Diabetes & Metabolism Journal

Volume 22(2); June 1998

Original Articles

Skeletal Muscle Glycogen Synthase in the Pathogenesis of Insulin Resistance.: Sung Woo Park; Korean Diabetes J. 1998;22(2):117-126. Published online January 1, 2001

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The Role of NO in Endothelial Cell Function and Insulin Action.: Sung Woo Ha; Korean Diabetes J. 1998;22(2):127-130. Published online January 1, 2001

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Autoantibodies and Polymorphism of the TNF gene in Autoimmune Diabetes Mellitus.: Myung Shik Lee; Korean Diabetes J. 1998;22(2):131-134. Published online January 1, 2001

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Measurement of Anti-38kD Antibody in Korean patients with Insulin-Dependent Diabetes Mellitus by Western Blot Analysis.: Sun Ja Kwon, Hong Kyu Lee, Hyeon Kyu Kim; Korean Diabetes J. 1998;22(2):135-144. Published online January 1, 2001

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Abstract PDF: BACKGROUND
Insulin-dependent diabetes mellitus (IDDM) is characterized by the destruction of pancreatic b-cells, which is associated with the genetic susceptibility and the production of antibodies to a numter of islet cell antigens(ICA). A possible target antigen, 38kD antigen, was suggested by the proliferation of CD4 T cells frorn a newly diagnosed patient in response to a 38kD polypeptide of the insulin-secretory-granule membrane. Autoantibody to a rat islet cell -protein of 38kD was detectable in the sera of diabetes-prone biobreeding rats by both immunoprecipitation and differential Westem blot analysis. Anti-38kD antibodies were also found to have a 76% sensitivity at the time of diagnosis in diabetic children by immunoprecipitation. In the Asian populations, it has been reported that clinical and immunologic characteristics of IDDM are quite different from those of Caucasians, say low prevalence of ICA. In Korean, there has never been reported the presence of the anti-38kD antibody. Moreover, the time-consuming and laborious nature of assay, such as T-cell proliferation and immuno-precipitation, makes it difficult to use for large population screenings. In the present study, we aimed to evaluate the prevalence of anti-38kD antibody as a immunologic marker in Korean IDDM patients by Western blot analysis. METHODS: Anti-38kD antibody was detected by Western blot analysis using the lysate of rat insulinoma cell line(RINmSF) as an antigenic source. ICA was determined by enzymatic immunohistochemical analysis. The prevalence of anti-38kD antibody and ICA was measured in 38 cases of IDDM, whose mean age at diagnosis and mean duration of IDDM were 25.2+14.2 years and 0.66+0.97 years, respectively. RESULTS: Using Western blot analysis with the lysate fraction of RIN cell, the prevalence of anti-38kD autoantibody(21.1%) in the IDDM paients was significantly higher than that in the control subjects(0.0%, P<0.05). Clinical characteristics between anti-38kD antibody-positive and -negative IDDM patients were not different. In immunohisto-chemical staining, ICA was detected in 18.2% of the IDDM patients, but not in the control subjects. The prevalence of anti-38kD antibody was 21.7%, 28.6% and 12.5% in the patients of less 1 year, 1 year and 2~4 years, respectively, showing no statistically significant difference in the prevalence according to the duration of IDDM. As previously reported, however, the prevalence of ICA decreased with increasing duration of IDDM. CONCLUSION: These results suggested that the anti-38kD autoantibody is a candidate of autoantibodies for the immunologic markers of Korean IDDM We expect the development of the more methods for the detection of anti-38kD in the future.

Analysis of the Persistence of Islet Cell Cytoplasmic Antibodies and Glutamic Acid Decarboxylase ( GAD ) 65 Antibodies in Type 1 Diabetic Children.: Hyoung Woo Lee, Kyu Chang Won; Korean Diabetes J. 1998;22(2):145-154. Published online January 1, 2001

