Association between BMI and risk of severe hypoglycaemia in type 2 diabetes.

AIM: This study aimed to assess the association between body mass index (BMI) and the development of severe hypoglycaemia in patients with type 2 diabetes (T2D), using nationwide data for the entire South Korean population. METHODS: The association between BMI and severe hypoglycaemia was retrospectively examined from claims and National Health examination data registered between 2002 and 2015. A total of 1,366,692 subjects assigned clinical codes for T2D and prescribed antihypoglycaemic agents were included. The primary outcome was an episode of severe hypoglycaemia after the baseline health examination. RESULTS: A total of 37,682 subjects (2.7%) experienced a new severe hypoglycaemic event during the follow-up period (mean: 8.6 years). An inverse J-shaped association was observed between BMI and severe hypoglycaemic events. The association between low BMI and high risk of severe hypoglycaemia was similar in subjects who had never smoked, did not consume alcohol, did not use insulin and had no major comorbidities, after adjusting for multiple confounding variables. This association was also found to be intensified in men, young people aged 30-49 years, those with major comorbidities and insulin users. CONCLUSION: BMI and severe hypoglycaemia were found to be inversely associated. Thus, those who fall into the category of having low BMI and high risk of severe hypoglycaemia should be warned about the risk of having a hypoglycaemic event and be properly informed about hypoglycaemia to minimize the risk of fatal hypoglycaemia-related outcomes.

Lipoprotein(a) predicts a new onset of chronic kidney disease in people with Type 2 diabetes mellitus.

AIMS: We investigated the association between lipoprotein(a) [Lp(a)] level and new-onset chronic kidney disease (CKD) in patients with Type 2 diabetes. METHODS: We conducted a prospective cohort study from March 2003 to December 2004 with a median follow-up time of 10.1 years. Patients aged 25-75 years with Type 2 diabetes and without CKD [estimated glomerular filtration rate (eGFR) ≥ 90 ml/min/1.73 m(2) ) were consecutively enrolled. The eGFR was measured at least twice every year , and new-onset CKD was defined as a decreased eGFR status of < 60 ml/min/1.73 m(2) using a Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation. RESULTS: Of the 862 patients who were enrolled, 560 (65.0%) completed the follow-up and 125 (22.3%) progressed to CKD. The mean age and duration of diabetes were 53.3 ± 9.6 and 7.5 ± 6.0 years, respectively. The baseline eGFR was 101.8 ± 11.3 ml/min/1.73 m(2) . After adjusting for multiple confounding factors, a Cox hazard regression analysis revealed that the third tertile of Lp(a) was significantly associated with the development of CKD during the observation period when compared with the first tertile [hazard ratio 2.12 (95% confidence interval 1.33-3.36); P = 0.001). CONCLUSIONS: In this prospective, longitudinal, observational cohort study, we demonstrated that the Lp(a) level was an independent prognostic factor for the future development of CKD in patients with Type 2 diabetes.

Cardiovascular autonomic dysfunction predicts acute ischaemic stroke in patients with Type 2 diabetes mellitus: a 7-year follow-up study.

AIMS: We investigated whether cardiovascular autonomic neuropathy (CAN) is associated with acute ischaemic stroke in patients with Type 2 diabetes. METHODS: From 1999 to 2000, cardiovascular autonomic function tests were conducted in patients with Type 2 diabetes (n = 1458). Patients were followed up between 2006 and 2007. Standard tests for CAN measured heart rate variability parameters [expiration-to-inspiration (E/I) ratio, responses to the Valsalva manoeuvre and standing]. Using the American Diabetes Association criteria, the CAN scores were determined from the results of each test as follows: 0 = normal, 1 = abnormal (total maximum score 3). We assessed the development of acute ischaemic stroke events. RESULTS: The prevalence of CAN at baseline was 55.7% (E/I 17.1%, Valsalva 39.4%, posture 27.3%) (n = 1126). During follow-up, 131 patients (11.6%) developed acute ischaemic stroke. The vascular events were more frequent in older patients (P < 0.001) and in those with diabetes of longer duration (P = 0.022), hypertension (P < 0.001) or diabetic retinopathy (P = 0.03) than in patients without vascular events. Patients with ischaemic stroke had higher creatinine levels (P = 0.045) and higher urine albumin excretion (P = 0.025) than those of patients without stroke. Cox proportional hazard regression analysis revealed that the CAN score was associated with the development of acute ischaemic stroke (total score 0 vs. 3, adjusted hazard ratio 2.7, 95% CI 1.3-5.5, P = 0.006). CONCLUSION: Cardiovascular autonomic dysfunction was significantly associated with the development of ischaemic stroke in patients with Type 2 diabetes.

