Low-dose pioglitazone can ameliorate learning and memory impairment in a mouse model of dementia by increasing LRP1 expression in the hippocampus.

Amyloid-ß (Aß) accumulation in the brain is a pathological feature of Alzheimer's disease (AD) and enhancing Aß clearance is a potential therapeutic strategy. Pioglitazone is a peroxisome proliferator-activated receptor-γ (PPAR-γ) agonist and is widely used to treat type 2 diabetes. We previously reported that low-dose pioglitazone increased the expression of low-density lipoprotein receptor-related protein 1 (LRP1), which upregulates the clearance of Aß, using human brain microvascular endothelial cells. We investigated whether low-dose pioglitazone can rescue the pathological phenotype and memory impairment in senescence-accelerated mouse prone-8 (SAMP8) mice by increasing LRP1 levels. SAMP8 mice were treated with vehicle or pioglitazone in dosages of 2 or 5 mg/kg/day for 7 weeks. In the water maze test, 2 mg/kg/day of pioglitazone significantly attenuated the increased escape latency in SAMP8 mice (p = 0.026), while 5 mg/kg/day of treatment did not. Compared with vehicle treatment, the hippocampi of SAMP8 mice with 2 mg/kg/day of pioglitazone exhibited fewer Aß deposits and reduced Aß1-40 levels, along with elevated LRP1 expression (p = 0.005). Collectively, our results proposed that a new therapeutic application of the PPAR-γ agonist for AD treatment should be considered at a lower dose than the conventional dose used to treat diabetes.

Prevalence and risk factors for reduced pulmonary function in diabetic patients: The Korea National Health and Nutrition Examination Survey.

BACKGROUND/AIMS: An association between reduced pulmonary function and diabetes has been observed. Our aim was to evaluate the prevalence and risk factors associated with reduced pulmonary function in diabetic patients. METHODS: We analyzed data from the Korea National Health and Nutrition Examination Survey 2011 to 2013. The study population included data from 8,784 participants (including 1,431 diabetics) aged ≥ 40 years. Reduced pulmonary function was defined as patients with restrictive (forced expiratory volume in 1 second/forced vital capacity [FEV1/FVC] ≥ 0.7 and FVC < 80% of predicted value) or obstructive (FEV1/FVC < 0.7) patterns. RESULTS: Subjects with diabetes had a higher prevalence of restrictive (18.4% vs. 9.4%, p < 0.001) and obstructive impairments (20% vs. 12.6%, p < 0.001) than those without diabetes. The adjusted odds ratios (aORs) (95% confidence interval [CI]) for obstructive and restrictive pulmonary impairment were 0.91 (0.75 to 1.11) and 1.57 (1.30 to 1.89), respectively. In the diabetes population, age (aOR, 1.04; 95% CI, 1.02 to 1.06), male sex (aOR, 1.40; 95% CI, 1.04 to 1.88), and body mass index (aOR, 1.15; 95% CI, 1.10 to 1.21) were independently associated with restrictive pulmonary impairment. Age (aOR, 1.12; 95% CI, 1.09 to 1.14), male sex (aOR, 4.24; 95% CI, 2.42 to 7.44), and smoking at any point (ever-smoker: aOR, 1.96; 95% CI, 1.16 to 3.33) were independent risk factors for obstructive pulmonary impairment in diabetics. Diabetes duration or glycated hemoglobin had no association with pulmonary impairment in diabetes. CONCLUSIONS: Subjects with diabetes had a higher risk of restrictive pulmonary impairment than those without diabetes after adjusting for confounding factors. Older age, male sex, body mass index, and smoking were associated with reduced lung function in diabetes.

Prevalence and risk factors of periodontitis among adults with or without diabetes mellitus.