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Abstract PDF: BACKGROUND
Type 1 diabetes mellitus is attributable to progressive autoimmune destruction of insulin-producing pancreatic islet cells, which result in absolute deficiency of insulin. Serum antibodies against islet antigens in patients with type 1 diabetes mellitus have been recognized. These include insulin autoantibodies, islet cell cytoplasmic antibodies(ICA) and glutamic acid decarboxylase(GAD) antibodies. Although, indirect immunofluorescence assay for measuring ICA have been studied as a marker for the loss of beta cell function and for monitoring the effects of immunosuppressive treatment at onset of type 1 diabetes mellitus, problem with reproducibility and standardization between laboratories still exist. Further, because the classic assays of glutamic acid decarboxylase(GAD) are still rather time-cansuming, a more simple and reproducible radioligand assay is widely used currently. Thus, this study was performed to evaluate the prevalence of cytoplasmic islet cell antibodies and glutamic acid decarboxylase antibodies in Korean patients with type 1 diabetes mellitus and to observe the associations of glutamic acid decarboxylase antibodies with islet cell cytoplasmic antibodies. METHODS: Patients with type 1 diabetes(n=26) and control(n=20) sera were used to develop quantitative antibody assays with in vitro synthesized recombinant S-methionine-labelled GAD, and protein A-sepharose to separate free from antibody-bound ligand. Also the sera were screened for conventional ICA-IgG by means of indirect immunotluorescence on section of blood group 0 human pancreas. Then, Positive sample were titered by doubling dilution. RESULTS: The overall prevalences of islet cell cytoplasmic antibodies and glutamic acid decarboxylase (GAD) antibodies in Korean patients with type 1 diabetes mellitus were 46%(12 of 26) and 39%(10 of 26) respectively. In a subset of these patients with recent onset type 1 diabetes mellitus(<1 year), the prevalence of islet cell cytoplasmic antibodies(ICA) and glutamic acid decarboxylase (GAD) antibodies were all 75%(3 of 4). The prevelances of islet cell cytoplasmic antibodies(ICA) and glutamic acid decarboxylase(GAD) antibodies were dereased in patients with long standing diabetes at 41%(9 of 22) and 32%(7 of 22) respectively. The frequency of glutamic acid decarboxylase(GAD) antibodies increased as the JDF units of islet cell cytoplasmic antibodies(ICA) increased. The frequency of islet cell cytoplasmic antibodies(ICA) increased as the GAD index increased. CONCLUSION: These results suggest that islet cell cytoplasmic antibodies(ICA) test by standard indirect immunofluorescence technique and glutamic acid decarboxylase(GAD) antibodies test by radioligand binding assay is useful for screening and diagnosis of Korean patient with type 1 diabetic children, But, long-term prospective studies on large cohorts of patients should be done to evaluate the predictive power and the prevalence of islet cell cytoplasmic antibodies and glutamic acid decarboxylase antibodies in Korean patients with type 1 diabetic children.

NcoI Restriction Fragment Length Polymorphism(RFLP) on the TNF-beta gene in Korean Patients with Type 1(insulin-dependent) Diabetes Mellitus.: Suk Kyeong Kim, Chan Soo Shin, Kyong Soo Park, Seong Yeon Kim, Hong Kyu Lee, Hun Ki Min, Tae Gun O; Korean Diabetes J. 1998;22(2):155-163. Published online January 1, 2001

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Abstract PDF: BACKGROUND
To investigate whether a TNF-g gene polymorphism is associated with the development of insulin-dependent diabetes mellitus, we analyzed the TNF-g gene polymorphism with restriction enzyme Ncol in 38 Korean patients with insulin -dependent diabetes mellitus(IDDM) and in 150 healthy controls. METHODS: Genomic DNA was extracted from white blood cells, and amplified by polymerase chain reaction(PCR) on 735 base pairs fragment of TNF-g gene with NcoI polymorpnic site. 735 bp PCR product was digested with NcoI restriction endonuclease, then analyzed by agarose gel electrophoresis to detect the NcoI restriction fragment length polymorphism(RFLP). The TNF-g alleles were divided into two types according to the electrophoresis patterns. TNF-b*1 allele, which contains the Ncol restriction site(CCATGG), should be digested 539 bp and 196 bp fragments. On the other hand, TNF-g*2 allele, which lacks the restriction site, only showed 735 bp fragment. RESULTS: Six out of 38(15.8%) IDDM patients were homozygous for the TNF-b*1 allele, 11(28.9%) were homozygous for the TNF-b*2 alleie, and 21 (55.3%) were TNF-b*1/*2 heterozygous compared to 21.7%, 30.7% and 49.3%(p=0.83), respectively, in control subjects. CONCLUSION: The TNF-b gene polymorphism was not associated with insulin-dependent diabetes mellitus in Korean subjects.