Long-term effects of a structured intensive diabetes education programme (SIDEP) in patients with Type 2 diabetes mellitus--a 4-year follow-up study.

AIMS: Patient education is a very important part of diabetes care. However, until now, little data has been presented about the long-term effectiveness of structured intensive diabetes education programmes (SIDEP) for people with Type 2 diabetes mellitus. METHODS: People with Type 2 diabetes (n = 547) hospitalized from December 1999 to December 2000 were randomly assigned to two groups. Two hundred and nineteen patients undertook an inpatient SIDEP and the remaining patients received conventional glycaemic control without intensive education. After discharge, all patients were monitored regularly. Laboratory data were obtained, and adherence to self-care behaviour was determined on a five-point scale by questionnaires completed annually. RESULTS: Of the patients who completed the SIDEP, 160 (73.1%) were followed up for more than 4 years. The mean HbA(1c) (7.9 +/- 1.2 vs. 8.7 +/- 1.6%; P < 0.05) and the frequency of hospitalization related to diabetes per patient per year (0.3 +/- 0.6 vs. 0.8 +/- 0.9; P < 0.05) was significantly lower in the SIDEP group than in the control group. The SIDEP group adhered more closely to self-care behaviour than the control group over 4 years (P < 0.05). People with Type 2 diabetes mellitus of longer duration and those treated with insulin had poorer HbA(1c) at follow-up. CONCLUSIONS: A well-designed, intensive patient education programme is necessary for people with diabetes. However, regular and sustained reinforcement with encouragement is also required to maintain optimal glycaemic control, especially in insulin-treated patients.

Changes in gene expression in beta cells after islet isolation and transplantation using laser-capture microdissection.

AIMS/HYPOTHESIS: The process of islet isolation can cause chemical and mechanical injury to beta cells. In addition, hyperglycaemia after islet transplantation can compromise beta cell function. The aim of this experiment was to evaluate changes in gene expression in endogenous islets using laser-capture microdissection (LCM). MATERIALS AND METHODS: Islets from B6AF1 mice were studied in situ in the pancreas as well as those freshly isolated or cultured for 24 h. Fresh islets were transplanted under the kidney capsule of syngeneic diabetic (streptozocin-induced) and non-diabetic mice. Frozen sections from all the samples were prepared for LCM to obtain beta cell-enriched tissue; RNA was extracted and amplified using T7 polymerase. RT-PCR was used to assess expression of selected genes critical for beta cell function (Ins, Ipf1 [previously known as Pdx1], Slc2a2 [previously known as GLUT2] and Ldha) and the stress response (Hmox1 [previously known as HO-1], Gpx1, Tnfaip3 [previously known as A20] and Fas). Immunostaining was also performed. RESULTS: In freshly isolated and cultured islets, insulin and Ipf1 mRNA levels were decreased by 40% (compared with islets in situ), while stress genes were upregulated. Comparison between in situ pancreatic islets and engrafted beta cells of cured mice showed declines in Ipf1 expression. CONCLUSIONS/INTERPRETATION: Our experiment, the first report to investigate changes in gene expression in endogenous islets using LCM, indicate that beta cells following islet isolation and residing in a foreign graft environment have decreased expression of genes involved in insulin production and increased expression of stress genes. Our data suggest that an islet graft, even in successful transplantation, may be different from endogenous islets in gene expression.

Methods and evaluations of MRI content-adaptive finite element mesh generation for bioelectromagnetic problems.

In studying bioelectromagnetic problems, finite element analysis (FEA) offers several advantages over conventional methods such as the boundary element method. It allows truly volumetric analysis and incorporation of material properties such as anisotropic conductivity. For FEA, mesh generation is the first critical requirement and there exist many different approaches. However, conventional approaches offered by commercial packages and various algorithms do not generate content-adaptive meshes (cMeshes), resulting in numerous nodes and elements in modelling the conducting domain, and thereby increasing computational load and demand. In this work, we present efficient content-adaptive mesh generation schemes for complex biological volumes of MR images. The presented methodology is fully automatic and generates FE meshes that are adaptive to the geometrical contents of MR images, allowing optimal representation of conducting domain for FEA. We have also evaluated the effect of cMeshes on FEA in three dimensions by comparing the forward solutions from various cMesh head models to the solutions from the reference FE head model in which fine and equidistant FEs constitute the model. The results show that there is a significant gain in computation time with minor loss in numerical accuracy. We believe that cMeshes should be useful in the FEA of bioelectromagnetic problems.

