Diabetes & Metabolism Journal

Volume 24(5); October 2000

Original Articles

The Changes in Insulin Secretion and GTPase Activity after the Exposure to High Glucose in Rat Pancreatic Islets.: Young Sun Hong, Yeon Ah Sung, Nan Ho Kyung; Korean Diabetes J. 2000;24(5):515-523. Published online January 1, 2001

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Abstract: BACKGROUND
Type 2 diabetes mellitus is characterized by defective glucose- induced and glucose-potentiated insulin secretion. Chronic elevation of glucose levels are considered to be a cause of impaired insulin secretion. It has been suggested that such defects in insulin secretion can be related to the alteration in stimulus-secretion coupling. Recent studies have provided evidences for the existence of guanine nucleotide-binding protein (G protein), and the regulatory role of G protein and GTPase activity in stimulus-secretion coupling in pancreatic islets. This study was performed to determine whether the exposure to high glucose concentration alters GTPase activity with decreased insulin secretion in pancreatic islets isolated from normal rats. METHODS: Pancreatic islets isolated from normal Sprague-Dawley rats were incubated in high (20 mM) and low (5 mM) glucose concentration for 48 hours. After incubation, glucose (20 mM) induced insulin secretion was measured. Then subcellular fractions of islets by homogenization and differential centrifugation were obtained and glucose induced inhibition of GTPase activities in each fraction was measured. RESULTS: 1) After 48 hour exposure to 5 mM and 20 mM glucose, insulin secretion in response to 20 mM glucose were 134.4+/-16.8 fmol/10 islets/hr and 90.0+/-10.2 fmol/10 islets/hr, respectively. After the exposure to high glucose, glucose-induced insulin secretion significantly decreased (p<0.05). 2) In each subcellular fraction, there was no significant difference between the islets exposed to 5 mM and 20 mM glucose in the degree of inhibition of GTPase activities by high glucose. CONCLUSION: The exposure to high glucose for 48 hours decreased insulin secretion without any significant differences in the degree of inhibition of GTPase activities. This results suggest that impaired insulin secretion by high glucose is not associated with the change in GTPase activity.

Quantification of the Pancreatic -cell Mass in Normal and Type 2 Diabetic Subjects in Korea.: Kun Ho Yoon, Seung Hyun Ko, Jung Min Lee, Sung Rae Kim, Sun Hee Seo, Moo Il Kang, Bong Yun Cha, Kwang Woo Lee, Ho Young Son, Sung Koo Kang, Yong Gui Kim, In Sung Moon, Myung Deuk Lee, Dong Ku Kim, Kyo Young Lee, Chan Suk Kang, Byung Ki Kim; Korean Diabetes J. 2000;24(5):524-532. Published online January 1, 2001