Effect of Troglitazone on Glucose Transport in Human Skeletal Muscle Cell Cultures from Obese Non-diabetic and Obese Non-insulin Dependent Diabetes Mellitus.: Theodore Ciaraldi, Robert R Henry, Kyong Soo Park, Hong Kyu Lee; Korean Diabetes J. 1998;22(2):164-172. Published online January 1, 2001

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Abstract PDF: BACKGROUND
Skeletal muscle is the principal tissue of insulin resistance in obese non-diabetic and non-insulin dependent diabetic(NIDDM) subjects. Troglitazone(Tgz), a member of thiazolidinedione class of compounds, has been shown to improve glucose tolerance in insulin resistant state. At the celluar level, troglitazone has been shown to improve insulin action in skeletal muscle, liver and adipose tissue. However, there has been little knowledge about the mechanism of this drug in human skeletal muscle from insulin resistant subjects. METHODS: To determine the effect of troglitzone on glucose transport(GT) in skeletal muscle of obese non-diabetic and obese NIDDM patients, muscle cultures from 7 obese nondiabetic and 8 obese NlDDM subjects were grown for 4 weeks and then fused for 4 days either with or without Tgz (05ug/mL). At the end of fusion, GT activity was measured and cells were harvested for the measurement of glucose transporter protein expression. RESULTS: Tgz treatment(4 days) increased GT activity dose-dependently in skeletal muscle cell culture of both obese non-diabetic and obese NIDDM subjects. 5ug/mL troglitazone increased basal GT by 2.3 +0.3 fold in obese non-diabetic and 5.7+1.3 fold in obese NIDDM subjects (p <0.05, respectively) Absolute rate of insulin-stimulated GT was significantly increased following Tgz treatment with no enhancement of the incremental response above basal value in either group. Total memhrane GLUTl protein increased 1.7+0.3 fold(p<0.05) following troglitazone treatment(5ug/mL) in NIDDM but were unchhanged in obese non-diabetic cells. GLUT4 protein levels were not affected by Tgz treatment in either group. CONCLUSION: Troglitazone increased both basal and insulin-stimulated GT activity without enhancing the incremental insulin response above basal value in muscle cultures from insulin resistant subjects. These results indicate that troglitazone is not an insulin sensitizer in muscle cultures but acts primarily by mimicking insulin's ability to stimulate basal glucose metabolism in the insulin resistant state of obesity and NlDDM

Association Between QTc Dispersion and Cardiovascular Autonomic Dysfuction in Non-insulin Dependent Dabetes Mellitus.: Jung Guk Kim, Hun Sik Park, Jick Hwa Nam, Byoung Ho Sin, Seong Mo Koo, Sung Woo Ha, Bo Wan Kim; Korean Diabetes J. 1998;22(2):173-181. Published online January 1, 2001

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Diabetic patients with autonomic dysfunction have worse prognosis, including an increased incidence, of sudden death, than those without autonomic dysfunction. This event may be due to sympathetic imbalance causing disturbances of ventricular repolarization. QT dispersion have recently been demonstrated to reflect dispersion of ventricular refractoriness and is a marker of arrhythmogenic potential. METHODS: Sixty diabetic patients and 31 normal subjects were studied. All patients had clinical test for cardiovascular autonomic dysfunction by Ewings method and defined as normal, early involved, definitely involved, severely involved and atypical group for 5 validated tests. Resting standard 12-lead electrocardiograms were recorded for measurement of QT dispersion, defined as the difference of longest QT interval and shortest QT interval, and corrected for heart rate using Bazetts formula. RESULTS: Twenty-seven dIiabetic patient were abnormal in cardiovascular autonomic function tests. In these patients corrected QT dispersion (QTc) were significantly longer compared to that 33 patients without autonomic dysfunction(47.4+14.7 vs 22.6+ 8.1msec p<0.001). And also there was significant difference of QTc dispersion between normal subject and diabetic patients with autonomic neuropathy group(20.5+9.2 vs 47.4+14.7msec p<0.001). But there was no difference between normal control and diabetic patients without autonomic neuropathy group. And QTc dispersion was not related to the presence ot nephropathy, retinopathy or peripheral polyneuropathy. We also found that there was no relationship between the severity of autonomic neuropathy and degree of Q7c dispersion. CONCLUSION: We concluded that QTc dispersion may be a good method for evaluation of cardiovascular autonomic neuropathy and increased QTc dispersion may be one of the markers of arrhythmia in diabetic patients with autonomic neuropathy.

