Melatonin ameliorates SGLT2 inhibitor-induced diabetic ketoacidosis by inhibiting lipolysis and hepatic ketogenesis in type 2 diabetic mice.

Sodium-glucose cotransporter-2 inhibitors (SGLT2i) are effective hypoglycemic agents that can induce glycosuria. However, there are increasing concerns that they might induce diabetic ketoacidosis. This study investigated the effect of melatonin on SGTL2i-induced ketoacidosis in insulin-deficient type 2 diabetic (T2D) mice. The SGLT2i dapagliflozin reduced blood glucose level and plasma insulin concentrations in T2D mice, but induced increases in the concentrations of plasma ß-hydroxybutyrate, acetoacetate, and free fatty acid and a decrease in the concentration of plasma bicarbonate, resulting in ketoacidosis. Melatonin inhibited dapagliflozin-induced ketoacidosis without inducing any change in blood glucose level or plasma insulin concentration. In white adipose tissue, melatonin inhibited lipolysis and downregulated phosphorylation of PKA, HSL, and perilipin-1. In liver tissue, melatonin suppressed cellular cyclic AMP levels and downregulated phosphorylation of PKA, AMPK, and acetyl-CoA carboxylase (ACC). In addition, melatonin increased hepatic ACC activity, but decreased hepatic CPT1a activity and acetyl-CoA content. These effects of melatonin on lipolysis and hepatic ketogenesis were blocked by pretreatment with melatonin receptor antagonist or PKA activator. Collectively, these results suggest that melatonin can ameliorate SGLT2i-induced ketoacidosis by inhibiting lipolysis and hepatic ketogenesis though cyclic AMP/PKA signaling pathways in T2D mice. Thus, melatonin treatment may offer protection against SGLT2i-induced ketoacidosis.

Octanoic acid potentiates glucose-stimulated insulin secretion and expression of glucokinase through the olfactory receptor in pancreatic ß-cells.

Olfactory receptors (ORs) are G protein-coupled receptors that mediate olfactory chemosensation, leading to the perception of smell. ORs are expressed in many tissues, but their functions are largely unknown. Here, we show that the olfactory receptor Olfr15 is highly and selectively expressed in both mouse pancreatic ß-cells and MIN6 cells. In addition, octanoic acid (OA), a medium-chain fatty acid, potentiates glucose-stimulated insulin secretion (GSIS). The OA-induced enhancement of GSIS was inhibited by Olfr15 knockdown. Treatment with a PLC inhibitor or an Ins(1,4,5)P3 receptor (IP3R) antagonist also blocked the OA-induced enhancement of GSIS. These results suggest that OA potentiates GSIS via Olfr15 though the PLC-IP3 pathway. Furthermore, long-term treatment with OA increased cellular glucose uptake in MIN6 cells by up-regulating the expression of glucokinase (GK). Moreover, this process was blocked by an IP3R antagonist and a Ca2+/calmodulin-dependent protein kinase kinase (CaMKK) inhibitor. Similarly, OA stimulated GK promoter activity, while either Olfr15 or CaMKIV knockdown blocked the stimulatory effect of OA on GK promoter activity. These results suggest that long-term treatment of OA induces GK promoter activity via Olfr15 through the IP3-CaMKK/CaMKIV pathway. In islets from type 2 diabetic mice, the expression level of Olfr15 and the OA-induced enhancement of GSIS were strongly reduced. Collectively, our results highlight the crucial role of the olfactory receptor Olfr15 in potentiating GSIS in pancreatic ß-cells, suggesting that Olfr15 may be an important therapeutic target in type 2 diabetes.

Evidence for glucagon-like peptide-1 receptor signaling to activate ATP-sensitive potassium channels in pancreatic beta cells.

