Kap Bum Huh

beta-Cell dysfunction rather than insulin resistance is the main contributing factor for the development of postrenal transplantation diabetes mellitus.

Background. Our study was undertaken to investigate the pathogenesisand possible risk factors for postrenal transplantation diabetes mellitus(PTDM). Methods. We recruited 114 patients with normal glucose tolerance(NGT) and performed both 75-g oral glucose tolerance tests (OGTT) and shortinsulin tolerance tests 1 week before and 9–12 months aftertransplantation. Results. The subjects were classified into three groups by WorldHealth Organization criteria on the basis of OGTT after transplantation: (a)36 (31.6%) subjects with normal glucose tolerance; (b) 51 (45.7%) subjectswith impaired glucose tolerance (IGT); and (c) 27 (23.7%) subjects withpostrenal transplantation diabetes mellitus. Dosages of steroid andcyclosporine were equivalent among the three groups. Before transplantation,the fasting and 2-hr plasma glucose and proinsulin/insulin (PI/I) ratios weresignificantly higher in the IGT and PTDM groups than in the NGT group, but theinsulin sensitivity index (ISI) was not significantly different among thethree groups. In addition, the area under the curve-insulin on OGTT wassignificantly lower in the PTDM group than in the NGT group. Aftertransplantation, however, the ISI was increased in all groups. Furthermore,the ISI and PI/I ratios revealed significantly higher values in the PTDM groupthan in the NGT group aftertransplantation. Conclusions. These results revealed that fasting and 2-hr plasma glucoselevels, as well as the proinsulin/insulin ratio before transplantation, areboth possible indicators of &bgr;-cell dysfunction and may be predictors forthe development of PTDM. Furthermore, &bgr;-cell dysfunction, rather thaninsulin resistance, was proven to be the main factor for the pathogenesis ofPTDM.

Association between nonalcoholic fatty liver disease and carotid intima-media thickness according to the presence of metabolic syndrome

OBJECTIVE Controversy exists as to whether the association between nonalcoholic fatty liver disease (NAFLD) and atherosclerosis is independent of other metabolic disorders. We examined the association between NAFLD and carotid intima-media thickness (IMT) according to the presence of metabolic syndrome (MetS). METHODS A cross-sectional analysis was performed among 556 men and 465 women, ages 30-79 years. The presence of NAFLD was evaluated ultrasonographically. Carotid IMT was determined ultrasonographically by the average of the maximal IMT at each common carotid artery. Independent associations between NAFLD and IMT were assessed using multiple linear and logistic regression models, after adjusting for age, sex, waist circumference, systolic blood pressure, fasting glucose, total/HDL-cholesterol ratio, smoking, and alcohol consumption. RESULTS After adjusting for major risk factors, subjects with NAFLD had greater carotid IMT than subjects without NAFLD (difference 0.034 mm, p=0.016). However, the difference in IMT was significant only in subjects with MetS (0.060 mm, p=0.015) and not in subjects without MetS (0.015 mm, p=0.384). Similarly, the NAFLD-associated adjusted odds ratio for increased IMT, defined as the sex-specific top quintile, was 1.63 (95% CI, 1.10-2.42) in all subjects and 2.08 (95% CI, 1.19-3.66) in subjects with MetS, but 1.18 (95% CI, 0.64-2.19) in subjects without MetS. When the analysis was performed according to the number of metabolic abnormalities, the NAFLD-IMT association was observed only in subjects with four or more abnormalities. CONCLUSION These results suggest that NAFLD is independently associated with carotid atherosclerosis only in people who have multiple metabolic abnormalities.

RAGE regulates BACE1 and Aβ generation via NFAT1 activation in Alzheimer’s disease animal model

The receptor for advanced glycation end products (RAGE) is a multiligand cell surface receptor, and amyloid P peptide (Aβ) is one of the ligands for RAGE. Because RAGE is a transporter of Aβ from the blood to the brain, RAGE is believed to play an important role in Alzheimers disease (AD) pathogenesis. In the present study, the role of RAGE in Aβ production was examined in the brain tissue of an AD animal model, Tg2576 mice, as well as cultured cells. Because β‐site APP‐cleaving enzyme 1 (BACE1), an essential protease for Aβ production, is up‐regulated in cells overexpressing RAGE and in RAGE‐injected brains of Tg2576 mice, the molecular mechanisms underlying RAGE, BACE1 expression, and Aβ production were examined. Because RAGE stimulates intracellular calcium, nuclear factor of activated T‐cells 1 (NFAT1) was examined. NFAT1 was activated following RAGE‐induced BACE1 expression followed by Aβ generation. Injection of soluble RAGE (sRAGE), which acts as a competitor with full‐length RAGE (fRAGE), into aged Tg2576 mouse brains reduced the levels of plaques, A.,BACE1, and the active form of NFAT1 compared with fRAGE‐injected Tg2576 mice. Taken together, RAGE stimulates functional BACE1 expression through NFAT1 activation, resulting in more Aβ production and deposition in the brain.— Cho, H. J., Son, S. M., Jin, S. M., Hong, H. S., Shin, D. H., Kim, S. J., Huh, K., Mook‐Jung, I. RAGE regulates BACE1 and Aβ generation via NFAT1 activation in Alzheimers disease animal model. FASEBJ. 23, 2639–2649 (2009)