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Abstract: BACKGROUND
There have been several reports about insulin secretory impairment in non-obese type 2 diabetic patients and even in impaired glucose tolerant subjects in Korea. Insulin secretory impairment might be induced by insufficient beta-cell mass, functional defects of beta-cells or both. To clarify the cause of impaired insulin secretion in type 2 non-obese diabetic patients in Korea, beta- cell masses were quantified in normal and type 2 diabetic subjects. METHOD: Normal pancreases were procured by 6 heart-beating non-diabetic donors under informed consent from relatives and approval of the university ethical committee. To quantify the beta cell mass and insulin content in various part of the pancreas, first we divided it into 3 parts: head, body and tail, and then each three parts were weighed and subdivided again into 8 segments equally. For diabetic patients, tissue sections were obtained from 15 partial or total pancreatectomized type 2 diabetic patients of any causes. After being fixed, tissues were immunostained using the Streptavidin-biotin-peroxidase method with anti-insulin antibody. Beta cells were counted by point count method. RESULTS: The mean value of total pancreas weight of normal subjects (n=6) was 77.1+/-14.6 g, that of mean relative volume of beta cells in the pancreas was 2.1+/- 0.9%, ranging from 1.4% to 3.1% (head 2.3+/-0.6%, body 1.8+/-0.2%, tail 2.2+/-0.4%). Mean value of total beta cell mass which was calculated from relative volume of beta-cells and weight of each portions was 1.3+/-0.3 g, ranging from 1.2 g to 1.9 g (head 0.6+/-0.3 g, body 0.4+/-0.2 g, tail 0.4+/-0.2 g). Mean insulin content per pancreas was 63.6+/-46.6 g, ranging from 27.8 to 137.2 g/pancreas (head 25.1+/- 19.1 g, body 20.8+/-15.5 g, tail 17.7+/-14.9 g). In diabetic patients, relative volume of beta cells in tissues were variable from 0.4% to 2.8% and there was good correlation between beta-cell mass and body mass index of the diabetic patients. However we can't find the correlation among relative volume of beta-cell, (r2=0.55, p<0.05) duration of diabetes and age. Remarkable heterogeneity for loss of beta-cells in the islets of diabetic patients was observed even in the same lobe of pancreas. There were no evidence of lymphocytic infiltration in the islets. CONCLUSION: Insufficient beta cell mass seems to be a main cause for insulin secretory impairment in non-obese type 2 diabetic patients in Korea.

Effect of Glycosaminoglycan on Proteinuria and Urinary N-acetyl- -D-Glucosaminidase Excretion in Otsuka Long-Evans Tokushima Fatty (OLETF) Rats.: Kyung Mook Choi, Dae Ryong Cha, Sang Youb Han, Dong Rim Kim, Nan Hee Kim, Sei Hyun Baik, Dong Seop Choi; Korean Diabetes J. 2000;24(5):533-540. Published online January 1, 2001

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Abstract: BACKGROUND
Increased loss of proteoglycan (PG) characterized by an increased loss of anionic charges in the basement membrane has been considered as one of main factors causing urinary loss of albumin. The glycosaminoglycans (GAGs) are linear polymers of repeated disaccharides and the GAG chains are covalently bound to core proteins, forming proteoglycans. It is known that urinary N-acetyl- -D-glucosaminidase (NAG) excretion is a sensitive marker of renal damage and is increased before other renal functional parameters. The aim of this study was to investigate whether GAG treatment is capable of influencing urinary protein and NAG excretion in Otsuka Long-Evans Tokushima Fatty (OLETF) rats which are known as type 2 diabetic animal model. METHODS: Fifteen male OLETF rats and twenty male Long-Evans Tokushima Otsuka (LETO) rats were used for this study. LETO rats are non-diabetic control rats. All OLETF rats were randomly assigned to 2 groups: control group (n=10) given only tap water and GAG group (n=5) feeding with GAG 10 mg/kg from 7 weeks to 55 weeks of age. Measurement of body weight, blood glucose, serum BUN and creatinine was performed periodically. 24-hour urine collection for measurement of urinary protein and NAG excretion was done at 17, 25, 37, 46, 55 weeks of age. RESULTS: 1) OLETF rats showed higher body weight, blood glucose, 24-hour urinary protein and NAG excretion compared with LETO rats. But serum concentration of BUN and creatinine were not different between OLETF and LETO rats. 2) GAG-treated OLETF rats exhibited lower urinary protein/creatinine excretion (17.48+/-0.50 vs 22.49+/-0.11 mg/mg Cr, p< 0.05) and NAG (17.40+/-5.94 vs 43.73+/- 7.44 nmol/h/mg Cr, p< 0.05) excretion compared with non-treated OLETF rats. But body weights, blood glucose, serum concentration of BUN and creatinine were not different between GAG-treated OLETF rats and non-treated OLETF rats. CONCLUSION: 1) The urinary excretion of NAG may be a possible early marker of diabetic nephropathy in OLETF rats. 2) Urinary protein and NAG excretion were decreased in the GAG-treated OLETF rats. GAG seems to have a protective effect against development of diabetic nephropathy.

