- The Role of Hypothalamic FoxO1 on Hyperphagia in Streptozotocin-Induced Diabetic Mice.
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Il Seong Nam-Goong, Jae Geun Kim, Se Jin Kim, Seong Jae Hur, Jin Woo Lee, Eun Sook Kim, Chang Ho Yun, Byung Ju Lee, Young Il Kim
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Korean Diabetes J. 2009;33(5):375-381. Published online October 1, 2009
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DOI: https://doi.org/10.4093/kdj.2009.33.5.375
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- BACKGROUND
Streptozotocin-induced diabetic animals are characterized by hyperphagia due to deficiencies of insulin and leptin. Forkhead box-containing protein of the O subfamily-1 (FoxO1) regulates energy homeostasis by regulating energy expenditure and food intake as well as mediating insulin and leptin signals in the hypothalamus. To identify the mediator of diabetic hyperphagia, we examined the effects of insulin or leptin on hypothalamic FoxO1 expression in a diabetic animal model. METHODS: Diabetes was induced in mice (C57BL/6) by intraperitoneal administration of streptozotocin (200 mg/kg). Stainless steel cannula was implanted into the lateral ventricle of the brain in each mouse. After three weeks, the mice were administered saline, insulin or leptin via intracerebroventricular (ICV) route. The medial hypothalamus was isolated to evaluate the mRNA expressions of FoxO1 and neuropeptides. RESULTS: Streptozotocin-induced diabetic mice exhibited significant elevations of blood glucose and food intake and significantly low levels of serum insulin and leptin. The levels of hypothalamic FoxO1 mRNA were significantly increased in diabetic mice. The hypothalamic expression of neuropeptide Y (NPY) mRNA was increased, but the expression of preproopiomelanocortin (POMC) mRNA was decreased in diabetic mice. ICV administration of insulin or leptin attenuated the upregulation of hypothalamic FoxO1 mRNA, and resulted in downregulation of NPY mRNA and upregulation of POMC mRNA in diabetic mice. CONCLUSION: We observed that the expression of hypothalamic FoxO1 mRNA was increased in streptozotocin-induced diabetic mice, and that it was significantly attenuated by central administration of insulin or leptin. These results suggest that hypothalamic FoxO1 is the direct mediator of diabetic hyperphagia.
- Clustering of Risk Variables in Insulin Resistance Syndrome in Jungup District, Korea.
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Sang Wook Kim, Myung Hoe Huh, Young Il Kim, Jin Yub Kim, Eun Sook Kim, Moo Song Lee, Joong Yeol Park, Sung Kwan Hong, Ki Up Lee
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Korean Diabetes J. 1999;23(6):843-856. Published online January 1, 2001
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Insulin resistance syndrome (IRS), a clustering of hypertension, impaired glucose tolerance, low HDL cholesterol and high triglyceride, is prevalent in Korea. We studied the correlational structure of IRS using factor analysis to evaluate whether a single process underlies in the clustering of these risk factors. METHODS: Factor analysis was performed using data from 1,018 non-diabetic subjects (388 men and 630 women) who participated in the Jungup epidemiological study. RESULTS: Factor analysis reduced 9 correlated risk factors to 4 independent factors, each reflecting a different aspect of IRS: hypertension factor (increased systolic and diastolic blood pressure), glucose intolerance factor (increased fasting and postload glucose), obesity factor (increased body mass index, waist circumference, and increased insulin), and dyslipidemia factor (increased trigly- cerides and decreased HDL cholesterol). Increased insulin was also loaded into dyslipidemia factor in men and glucose intolerance factor in women. These factors explained about 70% of the total variance in the data. Three factors such as the glucose intolerance factor, the dyslipidemia factor and the obesity factor, were linked through mutual association with hyperinsulinemia, while hypertension factor was not associated with hyperin- sulinemia. Age-adjusted mean BP by BMI tertile and fasting insulin level tertile for men and women increased progressively with increase in BMI in men and women. There was no significant elevation of mean BP according to increase in fasting insulin level. In contrast to premenopausal women in whom hyperinsulinemia show mutual association with the glucose intolerance factor, the dyslipidemia factor, and the obesity factor, hyperinsulinemia was only loaded into obesity factor in postmenopausal women. CONCLUSION: These results suggested that more than one process underlies the clustering of IRS. In sulin resistance alone did not seem to be the single underlying mechanism of IRS. Especially, hypertension was not correlated with hyperin- sulinemia.