Glucagon-like peptide-1 (GLP-1) is a gut peptide that promotes insulin release from pancreatic beta cells. GLP-1 has been shown to confer glucose-insensitive beta cells with glucose sensitivity by modulation of the activity of the ATP-sensitive potassium (KATP) channel. The channel closing effect of GLP-1, interacting with corresponding G-protein-coupled receptors, has been well established; however, to our knowledge, no study has shown whether GLP-1 directly induces activation of beta-cell KATP channels. Here, we aimed to evaluate whether the activation of beta-cell KATP channels by GLP-1 exists and affects intracellular Ca(2+) levels ([Ca(2+)]i). KATP channel activity was measured in isolated rat pancreatic beta cells by whole-cell perforated patch-clamp recordings with a diazoxide-containing pipette solution. Changes in [Ca(2+)]i and the subcellular localization of KATP channels were observed using the calcium-sensitive dye fura-4/AM and anti-Kir6.2 antibodies in INS-1 beta cells, respectively. To eliminate the well-known inhibitory effects of GLP-1 on KATP channel activity, channels were fully inhibited by pretreatment with methyl pyruvate and epigallocatechin-3-gallate. In the pretreated beta cells, GLP-1 and exendin-4 promptly activated the channels, reducing [Ca(2+)]i. The phosphoinositide 3-kinase (PI3K) inhibitor LY294002 blocked the effects of GLP-1 on channel activity. Moreover, phosphatidylinositol-3,4,5-trisphosphate mimicked the effects of GLP-1. These results suggested that beta-cell GLP-1 receptor signaling involved activation of KATP channels via a PI3K-dependent pathway. This alternative mechanism of GLP-1 function may act as a negative feedback pathway, modulating the glucose-dependent GLP-1 inhibition on KATP channel activity.

Infliximab partially alleviates the bite force reduction in a mouse model of temporomandibular joint pain.

Temporomandibular joint (TMJ) disorder is clinically important because of its prevalence, chronicity, and therapy-refractoriness of the pain. In this study, we investigated the effect of infliximab in a mouse model of TMJ pain using a specially-engineered transducer for evaluating the changes in bite force (BF). The mice were randomly divided into three groups (7 mice per group): the control group, the complete Freund's adjuvant (CFA) group, and the infliximab group. BF was measured at day 0 (baseline BF). After measuring the baseline BF, CFA or incomplete Freund's adjuvant was injected into both TMJs and then the changes in BF were measured at days 1, 3, 5, 7, 9, and 13 after the TMJ injection. For measuring the BF, we used a custom-built BF transducer. Control, CFA, and infliximab groups showed similar baseline BF at day 0. From day 1, a significant reduction in BF was observed in the CFA group, and this reduction in BF was statistically significant compared to that in the control group (P < 0.05). This reduction in BF was maintained until day 7, and BF started to recover gradually from day 9. In the infliximab group also, the reduction in BF was observed on day 1, and this reduction was maintained until day 7. However, the degree of reduction in BF was less remarkable compared to that in the CFA group. The reduction in BF caused by injection of CFA into the TMJ could be partially alleviated by the injection of anti-tumor necrosis factor alpha, infliximab.

Melatonin prevents pancreatic ß-cell loss due to glucotoxicity: the relationship between oxidative stress and endoplasmic reticulum stress.

Prolonged hyperglycemia results in pancreatic ß-cell dysfunction and apoptosis, referred to as glucotoxicity. Although both oxidative and endoplasmic reticulum (ER) stresses have been implicated as major causative mechanisms of ß-cell glucotoxicity, the reciprocal importance between the two remains to be elucidated. The aim of this study was to evaluate the differential effect of oxidative stress and ER stress on ß-cell glucotoxicity, by employing melatonin which has free radical-scavenging and antioxidant properties. As expected, in ß-cells exposed to prolonged high glucose levels, cell viability and glucose-stimulated insulin secretion (GSIS) were significantly impaired. Melatonin treatment markedly attenuated cellular apoptosis by scavenging reactive oxygen species via its plasmalemmal receptor-independent increase in antioxidant enzyme activity. However, treatments with antioxidants alone were insufficient to recover the impaired GSIS. Interestingly, 4-phenylbutyric acid (4-PBA), a chemical chaperone that attenuate ER stress by stabilizing protein structure, alleviated the impaired GSIS, but not apoptosis, suggesting that glucotoxicity induces oxidative and ER stress independently. We found that cotreatment of glucotoxic ß-cells with melatonin and 4-PBA dramatically improved both their survival and insulin secretion. Taken together, these results suggest that ER stress may be the more critical mechanism for prolonged high-glucose-induced GSIS impairment, whereas oxidative stress appears to be more critical for the impaired ß-cell viability. Therefore, combinatorial therapy of melatonin with an ER stress modifier may help recover pancreatic ß-cells under glucotoxic conditions in type 2 diabetes.