Limitation of Validity of Homeostasis Model Assessment as a Index of Insulin Resistance.: Yong Seok Yun, Seok Won Park, Young Duk Song, Hyo Kyung Park, Oh Yoen Kim, Chul Woo Ahn, Jae Hyun Nam, Su Youn Nam, Bong Soo Cha, Chong Ho Lee, Sumg Gil Lim, Kyung Rae Kim, Hyun Chul Lee, Kap Bum Huh; Korean Diabetes J. 2000;24(5):541-551. Published online January 1, 2001

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Abstract: BACKGROUND
Homeostasis model assessment of insulin resistance (HOMAIR) had been proposed as a simple and inexpensive alternative to other complex procedures measuring insulin resistance. We evaluated the validity of HOMAIR, comparing to total glucose disposal rate measured by euglycemic clamp test in 63 subjects with normal glucose tolerance, 21 with impaired glucose tolerance and 47 with type 2 DM. METHODS: HOMAIR and HOMA cell function (Homeostasis model assessment of cell function) were calculated with formula described by Matthews [HOMAIR: fasting insulin ( U/mL) X fasting glucose (mmol/L) / 22.5, HOMA cell function: 20 X fasting insulin ( U/mL) / (fasting glucose (mmol/L) - 3.5)]. 2-hour euglycemic (5 mmol/L) hyper insulinemic (717 pmol/L) clamp test were carried out. RESULTS: The strong inverse correlation (r=-0.658, <0.001) was shown between log transformed HOMAIR and total glucose disposal rates. The agreement of two methodes in the categorization according to insulin resistance was moderate (weighed kappa=0.45). The magnitude of correlation coefficients were smaller in subjects with lower BMI (BMI < 23.7 kg/m2, r = -0.441 vs BMI > or = 23.7 kg/m2, r = -0.693, p = 0.0183), lower HOMA cell function (HOMA cell function < 57.2, r = -0.514 vs HOMA cell function > or = 57.2, r = -0.773, p = 0.0091) and higher fasting glucose levels (fasting glucose < 102 mg/dL, r = -0.697 vs fasting glucose > or = 102 mg/dL, r = -0.59, p = 0.0735). The results of correlation analysis was not significant in diabetics with lower BMI. CONCLUSION: Limitation of validity of HOMAIR should be carefully considered in subjects with lower BMI and lower fasting insulin to glucose levels, such as lean type 2 diabetes with insulin secretory defects.

Correlation between Basal Insulin Requirements and Daily Administered Insulin Dosage in Diabetes.: Min Kyong Moon, Jong Ho Ahn, Tae Yong Kim, Won Shik Shinn, Soo Lim, Young Min Cho, Kyong Soo Park, Seong Yeon Kim, Hong Kyu Lee; Korean Diabetes J. 2000;24(5):552-559. Published online January 1, 2001

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Abstract: BACKGROUND
In patients who need insulin therapy, it is difficult to assess insulin requirements because of individual variability in insulin sensitivity and secretion. The aim of this study is to know that it is possible to achieve rapidly and efficiently normoglycemia based on insulin infusion algorithm and whether there is correlation between basal insulin requirements and daily administered total insulin dose. METHODS: Total 34 patients were enrolled. Insulin infusion was begun at 2:00 p.m., and bedside blood glucose concentration was measured at hourly intervals. The rate of insulin infusion was adjusted according to blood glucose levels. We compared insulin requirements to maintain normoglycemia (basal insulin requirements) with daily administered total insulin dose. RESULTS: At start, the mean blood glucose concentration was 14.9+/-4.7 mmol/L; by the first hour, it was 10.7+/-3.6 mmol/L; by the second hour, it was 7.4+/-3.1 mmol/L; when the infusion was discontinued, it was 5.7+/-1.0 mmol/L. This algorithm successfully inducted normoglycemia in all patients within 3.5+/-1.8 h. There was significant correlation between basal insulin requirements and daily administered total insulin dosage. And, daily administered insulin dose had significant correlation with first hour glucose concentration, first hour insulin infusion rate, second hour glucose concentration, second hour insulin infusion rate, and glucose concentration at the end. CONCLUSIONS: We concluded that normoglycemia can be achieved rapidly and efficiently based on insulin infusion algorithm. The present study suggested that we could predict daily insulin requirements through basal insulin requirements that we measured.