- Leptin Concentration in Diabetin and Non-diabetin Subjects in the Community Population.
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Kee Up Lee, Seong Kwan Hong, Sang Wook Kim, Young Il Kim, Yun Ey Chung, Moo Song Lee, Joong Yeoul Park, Jin Yup Kim
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Korean Diabetes J. 1999;23(4):592-600. Published online January 1, 2001
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It has been suggested that adipose tissue releases leptin, a satiety factor, which circulates in blood and acts on the hypothalamus to suppress appetite. However, serum leptin concentration in obese human subjects is higher than that in lean subjects, suggesting leptin resistance. Although there have been several studies investigating serum leptin concentrations in Korean subjects, there has been no population-based study. This study was undertaken to investigate serum leptin concentration and associated factors in diabetic and non-diabetic subjects living in a rural area of Korea. METHOD: Among 898 subjects originally included in the Jung-up epidemiologic study, 119 men and 124 women with varying degrees of glucose tolerance were randomly selected. Serum leptin concentration was measured by radioimmunoassay. RESULTS: In agreement with previous studies, women had significantly higher serum leptin concentration than men. Serum leptin concentration in Korean men and women was apparently lower than in other populations, even after adjustment for BMI. Leptin concentration was not different among the three groups of glucose tolerance (normal glucose tolerance, impaired glucose tolerance and diabetes). Serum leptin concentration was positively correlated with serum true insulin, proinsulin and BMI in non-diabetic subjects. Serum leptin concentration was also significantly related with serum proinsulin/true insulin ratio in non-diabetic women. CONCLUSION: Serum leptin concentration in Korean subjects was lower than that reported in other populations. Serum leptin concentration was associated with BMI, serum true insulin and proinsulin levels in non-diabetic subjects, but not in diabetic ubjects.
- Microalbuminuria in Diabetic and Non-diabetic Subjects: A population Based Study.
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Young Il Kim, Yun Ey Chung, Jin Yup Kim, Sang Wook Kim, Eun Sook Kim, Moo Song Lee, Joong Yeoul Park, Sung Kwan Hong, Ki Up Lee
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Korean Diabetes J. 1999;23(1):79-86. Published online January 1, 2001
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Microalbuminuria is associated with increased cardiovascular mortality in type 2 diabetic patients and non-diabetic subjects. This study was undertaken to determine the prevalence ot microalbuminuria among diabetic and non-diabetic subjects in Korea and to determine the factors associated with microalbuminuria. METHOD: A sample of 1,791 subjects aged > 40 years living in Jungup district were selected from the 28,380 inhabitants using a random cluster sampling method. Among these subjects, 1,006 of them (56.1%) underwent the 75 g oral glucose tolerance test that was also part of the timed overnight urine collection. 46 subjects were excluded because they had signs of urinary tract infection (n=41) or overt proteinuria (n=5). Microalbuminuria was defined as urinary albumin excretion rate (UAER) between 20 and 200 pg/min. RESULTS: Subjects with microalbuminuria had a higher weight and body mass index (BMI), abdominal circumference, systolic and diastolic blood pressure (BP), fasting and 2hr plasma glucose, fasting semm insulin and proinsulin concentrations than subjects without microalbuminuria. The prevalence of micro- albuminuria increased as the glucose tolerance worsened[6.0% in normal glucose tolerance, 11.8% in impaired glucose tolerance (IGT) and 21.8% in diabetes, respectively; x trend=25.9, p<0.(0001]. Mean UAER of subjects with hypertension was greater than that of subjects without hypertension (7.8+0.9ug/min vs. 9.6+0.7ug/min, p<0.001). Univariate analysis revealed that the UAER was significantly (p<0.05) correlated with weight and BMI, abdominal circumference, systolic and diastolic BP, fasting and 2hr plasma glucose, fasting serum insulin and proinsulin after sex-adjustment. Multiple regression analysis revealed that weight or BMI, diastolic BP, 2hr plasma glucose and fasting serum insulin were independently associated with UAER in non-diabetic subjects. CONCLUSION: The present study demonstrates that the prevalence of microalburninuria is higher in patients with glucose intolerance. The association of the UAER with BMI, diastolic BP, 2hr plasma glucose and fasting serum insulin suggest that microalbuminuria is a feature of the insulin resistance syndrome.