Reference Standards for C-Peptide in Korean Population: A Korean Endocrine Hormone Reference Standard Data Center Study.

BACKGRUOUND: The Korean Endocrine Hormone Reference Standard Data Center (KEHRS DC) has created reference standards (RSs) for endocrine hormones since 2020. This study is the first of its kind, wherein the KEHRS DC established RSs for serum Cpeptide levels in a healthy Korean population. METHODS: Healthy Korean adults were recruited from May 2021 to September 2023. After excluding participants according to our criteria, serum samples were collected; each participant could then choose between fasting glucose only or fasting glucose plus an oral glucose tolerance test (OGTT). If their sample showed high glucose (≥100 mg/dL) or hemoglobin A1c (HbA1c) (≥5.70%), their C-peptide levels were excluded from analyzing the RSs. RESULTS: A total of 1,532 participants were recruited; however, only the data of 1,050 participants were analyzed after excluding those whose samples showed hyperglycemia or high HbA1c. Post-30-minute OGTT data from 342 subjects and post-120-minute OGTT data from 351 subjects were used. The means±2 standard deviations and expanded uncertainties of fasting, post-30-minute and 120-minute OGTT C-peptide levels were 1.26±0.82 and 0.34-3.18, 4.74±3.57 and 1.14-8.33, and 4.85±3.58 and 1.25-8.34 ng/mL, respectively. Serum C-peptide levels correlated with obesity, serum glucose levels, and HbA1c levels. CONCLUSION: The RSs for serum C-peptide levels established in this study are expected to be useful in both clinical and related fields.

TNF-α polymorphisms and coronary artery disease: association study in the Korean population.

Coronary artery disease (CAD) results from atherosclerosis, a chronic inflammatory disease mediated in part by proinflammatory cytokines, particularly tumor necrosis factor-α (TNF-α), which is expressed by atherosclerotic plaques. In this study, we investigated whether TNF-α gene promoter polymorphisms affect the incidence of CAD in Koreans by genotyping. 404 Control subjects and 197 patients who previously received a coronary artery stent for the G/A, C/T, and C/A polymorphisms at position -238, -857 and -863, respectively. The G/G, G/A and A/A genotypes at position -238 occurred in 85.8%, 14.2% and 0% CAD patients and 91.8%, 7.9% and 0.3% control subjects, respectively. The G/A polymorphisms at position -238 were significantly associated with CAD when assuming a dominant model of inheritance (OR = 1.87; 95% CI = 1.10-3.20; P = 0.02), and A allele carriers had a significantly increased risk of developing CAD relative to the G allele (OR = 1.74; 95% CI = 1.04-2.92; P = 0.03). However, the polymorphisms at positions -857 and -863 were not associated with CAD. Haplotype-based analysis revealed the CAD and control groups differed significantly in the frequencies of haplotype ACC at positions -238, -857 and -863 (OR = 1.77; 95% CI = 1.05-2.98; P = 0.03). This was confirmed by multivariate analysis after adjusting body mass index and the presence of diabetes and hypertension (OR = 2.06; 95% CI = 1.15-3.68; P = 0.015). Thus, the -238A allele of TNF-α is associated with an increased risk of CAD and could be used as predictor for CAD in Koreans. Further studies are needed to elucidate the clinical implications of these findings.

Association of promoter region single nucleotide polymorphisms at positions -819C/T and -592C/A of interleukin 10 gene with ischemic heart disease.

OBJECTIVE: Ischemic heart disease (IHD) is a disease characterized by ischemia of the heart muscle, usually due to coronary artery disease. Interleukin-10 (IL10) is a proinflammatory cytokine known to protect endothelial function. In this study, we investigated the association of promoter region polymorphisms of the IL10 gene with IHD. METHODS: We recruited 313 control and 173 IHD patients. The selected SNPs in IL10 were genotyped using pyrosequencing. RESULTS: SNPs at positions -592C/A and -819C/T were statistically associated with IHD (P = 0.014 and P = 0.037). Similarly, the mean value of C-reactive protein in the C allele at -592C/A and -819C/T was significantly higher than that in the A allele at -592C/A (P = 0.026) and T allele at -819C/T (P = 0.026). The presence of hypertension in the C allele at -592C/A and -819C/T was significantly more frequent than that in the A allele at -592C/A (P = 0.044) and T allele at -819C/T (P = 0.044). In the haplotype of two SNPs (-592C/A and -819C/T), one haplotype (CC) presented an association with IHD (P = 0.012). CONCLUSIONS: These results indicate that the C allele with SNPs at position -592C/A and -819C/T of IL10 gene may be associated with IHD in the Korean population.