The Correlations between DHEA, DHEA-S and Insulin Resistance Parameters in Korean.: Ie Byung Park, Dong Seop Choi; Korean Diabetes J. 1998;22(2):182-191. Published online January 1, 2001

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Abstract PDF: BACKGROUND
DHEA-S(dehydroepiandrosterone-sulfate) is the most abundantly produced adrenal steroid, but its physiological role has not been established yet. Increasing evidence suggests that insulin may act to lower serum DHEA-S levels in human. Some epidemiological studies report that serum DHEA, DHEA-S levels are reduced in pathological states characterized by insulin resistance and hyperinsulinemia such as obesity, hypertension, and untreated type 2 diabetes mellitus. This study was undertaken to investigate the relationship between DHEA, DHEA-S and insulin resistance parameters, such as BMI, blood pressure, fasting blood glucose (FBG), basal insulin level and lipid profile in Korean subjects. METHODS: The subjects were 369 Koreans(223 men, 146 women, age range: 15~75 year old) who visited the Anam Hospital for health check-up. In the morning, height, weight and blood pressure were measured and blood samples were collected for determinations of FBG, insulin, lipid profile, DHEA-S and DHEA. RESULTS: There was an inverse correlation between advancing age and serum DHEA, DHEA-S concentrations in all subjects. Although there was no significant correlation between advancing age and basal insulin levels or G/1(glucose/insulin) ratio, there were significant correlations between advancing age and insulin resistance parameters, such as BMI, diastolic BP, systolic BP, total cholesterol, triglyceride, LDL-cholesterol and FBG. In men under 50 years, DHEA was positively correlated with total cholesteral and HDL-cholesterol and negatively correlated with basal insulin level(p<0.05) and G/I ratio(p<0.001), But, in men over 50 years and in women, the correlation between DHEA, DHEA-S and other parameters was not observed. CONCLUSION: No consistent associations of DHEA, DHEA-S with various parameters of insulin resistance were observed in Koreans. However, in men under 50 years of age, DHEA and DHEA-S were associated with parameters of insulin resistance syndrome, suggesting that DHEA and DHEA-S may be related with insulin resistance only in this group.

Changes in Serum True Insulin and C-peptide Levels during Oral Glucose Tolerance Test in Koreans with Glucose Intolerance.: Young Il Kim, Chul Soo Choi, Sang Wook Kim, Hong Kyu Kim, Chul Hee Kim, Joong Yeol Park, Sung Kwan Hong, Ki Up Lee; Korean Diabetes J. 1998;22(2):192-198. Published online January 1, 2001

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Abstract PDF: BACKGROUND
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.

Short Insulin Tolerance Test(SITT) for the Determination of in vivo Insulin Sensitivity-A Comparison with Euglycemic Clamp Test.: Seok Won Park, Yong Seok Yun, Churl Woo Ahn, Jae Hyun Nam, Suk Ho Kwon, Min Kyung Song, Seol Hye Han, Bong Soo Cha, Young Duk Son, Hyun Chul Lee, Kap Bum Huh; Korean Diabetes J. 1998;22(2):199-208. Published online January 1, 2001

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Abstract PDF: BACKGROUND
The euglycemic hyperinsulinemic clamp technique is currently regarded as gold standard for measuring insulin sensitivity, but it requires sophisticated equipment and highly trained personnel. We investigated the reliability of short insulin tolerance test as a simple tesl to measure in vivo insulin sensitivity. METHODS: Short insulin tolerance test(SITT) and euglyeemic hyperinsulinemic clamp test were performed at random order in 14 healthy subjects and 10 abnormal glucose tolerant subjects. The plasma glucose disappearance rate(kitt: %/min) after iv injection of regular insulin(0.1U/kg) was determinecl and compared to insulin sensitivitv indices(M, M/I) of euglycemic hyperinsulinemic clamp test. RESULTS: The mean Kitt value of healthy subjects was 3.50+0.75%/min and that of subjects with abnormal glucose tolerance was 2.56+0.56%/min. Changing sampling time from 15 min to 18~21 min and sampling interval from 3 min to 1.5 min had no influence on Kitt value. Kitt values were reproducible in six subjects, with a CV of 8.8+2.0%. There was a highly significant correlations between the Kitt value derived from SITT and M or M/I derived from euglycemic hyperinsulinemic clamp test. There were no significant adverse effects including hypoglycemic symptom while performing SITT. CONCLUSION: SITT is simple, safe, rapid to perform, and provides reliable index of in vivo insulin sensitivity. It seems particularly suitable for studies involving large series of subjects or including repeated evaluation of insulin sensitivity.