Low-Dose Growth Hormone Treatment with Diet Restriction Accelerates Body Fat Loss, Exerts Anabolic Effect and Improves Growth Hormone Secretory Dysfunction in Obese Adults

Growth hormone (GH) can induce an accelerated lipolysis. Impaired secretion of GH in obesity results in the consequent loss of the lipolytic effect of GH. Dietary restriction as a basic treatment for obesity is complicated by poor compliance, protein catabolism, and slow rates or weight loss. GH has an anabolic effect by increasing insulin-like growth factor (IGF)-I. We investigated the effects of GH treatment and dietary restriction on lipolytic and anabolic actions, as well as the consequent changes in insulin and GH secretion in obesity. 24 obese subjects (22 women and 2 men; 22–46 years old) were fed a diet of 25 kcal/kg ideal body weight (IBW) with 1.2 g protein/kg IBW daily and were treated with recombinant human GH (n = 12, 0.18 U/kg IBW/week) or placebo (n = 12, vehicle injection) in a 12-week randomized, double-blind and placebo-controlled trial. GH treatment caused a 1.6-fold increase in the fraction of body weight lost as fat and a greater loss of visceral fat area than placebo treatment (35.3 vs. 28.5%, p < 0.05). In the placebo group, there was a loss in lean body mass (–2.62 ± 1.51 kg) and a negative nitrogen balance (–4.52 ± 3.51 g/day). By contrast, the GH group increased in lean body mass (1.13 ± 1.04 kg) and had a positive nitrogen balance (1.81 ± 2.06 g/day). GH injections caused a 1.6-fold increase in IGF-I, despite caloric restriction. GH response to L-dopa stimulation was blunted in all subjects and it was increased after treatment in both groups. GH treatment did not induce a further increase in insulin levels during an oral glucose tolerance test (OGTT) but significantly decreased free fatty acid (FFA) levels during OGTT. The decrease in FFA area under the curve during OGTT was positively correlated with visceral fat loss. This study demonstrates that in obese subjects given a hypocaloric diet, GH accelerates body fat loss, exerts anabolic effects and improves GH secretion. These findings suggest a possible therapeutic role of low-dose GH with caloric restriction for obesity.

Oncogenic osteomalacia associated with mesenchymal tumour detected by indium‐111 octreotide scintigraphy

In a 40‐year‐old man who had suffered from vague and generalized bone pains for 7 years due to oncogenic osteomalacia, the causative tumour was finally detected by Indium‐111 octreotide scintigraphy. Some characteristics of the tumour associated with oncogenic osteomalacia, such as its size, growth rate, location and origin, often make the diagnosis difficult. However, the recent discovery of somatostatin receptors in mesenchymal tumours, which are the most common cause of oncogenic osteomalacia, has raised the possibility of early detection of this devastating disorder. Here, we report that radiolabelled octreotide scintigraphy has a potential role as a diagnostic tool in oncogenic osteomalacia. However, the exact role of somatostatin receptors in tumours associated with oncogenic osteomalacia still remains elusive.

The Prevalence of the Metabolic Syndrome in Korean Adults: Comparison of WHO and NCEP Criteria

The aims of this study were to compare the prevalence of the metabolic syndrome according to the WHO and NCEP ATP III criteria in Korean adults, and to compare the prevalence of the metabolic syndrome with the results in previous Korean studies. The study comprised 1,230 subjects (627 men, 603 women) aged 30-79 years (mean 52.4±10.3 years) who underwent medical check-up from April to June, 2001 in the Korea Association of Health (KAH). The prevalence of the metabolic syndrome according to the modified WHO criteria was 21.8% of men and 19.4% of women. However, the prevalence was increased 1.6 times (34.2%) in men and 2.0 times (38.7%) in women using the modified NCEP criteria. The prevalence of the metabolic syndrome has varied widely according to differences in the criteria. Thus, further studies are necessary to define the appropriate criteria of the metabolic syndrome for Korean adults.

Effects of growth hormone on insulin resistance and atherosclerotic risk factors in obese type 2 diabetic patients with poor glycaemic control

Objective  We aimed to evaluate the combined effects of GH treatment and diet restriction on lipolysis and anabolism, insulin resistance and atherosclerotic risk factors in obese patients with type 2 diabetes mellitus (T2DM).