Reconstruction of defects after excision of facial skin cancer using a venous free flap.

After extensive excision of skin cancer on the face, or when skin cancer is located on the 3-dimensional structures of the face, reconstruction with a local flap can be impossible, or clinicians are reluctant to reconstruct defects with a skin graft because of postoperative contraction, hyperpigmentation, or other complication. Instead, an arterialized venous free flap can be used as an alternative method of reconstruction to prevent distortion and recurrence. Eight patients underwent surgery with an arterialized venous-free flap. We evaluated the cosmetic results using ordinary scale methods on the basis of 4 categories (color, contour, texture, and distortion of surrounding structures) and recurrence and metastases of skin cancer physically. The follow-up period ranged between 24 and 48 months, with an average of 33 months. All of the soft-tissue defects made by excising the tumor were reconstructed with good outcomes, except for 1 case. Regarding the cosmetic evaluation, the color was fair, the contour and texture were good, absence of distortion of surrounding structures was excellent, and the overall results in most all cases were good. There were no recurrences or metastases during the follow-up period. The arterialized venous free flap is an alternative plan among several reconstruction methods when skin cancer on the face is extensively excised.

Comparison of Serum PCSK9 Levels in Subjects with Normoglycemia, Impaired Fasting Glucose, and Impaired Glucose Tolerance.

We investigated proprotein convertase subtilisin/kexin type 9 (PCSK9) concentrations in individuals with normoglycemia, impaired fasting glucose (IFG), and impaired glucose tolerance (IGT). This was a pilot, cross-sectional study including 92 individuals who had not been diagnosed with or treated for diabetes. We measured PCSK9 levels in three groups of subjects; namely, normoglycemia (n=57), IFG (n=21), and IGT (n=14). Individuals with IFG and IGT showed higher PCSK9 concentrations than those in the normoglycemic group, with the highest serum PCSK9 concentrations found in individuals with IGT (55.25±15.29 ng/mL for normoglycemia, 63.47±17.78 ng/mL for IFG, 72.22±15.46 ng/mL for IGT, analysis of variance P=0.001). There were no significant differences in high- or low-density lipoprotein cholesterol among groups. Serum PCSK9 levels are increased in patients with prediabetes compared to subjects with normoglycemia.

Regulation of Adipsin Expression by Endoplasmic Reticulum Stress in Adipocytes.

Adpsin is an adipokine that stimulates insulin secretion from ß-cells and improves glucose tolerance. Its expression has been found to be markedly reduced in obese animals. However, it remains unclear what factors lead to downregulation of adipsin in the context of obesity. Endoplasmic reticulum (ER) stress response is activated in various tissues under obesity-related conditions and can induce transcriptional reprogramming. Therefore, we aimed to investigate the relationship between adipsin expression and ER stress in adipose tissues during obesity. We observed that obese mice exhibited decreased levels of adipsin in adipose tissues and serum and increased ER stress markers in adipose tissues compared to lean mice. We also found that ER stress suppressed adipsin expression via adipocytes-intrinsic mechanisms. Moreover, the ER stress-mediated downregulation of adipsin was at least partially attributed to decreased expression of peroxisome proliferator-activated receptor γ (PPARγ), a key transcription factor in the regulation of adipocyte function. Finally, treatment with chemical chaperones recovered the ER stress-mediated downregulation of adipsin and PPARγ in vivo and in vitro. Our findings suggest that activated ER stress in adipose tissues is an important cause of the suppression of adipsin expression in the context of obesity.

Efficacy and Tolerability of Pitavastatin Versus Pitavastatin/Fenofibrate in High-risk Korean Patients with Mixed Dyslipidemia: A Multicenter, Randomized, Double-blinded, Parallel, Therapeutic Confirmatory Clinical Trial.

