Glucagon secretion and its association with glycaemic control and ketogenesis during sodium-glucose cotransporter 2 inhibition by ipragliflozin in people with type 1 diabetes: Results from the multicentre, open-label, prospective study.

AIM: Clinical trials showed the efficacy of sodium-glucose cotransporter 2 inhibitors for type 1 diabetes (T1D) by significant reductions in body weight and glycaemic variability, but elevated susceptibility to ketoacidosis via elevated glucagon secretion was a potential concern. The Suglat-AID evaluated glucagon responses and its associations with glycaemic control and ketogenesis before and after T1D treatment with the sodium-glucose cotransporter 2 inhibitor, ipragliflozin. METHODS: Adults with T1D (n = 25) took 50-mg open-labelled ipragliflozin daily as adjunctive to insulin. Laboratory/clinical data including continuous glucose monitoring were collected until 12 weeks after the ipragliflozin initiation. The participants underwent a mixed-meal tolerance test (MMTT) twice [before (first MMTT) and 12 weeks after ipragliflozin treatment (second MMTT)] to evaluate responses of glucose, C-peptide, glucagon and ß-hydroxybutyrate. RESULTS: The area under the curve from fasting (0 min) to 120 min (AUC0-120min) of glucagon in second MMTT were significantly increased by 14% versus first MMTT. The fasting and postprandial ß-hydroxybutyrate levels were significantly elevated in second MMTT versus first MMTT. The positive correlation between postprandial glucagon secretion and glucose excursions observed in first MMTT disappeared in second MMTT, but a negative correlation between fasting glucagon and time below range (glucose, <3.9 mmol/L) appeared in second MMTT. The percentage changes in glucagon levels (fasting and AUC0-120min) from baseline to 12 weeks were significantly correlated with those in ß-hydroxybutyrate levels. CONCLUSIONS: Ipragliflozin treatment for T1D increased postprandial glucagon secretion, which did not exacerbate postprandial hyperglycaemia but might protect against hypoglycaemia, leading to reduced glycaemic variability. The increased glucagon secretion might accelerate ketogenesis when adequate insulin is not supplied.

Novel endoscopic duodenal observation protocol based on Seven Pictures Rule for detecting duodenal neoplasms during esophagogastroduodenoscopy: Prospective observational study.

OBJECTIVES: No protocol for esophagogastroduodenoscopic examination of the duodenum has been established. We examined the feasibility and ability to detect neoplasms of a novel duodenal examination protocol. METHODS: This was a two-facility, prospective, observational study. Our protocol, the Seven Pictures Rule (7PR), requires pictures of the following seven locations: anterior and posterior to the bulb, area of and contralateral to the superior duodenal angle, area of and contralateral to the ampulla, and the transverse duodenum. The primary outcome was rate of completion of 7PR. Secondary outcomes were overall rates of detecting neoplasms, rates of detecting neoplasms for each location, examination time, and completion rates for standard or ultrathin endoscopes. RESULTS: There were 1549 participants. The 7PR completion rate was 81.1% and the detection rates of overall neoplasms, adenomas, and carcinomas were 0.84%, 0.71%, and 0.06%, respectively. The area in which most neoplasms was detected was contralateral to the ampulla (69.2%), and the fewest the transverse duodenum (0%). Mean duration of duodenal examination was 53.1 s. Completion rates for standard vs. ultrathin were 84.4% (1077/1276) vs. 65.6% (179/273) (P < 0.01), respectively. CONCLUSIONS: Seven Pictures Rule is acceptable for duodenal examination and a potential quality indicator.

DNA Aptamer Raised against Advanced Glycation End Products Improves Sperm Concentration, Motility, and Viability by Suppressing Receptors for Advanced Glycation End Product-Induced Oxidative Stress and Inflammation in the Testes of Diabetic Mice.

Type 2 diabetes mellitus (T2DM) is a risk factor for male infertility, but the underlying molecular mechanisms remain unclear. Advanced glycation end products (AGEs) are pathogenic molecules for diabetic vascular complications. Here, we investigated the effects of the DNA aptamer raised against AGEs (AGE-Apt) on testicular and sperm abnormalities in a T2DM mouse model. KK-Ay (DM) and wild-type (non-DM) 4- and 7-week-old male mice were sacrificed to collect the testes and spermatozoa for immunofluorescence, RT-PCR, and histological analyses. DM and non-DM 7-week-old mice were subcutaneously infused with the AGE-Apt or control-aptamer for 6 weeks and were then sacrificed. Plasma glucose, testicular AGEs, and Rage gene expression in 4-week-old DM mice and plasma glucose, testicular AGEs, oxidative stress, and pro-inflammatory gene expressions in 7-week-old DM mice were higher than those in age-matched non-DM mice, the latter of which was associated with seminiferous tubular dilation. AGE-Apt did not affect glycemic parameters, but it inhibited seminiferous tubular dilation, reduced the number of testicular macrophages and apoptotic cells, and restored the decrease in sperm concentration, motility, and viability of 13-week-old DM mice. Our findings suggest that AGEs-Apt may improve sperm abnormality by suppressing AGE-RAGE-induced oxidative stress and inflammation in the testes of DM mice.

