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10 "Proinsulin"
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Impaired Insulin Secretion in Normoglycemic Offspring of Patients with Type 2 Diabetes.
Eun Kyung Byun, Young Sun Hong, Jee Young Oh, Yeon Ah Sung, Yeon Jin Jang
Korean Diabetes J. 2003;27(1):39-48.   Published online February 1, 2003
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BACKGROUND
Although it is well known that insulin secretory defects and insulin resistance are major pathogenetic factors of type 2 diabetes, their relative importance still remains controversial in various ethnic groups. Increased levels of proinsulin, and the proinsulin/insulin (PI/I) ratio, are considered markers of pancreatic dysfunction, and predictors for the development of type 2 diabetes. To reveal which pathogenetic abnormality is most prominent in Koreans with type 2 diabetes, we measured the insulin sensitivity and secretory capacity in the normal glucose tolerant offspring of patients with type 2 diabetes. METHODS: Sixty-two offspring, with normal glucose tolerance (mean age 40.4+/-6.5 BMI 23.4+/-2.7 kg/m2), of type 2 diabetes parents, were compared with and 20, age and BMI-matched control subjects, with on family history of diabetes. We measured the serum levels of proinsulin (PI), specific insulin (I), and C-peptide(C) and calculated the PI/I and C/I ratios, as parameters of hepatic insulin clearance. The insulin sensitivity index (SI) was measured by the intravenous glucose tolerance test (IVGTT) using the MINMOD program, as a marker of insulin sensitivity. The acute insulin response to glucose (AIRg), AIRg by product, SI and the area under the insulin curve (AUCinsulin) were measured by IVGTT, and used as a marker of the insulin secretory capacity. We also evaluated the association between the proinsulin and insulin secretory capacities. RESULTS: Offspring of the type 2 diabetic patients had significantly lower AIRg SI and AUCinsulin (p<0.05), and tended to have lower AIRg (p=0.06), than the control subjects. However, there was no significant difference in the SI between the two groups. However, with the proinsulin, and the insulin, PI/I and C/I ratios, not significant differences were found between the offspring and the control subjects, and the PI/I ratio was not correlated with AIRg, AIRg x SI or SI. CONCLUSION: Insulin secretory defect could be a more prominent factor in the development of type 2 diabetes in Koreans, with no change in the proinsulin secretion.
Serum Proinsulin, Proinsulin/Total Insulin Ratio and Insulin Resistance in Elderly-onset Type 2 Diabetes.
Yoon Ju Oh, Young Ju Park, Young Wan Kim, Sung Ki Kim, Seong Bin Hong, Yoe Joo Kim, Mi Rim Kim, Moon Suk Nam, Yong Seong Kim
Korean Diabetes J. 2001;25(2):113-124.   Published online April 1, 2001
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BACKGROUND
It is well known that the concentration of serum proinsulin and the ratio of proinsulin/total insulin (P/I) are elevated in type 2 diabetes. Proinsulin is produced by the ribosome in pancreatic beta cells, undergoes maturation in Golgi body and exists in the form of secretory granules. Immature granules possess disproportionately large amount of proinsulin. When there is increased demand of insulin caused by diabetes, higher level of proinsulin is secreted from immature granules of dysfunctioning beta cells. Thus, the elevated concentration of proinsulin and the increased ratio of P/I are considered to be the markers of pancreatic dysfunction and predictors for the future development of diabetes. The elderly-onset type 2 diabetes is also thought to develop due to both dysfunction of insulin secretion by impaired beta cell with aging and increased insulin resistance in peripheral tissue due to less muscle mass and more fat. However, it is still controversial as to which mechanism is predominant in the development of type 2 diabetes. METHODS: We measured the levels of fasting blood glucose, serum proinsulin and specific human insulin by using radioimmunoassay kit, and calculated the P/I ratio and insulin sensitivity index in normal adults (40or=60, n=35) and also in the newly-diagnosed elderly type 2 diabetes (age>or=60, n=24). RESULTS: The concentration of serum proinsulin and the ratio of P/I in normal adults over age 40 were 7.70+/-6.08 pmol/L and 0.13+/-0.10, respectively. The concentration of proinsulin in the normal adult, normal elderly and elderly diabetes group were 6.50+/-3.71, 11.17+/-8.30 and 16.75+/-11.68 pmol/L. The differences among three groups were statistically significant (p= 0.0001). The P/I ratios for each of the three groups were 0.11+/-0.05, 0.17+/-0.12 and 0.16+/-0.08 (p=0.0004). P/I ratios in the elderly control and elderly diabetes were higher than that of the normal adult group. Insulin sensitivity index (ISI, 10,000/(basal glucose X basal insulin)) of elderly diabetes (1.19+/-0.89) was lower when compared with the indices of other groups (40or=60 control; 2.27+/-1.11, p=0.0001). CONCLUSION: Although the age-related reduction of pancreatic insulin secretory function attributes to the pathogenesis of old-age onset type 2 diabetes, it appears that the decreased insulin sensitivity may serve as more important factor in the development of the disease.