PURPOSE: Dyslipidemia is an important risk factor for cardiovascular disease (CVD). Statins are known to effectively reduce not only low-density lipoprotein cholesterol (LDL-C) level but also death and nonfatal myocardial infarction due to coronary heart disease. The risk for CVD from atherogenic dyslipidemia persists when elevated triglyceride (TG) and reduced high-density lipoprotein cholesterol (HDL-C) levels are not controlled with statin therapy. Therefore, statin/fenofibrate combination therapy is more effective in reducing CVD risk. Here, we assessed the efficacy and tolerability of pitavastatin/fenofibrate combination therapy in patients with mixed dyslipidemia and a high risk for CVD. METHODS: This multicenter, randomized, double-blind, parallel-group, therapeutic-confirmatory clinical trial evaluated the efficacy and tolerability of fixed-dose combination therapy with pitavastatin/fenofibrate 2/160 mg in Korean patients with a high risk for CVD and a controlled LDL-C level (<100 mg/dL) and a TG level of 150-500 mg/dL after a run-in period with pitavastatin 2 mg alone. In the 8-week main study, 347 eligible patients were randomly assigned to receive pitavastatin 2 mg with or without fenofibrate 160 mg after a run-in period. In the extension study, patients with controlled LDL-C and non-HDL-C (<130 mg/dL) levels were included after the completion of the main study. All participants in the extension study received the pitavastatin/fenofibrate combination therapy for 16 weeks for the assessment of the tolerability of long-term treatment. FINDINGS: The difference in the mean percentage change in non-HDL-C from baseline to week 8 between the combination therapy and monotherapy groups was -12.45% (95% CI, -17.18 to -7.72), and the combination therapy was associated with a greater reduction in non-HDL-C. The changes in lipid profile, including apolipoproteins, fibrinogen, and high-sensitivity C-reactive protein from baseline to weeks 4 and 8 were statistically significant with combination therapy compared to monotherapy at all time points. Furthermore, the rates of achievement of non-HDL-C and apolipoprotein B targets at week 8 in the combination therapy and monotherapy groups were 88.30% versus 77.98% (P = 0.0110) and 78.94% versus 68.45% (P = 0.0021), respectively. The combination therapy was well tolerated, with a safety profile similar to that of statin monotherapy. IMPLICATIONS: In these Korean patients with mixed dyslipidemia and a high risk for CVD, combination therapy with pitavastatin/fenofibrate was associated with a greater reduction in non-HDL-C compared with that with pitavastatin monotherapy, and a significantly improvement in other lipid levels. Moreover, the combination therapy was well tolerated, with a safety profile similar to that of statin monotherapy. Therefore, pitavastatin/fenofibrate combination therapy could be effective and well tolerated in patients with mixed dyslipidemia. ClinicalTrials.gov identifier: NCT03618797.

Forkhead transcription factor FoxO1 inhibits insulin- and transforming growth factor-beta-stimulated plasminogen activator inhibitor-1 expression.

Elevated levels of plasminogen activator inhibitor-1 (PAI-1) are considered a risk factor for chronic liver disease in patients with hyperinsulinemia. Insulin increases the expression of PAI-1, and inactivates the forkhead box-containing protein FoxO1. We were interested in whether the inactivation of FoxO1 is involved in the activation of PAI-1 expression under conditions of insulin stimulation. Here, we examined whether adenoviral-mediated expression of a constitutively active form of FoxO1 (Ad-CA-FoxO1) inhibited insulin-stimulated PAI-1 expression in human HepG2 hepatocellular liver carcinoma cells and mouse AML12 hepatocytes. Treatment of cells with insulin increased PAI-1 gene expression, and this effect was abolished by Ad-CA-FoxO1. Insulin also increased the transforming growth factor (TGF)-beta-induced expression of PAI-1 mRNA, and Ad-CA-FoxO1 inhibited this effect. Transient transfection assays using a reporter gene under the control of the PAI-1 promoter revealed that CA-FoxO1 inhibits Smad3-stimulated PAI-1 promoter activity. Taken together, our results indicate that FoxO1 inhibits PAI-1 expression through the inhibition of TGF-beta/Smad-mediated signaling pathways. Our data also suggest that in the hyperinsulinemic state, FoxO1 is inactivated by increased levels of insulin, and does not function as an inhibitor of TGF-beta-induced PAI-1 expression.

Effect of two different doses of intravitreal bevacizumab with temporal retina-sparing laser photocoagulation for retinopathy of prematurity.