Clinical characteristics of diabetic ketoacidosis in Korea over the past two decades.

AIMS: The aim of this study was to investigate changes in the clinical characteristics of diabetic ketoacidosis (DKA) in Korea over the last two decades. METHODS: A retrospective medical record review of all episodes of DKA from 1982 to 2002 in four University-affiliated urban hospitals in Korea was performed. A total of 255 episodes of DKA (217 patients) were identified and divided into three consecutive 7-year periods to compare trends over time. Clinical characteristics including precipitating factors and hospital mortality were analyzed. RESULTS: A dramatic increase in DKA admissions has occurred over the last two decades, accompanied by a marked increase in admissions of diabetic patients. The clinical characteristics of DKA remained constant over the observation period. Non-compliance to treatment was the most common precipitating factor of DKA. A total of 30 patients died in hospital (11.8% of all episodes). Older age and infection appeared to influence mortality. CONCLUSIONS: Our results suggest that rapidly increasing episodes of DKA in Korea, in parallel with increases in the numbers of diabetic patients, continue to be associated with significant mortality.

Dexamethasone suppresses the expansion and transdifferentiation of transplanted porcine neonatal pancreas cell clusters (NPCCs) into beta-cells in normal nude mice.

OBJECTIVES: This study was performed to investigate the effect of dexamethasone on the expansion and transdifferentiation of transplanted neonatal pancreas cell clusters (NPCCs) in vivo. METHODS: Porcine NPCCs were generated from 1 to 3-day-old neonatal pigs. After transplantation (Tx) of 4000 islet equivalents (IEqs) of NPCCs beneath the renal subcapsular space of normoglycemic nude mice, dexamethasone (Dx, 1 mg/kg) or vehicles were injected daily. Intraperitoneal glucose tolerance testing (ip-GTT) was performed at 4 weeks (n = 4) and 10 weeks (n = 7) after Tx. After harvesting the grafts, total graft and beta-cell graft mass were determined by morphometric analysis. RESULTS: Although the mean value of AUCg was elevated in the Dx-treated group at 10 weeks after Tx, the glucose levels of all the animals by ip-GTT were within the normal range. At 10 weeks after Tx, the relative volume, absolute mass of beta-cells in the graft, and total graft mass were significantly lower in the Dx-treated group (relative volume of beta-cells: 22.0% versus 35.3%, P < 0.05; beta-cells mass: 1.0 +/- 1.2 mg versus 2.2 +/- 5.6 mg, P < 0.05, total graft mass: 4.4 +/- 5.4 mg versus 6.3 +/- 1.3 mg, P < 0.05, Dx-treated versus control), but there was no difference at 4 weeks. Morphologically prominent cystic structures were observed in the Dx group at 10 weeks. CONCLUSION: Our results suggest that dexamethasone suppresses the expansion and transdifferentiation of transplanted porcine NPCCs into beta-cells in normal nude mice.

Expression of the intermediate filament vimentin in proliferating duct cells as a marker of pancreatic precursor cells.

OBJECTIVES: The expression of the intermediate filament (IF) vimentin, usually considered a marker of mesenchymal cells, has been observed in the epithelial cells during embryogenesis, carcinogenesis, and dedifferentiation, suggesting that it might be useful as a marker of proliferating precursor cells in the pancreas. METHODS: Rat pancreata at E18 and at different time points after partial pancreatectomy (Px) and human and neonatal pig pancreatic tissue sections and monolayer cultured pancreatic duct cells were observed. All tissues were simultaneously immunostained with pancytokeratin and vimentin antibodies. In costained duct cells, PDX-1 or PCNA expression was also analyzed using confocal microscope images. RESULTS: In the rat embryonic pancreas at E18, all epithelial cells that formed ductlike structures expressed both cytokeratin and vimentin IF, whereas no duct cells costained for IF in the adult rat or neonatal pig pancreas. Such costaining reappeared in the following order: common pancreatic duct, main ducts, foci of regeneration and then disappeared completely at 30 days after Px. In humans, costaining was found in only 1 diabetic patient's pancreatic section, which was accompanied by massive duct cell proliferation. In monolayer culture, most of the duct cells of human and neonatal pigs coexpressed both IF proteins. Only a few costained duct cells also expressed PDX-1, and most of those cells were also stained with PCNA in rat embryonic pancreas and regenerating foci after partial Px. CONCLUSIONS: Vimentin IF expression might be a useful marker for pancreatic precursor cells and could be used to investigate the concept of the dedifferentiation of fully matured duct cells during the process of the beta-cell neogenesis.