Comparison of the New Diagnostic Criteria for Diabetes Mellitus Recommended by the Expert Committee of the American Diabetes Association with the Criteria by the NDDG or WHO in Koreans with Fasting Plasma Glucose between 110 and 139 mg / dL.: Yeo Joo Kim, Moon Suk Nam, Mi Rim Kim, Yong Seong Kim, Kwan Woo Lee, Hyeon Man Kim, Choon Hee Chung, Su Youn Nam, Bong Soo Cha, Kyung Rae Kim, Hyun Chul Lee, Sam Kweon, Yong Wook Cho, Kap Bum Huh; Korean Diabetes J. 1998;22(2):209-217. Published online January 1, 2001

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Abstract PDF: BACKGROUND
The current diagnostic criteria for diabetes mellitus announced by National Diabetes Data Group(NDDG) in 1979 were revised by Expert Committee of World Health Organization(WHO) in both 1980 and 1985. However, according to advancement in the knowledge of the etiology and pathogenesis of diabetes mellitus, the International Expert Committee working under the sponsorship of the American Diabetes Association(ADA) decided to adopt the resolution proposing that the criteria of fasting glucose level applied to diagnosis of diabetes mellitus should be lowered at the 57 ADA conference held in Boston, USA in June 1997(97 ADA). Hereupon, by comparing the diagnostic criteria of the former (NDDG/WHO) with the later, the authors have examined the usefulness of new diaignostic criteria, 97 ADA. METHOD: We collected the data from 13 university hospitals in Korea which contain the results of 75 gram oral glucose tolerance test(OGTT) for 532 Kareans between 110 and 139 mg/dL in fasting plasma glucose. We have then evaluated the results by classifying and comparing them in accordance with the criteria of NDDG/WHO and 97 ADA, respectively. RESULTS: 1. The number which tested for oral glucose tolerance was 532 and the majority of tests have been carried out between 110 and 119 mg/dL in fasting plasma glucose. 2. When we have classified the same results of OGTT by respective diagnostic criteria of NDDG/ WHO and 97 ADA, the NDDG/WHO have diagnosed 50.4%(268/532) of the total number of people as diabetes mellitus, while the '97 ADA has shown that only 33.1%(176/532) of it corresponded to the same diagnosis. On the other hand, the diagnosis rate of impaired fasting glucose(IFG) or impaired glucose tolerance(IGT) has shown 28.8~ 31.8%(NDDG/ WHO) and 66.9%(97 ADA), respectively. 3. Following the diagnostic criteria of the 97 ADA, we have separated the results into two groups which were above and below 126 mg/dL in fasting glucose. In addition, when we have again classified two groups by the criteria of the NDDG/WHO, the group above 126mg/dL in fasting glucose, which was all diagnosed as diabetes mellitus in 97 ADA has represented a ratio of 72.2%(127/176) in same diagnosis. However, within the group below 126mg/ dL, in fasting glucose being classitied as IFG in the 97 ADA, its diagnosis rate of diabetes mellitus has also shown 39.7%(141/356) applying to the criteria of the NDDG/WHO. CONCLUSION: The criteria of the 97 ADA can simply make a diagnosis of diabetes mellitus with fasting plasma glucose and additionally fmd out the IFG whose rate is 17.9 20% regarded as a normal condition by NDDG/WHO, whereas the existing criteria of the NDDG/WHO have to carry out the OGTT which is difficult in clinics. However, since among the patients ot 50.4% diagnosed as diabetes mellitus by NDDG/WHO, the 97 ADA classifies 17.3% of them as IFG, it is regarded that the need of OGTT for the diagnosis of diabetes mellitus can not be passed over in the future.