Randomized Controlled Trial

The Effects of Teaching Methods on the Dietary Compliance and Hemoglobin A1c Level in Patients with Diabetes Mellitus.: Sung Oh Chung, O Keum Song, Jae Min Ko, Jun Hwan Wi, Tae Hoon Lee, Ju Hyup Yum, Dae Kyoung Cho, Jin Hee Son, Hong Woo Nam, Hyung Joon Yoo, Young Nam Lee, Sung Gon Kim, Hyun Kyung Moon, Eul Sang Kim; Korean Diabetes J. 2000;24(5):560-573. Published online January 1, 2001

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Abstract: BACKGROUND
Diet control plays an important role in diabetic management, but it is often hard for diabetic patients to follow the dietary control program. Poor dietary compliance leads to metabolic derangements in patients with diabetes and it may derive mainly from defects in dietary education program rather than from patients themselves. Therefore, we performed a randomized prospective study to compare the effects of three different teaching methods for diet control. METHODS: Forty eight diabetic patients with poor glycemic control (mean HbA1c 11.4+/-1.5%) were enrolled during hospitalization and allocated at random to three different teaching methods i.e. Conventional diet sheet instruction (Group 1), Food recording on every meal (Group 2), and Meal time demonstration (Group 3). For evaluation, knowledge about DM diet and barriers to diet control were assessed by a questionnaire. Consistency in carbohydrate intake (Coefficient of variation) and serial HbA1C measurements were used for the estimation of dietary compliance and glycemic control respectively. RESULTS: During five months' follow-up period, there was no remarkable improvement in knowledge about diabetic diet control, dietary compliance and glycemic control in Group 1 patients. But both dietary compliance and glycemic control improved in Group 2 and 3 patients during follow-up period. In Group 2 CV (Coefficient of Variation ) fell from 36.4+/-15.2% to 27.7+/-17.3% and in Group 3 from 32.1+/-9.6% to 23.2+/-10.5% (p<0.05). In Group 2 HbA1c fell from 12+/-2.2% to 8.3 +/-2.0% and in Group 3 from 11.5+/-2.0% to 7.5+/-1.9% (p<0.01). The change of HbA1c level showed an appreciable correlation with dietary compliance (r= 0.75). Among the perceived barriers to dietary practice in patients of Group 2 and Group 3, extrinsic factors related to knowledge lowered during the intervention (p<0.05). Even though Group 3 patients had good dietary compliance, they still felt that intrinsic factors related to motive and attitude were the major barriers at the end of the study (p<0.05). CONCLUSION: We found that meal time demonstration teaching method may improve dietary compliance and glycemic control compared with the conven tional diet sheet instruction method.

Original Articles

The Effect of Acute Hyperglycemia on Endothelial Function in Type 2 Diabetes.: Sang Jun Lee, Dong Wook Lee, In Kyu Lee; Korean Diabetes J. 2000;24(5):574-586. Published online January 1, 2001