Effects of olmesartan and amlodipine on blood pressure, endothelial function, and vascular inflammation.

BACKGROUND: Anti-hypertensive drugs can improve vascular endothelial function. However, the mechanism remains to be elucidated. OBJECTIVES: This study sought to investigate mechanisms of anti-hypertensive drugs on improvement of vascular endothelial function in patients with essential hypertension. METHODS: Forty-five patients (mean age 58.5 ± 11.2 years) with uncontrolled essential hypertension were randomly assigned to receive olmesartan, an angiotensin II type 1 receptor blocker (ARB) (N = 23), or amlodipine, a calcium channel blocker (CCB) (N = 22), for 6 months. Endothelial function was evaluated by flow-mediated dilatation (FMD) of the brachial artery. Vascular inflammation was measured by blood-normalized standardized uptake value, known as a target-to-background ratio (TBR) within the carotid arteries using 18F-fluorodeoxyglucose-positron emission tomography combined with computed tomography. RESULTS: There were no significant differences of baseline clinical data between the ARB and CCB groups. Both anti-hypertensive drugs comparably lowered blood pressure and increased %FMD. TBR values were reduced by olmesartan (P < .001), while blood pressure variability was decreased by amlodipine (P = .004). Changes in %FMD from baseline (Δ%FMD) were inversely associated with ΔTBR in the olmesartan group (r = - .606, P = .003) and with Δsystolic blood pressure variability in the amlodipine group (r = - .434, P = .039). CONCLUSION: Our study indicated that olmesartan and amlodipine could improve endothelial function in patients with essential hypertension in different manners, suppression of vascular inflammation, and decrease in blood pressure variability, respectively.

Does Deep Learning Enhance the Estimation for Spatially Explicit Built Environment Stocks through Nighttime Light Data Set? Evidence from Japanese Metropolitans.

Built environment stocks have attracted much attention in recent decades because of their role in material and energy flows and environmental impacts. Spatially refined estimation of built environment stocks benefits city management, for example, in urban mining and resource circularity strategy making. Nighttime light (NTL) data sets are widely used and are regarded as high-resolution products in large-scale building stock research. However, some of their limitations, especially blooming/saturation effects, have hampered performance in estimating building stocks. In this study, we experimentally proposed and trained a convolution neural network (CNN)-based building stock estimation (CBuiSE) model and applied it to major Japanese metropolitan areas to estimate building stocks using NTL data. The results show that the CBuiSE model is capable of estimating building stocks at a relatively high resolution (approximately 830 m) and reflecting spatial distribution patterns, although the accuracy needs to be further improved to enhance the model performance. In addition, the CBuiSE model can effectively mitigate the overestimation of building stocks arising from the blooming effect of NTL. This study highlights the potential of NTL to provide a new research direction and serve as a cornerstone for future anthropogenic stock studies in the fields of sustainability and industrial ecology.

Endoscopic Ligation with O-Ring Closure for Mucosal Defects after Rectal Endoscopic Submucosal Dissection: A Feasibility Study (with Video).

INTRODUCTION: Mucosal defect closure after colorectal endoscopic submucosal dissection (ESD) may prevent post-ESD adverse events. Delayed bleeding is a particular concern in the rectum due to the presence of numerous blood vessels. However, rectal defect closure often fails due to the thick rectal wall. This study aimed to examine the feasibility of our newly developed endoscopic ligation with O-ring closure (E-LOC) for defects after rectal ESD. METHODS: This was a prospective observational study conducted at a single institution. After excluding 2 patients with tumors mostly extending into the anal canal, the study cohort comprised 30 consecutive patients who underwent ESD of rectal neoplasms between July 2020 and July 2021. E-LOC using an endoscopic variceal ligation device was performed for closing mucosal defects after rectal ESD. The primary outcome was the complete closure rate. The secondary outcomes were the delayed bleeding rate, E-LOC procedure time, sustained closure rates on postoperative day (POD) 3, and E-LOC-associated complications. RESULTS: Complete closure of the defect (median defect size 29.0 mm) was successfully achieved in 24 cases (80%). Delayed bleeding occurred in one case with incomplete closure (3.3%). The median E-LOC procedure time was 25.5 min (interquartile range, 20.0-30.0 min). The sustained closure rates were 83.3% (20/24) on POD 3 in the 24 cases with complete closure. No E-LOC-associated complications occurred. DISCUSSION/CONCLUSIONS: E-LOC was feasible for defect closure after rectal ESD, and probably led to a decreased incidence of delayed bleeding.