Hypodipsic hypernatremia with intact AVP response to non-osmotic stimuli induced by hypothalamic tumor: a case report.

Anatomical lesions of hypothalamic area associated with hypodipsic hypernatremia have been reported only rarely. We report here a case of hypodipsic hypernatremia induced by a hypothalamic lesion. A 25-yr-old man, who had been treated with radiation for hypothalamic tumor 5-yr before, was admitted for evaluation of hypernatremia and hypokalemia. He never felt thirst despite the elevated plasma osmolality and usually refused to drink intentionally. Plasma arginine vasopressin (AVP) level was normal despite the severe hypernatremic hyperosmolar state and urine was not properly concentrated, while AVP secretion was rapidly induced by water deprivation and urine osmolality also progressively increased to the near maximum concentration range. All of these findings were consistent with an isolated defect in osmoregulation of thirst, which was considered as the cause of chronic hypernatremia in the patient without an absolute deficiency in AVP secretion. Hypokalemia could be induced by activation of the renin-angiotensin-aldosterone system as a result of volume depletion. However, inappropriately low values of plasma aldosterone levels despite high plasma renin activity could not induce symptomatic hypokalemia and metabolic alkalosis. The relatively low serum aldosterone levels compared with high plasma renin activity might result from hypernatremia. Hypernatremia and hypokalemia were gradually corrected by intentional water intake only.

The effect of cilostazol on glucose tolerance and insulin resistance in a rat model of non-insulin dependent diabetes mellitus.

BACKGROUND: It has been reported that many peripheral vasodilating drugs might improve insulin resistance. Cilostazol, a antithrombotic agent, increases peripheral blood flow in non-insulin dependent diabetic patients. The effect of cilostazol treatment on insulin resistance in streptozotocin (STZ)-induced non-insulin dependent diabetic Wistar rats was examined. METHODS: About a half of two-day old neonate siblings were injected intraperitoneally with STZ and maintained for six months, at which time they were compared with age-matched control rats for intraperitoneal glucose tolerance test (IPGTT) and for glucose infusion rate (GINF) in a euglycemic hyperinsulinemic glucose-clamp study. After that, these studies were also performed after feeding rat chow containing cilostazol (100 mg/kg/day) to rats with STZ-induced non-insulin dependent diabetes mellitus for four-weeks and compared with those of age-matched control rats. RESULTS: In the intraperitoneal glucose tolerance test studies, plasma glucose levels of STZ-induced non-insulin dependent diabetic rats were significantly higher and plasma insulin levels significantly lower than those of age-matched control rats in the age of six months. Glucose infusion rate was lower in STZ-induced non-insulin dependent diabetic rats than those of age-matched control rats. However, after a four-week cilostazol treatment, glucose infusion rate of STZ-induced non-insulin dependent diabetic rats was not significantly different from that of control rats. CONCLUSION: These findings suggested that cilostazol may improve insulin resistance in STZ-induced non-insulin dependent diabetic rats.

Survival of a GFP-Labeled Polychlorinated Biphenyl Degrading Psychrotolerant Pseudomonas spp. in 4 and 22 degrees C Soil Microcosms.

The green fluorescent protein gene (gfp) was inserted into the chromosome of Pseudomonas spp. Cam-1 and Sag-50G, two psychrotolerant polychlorinated biphenyl (PCB)-degrading bacteria. The gfp-transformed microorganisms, designated Cam-1-gfp1, Cam-1-gfp2, Sag-50G-gfp1, and Sag-50G-gfp2, exhibited green fluorescence under an epifluorescent microscope. The gfp was inserted into the chromosome of each psychrotolerant strain and was stable with no apparent adverse affects on the metabolism and growth of each organism. Activity of gfp-transformed microorganisms against biphenyl and 2,3-dichlorobiphenyl was determined by assaying for BphC activity and by resting cell assays. The patterns of BphC activity at two different growth temperatures in batch cultures were similar for each of the gfp-transformed microorganisms. Resting cell assays of both the parent strains (Cam-1, Sag-50G) and the gfp-transformed strains (Cam-1-gfp1, Cam-1-gfp2, Sag-50G-gfp1, Sag-50G-gfp2), grown on glycerol or glucose, exhibited BphC activity to a lesser extent and at a slower rate than those observed for biphenyl grown cells. In addition, all gfp-transformed microorganisms degraded 2,3-dichlorobiphenyl (2,3-DCB) in broth to the same extent as the parent strains. When Cam-1-gfp1 and Sag-50G-gfp1 were used as a bioremediation amendment in soil microcosms spiked with 2,3-DCB, both strains survived in high numbers (5.6 to 7.9 log cfu g?1 and 5.6 to 8.0 log cfu g?1) when inoculated into nonsterilized soil over 16 weeks at 22 degrees C and 18 weeks at 4 degrees C, respectively. Biodegradation of 2,3-DCB was enhanced with the microbial amendment; however, the addition of sunflower oil did not help the PCB degrading bacteria and may have enhanced the growth of the indigenous population, thereby decreasing the amended PCB-degrading population.