BACKGROUND/AIMS: This study examined prevalence and risk factors of periodontitis in representative samples of Korean adults, with and without diabetes mellitus (DM). METHODS: Data from the 2012 Korean National Health and Nutritional Examination Survey were analyzed. A total of 4,477 adults (≥ 30 years old) were selected from 8,057 individuals who completed a nutrition survey, a self-reported general health behavior questionnaire, an oral examination, an oral hygiene behaviors survey, and laboratory tests. DM was defined as a fasting plasma glucose ≥ 126 mg/dL, or self-reported diagnosed diabetes, or current use of oral hypoglycemic agents and/or insulin. The community periodontal index was used to assess periodontitis status and comparisons between the periodontitis and the non-periodontitis group, were performed, according to the presence of DM. Risk factors for periodontitis in adults with DM and without DM were evaluated by multiple logistic regression analysis. RESULTS: The prevalence of periodontitis was significantly higher in adults with DM (43.7%) than in those without DM (25%, p < 0.001). In adults without DM, risk factors for periodontitis were older age, male, urban habitation, waist circumference, smoking, oral pain, and less frequent tooth brushing. Significant risk factors for periodontitis in adults with DM were the smoking, oral pain, and not-using an oral hygiene product. CONCLUSIONS: Adults with DM have an increased risk of periodontitis than those without DM. Current smoking and oral pain increase this risk. Using an oral hygiene product can reduce risk of periodontal disease in adults with DM.

1,5-anhydroglucitol as a useful marker for assessing short-term glycemic excursions in type 1 diabetes.

BACKGROUND: Type 1 diabetes is associated with more severe glycemic variability and more frequent hypoglycemia than type 2 diabetes. Glycemic variability is associated with poor glycemic control and diabetic complications. In this study, we demonstrate the clinical usefulness of serum 1,5-anhydroglucitol (1,5-AG) for assessing changes in glycemic excursion in type 1 diabetes. METHODS: Seventeen patients with type 1 diabetes were enrolled in this study. A continuous glucose monitoring system (CGMS) was applied twice at a 2-week interval to evaluate changes in glycemic variability. The changes in serum glycemic assays, including 1,5-AG, glycated albumin and hemoglobin A1c (HbA1c), were also evaluated. RESULTS: Most subjects showed severe glycemic excursions, including hypoglycemia and hyperglycemia. The change in 1,5-AG level was significantly correlated with changes in the glycemic excursion indices of the standard deviation (SD), mean amplitude of glucose excursion (MAGE), lability index, mean postmeal maximum glucose, and area under the curve for glucose above 180 mg/dL (r=-0.576, -0.613, -0.600, -0.630, and -0.500, respectively; all P<0.05). Changes in glycated albumin were correlated with changes in SD and MAGE (r=0.495 and 0.517, respectively; all P<0.05). However, changes in HbA1c were not correlated with any changes in the CGMS variables. CONCLUSION: 1,5-AG may be a useful marker for the assessment of short-term changes in glycemic variability. Furthermore, 1,5-AG may have clinical implications for the evaluation and treatment of glycemic excursions in type 1 diabetes.

Effect of cilostazol on carotid intima-media thickness in type 2 diabetic patients without cardiovascular event.

We investigated the efficacy of cilostazol treatment for 2 years on the attenuation of carotid intima-media thickness (IMT) progression in type 2 diabetic patients without cardiovascular disease history, as compared with other antiplatelet agents. We recruited a total of 230 type 2 diabetic patients who had undergone IMT measurement twice within 1.5-2.5 years (mean 2.06 ± 0.32 years) interval. Among these participants, we classified them into three groups according to antiplatelet agent administration at baseline: Group I (n = 66), antiplatelet naïve; Group II (n = 75), other antiplatelet agent administration; and Group III (n = 50), cilostazol administration. We then analyzed the changes in clinical characteristics from baseline to 2 years. The changes in annual mean IMT at 2 years were 0.019 ± 0.045 mm/year, -0.001 ± 0.058 mm/year, and -0.019 ± 0.043 mm/year for Group I, II, and III, respectively (P < 0.001). Mean change in total cholesterol, low-density lipoprotein-cholesterol, and triglyceride compared with baseline decreased the most in Group III even after adjustment for statin use. We also observed that the odds ratio of carotid IMT progression at 2 years was the lowest in patients who were treated with cilostazol even after adjustment for change of metabolic parameters. When we categorized patients according to baseline carotid IMT tertile, the efficacy of cilostazol against carotid IMT progression was significant only when baseline IMT was over 0.662 mm (mean 0.801). Two-year treatment with cilostazol strongly inhibited carotid IMT progression compared to other antiplatelet agents in type 2 diabetic patients. This beneficial effect of cilostazol was significant when baseline IMT was thicker than 0.662 mm (mean 0.801 mm).

High prevalence of spine­femur bone mineral density discordance and comparison of vertebral fracture risk assessment using femoral neck and lumbar spine bone density in Korean patients.