Comparison of purse-string suture versus over-the-scope clip for gastric endoscopic full-thickness closure: traction and leak pressure testing in ex vivo porcine model.

BACKGROUND: The recently developed endoscopic full-thickness resection technique requires reliable closure. The main closure methods are the purse-string suture (PSS) technique and over-the-scope clip (OTSC) technique; however, basic data on the closure strength of each technique are lacking. This study was performed to compare the closure strengths of these two methods in an ex vivo porcine model. METHODS: In the traction test, a virtual 5-cm full-thickness closure line was closed by the following six methods three times each: conventional hemoclips, mucosal PSS, seromuscular PSS, mucosal OTSC, seromuscular OTSC, and surgical suture. The primary endpoint was the tension at the starting point of dehiscence, measured in Newtons (N) by an automatic traction machine. In the leak test, a 15-mm gastric full-thickness defect was closed by PSS or OTSC six times each, and the closed stomach was then pressurized in a water container. The primary endpoint was the leak pressure when air bubbles appeared. The secondary endpoints were the procedure time and presence of complete inverted closure. RESULTS: The mean tension was 2.16, 3.68, 5.15, 18.30, 19.30, and 62.40 N for conventional hemoclips, mucosal PSS, seromuscular PSS, mucosal OTSC, seromuscular OTSC, and surgical suture, respectively. Complete inverted closure was observed for seromuscular PSS, seromuscular OTSC, and surgical suture. The mean leak pressure was 13.7 and 24.8 mmHg in the PSS and OTSC group, respectively (P < 0.01). The mean procedure time was 541 and 169 s in the PSS and OTSC group, respectively (P < 0.01). Complete inverted closure was observed in OTSC alone. CONCLUSION: The OTSC, which allows complete inverted closure, showed greater closure strength than PSS. Considering the size limitation suitable for single OTSC, a therapeutic strategy for closing the larger size is further warranted.

SMTP-44D Inhibits Atherosclerotic Plaque Formation in Apolipoprotein-E Null Mice Partly by Suppressing the AGEs-RAGE Axis.

SMTP-44D has been reported to have anti-oxidative and anti-inflammatory reactions, including reduced expression of receptor for advanced glycation end products (RAGE) in experimental diabetic neuropathy. Although activation of RAGE with its ligands, and advanced glycation end products (AGEs), play a crucial role in atherosclerotic cardiovascular disease, a leading cause of death in diabetic patients, it remains unclear whether SMTP-44D could inhibit experimental atherosclerosis by suppressing the AGEs-RAGE axis. In this study, we investigated the effects of SMTP-44D on atherosclerotic plaque formation and expression of AGEs in apolipoprotein-E null (Apoe-/-) mice. We further studied here whether and how SMTP-44D inhibited foam cell formation of macrophages isolated from Apoe-/- mice ex vivo. Although administration of SMTP-44D to Apoe-/- mice did not affect clinical or biochemical parameters, it significantly decreased the surface area of atherosclerotic lesions and reduced the atheromatous plaque size, macrophage infiltration, and AGEs accumulation in the aortic roots. SMTP-44D bound to immobilized RAGE and subsequently attenuated the interaction of AGEs with RAGE in vitro. Furthermore, foam cell formation evaluated by Dil-oxidized low-density lipoprotein (ox-LDL) uptake, and gene expression of RAGE, cyclin-dependent kinase 5 (Cdk5) and CD36 in macrophages isolated from SMTP-44D-treated Apoe-/- mice were significantly decreased compared with those from saline-treated mice. Gene expression levels of RAGE and Cdk5 were highly correlated with each other, the latter of which was also positively associated with that of CD36. The present study suggests that SMTP-44D may inhibit atherosclerotic plaque formation in Apoe-/- mice partly by blocking the AGEs-RAGE-induced ox-LDL uptake into macrophages via the suppression of Cdk5-CD36 pathway.