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Abstract: BACKGROUND
Multiple studies in patients with diabetes demonstrate impaired endothelial-dependent vasodilation. But the mechanisms of vascular dysfunction in type 2 diabetes are still controversial. Some risk factors, such as dyslipidemia, hypertension and obesity, are commonly associated with type 2 diabetes. These risk factor may cause endothelial dysfunction. And hyperglycemia may have a specific role in the increased risk of vascular complications in diabetes but it remains unclear. The purpose of this study was to examine whether endothelial dysfunction occurs when acute hyperglycemia is induced by oral glucose loading. METHOD: Using the high-resolution ultrasound, we measured flow-mediated vasodilation (endothelial dependent vasodilation: FMD) during oral glucose tolerance test in 11 men (mean age: 59+/-5 years) with type 2 diabetes without chronic diabetic complications. For statistical analysis, we used paired t-test, generalized linear method (GLM) to compare FMD before and after glucose loading. RESULT: Flow-mediated vasodilation was diminished after glucose loading (13.2+/- 6.4%, 7.3+/-3.3*%, 12.8+/-5.6%, in fasting, at 1- and 2-h, respectively; *p<0.001 vs fasting). Superoxide anion formation by neutrophils was increased after glucose loading (4.65+/-2.8, 6.17+/-2.2, in fasting, at 1-h respectively: p<0.05 vs fasting)( 10-7nmol/106cells/30min). Endothelial independent vasodilation was not significantly affected by glucose loading. The concentration of triglyceride were not changed after glucose loading. CONCLUSION: This study shows that acute hyperglycemia induced by 75 gm oral glucose intake results in endothelial dysfunction. These results suggest that prolonged and repeated hyperglycemia may play an important role in the developement and progression of vascular complication in diabetes.

Efficacy and Safety of beraprost sodium in Type 2 Diabetic Subjects Complicated with Arteriosclerosis Obliterans (ASO): A Prospective, Multicenter, Open Clinical Study.: Yeon Sahng Oh, Young Deuk Song, Moon Kyu Lee, Young Seol Kim, Ho Young Son; Korean Diabetes J. 2000;24(5):587-602. Published online January 1, 2001

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Abstract: BACKGROUND
Beraprost sodium (BPS) is a new stable, orally active prostaglandin I2 analogue with antiplatelet and vasodilating properties. We performed an prospective, multicenter, open clinical trial to assess the efficacy and safety of BPS in type 2 diabetic patients complicated with arteriosclerosis obliterans (ASO). METHOD: We recruited 34 type 2 diabetic patients complicated with ASO at 5 different university hospitals. Patients received BPS 40 g tid for 6-week. Patients performed a subjective and objective assessment of treatment usefulness at 2- and 6-week. Safety was assessed by obtaining clinical data and history. RESULTS: There was a significant difference between before and after treatment for changes regarding the items "chillness", "numbness" and "rest pain". An improve ment in intermittent claudication distance at the 2-or 4-week interval was achieved. Ankle Pressure Index (API) was not statistically different. The side effects including fever, myalgia, indigestion were subtle and the patients' compliance is good. CONCLUSION: These results show that BSP is an effective and safe symptomatic treatment of Type 2 diabetic patients with ASO.

Intima-media Thickness of the Common Carotid Artery and Carotid Atherosclerotic Plaques as Predictors for Occurrence of Clinical Macrovascular Complication in Type 2 Diabetes.: Byoung Hyun Park, Chung Gu Cho; Korean Diabetes J. 2000;24(5):603-613. Published online January 1, 2001