The Role of beta-cell Dysfunction and Insulin Resistance in the Development of Post-renal Transplantation Diabetes Mellitus.
Jae Hyun Nam, Hyun Chul Lee, Churl Woo Ahn, Jang Il Mun, Soon Il Kim, Kiil Park, Young Duk Song, Sung Kil Lim, Kyung Rae Kim, Kap Bum Huh
Korean Diabetes J. 2000;24(4):485-514.   Published online January 1, 2001
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BACKGROUND
Our study was undertaken to investigate the pathogenesis and possible risk factors for post-renal transplantation diabetes mellitus (PTDM). METHODS: we recruited 114 patients with normal glucose tolerance, and performed the 75 g oral glucose tolerance tests (OGTT) and the short insulin tolerance tests 1 week before and 9~12 months after transplantation, respectively. RESULTS: The subjects were classified into three groups on the basis of OGTT after transplantation by WHO criteria: 1) 36 (31.6%) subjects with normal glucose tolerance; 2) 51 (45.7%) subjects with impaired glucose tolerance; and 3) 27 (23.7%) subjects with post-renal transplantation diabetes mellitus. Dosages of steroid and cyclosporin-A (CsA) were equivalent among the 3 groups. Before transplantation, the fasting and 2-h plasma glucose, and proinsulin/insulin (PI/I) ratios were significantly higher in the IGT and PTDM groups than in the NGT group, but insulin sensitivity index (ISI) was not different among 3 groups. In addition, the area under the curve (AUC)-insulin on OGTT was significantly lower in the PTDM group than in the NGT group. After transplantation, however, ISI was increased in all groups. Furthermore, the ISI and PI/I ratios revealed significantly higher values in the PTDM group than in the NGT group after transplantation. CONCLUSION: These results revealed that fasting and 2-h plasma glucose levels, as well as proinsulin/insulin ratio before transplantation, which may all be indicators of beta-cell dysfunction, could be the predictors for the development of PTDM and beta-cell dysfunction rather than insulin resistance was proved to be the main factor for the pathogenesis of PTDM.
Plasma Proinsulin Secretion in Impaired Glucose Tolerance and Newly Diagnosed Type 2 Diabetes Mellitus.