Reduced erythropoietin responsiveness to anemia in diabetic patients before advanced diabetic nephropathy

We often encounter diabetic patients with anemia in whom the causes of anemia were not clearly identified despite differential hematologic studies. We therefore studied the clinical and biochemical characteristics of diabetic patients with anemia of uncertain cause and measured erythropoietin (Epo) concentrations in 35 diabetic subjects without significant diabetic renal disease. Among 62 medical records of diabetic patients with anemia, showing no evidence of advanced diabetic nephropathy (creatinine clearance > or = 30 mg/kg/1.73 m2), the causes of the anemia were not able to be identified in 28 cases (45.2%). In addition, we enrolled 35 diabetic patients with uncertain causes of anemia in order to evaluate the serum Epo responsiveness to anemia, and compared levels to a group of non-diabetic subjects also with anemia. The serum Epo concentrations of diabetic patients (17.6 +/- 8.1 mIU/ml) were significantly lower than those of non-diabetic patients with similar degree of decrease in hemoglobin concentrations (144.9 +/- 108.0 mIU/ml, P<0.001). The hemoglobin concentrations of diabetic patients correlated with creatinine clearance (r = 0.34, P = 0.03), serum creatinine (r = -0.49, P = 0.003) and albumin excretion rate (r = -0.44, P = 0.009), but showed no relation to age, duration of diabetes, glycated hemoglobin, presence of retinopathy or neuropathy. We concluded that reduced Epo responsiveness to anemia could explain the anemia present in diabetic patient but without advanced diabetic nephropathy. This may reflect early renal interstitial damage.

Long-term administration of acipimox potentiates growth hormone response to growth hormone-releasing hormone by decreasing serum free fatty acid in obesity

Obesity is associated with an impairment of normal growth hormone (GH) secretion and blunted responses to all stimuli. A high plasma free fatty acid (FFA) level is frequently observed in obesity. FFA participates in the regulation of pituitary GH secretion. To determine whether the derangement of GH secretion in obesity is associated with high plasma FFA levels, tests with GH-releasing hormone (GHRH) and acipimox (ACX), an antilipolytic agent able to decrease FFA, were undertaken in six obese subjects and seven normal control subjects. In addition, the effect of prolonged suppression of FFA level on GH response to GHRH after administration of ACX for 1 month was also examined in each of the obese subjects. The GH response in obese subjects (median, 9.1 microg/L) to GHRH (1-29) (1 microg/kg intravenously [IV]) was significantly blunted as compared with normal control subjects (23.5 microg / L, P < .05). Basal FFA levels were higher in obese subjects (855.2 microEq / L than in normal control subjects (514.6 microEq / L, P < .05). One-dose ACX (500 mg) decreased FFA levels in both obese and normal subjects: the lowest FFA levels in obese subjects (158.3 microEq/L 2 to 2.5 hours after ACX were similar to those of normal control subjects (108.7 microEq/L). One-dose ACX potentiated GHRH-stimulated GH response in both obese and normal subjects. GH responses potentiated by ACX in obese subjects (27.1 microg/L) were similar to GH responses to GHRH in normal control subjects, but lower than in normal subjects treated with ACX plus GHRH (58.5 microg / L, P < .05). Thereafter, all of the obese subjects were treated with ACX for 1 month, after which the ACX plus GHRH tests were repeated. After 1 month of acipimox administration in the obese subjects, GH responses (38.8 microg/L) were significantly higher than those of obese subjects treated with GHRH and one-dose ACX plus GHRH (P < .05). They were similar to GH responses of normal control subjects receiving the one-dose ACX plus GHRH test. In conclusion, in obesity the prolonged suppression of FFA levels induced by long-term administration of ACX potentiated somatotrope responsiveness, likely acting at the pituitary level, suggesting that the duration of FFA suppression had an important relation to the magnitude of GH response.

Tumor Necrosis Factor (TNF-α) and C-reactive Protein (CRP) are Positively Associated with the Risk of Chronic Kidney Disease in Patients with Type 2 Diabetes

Purpose Chronic low-grade inflammation may induce chronic kidney disease in patients with type 2 diabetes. This study investigated the relation between inflammatory biomarkers and chronic kidney disease in patients with type 2 diabetes, which has not yet been reported in Asian populations. Materials and Methods A cross-sectional study was performed in 543 patients recruited from diabetic clinics for an ongoing, prospective study. Multivariate logistic regression was used to evaluate the association between inflammatory biomarkers and the presence of chronic kidney disease (estimated glomerular filtration rate < 60 mL/min per 1.73 m2 by the simplified Modification of Diet in Renal Disease equation using plasma creatinine). Results The risk of chronic kidney disease increased in the highest quartiles of C-reactive protein (CRP) [multivariate odds ratio (OR) = 3.73; 95% CI = 1.19-1.70] and tumor necrosis factor-α (multivariate OR = 4.45; 95% CI = 1.63-12.11) compared to the lowest quartiles after adjustments for age, sex, zinc intake, and other putative risk factors for chronic kidney disease. Conclusion Our results suggest that CRP and tumor necrosis factor-α may be independent risk factors for chronic kidney disease in patients with type 2 diabetes. A causal mechanism of this association should be evaluated in a follow-up study of Korean patients with type 2 diabetes.