- Prevalence of Insulin Resistance Syndrome in Subjects Living in Jungup District , Korea.
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Sang Wook Kim, Jin Yub Kim, Eun Sook Kim, Young Il Kim, Moo Song Lee, Hyeong Ho Kim, Joong Yeoul Park, Sung Kwan Hong, Ki Up Lee
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Korean Diabetes J. 1999;23(1):70-78. Published online January 1, 2001
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The clustering of hypertension, impaired glucose tolerance, low HDL cholesteml and high triglyceride is known as insulin resistance syndrome (IRS). We studied the prevalence of insulin resistance syndrome among subjects living in Jungup district, Korea. METHODS: Among a total of 151,000 subjects over 40 years of years living in Jungup district, a sample of 1,791 was selected using a random cluster sampling method. Oral glucose tolerance test revealed 1,018 subjects with normal or impaired glucose tolerance. The IRS was defined as the coexistence of two or more components of triad; hypertension, impaired glucose tolerance and dyslipidemia (triglycerides >= 200mg/dL and HDL <45 mg/dL for woman, HDL < 35 mg/dL for men). RESULTS: Twenty-one percent of men and 45% of women were obese and 50.8% and 61.9% were hypertensive. Eleven percent of men and 16 percent of women were found to have dyslipidemia. The prevalence of impaired glucose tolerance was 10.2% for men and 15.7% for women. The prevalence of IRS in the Jungup population was 12.8% for men and 19.6% for women. The prevalence of IRS increased according to the plasma level of insulin. There was a positive correlation between the number of components of IRS and the level of fasting plasma insulin. CONCLUSION: We conclude that the prevalence of IRS is high in Korean subjects. The close correlation between the IRS components and fasting insulin level suggests that cardiovascular risk is associated with insulin resistance.
- Prevalence of Diabetes Mellitus and Impaired Glucose Tolerance in Korean Adults Living in Jungup District, South Korea.
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Young Il Kim, Chul Soo Choi, Sang Wook Kim, Jong Soo Lee, Hyeong Ho Kim, Moo Sung Lee, Sang Il Lee, Joong Yeoul Park, Sung Kwan Hong, Ki Up Lee
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Korean Diabetes J. 1998;22(3):363-371. Published online January 1, 2001
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Similar to other countries that underwent industrialization in recent years, the prevalence of diabetes has increased dramatically in Far East Asian countries. While the prevalence of diabetes in South Korean adults was estimated to be less than 0.5% in 1960s, a recent study from Yonchon County showed a dramatic increase to 7.2%. This was the only study performed in population-based subjects. We studied the prevalence of diabetes and impaired glucose tolerance(IGT) among subjects living in Jungup clistrict, Chonlabuk-do, South Korea. METHODS: Among a total of 28,380 subjects aged over 40 years living in Jungup district a sample of 1,791 subjects living in six villages was selected using a random cluster sampling method. Among these subjects, 1,108 subjects(61.9%) completed 75g oral glucose tolerance test(OGTT). RESULTS: When the WHO criteria were used, the prevalence of diabetes and IGT were 7.1% and 8.5%, respectively, after correction for Segi's standard world population. Among the diabetic subjects, 62% of the patients did not know that they had diabetes previously. When the 1997 ADA criteria after OGTT were employed, the prevalence of diabetes and IGT/IFG(impaired fasting glucose) was 8.5% and 11.1%, respectively. The mean body mass index(BMI) of whole subjects was 22.9+2.7 for men and 24.3+3.2kg/m for women. Among subjects with normal glucose tolerance, IGT and diabetes, 31.5%, 42.3% and 50.0% of subjects were currently obese(BMI >25kg/m), respectively. The prevalence of both diabetes and IGT increased with inereasing waist-to-hip ratio(WHR) in men and women. On the other hand, the prevalence of diabetes and glucose intolerance increased with increasing BMI only in women but not in men. CONCLUSION: The prevalence of diabetes and IGT in the present study was quite similar to that in the previous Yonchon study. This prevalence of diabetes is higher than or similar to that reported in the Caucasian(~ 3% 8%), even though mean BMI of this community population(23.9 kg/m) is lower than that in the Caucasian (24.5~28.0 kg/m). It can be speculated that Far East Asian penple are more prone to develop diabetes for their degree of obesity.
- Effects of Free Fatty Acids on Glutathione Redox Status in Cultured Endothelial Cells.