Differential Activation of the Renal Renin-Angiotensin System Components in Diabetic Rats.: Woon Jung Kim, Mi Young Lee, Tae Hyung Kim, Eun Kyoung Yang, Won Jung Lee; Korean Diabetes J. 1998;22(2):218-230. Published online January 1, 2001

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Abstract PDF: BACKGROUND
The renin-angiotensin system(RAS) plays an important role in the physiologic regulation of the renal microcirculation and may contribute to the imbalance of resistances present at the preglomerular and postglomerular sites whirh are responsible for glomerular capillary hypertension, a major injurious factor in the diabetic kidney. Blockade of angiotensin(Ang II) with angiotensin converting enzyme(ACE) inhibitor or Ang II receptor antagonists reduces glomerular injury. However, the relationship between diabetes and the RAS is unclear. METHOD: To investigate changes of gene expression of the renal renin-angiotensin system in diabetic nephropathy, mRNA levels of the RAS components were determined with the methods of Northern blot and RT-PCR in streptozotocin-induced diabetic(STZ-D) rats. Sprague-Dawley rats(240~260 g) were made diabetic by double i.p. injections of 45 mg/kg STZ. Result: Plasma renin concentration increased significantly at the onset of diabetes, and then suppressed at 4 and 8 week sof diabetes. Changes in renal renin content and mRNA levels were in parallel with plasma renin concentration during 8 weeks of diabetes. Renal angiotensinogen mRNA levels of the STZ-D rats decreased initially and then returned to the baseline with the progression of diabetes. Gene expression of angiotensin II-AT1 receptor subtypes, AT1a and AT1b, was not significantly changed during 8 wk of diabetes. Plasma and renal ACE activity increased significantly at 4 and 8 wk of diabetes. CONCLUSION: Results of the present study show a marked decrease in renal renin mRNA levels and renin concentration, but significant increase in ACE activity in chronic diabetic rats. When considering renoprotective effect of ACE inhibitors and AT receptor antagonists, the present result may suggest an increased intrarenal generation of Ang II and its pathophysiologic role in diabetic nephropathy. However, further studies are required to clarify meanings of the differential activation of the renal renin-angiotensin system components in diabetic rats.

Effect of Exercise Training on Insulin Sensitivity and Intracellular Glucose Metabolism in Skeletal Muscle of High Fat-fed Rats.: Chul Hee Kim, Joong Yeol Park, Sung Kwan Hong, Kyong Soo Park, Hong Kyu Lee, Ki Up Lee; Korean Diabetes J. 1998;22(2):231-242. Published online January 1, 2001

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Abstract PDF: BACKGROUND
Insulin resistance is a major characteristic of non-insulin-dependent diabetes mellitus and obesity. Many studies have indicated that increased intake of fat are associated with obesity and insulin resistance. On the other hand, chronic exercise is known to improve insulin sensitivity. However, the mechanisms by which high fat diet induces insulin resistance and exercise trainmg improves insulin sensitivity are not established. This study was undertaken to examine the mechanisms by which high fat diet and exercise training affect the insulin sensitivity in the whole body and in skeletal muscles. METHODS: Male Sprague-Dawley rats were divided into three groups: high fat sedentary group, high fat exercise group, and control(low fat sedentary) group. High fat diet consists of 66.5% fat and 12.5% carbohydrate, and control(low fat) diet consists of 12 5% fat and 66.5% carbohydrate. Exercise training was performed by swimming three hours per day. After 3 weeks, animals underwent hyperinsulinemic euglycemic clamp study to measure whole body glucose metabolic fluxes. Glycogen synthase activity and glucose-6-phosphate (G-6-P) levels were measured in skeletal muscle at the end of the clamp study. RESULTS: In the high fat diet group, whole body glycolysis and glycogen synthesis were decreased. Exercise training reversed the insulin resistance induced by high fat diet by increasing both glycolysis and glycogen synthesis. Glycogen synthase activity in skeletal muscle was reduced in high fat diet group, and it was partially reversed by exercise training. G-6-P level in skeletal muscle was increased in high fat diet group, and it was further increased by exercise training. CONCLUSION: These results suggested that the insulin resistance in high fat diet-fed rats is due to the impairment in glucose metabolism at sites distal to G-6-P, i.e. glycolysis and glycogen synthesis. In contrast, the improvement in insulin sensitivity by exercise training in high fat-fed rats is primarily due to the increased glucose metabolic flux proximal to G-6-P, i.e. glucose transport and phosphorylation.

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