholine (Ach), NG-monomethyl- L-arginine (L-NMMA) and N-nitro-L-arginine methylester (L-NAME) in Bovine aortic endothelial cells (BAECs), were examined. RESULTS: The results were as follows: 1. In relation to the time course, the production of eNOS was increased, but was decreased after 8 hours of incubation. The production of eNOS in the L-NMMA and L-NAME treated groups was significantly decreased compared with that of the controls (p<0.05). 2. The specific insulin bindings to the receptors of the endothelial cells were maximized within 20 mins, and then decreased. At 20 mins, the binding rate of the L-NMMA treated group was significantly decreased compared to that of the controls. At a concentration of 0.4ng/ml of unlabelled insulin, the specific insulin binding of the L-NMMA treated group was significantly decreased compared to that of the controls (p<0.05). 3. The internalization of 125I-insulin into the endothelial cells, as assessed by the acid washing dissociation method, occurred rapidly. The internalized radioactivity of 125I-insulin, at 20 mins, was significantly increased in the BK and Ach groups compared with the controls (p<0.05). 4. The recycling of the internalized insulin receptors showed no significant differences between the study groups, but the recycling was slightly delayed compared with controls in the Ach group. CONCLUSION: In conclusion, the NO generating substances, BK and Ach, and the inhibitory substance, L-NMMA, may influence the binding and internalization of insulin-insulin receptors. Our results suggest that NO might contribute to the transcytosis of insulin in BAECs

Changes in the Amount and Function of Gi Protein in the Liver Cells of Streptozotocin-Induced Diabetic Rats.: Sun Myeong Ock, Hyun Shik Son, Oak Kee Hong, Jung Min Lee, Sung Rae Kim, Sang Ah Chang, Kun Ho Yoon, Moo Il Kang, Bong Yun Cha, Kwang Woo Lee, Ho Young Son, Sung Koo Kang; Korean Diabetes J. 2000;24(6):666-677. Published online January 1, 2001

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Abstract PDF: BACKGROUND
The functional and expressional changes of Gi proteins in diabetes have been investigated extensively, no agreement has been reached in the results. Moreover, studies using rats with different diabetic duration, and using subunits (Gialpha) of Gi proteins are lacking in literatures. Thus, we assessed the changes according to the duration of diabetes and examined the expressional changes of Gialphaand functional changes of Gi proteins in hepatocytes from streptozotocin-induced diabetic rats. METHODS: Male Sprague-Dawley rats were injected with streptozotocin to induce diabetes ; 1, 2, 3 and 5 weeks after the onset of diabetes, livers from the control and diabetic rats were fractionated into homogenate, interface, and plasma membrane. The levels of Gialpha1&2, Gialpha3 were quantified with western blots in each fraction. The functional changes of Gi proteins were evaluated by performing pertussis toxin-catalyzed ADP-ribosylation and measuring GTP S binding activity. RESULTS: 1) Gialpha2 and Gialpha3 were present mainly in the plasma membrane of hepatocytes in the diabetic and control rats, but the levels of these subunits were significantly higher in the diabetic rates than in the control rats (p<0.01). The levels of these subunits were not affected by the duration of diabetes. 2) In streptozotocin-induced diabetic rats, the levels of ADP-ribosylation of Gi proteins in liver plasma membranes decreased when pertussis toxin-catalyzed ADP-ribosylation was performed with liver tissues. However, the levels of these proteins were not affected by the duration of diabetes. 3) For the GTP S binding activity of Gi proteins in liver plasma membranes, the diabetic rats showed significantly less activity than the control rats (p<0.01). However, the activity was not affected by the duration of diabetes. The activity was somewhat restored by the insulin treatment of liver plasma membranes in diabetic rats. CONCLUSION: These results suggest that the insulin-deficient diabetic state induces the quantitative and functional changes in Gi proteins of hepatocytes regardless of the duration of diabetes. Therefore, these changes in Gi proteins may be the important compensatory reactions for the insulin resistance occurring in the insulin deficient state.

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