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Joong Yeol Park, Chul Hee Kim, Yun Ey Chung, Hong Kyu Kim, Young Il Kim, Sung Kwan Hong, Jae Dam Lee, Ki Up Lee
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Korean Diabetes J. 1998;22(3):262-270. Published online January 1, 2001
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Although plasma free fatty acids (FFA) are frequently elevated in diabetes mellitus, its role in the pathogenesis of diabetic vascular complications has not been well investigated. Recent stuclies reported that FFA may cause endothelial dysfunction through an enhancement of oxidative damage by decreasing glutathione redox cycle, an important anti-oxidant defense system in endothelial cells. In this study, we examined the effects of increased availability of FFA on intracellular glutathione redox cycle. METHODS: Bovine pulonary endothelial cells were exposed to 90 umol/L linoleic acid with or without 0.1 mM 2-bromopalmitate, an inhibitor of mitochondrial fatty acid oxidation, for 6hr. Components of the glutathione redox cycle such as total glutathione, reduced glutathione(GSH) and oxidized glutathione(GSSG) concentrations were measured by HPLC. RESULTS: Total glutathione concentration in cultured endothelial cells exposed to linoleic acid was significantly lower than that in control cells (10.8+ 0.5 vs 14.1+0.8 umol/g protein, P<0.05). Linoleic acid significantly decreased GSH concentrations (10.5+0.4 vs. 13.8+0.5 pmol/g protein, P<0.05) and the ratio of GSH/GSSG(26.3+1.3 vs. 47.0+2,1, P<0.05). Compared to cells exposed linoleic acid alone, total glutathione(13.5+0.5umol/g protein, P<0.05) and GSH concentration(13.2+0.4 pmol/g protein, P<0.05) significantly increased in cells treated with 2-bromopalmitate and linoleic acid. The ratio of GSH/GSSG in cells treated with 2-bromopalmitate and linoleic acid was higher th.an that in cells exposed to linoleic acid alone(44.1+1.3, P<0.05). CONCLUSION: Increased provision of FFA resulted in a derangement of glutathione redox cycle in cultured endothelial cells, which appears to be related to an increase in mitochondrial FFA oxidation. These results suggested that FFA can increase the risk of diabetic vascular complications.
- Changes in Serum True Insulin and C-peptide Levels during Oral Glucose Tolerance Test in Koreans with Glucose Intolerance.
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Young Il Kim, Chul Soo Choi, Sang Wook Kim, Hong Kyu Kim, Chul Hee Kim, Joong Yeol Park, Sung Kwan Hong, Ki Up Lee
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Korean Diabetes J. 1998;22(2):192-198. Published online January 1, 2001
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Previous studies have shown that progression from normal glucose tolerance(NGT) to impaired glucose tolerance(IGT) is associated with the development of insulin resistance and hyper-insulinemia, while further progression from IGT to NIDDM results from an inability of the 8-cell to maintain high rate of insulin secretion. However, it is not established whether similar findings are also observed in Korean subjects with glucose intolerance. The aim of this study was to examine insulin secretory response after oral glucose stimulation in obese and non-obese Korean subjects according to varying degree of glucose intolerance. METHODS: Eighty eight Korean men underwent 75g oral glucose tolerance test. The subjects were classified into NGT(n=30), IGT(n=23), NIDDM(n= 35) according to National Diabetes Data Group criteria. Obesity was defined as body mass index (BMI) > 25 kg/m . Serum true insulin and C-peptide concentrations were measured by radioimmunoassay. RESULTS: Fasting serum true insulin and C-peptide levels were not different from each other among NGT, IGT and NIDDM groups, both in obese and non-obese subjects. Obese subjects with IGT had significantly higher serum true insulin and C-peptide levels at 120 min than those in NGT subjects, but the levels at 30 and 60 min were not different. On the other hand, non-obese subjects with IGT had lower serum true insulin level at 30 min and lower serum C-pepitde level at 60 min compared to those in NGT subjects. True insulin and C-pepitde levels at 30 and 60 min were significantly lower in patients with NIDDM than in those with NGT, both in obese and non-obese subjects. CONCLUSION: Hyperinsulinemia, especially at a later phase of oral glucose tolerance test, is apparent in obese subjects with IGT. On the other hand, early phase insulin secretory defect is prominent in non-obese subjects with IGT. These results suggest that impaired insulin secretion may play a primary role in the pathogenesis of non-obese NIDDM in Korea.