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Abstract: BACKGROUND
This study was undertaken to investigate that intima-media thickness and plaque of the carotid artery, as measured by high resolution B-mode ultrasonography, can be used as predictors for occurrence of clinical macrovascular complication in type 2 diabetes patients. METHODS: High resolution B-mode ultrasonographic examination was performed in 39 type 2 diabetes, including 16 diabetes with macrovascular complication, and in 18 non-diabetic control subjects. Concurrently serum total cholesterol, HDL cholesterol, triglyceride, lipoprotein (a), HbA1c, C-peptide levels and body mass index (BMI) were measured and history of hypertension, smoking, duration of diabetes and occurrence of macrovascular complication during the last 6 months were investigated. RESULTS: 1) Significant differences in common carotid IMT (0.72+/-0.08 mm, vs 0.93+/- 0.26 mm), existence of atherosclerotic plaque (50%, vs 69%), plaque number (0.5+/- 0.86, vs 0.69+/-2.37) and carotid stenosis (0%, vs 18%) were found between control and type 2 diabetes (p<0.05). 2) Significant differences in age (67.63+/-4.30, vs 60.6+/-12.0), lipoprotein (a) (63.65+/- 32.2 mg/dL, vs 35.22+/-34.74 mg/dL), common carotid IMT (1.08+/-0.27 mm, vs 0.82+/- 0.20 mm), existence of atherosclerotic plaque (87.5%, vs 56.5%), plaque number (2.88+/-3.16, vs 0.91+/-1.02), end diastolic ventricular septal thickness (10.82+/-1.88 mm, vs 8.76+/-2.92 mm) and end diastolic left ventricular posterior wall thickness (10.79+/-1.60 mm, vs 9.1+/-2.56 mm) were found between type 2 diabetes patients with macrovascular complication and without macrovascular complication (p<0.05). 3) Age (r=0.363, p=0.023), hypertension (r=0.32, p=0.047), carotid plaque existence (r=0.377, p=0.018) and plaque number (r=0.662, p=0.000) showed a correlation with the IMT in type 2 diabetes. 4) Most common involving site of atherosclerotic plaques was carotid bulb and more extensive involvement was showed in type 2 diabetes with macrovascular complication than without macrovascular complication. 5) The sensitivity of common carotid IMT (> control mean IMT + 2 SD; >1.22 mm) for prediction of macrovascular complication in type 2 diabetes patients was 25%, the specificity 95.7%, the positive predictive value 80%, the negative predictive value 61.8%. 6) The sensitivity of existence of carotid plaque for prediction of macrovascular complication in type 2 diabetes patients was 87.5%, the specificity 60.9%, the positive predictive value 60.9%, the negative predictive value 87.5%. CONCLUSION: Increases in IMT and plaque of the carotid artery, as measured by high resolution B-mode ultrasonography, can be used as predictors for occurrence of clinical macrovascular complication in type 2 diabetes patients.

Case Report

Two Cases of Hyperamylasemia not Aassociated with Acute Pancreatits in Non-ketotic Hyperosmolar Syndrome.: Jong Hyung Choi, Doo Man Kim, Han Su Cho, Ki Sung Lee, Ji Young Seo, Hyun Kyoo Kim, Cheol Soo Choi, Sung Hee Ihm, Jae Myung Yu, Moon Ki Choi, Hyung Joon Yoo, Sung Woo Park; Korean Diabetes J. 2000;24(5):614-618. Published online January 1, 2001

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Abstract: The serum amylase level is widely used as a screening test for acute pancreatitis and rises also in a wide variety of diseases involving the pancreas, salivary glands, intestines, liver, genitourinary tract, and lung, in metabolic aberrations such as diabetic ketoacidosis, and even during normal pregnancy. Although it is commonly assumed that the diseased organ is releasing amylase into the serum, in many conditions the precise relationship between the hyperamylasemia and the condition is not clear. Serum amylase is abnormally elevated in more than 60% of patients with diabetic ketoacidosis, but increased pancreatic enzyme activity, even in combination with abdominal pain, should not be diagnosed as acute pancreatitis. In nonketotic hyperosmolar syndrome, elevated serum amylase level without pancreatitis has not been reported. Nonketotic hyperosmolar syndrome is usually a complcation of type 2 DM and characterized by severe hyperosmolarity (serum osmolality> or =320 mOsm/L), hyperglycemia (serum glucose> or = 600 mg/dL) and dehydration. We experienced two cases of nonketotic hyperosmolar syndrome with elevated serum amylase. Serum amylase level was 1556 U/L in first case, 229 U/L in second case. Two patients did not complain of abdominal pain, nausea, vomiting and abdomen CT with enhancement showed the normal pancreases.

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