This study aims to compare the efficacy and safety between two different doses of intravitreal bevacizumab (IVB) injection with temporal retina-sparing laser (TRSL) photocoagulation for retinopathy of prematurity (ROP). We retrospectively evaluated 22 eyes of ROP infants who underwent IVB combined with partial TRSL for stage 3+ zone I or posterior zone II ROP. Laser photocoagulation was applied on the avascular retina, sparing two-disc-diameter width temporal avascular area anterior to ridge. A half dose (0.625 mg) or minimal dose (0.25 mg) of IVB was conducted. Four eyes in minimal dose group were retreated with IVB and laser photocoagulation on the spared retina. Of those 4 retreated eyes, three developed preretinal hemorrhage around the ridge after the first treatment, resulting in fibrotic macular dragging. A half dose of IVB may be more effective than a minimal dose with partial TRSL for ROP. Preretinal hemorrhage may be a harbinger of poor prognosis.

Negative Association of Hepatitis B Virus With Hearing Impairment.

PURPOSE: Hearing impairment is one of the most common chronic diseases causing deterioration of the quality of life in elderly individuals. Several viral infections have been suggested to cause hearing impairment. We investigated association of hepatitis B virus (HBV) infection with hearing impairment using a representative sample of the Korean population. METHOD: Participants included 6,583 men and 8,702 women, who were ≥ 20 years of age from the Korea National Health and Nutritional Examination Surveys of the Korean population (2010-2012). Air-conduction pure-tone thresholds were measured in a soundproof booth using an automatic audiometer for each ear at 6 frequencies (500, 1000, 2000, 3000, 4000, and 6000 Hz). An audiometric test and a laboratory examination, including an HBV surface antigen (HBsAg) test, were performed. RESULTS: Subjects who are HBsAg positive had lower average of pure-tone thresholds and lower prevalence of hearing impairment at both low/mid and high frequency compared with those without. Adjusted means of hearing thresholds were also lower among subjects who are HBsAg positive compared with subjects who are HBsAg negative. After the adjustment for age and gender, the odds of high-frequency mild hearing impairment were lower for subjects with HBV infection. In the multiple logistic regression analyses adjusting for confounding variables, the significant negative association between HBV infection and high-frequency mild hearing impairment still remained. CONCLUSIONS: Contrary to previous reports, subjects who are HBsAg positive had a lower prevalence of hearing impairment compared with subjects who are HBsAg negative. Further studies are warranted to investigate the underlying mechanism regarding their negative relationship.

Metformin stimulates IGFBP-2 gene expression through PPARalpha in diabetic states.

The anti-diabetic drug, metformin, exerts its action through AMP-activated protein kinase (AMPK), and Sirtuin (Sirt1) signaling. Insulin-like growth factor (IGF)-binding protein 2 (IGFBP-2) prevents IGF-1 binding to its receptors, thereby contributing to modulate insulin sensitivity. In this study, we demonstrate that metformin upregulates Igfbp-2 expression through the AMPK-Sirt1-PPARα cascade pathway. In the liver of high fat diet, ob/ob, and db/db mice, Igfbp-2 expression was significantly decreased compared to the expression levels in the wild-type mice (p < 0.05). Upregulation of Igfbp-2 expression by metformin administration was disrupted by gene silencing of Ampk and Sirt1, and this phenomenon was not observed in Pparα-null mice. Notably, activation of IGF-1 receptor (IGF-1R)-dependent signaling by IGF-1 was inhibited by metformin. Finally, when compared to untreated type 2 diabetes patients, the metformin-treated diabetic patients showed increased IGFBP-2 levels with diminished serum IGF-1 levels. Taken together, these findings indicate that IGFBP-2 might be a new target of metformin action in diabetes and the metformin-AMPK-Sirt1-PPARα-IGFBP-2 network may provide a novel pathway that could be applied to ameliorate metabolic syndromes by controlling IGF-1 bioavailability.

Polyglandular Autoimmune Syndrome Type III with Primary Hypoparathyroidism.