Byoung Ho Kong, Seung Jin Choi, Jae Tack Kim, Yeon Shang Oh, Soon Hyun Shinn
Korean Diabetes J. 2000;24(4):467-475.   Published online January 1, 2001
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BACKGROUND
Type 2 diabetes mellitus is characterized beta cell dysfunction and insulin resistance but the relative roles of the two factors are different in various ethnic groups. The changes in plasma proinsulin levels is thought to be a marker for the beta-cell dysfunction. To study the role of beta cell dysfunction in the pathogenesis of type 2 diabetes mellitus we compared the concentrations of plasma insulin, C-peptide and proinsulin among the control group, impaired glucose tolerance (IGT) group and newly diagnosed Type 2 Diabetes Mellitus (DM) group during the oral glucose tolerance test. METHODS: In 47 newly diagnosed patients with type 2 DM, 9 IGT and 13 controls the 75g oral glucose tolerance test (OGTT) were performed and samples were analyzed for glucose, insulin, C-peptide and proinsulin. RESULTS: 1) In IGT group plasma insulin, C-peptide and proinsulin concentrations were increased markedly during OGTT but were blunted in type 2 diabetes group. 2) The basal plasma proinsulin level was 7.7+/-4.4 pmol/L in control group, 15.2+/-6.9 pmol/L (p<0.005) in IGT group, and 16.9+/-8.3 pmol/L (p<0.005) in type 2 DM group, and the proinsulin levels at 60 min, 90 min, 120 min during OGTT were significantly elevated in IGT group than those of control group. 3) The plasma proinsulin/insulin ratio were significantly increased in IGT group and type 2 DM group at basal and 30 min during OGTT. 4) The proinsulin response areas were significantly increased in IGT group (110.7+/- 13.1 pmol/L/hr, p=0.048) than those of control group (73.6+/-5.1 pmo l/L/hr) and type 2 DM group (80.5+/-5.9 pmol/L/hr). CONCLUSION: Beta cell secretory defects such as proinsulin secretion were present in impaired glucose tolerance and the changes of insulin secretory function might have a role in the pathogenesis of type 2 DM.
The Stimulatory Effect of IL-1on The Insulin Secretion and Its Relating Factors.
In Kyung Jeong, Seung Hoon Oh, Tong Mook Kang, Jae Hoon Jeong, Yong Ki Min, Myung Shik Lee, Moon Kyu Lee, Kwang Won Kim
Korean Diabetes J. 2000;24(4):431-443.   Published online January 1, 2001
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BACKGROUND
The inhibitory effect of IL-1 on the insulin secretion has been validated in pathogenesis of type 1 diabetes, but complex results about the stimulatory effect of IL-1 have been reported. The aims of this study are to clarify the effects of IL-1 on insulin secretion of pancreatic islets and to investigate the mechanisms in terms of preproinsulin synthesis, inducible NOS expression, and calcium channel activity. METHODS: Islets were isolated from male Sprague-Dawley (SD) rat by modified Lacy-Kostianovsky's method. After islets were treated with different concentrations (0, 0.5, 5, 50, 500 pmol/L) and exposure time (2, 6, 24 hours) of IL-1 , morphology, viability, static stimulation of insulin to glucose, insulin content, preproinsulin mRNA expression, iNOS mRNA expression and calcium channel activity were measured. RESULTS: 1) Viability of islets was reduced in high concentrations of long term exposure of IL-1 . 2) Insulin secretion was stimulated in islets treated with 5, 50, and 500 pmol/L of IL-1 for 2 hours and 0.5 pmol/L for 6 hours. It was inhibited in 5, 50, and 500 pmol/L for 6 and 24 hours. 3) Insulin content was not significantly different regardless of concentration and exposure time of IL-1 . 4) Preproinsulin mRNA expression increased in islets treated with 50, 500 pmol/L of IL-1 for 2 hours. After 24 hours, it decreased in dose dependent manner. 5) iNOS mRNA expression was detectable after 2 hours in the presence of IL-1 , peaks at 6 hour and decreased after 24hours. It was increased above 5 pmol/L of IL-1 in dose dependent manner. 6) Activities of the voltage-dependent Ca2+ channels were not different among groups. CONCLUSION: IL-1 plays a positive role in terms of insulin secretion and insulin synthesis in high concentration of short term or low concentration of long term. These effects of IL-1 might be neither dependent of iNOS pathway nor Ca2+ channel activity.
Leptin Concentration in Diabetin and Non-diabetin Subjects in the Community Population.