- Changes of Glomerular Filtration Rate and Urinary Albumin Excretion Rate in NIDDM patients with Microalbuminuria.
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Hyo Jung Kim, Jung Min Koh, Eun Sug Shin, Yun Ey Chung, Young Il Kim, Chul Hee Kim, Joong Yeol Park, Sung Kwan Hong, Ki Up Lee
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Korean Diabetes J. 1997;21(4):414-424. Published online January 1, 2001
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We previously suggested that micro-albuminuria in the presence of retinopathy may represent a state of real incipient diabetic nephropathy with declining glomerular filtration rate(GFR), while the meaning of microalbuminuria in the absence of retinopathy may be more heterogeneous. This study was performed to further test this hypothesis. METHODS: We prospectively followed up the changes in GFR and urinary albumin excretinn rate (UAE) in microalbuminuric NIDDM patients with or without diabetic retinopathy for 3.1 years. RESULTS: 1) Among 45 patients who completed the followup, 27 had retinopathy from the baseline(group A), while 18 patients did not have retinopathy throughout the study(group B). 2) UAE at baseline was not statistically different between the group A and group B. During follow-up, VAE remained stable in the group B patients(40.0 [20.5 ~ 158.0) to 60.0[20.2 ~ 231.0] ug/min, NS). On the other hand, UAE significantly increased in the group A patients(47.9[20.0~186.0] to 140.0[24.5~2862.0] ug/min, P <0.001). 3) Thirty percent of the group A patients(8/27) progressed to overt proteinuria, while 11%(2/18) of the group B patients developed overt proteinuria(NS). 4) GFR significantly decreased both in the group A (113.0+21.2 to 89.1+24.0 mL/min/1.73 m, P < 0,001) and in the group B patients(134.1+27.2 to 121.5+27.3 mL/min/1.73 m, P<0.01). However, the magnitude of change in GFR was significantly higher in the group A than in the group B patients(7.7+7.6 vs 3.9+4.2 mL/min/1.73 m /year, P <0.05), 5) Multiple logistic regression analysis revealed that the presence of retinopathy was a independent risk factor for faster decline in GFR. CONCLUSION: It appears that clinical course is different in NIDDM patients with microalbuminuria, according to the presence or absence of diabetic retinopathy. Microalbuminuria in the presence of retinopathy predicts aggravation of albuminuria and decline in GFR. In contrast, the renal function in microalbuminuric NIDDM patients in the absence of retinopathy may remain stable for years.
- Effects of Free Fatty Acid on Insulin Secretion in Cultured Rat Pancreatic Islets.
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Hong Kyu Kim, Young Il Kim, Chul Hee Kim, Joong Yoel Park, Sung Kwan Hong, Jae Dam Lee, Ki Up Lee
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Korean Diabetes J. 1997;21(4):381-387. Published online January 1, 2001
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It has been recently suggested that enhanced fat oxidation is responsible for the abnormal insulin secretory pattern in non-insulin-dependent diabetes mellitus. This study was undertaken to assess the effect of chronic exposure of pancreatic islets to free fatty acid on insulin secretion. METHODS: Rat pancreatic islets were cultured in various concentrations of glucose(5.5, 11, 27 mM) for 48 hrs with or without addition of free fatty acid(90 upM linoleic acid), and the basal and glucose-stimulated insulin secretion were measured. The effect of fatty acid oxidation inhibitor(2-bromopalmitate) was also tested. RESULTS: Islets cultured in high glucose concentrations showed a marked increase in basal insulin secretion. Free fatty acid stimulated the basal insulin secretion in islets cultured at 5.5 or 11 mM glucose, but no additional effect was seen in islets eultured at 27 mM glucose. In contrast, glucose-stimulated insulin secretion was decreased in islets cultured in high glucose media. Exposure to free fatty acid exerted an additive inhibitory effect on glucose-induced insulin secretion in islets cultured at 5.5 or 1 1 mM glucose, but not in islets cultured at 27M glucose, An inhibitor of fatty acid oxidation, 2-bromopalmitate, prevented the fatty acid-induced changes in both basal and glucosestimulated insulin secretion. CONCLUSION: These results showed that longterm exposure of pancreatic islets to free fatty acid altered the dynamics of insulin secretion, probably through a glucosefatty acid cycle.
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