Polyglandular autoimmune syndrome is defined as multiple endocrine gland insufficiencies accompanied by autoimmune diseases of the endocrine and nonendocrine system. After Schmidt introduced a case of nontuberculosis adrenal gland dysfunction with thyroiditis in 1926, Neufeld defined polyglandular autoimmune syndrome by I, II, and III subtypes in 1980 by their presentation of occurrence age, heredity methods, relationship with human leukocyte antigen, and accompanying diseases. We report a case of a 32-year-old female with polyglandular autoimmune syndrome III accompanied by type 1 diabetes mellitus that was treated with insulin (36 units per day) for 11 years. She had insulin deficiency and Hashimoto thyroiditis as an autoimmune disorder. In addition, she had several features similar to Albright's hereditary osteodystrophy including short stature, truncal obesity, round face, short neck, low intelligence (full IQ 84), and decreased memory. Although Albright's hereditary osteodystrophy is morphological evidence of pseudohypoparathyroidism or pseudopseudohypoparathyroidism, she had primary hypoparathyroidism on laboratory results. Here, we report a case of polyglandular autoimmune syndrome III with type 1 diabetes mellitus, autoimmune thyroiditis, and primary hypoparathyroidism, accompanied by clinical features similar to Albright's hereditary osteodystrophy.

Green tea extract with polyethylene glycol-3350 reduces body weight and improves glucose tolerance in db/db and high-fat diet mice.

Green tea extract (GTE) is regarded to be effective against obesity and type 2 diabetes, but definitive evidences have not been proven. Based on the assumption that the gallated catechins (GCs) in GTE attenuate intestinal glucose and lipid absorption, while enhancing insulin resistance when GCs are present in the circulation through inhibiting cellular glucose uptake in various tissues, this study attempted to block the intestinal absorption of GCs and prolong their residence time in the lumen. We then observed whether GTE containing the nonabsorbable GCs could ameliorate body weight (BW) gain and glucose intolerance in db/db and high-fat diet mice. Inhibition of the intestinal absorption of GCs was accomplished by co-administering the nontoxic polymer polyethylene glycol-3350 (PEG). C57BLKS/J db/db and high-fat diet C57BL/6 mice were treated for 4 weeks with drugs as follows: GTE, PEG, GTE+PEG, voglibose, or pioglitazone. GTE mixed with meals did not have any ameliorating effects on BW gain and glucose intolerance. However, the administration of GTE plus PEG significantly reduced BW gain, insulin resistance, and glucose intolerance, without affecting food intake and appetite. The effect was comparable to the effects of an α-glucosidase inhibitor and a peroxisome proliferator-activated receptor-γ/α agonist. These results indicate that prolonging the action of GCs of GTE in the intestinal lumen and blocking their entry into the circulation may allow GTE to be used as a prevention and treatment for both obesity and obesity-induced type 2 diabetes.

Effect of Green Tea Extract/Poly-γ-Glutamic Acid Complex in Obese Type 2 Diabetic Mice.

BACKGROUND: The increasing prevalence of type 2 diabetes mellitus (T2DM) is associated with the rapid spread of obesity. Obesity induces insulin resistance, resulting in ß-cell dysfunction and thus T2DM. Green tea extract (GTE) has been known to prevent obesity and T2DM, but this effect is still being debated. Our previous results suggested that circulating green tea gallated catechins (GCs) hinders postprandial blood glucose lowering, regardless of reducing glucose and cholesterol absorption when GCs are present in the intestinal lumen. This study aimed to compare the effect of GTE with that of GTE coadministered with poly-γ-glutamic acid (γ-PGA), which is likely to inhibit the intestinal absorption of GCs. METHODS: The db/db mice and age-matched nondiabetic mice were provided with normal chow diet containing GTE (1%), γ-PGA (0.1%), or GTE+γ-PGA (1%:0.1%) for 4 weeks. RESULTS: In nondiabetic mice, none of the drugs showed any effects after 4 weeks. In db/db mice, however, weight gain and body fat gain were significantly reduced in the GTE+γ-PGA group compared to nondrug-treated db/db control mice without the corresponding changes in food intake and appetite. Glucose intolerance was also ameliorated in the GTE+γ-PGA group. Histopathological analyses showed that GTE+γ-PGA-treated db/db mice had a significantly reduced incidence of fatty liver and decreased pancreatic islet size. Neither GTE nor γ-PGA treatment showed any significant results. CONCLUSION: These results suggest that GTE+γ-PGA treatment than GTE or γ-PGA alone may be a useful tool for preventing both obesity and obesity-induced T2DM.