Computational Screening and Experimental Validation of Inhibitor Targeting the Complex Formation of Grb14 and Insulin Receptor.

The development of drugs targeting gene products associated with insulin resistance holds the potential to enhance our understanding of type 2 diabetes mellitus (T2DM). The virtual screening, based on a three-dimensional (3D) protein structure, is a potential technique to accelerate the development of molecular target drugs. Among the targets implicated in insulin resistance, the genetic characterization and protein function of Grb14 have been clarified without contradiction. The Grb14 gene displays significant variations in T2DM, and its gene product is known to inhibit the function of the insulin receptor (IR) by directly binding to the tyrosine kinase domain. In the present study, a virtual screening, based on a 3D structure of the IR tyrosine kinase domain (IRß) in complex with part of Grb14, was conducted to find compounds that can disrupt the complex formation between Grb14 and IRß. First, ten compounds were selected from 154,118 compounds via hierarchical in silico structure-based drug screening, composed of grid docking-based and genetic algorithm-based programs. The experimental validations suggested that the one compound can affect the blood glucose level. The molecular dynamics simulations and co-immunoprecipitation analysis showed that the compound did not completely suppress the protein-protein interaction between Grb14 and IR, though competitively bound to IR with the tyrosine kinase pseudosubstrate region in Grb14.

Efficacy of endoscopic ligation with O-ring closure for prevention of bleeding after gastric endoscopic submucosal dissection under antithrombotic therapy: a prospective observational study.

BACKGROUND: We examined the efficacy of a novel endoscopic ligation technique with O-ring closure (E-LOC) to prevent bleeding after gastric endoscopic submucosal dissection (ESD) under antithrombotic therapy. METHODS: This single-center prospective study involved consecutive patients who were taking antithrombotic agents and underwent gastric ESD. E-LOC was performed by anchoring the nylon loop with hemoclips on both defect edges and/or the exposed muscle layer, and using O-ring band ligation around these deployed clips. The primary outcome was post-ESD bleeding rate. Secondary outcomes were complete closure rate, procedure time, sustained closure rate, and complications. RESULTS: 48 patients were finally analyzed. The post-ESD bleeding rate was 0 %, the complete closure rate was 97.9 %, and the mean closure time was 29.9 minutes. The sustained closure rate was 95.8 % at postoperative day 2-3 and 33.3 % at postoperative day 10-11. No complications occurred. CONCLUSION: E-LOC may be an effective option for closing mucosal defects after gastric ESD under antithrombotic therapy. However, the preventive effect on post-ESD bleeding should be further investigated in high risk groups.

Guidewire-assisted over-the-scope clip delivery method into the distal intestine: a case series.

BACKGROUND: The Over-the-scope clip (OTSC) has been recently introduced for multiple purposes, including refractory bleeding, perforation, fistula, and anastomotic dehiscence of the gastrointestinal tract. However, no easy access techniques for delivering OTSCs to distant sites have been described. Therefore, we have developed a simple and safe guidewire-assisted OTSC delivery (GOD) method for use on the distal intestine. This study aimed to investigate the technical feasibility and safety of the method. MATERIAL AND METHODS: Between June 2018 and April 2019, all eight patients who underwent the GOD method were retrospectively examined. The primary outcome was the successful rate of OTSC delivery to the lesion without complications. The secondary outcomes were GOD procedure time, total procedure time, technical and clinical OTSC success rates, and GOD- and OTSC-associated complications. RESULTS: The rate of successful OTSC delivery was 100%. The median procedure time of GOD was 21 min (range 8-29). The median total procedure time was 38.5 min (range 26-41). The technical and clinical success rates of OTSC were 100% and 75% (6/8), respectively. No GOD- or OTSC-associated complications occurred. CONCLUSIONS: The GOD method is a feasible and safe technique for delivering OTSC toward the small and proximal large intestine.

Long-term outcomes of over-the-scope clip for refractory gastrointestinal diseases.