The aim of this study was to evaluate the prevalence of spine­femur discordance, and to compare the effectiveness of femoral neck (FN) and lumbar spine (LS) bone mineral density (BMD) for estimation of the risk of vertebral fractures. Women who were evaluated with dual energy X-ray absorptiometry between January 2001 and December 2005 were enrolled in this study. Vertebral fracture risk was calculated using initial FN and LS BMD. The follow-up vertebral X-rays from all subjects were reviewed, and the calculated estimated risk using the Fracture Risk Assessment Tool (FRAX(®)) was compared with the actual prevalence of vertebral fractures during the follow-up period. Among a total of 443 women with a mean age of 58.5 years, 130 women (29.3 %) demonstrated femur­spine discordance (i.e., a difference between FN and LS BMD of [1 SD). Most subjects having discordance showed lower LS BMD (73.1 %) compared to FN BMD. During the mean 7-year follow-up period, 12 (2.7 %) vertebral fractures occurred. In cases with high estimated fracture risk ([20 % for estimated fracture risk), using LSBMD significantly reflected the actual vertebral fracture in total subjects [odds ratio (OR) 19.29, 95 % confidence interval (CI) 4.21­88.46], in subjects with spine­femur discordance (OR 16.00, 95 % CI 1.91­134.16), and in subjects with spine­femur discordance having lower LSBMD (OR 20.67, 95 % CI 1.63­262.71). In comparison, the estimated risk using FN BMD did not reflect the actual occurrence of vertebral fractures. In conclusion, a significant number of Korean subjects exhibited spine­femur discordance, and LS BMD might be more appropriate for estimation of vertebral fracture risk.

Refocusing Peroxisome Proliferator Activated Receptor-α: A New Insight for Therapeutic Roles in Diabetes.

Although glucose-lowering treatment shows some risk lowering effects in cardiovascular diseases, risks of macrovascular and microvascular complications have still remained, and development of new therapeutic strategies is needed. Recent data have shown that peroxisome proliferator activated receptor-α (PPAR-α) plays a pivotal role in the regulation of lipid homeostasis, fatty acid oxidation, cellular differentiation, and immune response such as inflammation or vascularization related to diabetic complication. This review will re-examine the metabolic role of PPAR-α, summarize data from clinical studies on the effect of PPAR-α agonist in diabetes, and will discuss the possible therapeutic role of PPAR-α activation.

Rosiglitazone attenuates casein-induced hepatic endoplasmic reticulum stress in Sprague-Dawley rats: a novel model of endoplasmic reticulum stress.

The proteins found in cow milk have been reported to cause systemic inflammation. Endoplasmic reticulum (ER) stress is known to be involved in the development of several metabolic disorders including insulin resistance and non-alcoholic fatty liver disease. However, the effect of thiazolidinediones (TZDs) on ER stress is still controversial. This is why we want to investigate in this study whether casein, which is the major protein in cow's milk, induces ER stress in the liver and whether rosiglitazone can attenuate these changes. Nine-week-old male Sprague-Dawley (SD) rats were separated into three groups: (1) vehicle treated; (2) daily subcutaneous injections of 1 mL 10% casein; (3) daily subcutaneous injection of 1 mL 10% casein and rosiglitazone 4 mg/[kg d]. After 6 weeks, body weight, food intake, glucose and lipid parameters, and serum AST/ALT levels were measured after an overnight fast. Real time RT-PCR and immunohistochemical staining for various ER stress markers were performed, and a TUNEL analysis was also performed. After 6 weeks, casein injection induced weight reduction, systemic inflammation, and hepatic dysfunction in SD rats. Casein injection increased both the gene and protein expression of ER stress markers in the liver and also caused hepatocyte apoptosis. Rosiglitazone treatment attenuated casein-induced systemic inflammation, ER stress, deteriorated liver function, and increased apoptosis. In conclusion, our results may provide further insight into the effects of casein on chronic inflammatory diseases, and to have a better understanding of the mechanism of the anti-inflammatory properties of rosiglitazone regardless of its hypoglycemic effect.

Analysis of 18F-fluorodeoxyglucose positron emission tomography findings in patients with pituitary lesions.