New ADA criteria in the Korean population: fasting blood glucose is not enough for diagnosis of mild diabetes especially in the elderly.

BACKGROUND: To compare the 1997 American Diabetes Association (ADA) criteria with the 1985 World Health Organization (WHO) criteria in categorization of the diabetes diagnostic status of Koreans and to define clinical characteristics of subjects diagnosed differently by the two criteria. METHODS: In 810 Korean subjects, we analyzed blood glucose and insulin response during 75 g oral glucose tolerance test (OGTT). According to current WHO criteria, the cutoff values of FPG which distinguish normal and IGT from diabetes were determined. Then the subjects were categorized according to both WHO and ADA criteria. The clinical characteristics of the subjects with different diagnostic categories by the two criteria were defined. RESULTS: The FPG cut point distinguishing diabetes from IGT was 117 mg/dl, and from normal was 110 mg/dl. The overall agreement between the ADA criteria and the WHO criteria was moderate, as reflected in the kappa of 0.45. 141 of subjects categorized diabetes by WHO criteria were not diagnosed with ADA criteria. These discordant subjects were older in age and showed blunted early insulin response than concordant normal subjects. CONCLUSION: These results suggest that mild diabetes by the WHO criteria, especially in the elderly, would not be diagnosed as diabetes by the ADA FPG criteria only. Thus, in a group at high risk for developing diabetes or in a relatively older age group, we should continue using the OGTT.

The effect of long-term glycaemic control on serum lipoprotein(a) levels in patients with Type 2 diabetes mellitus.

AIMS: To examine whether long-term glycaemic control affects lipoprotein(a) (Lp(a)) levels in patients with Type 2 diabetes mellitus. METHODS: Eighty-nine Type 2 diabetic patients (38 men, 51 women) were recruited from the diabetes clinic. Based on HbA1c concentrations at baseline, patients were divided into two groups: those with HbA1c < 8.0% (n =45) and those with HbA1c > or = 8.0% (n=44). Comparisons of Lp(a) levels were made between both groups. The effect of long-term glycaemic control on Lp(a) levels was investigated in a subgroup of 20 patients, selected from those with baseline HbA1c > or = 8%. All these patients were treated with a goal of HbA1c <7%. RESULTS: Lp(a) levels were not significantly different between those with HbA1c< 8.0% and those with HbA1c, > or = 8.0%. No correlation between Lp(a) and HbA1c or fasting blood glucose levels was noted in diabetic patients as a whole. After 2 years of intensive glycaemic control, all patients exhibited remarkable improvement of therapy: their average HbA1c levels were 6.5 +/- 0.7%, being < 7% in 70% of patients. However, no change in Lp(a) levels were observed after 2 years (19.5 +/- 14.8-21.4 +/- 13.4 mg/dl, P = 0.390). CONCLUSION: These results indicate that improvement of glycaemic control does not affect serum Lp(a) levels in patients with Type 2 diabetes mellitus.

Estimation of mean frequency and variance of ultrasonic Doppler signal by using second-order autoregressive model.

In order to estimate the mean frequency and variance of the diagnostic ultrasound Doppler signal in the presence of clutter noise, a new estimator using a second-order autoregressive (AR) model, called the AR estimator, is proposed. The sampled signal that contains information of both the Doppler signal and clutter is described by the second-order AR model with two poles. The mean frequency and variance of a unidirectional Doppler signal can be estimated, respectively, from the phase and the magnitude of the pole, with larger phase between the two poles. If the clutter is not completely rejected, all conventional estimators, including the autocorrelation (AC) estimator, result in erroneous estimations for the mean frequency and variance of the Doppler signal, whereas the AR estimator gives an accurate estimation. In the absence of clutter, however, the performance of both the AC and AR estimators are similar. If the blood flows in both directions in a sample volume and the clutter is rejected to the extent that it no longer obscures the Doppler signal, the proposed method can estimate simultaneously the mean frequencies and variances of both the forward and reverse blood flows. The performance of the proposed AR estimator was compared with that of the AC estimator by computer simulations and experiments, and it was found that when the number of available sampled data is small, the AR estimator does not require the use of a clutter filter, which simplifies Doppler signal detection.