Kee Up Lee, Seong Kwan Hong, Sang Wook Kim, Young Il Kim, Yun Ey Chung, Moo Song Lee, Joong Yeoul Park, Jin Yup Kim
Korean Diabetes J. 1999;23(4):592-600.   Published online January 1, 2001
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BACKGROUND
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.
Plasma Proinsulin Levels among the Control, Impaired Glucose Tolerance and Type 2 Diabetes Mellitus during Oral Glucose Tolerance Test.
Mi Deok Lee, Young Uck Kim, Hong Seung Kim, Young Goo Shin, Choon Hee Chung
Korean Diabetes J. 1999;23(2):147-154.   Published online January 1, 2001
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BACKGROUND
Increased secretion of proinsulin has been associated with beta-cell dysfunction. Hyper-proinsulinemia is suggested to be a predictor for the progression of IGT to type 2 DM. In this study, we compared the concentration of insulin, C-peptide and proinsulin levels among the control group, IGT and type 2 DM group during the oral glucose tolerance test. We investigated whether hyperproinsulinemia was an effective predictor of beta-cell impairment befre the clinical onset of type 2 diabetic subjects. METHODS: We studied proinsulin, insulin(using an assay that display appreciable cross-reactivity with proinsulin) and proinsulin:insulin ratio during the oral glucose tolerance test in 14 controls, 20 IGT and 20 type 2 DM. We also compared proinsulin, proinsulin response areas and proinsulin:insulin ratio among the three groups. RESULTS: There were no significant differences in the baseline and 30min proinsulin levels among three groups. However, proinsulin response areas in IGT were higher than those in other groups. Baseline proinsulin/insulin ratio and post-load proinsulin/ insulin ratio were not significantly different among the three groups. In IGT group, the proinsulin response after glucose loading was rapidly increased, but was blunted in diabetic patients. CONCLUSION: We suggest that pancreatic beta cell dysfunction was ongoing before the clinical onset of DM and hyperproinsulinemia, especially the proinsulin response areas during oral GTT may be a predictor for the development of type 2 DM.
Insulin Secretory Dysfunction in the Patients with Untreated Hyperthyroidism.
Moon Suk Nam, Seung Yong Shin, Young Wan Kim, Seong Bin Hong, Yeo Joo Kim, Mi Rim Kim, Won Sick Choe, Yong Seong Kim
Korean Diabetes J. 1998;22(3):320-327.   Published online January 1, 2001
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BACKGROUND
Abnormal glucose metabolism with impaired glucose tolerance has been documented in patients with thyrotoxicosis, but the pathogenesis is not fully understood. Therefore, the aim of the present study was to study the secretory dysfunction of pancreatic 9-cell and to confirm hyperinsulinemia and hyperproinsulinemia during oral glucose tolerance test(OGTT) in patients with thyrotoxicosis. METHODS: After an overnight fast, 75 g OGTT was performed in 10 patients with hyperthyroidism and in 10 healthy control subjects matched for age, sex and hody mass index. Plasma insulin(immuno-reactive insulin, IRI), C-peptide, proinsulin levels were measured by radioimmunoassay. RESULTS: Fasting plasma glucose, insulin and C-peptide levels were similar in the two groups, but plasma proinsulin level was increased in patients with hyperthyroidism(p<0.05). A twofold rise of plasma proinsulin and the proinsulin/insulin ratio was also found in patients with hyperthyroidism during OGTT. The molar ratio of C-peptide and insulin(IRI) was similar in the two groups. CONCLUSION: Hyperinsulinemia and hyperproinsulinemia were found in patients with hyperthyroidism compared with controls. Disproportionally increased proinsulin level suggested a pancreatic secretory dysfunction in the patients with hyperthyroidism.
Serum Fasting Proinsulin Level as a Predictor for Development of NIDDM in Korean Subjects.