BACKGROUND/AIMS: Although magnetic resonance imaging (MRI) is a good visual modality for the evaluation of pituitary lesions, it has limited value in the diagnosis of mixed nodules and some cystic lesions. We evaluated the usefulness of (18)F-fluorodeoxyglucose positron emission tomography (FDG PET) for patients with pituitary lesions. METHODS: (18)F-FDG PET and MRI were performed simultaneously in 32 consecutive patients with pituitary lesions. The relationships between FDG uptake patterns in PET and MRI findings were analyzed. RESULTS: Of 24 patients with piuitary adenomas, 19 (79.2%) showed increased uptake of (18)F-FDG in the pituitary gland on PET scans. All patients with pituitary macroadenomas showed increased (18)F-FDG uptake on PET scans. Meanwhile, only five (50%) of the 10 patients with pituitary microadenomas showed positive PET scans. Interestingly, of two patients with no abnormal MRI findings, one showed increased (18)F-FDG uptake on PET. For positive (18)F-FDG uptake, maximum standardized uptake values (SUV(max)) > 2.4 had 94.7% sensitivity and 100% specificity. In addition, SUV(max) increased in proportion to the size of pituitary adenomas. Most cystic lesions did not show (18)F-FDG uptake on PET scans. CONCLUSIONS: About 80% of pituitary adenomas showed positivity on PET scans, and SUV(max) was related to the size of the adenomas. PET may be used as an ancillary tool for detection and differentiation of pituitary lesions.

Balsamic Vinegar Improves High Fat-Induced Beta Cell Dysfunction via Beta Cell ABCA1.

BACKGROUND: The aim of this study was to investigate the effects of balsamic vinegar on ß-cell dysfunction. METHODS: In this study, 28-week-old Otsuka Long-Evans Tokushima Fatty (OLETF) rats were fed a normal chow diet or a high-fat diet (HFD) and were provided with tap water or dilute balsamic vinegar for 4 weeks. Oral glucose tolerance tests and histopathological analyses were performed thereafter. RESULTS: In rats fed both the both chow diet and the HFD, the rats given balsamic vinegar showed increased insulin staining in islets compared with tap water administered rats. Balsamic vinegar administration also increased ß-cell ATP-binding cassette transporter subfamily A member 1 (ABCA1) expression in islets and decreased cholesterol levels. CONCLUSION: These findings provide the first evidence for an anti-diabetic effect of balsamic vinegar through improvement of ß-cell function via increasing ß-cell ABCA1 expression.

High prevalence of both anti-insulin and anti-insulin receptor antibodies in Korean patients with insulin autoimmune syndrome.

We performed a retrospective pooled analysis of 28 patients who had been diagnosed with insulin autoimmune syndrome and evaluated the prevalence of anti-insulin receptor antibodies. Dual positivity for anti-insulin and anti-insulin receptor antibodies was common (53.8%). However, these patients had a similar phenotype compared with insulin receptor antibody-negative patients.

Effect of teriparatide on pregnancy and lactation-associated osteoporosis with multiple vertebral fractures.

Pregnancy and lactation-associated osteoporosis (PLO) is very rare, but it can cause severe vertebral compression fractures with disabling back pain. PLO patients have commonly been treated with antiresorptive agents against high bone turnover. There are, however, some concerns regarding the use of bisphosphonates: (1) PLO occurs during the first pregnancy with a high possibility of recurrence during the second pregnancy, (2) long-term outcomes of bisphosphonates in PLO are lacking, and (3) there is a possibility of bisphosphonates accumulated in the bones crossing the placenta. Therefore, alternative therapies must be considered. We analyzed the effect of teriparatide (TPTD), the human recombinant parathyroid hormone (1-34), for 18 months in three women with PLO. Multiple vertebral fractures with severe back pain appeared within 6 months after their first childbirth. Two of them had a family history of osteoporosis. Lactation was discontinued immediately after diagnosis of PLO. Calcium carbonate, cholecalciferol, and TPTD were prescribed. The back pain immediately resolved. Bone mineral density (BMD) increased by 14.5-25.0% (mean 19.5%) at the lumbar spine and by 9.5-16.7% (mean 13.1%) at the femoral neck, after 18 months of treatment. The final Z scores in these PLO patients were nearly normalized. Two women had a second baby without any complication. BMD significantly improved after 18 months of treatment with TPTD without further fractures. In conclusion, TPTD should be considered to avoid long-term morbidity in young patients with PLO and is highly encouraged for use in PLO patients with multiple vertebral fractures.