Geon Sang Park, Chan Soo Shin, Kyong Soo park, Seong Yeon Kim, Hong Kyu Lee, Sun Ja Kwon, Yong Soo Park
Korean Diabetes J. 1997;21(4):365-371.   Published online January 1, 2001
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BACKGROUND
Proinsulin is raised in people with NIDDM. Hyperproinsulinemia is thought to be a predictor for the subsequent development of NIDDM. We studied to investigate whether hyperproinsulinemia can predict the development of NIDDM in Korean subjects. METHOD: This study was performed as a nested case-control study. The case group was 67 newly developed diabetic patients out of 1193 initially non-diabetic cohott in Yonchon county. We have also selected 66 age-sex-B541-WHR matched control group who remain non-diabetic for 2 years. We compared baseline insulin, proinsulin and proinsulin/insulin ratio between two groups, RESULTS: There was no significant difference in baseline fasting insulin levels[46,77+/-17.3 vs 42.87+/- 11.6(pmol/L)] between converters to diabetes and non-converters. However, the baseline proinsulin levels in converters to diabetes were higher than those in non-converters.[16.07+/-14.3 vs 8.72+/-5.2(pmol/L)) The baseline proinsulin/imulin ratio in converters was also higher than those in non-converters. [0.30+/-0.17 vs 0.20+/-0.10] CONCLUSION: The results suggest that fasting hyper-proinsulinemia may be a predictor for subsequent development of NIDDM in Korean subjects.
Serum Proinsulin Responses during Oral Glucose Tolerance Test in patients with Non-insulin Dependent Diabetes Mellitus.
Moon Suk Nam, Seong Bin Hong, Yeo Joo Kim, Mi Rim Kim, Yong Seong Kim, In Young Hyun, In Ho Kwak
Korean Diabetes J. 1997;21(4):356-364.   Published online January 1, 2001
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AbstractAbstract PDF
BACKGROUND
When insulin is secreted from the pancreas, a small amount of proinsulin is also secreted at the same time. Pancreatic beta cell may release immature granules richer in proinsulin contents as well as mature granules in the over-stirnulated state. The significance of hyperproinsulinemia was recently reevaluated in the pathogenesis of non-insulin dependent diabetes mellitus(NIDDM). We studied proinsulin response at fasting and oral glucose tolerance test(OGTT) in NIDDM with a simple and sensitive human proinsulin radioimmunoassay system. METHODS: 22 new onset non-obese NIDDM patients and 11 matched healthy controls were selected for the study. The NIDDM group was divided into 3 groups(group 1; 7.8, group 2; 7.8~11, group 3; 11.0 mmol/L) according to the fasting plasma glucose level. After an overnight fast, a 75 g OGTT was performed and samples were analyzed with proinsulin and specific human insulin radioimmunoassay kits. RESULTS: The basal serum proinsulin level was reported as 9.29+/-4.19 pmol/L in normal control and as 18.09+/-9.32 pmol/L(p=0.04, compared with control) in diabetic group. The values in NIDDM group 1 and 2(18.07+/-9.D2; p=0.04, 21.60+/-6.98; p=0.03) were higher than in control. The molar ratia of the basal proinsulin to total insulin were also increased in NIDDM group 1 and 2(0.24, 0.28) than in control subjmts(0.13, p=0.03). The basal proinsulin and proineulin/total insulin ratio were highest in the group 2(p 0,05, than group 3). During oral glucose loading, the proinsulin response increased more slowly than total insulin response. The proinsulin and proinsulin/ total insulin ratio during oral glucose loading were higher in NIDDM group 1 and group 2 than cantrols. CONCLUSION: The basal proinsulin level in diabetic group was higher than in normal control. The proinsulin responses during oral glucose loading were higher in diabetic group 1 and 2 than controls. The proinlulin response increased more slowly than total insulin response during oral glucose loading. So we conclude that the proinsulin secretion frorn pancreatic beta cell is impaired in diabetic group. The mechanism about the metabolic pathway of the proinsulin secretion should be studied more.

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