BACKGROUND: The Over-The-Scope Clip (OTSC) can effectively treat refractory gastrointestinal diseases. However, most reports have focused on short-term effectiveness. We examined clinical outcomes of the deployed clips and long-term characteristics. MATERIAL AND METHODS: Of 47 patients with OTSC treatment, 35 with follow-up periods of ≥3 months were retrospectively examined. The indications were 11 bleedings, 17 perforations, and seven fistulas. The observation period was defined as medium-term (3 to <12 months) or long-term (≥12 months). The primary outcome was the clinical success rate without disease recurrence. The secondary outcomes were the complication rate, survival duration, and clip retention rate. RESULTS: The medium- and long-term clinical success rates were 100% during the observation period (median, 44 months; range, 3-78 months). The complication rate was 2.9% (n = 1). The median survival time was 1,634 days for bleeding, 1,757 days for perforation, and 444 days for fistulas. The overall clip retention rates were 56.4%, 38.1%, 30.9%, and 25.9% after one, six, and 12 months and at the final follow-up, respectively. The average clip retention duration was 244 days in bleeding, 656 days in perforations, and 188 days in fistulas. CONCLUSIONS: Regardless of clip detachment, the OTSC can be effective in long-term.

Wafer paper and ring-mounted polyglycolic acid sheet method for shielding artificial gastric floor.

BACKGROUND: The management of postoperative bleeding, after gastric endoscopic submucosal dissection (ESD), has become particularly important because of the recent increase in antithrombotic use. Endoscopic shielding with polyglycolic acid (PGA) sheets has been shown to be effective. However, shrinkage and early displacement of the sheet remain challenges. This study aimed to determine the efficacy and safety of our developed method, named wafer paper and ring-mounted PGA sheet (WaRP). MATERIAL AND METHODS: Twenty-four patients with antithrombotic uptake who underwent the WaRP method following gastric ESD were retrospectively examined. This involved the delivery of a PGA sheet wrapped in wafer paper with ring-thread, and its fixation on the gastric floor using hemoclips. The primary outcome was the technical success rate of the WaRP, and several secondary outcomes were evaluated. RESULTS: The technical success rate of WaRP was 100%. The procedure lasted a mean of 10.5 min (SD 6.7 min). The prevalence of complete retention at follow-up endoscopy was 83.3% (20/24). There were no WaRP-associated complications, but post-ESD hemorrhage occurred in two patients undergoing hemodialysis (8.3%). CONCLUSIONS: The WaRP method is a simple and reliable means of PGA sheet delivery and placement that reduces the incidence of post-ESD hemorrhage.

A Novel Mucidosphaerium sp. Downregulates Inflammatory Gene Expression in Skin and Articular Cells.

CONTEXT: Hot-spring therapy is occasionally used for the treatment of inflammatory diseases. Microorganisms might contribute to the anti-inflammatory functions seen in thermal mud therapies. Natural microorganisms, derived from traditional spa resorts, could be useful as a preventive strategy for alternative medical applications. OBJECTIVE: The aim of the study was to find effective microalgae from prominent hot springs to use for the treatment of inflammatory diseases. DESIGN: The research team performed an in-vitro study. Microalgae, derived from Beppu hot springs, were isolated and homogeneously cultured. SETTING: The study took place at the Saravio Central Institute at Saravio Cosmetics in Oita, Japan and the Department of Bioscience and Biotechnology in the Graduate School of Agriculture at Shinshu University in Nagano, Japan. INTERVENTION: For identification, the 18S ribosomal RNA genes of microalgae were investigated by DNA sequencing and homology search, together with microscopic observation. OUTCOME MEASURES: To examine the pharmacological activities of the algal extracts, real-time polymerase chain reactions were performed, using either primary dermal fibroblasts (DFs), dermal papilla cells (DPCs), or fibroblast-like synoviocytes (FLSs). To test the antioxidant activity, both the oxygen radical absorbance capacity and the generation of intracellular reactive oxygen species (ROS) were evaluated. RESULTS: A novel strain of green algae, Mucidosphaerium sp., was isolated from a Beppu hot spring. The algal extract downregulated gene-expression levels of pro-inflammatory cytokines, such as interleukin-1ß (IL-1ß), IL-6, and tumor necrosis factor- alpha (TNF-α), in various primary cells pre-exposed to IL-1ß. The protein level of the risk factors was concomitantly reduced. In addition, the algal extract suppressed the IL-1ß-induced upregulation of cyclooxygenase-2, nerve growth factor, and matrix metalloproteinase-1 (MMP-1) and MMP-3 in DFs. It also inhibited that of MMP-1, -3, and -9 in FLSs. Moreover, the extract inhibited total MMP protease activities. The microalgae decreased the intracellular reactive oxygen species (ROS) level in FLSs with an antioxidant activity of 178.3 ± 0.9 µmol of trolox equivalent/g. CONCLUSIONS: The present study showed that the novel Mucidosphaerium sp., derived from a Beppu hot spring, suppressed inflammatory reactions in both cutaneous and articular cells, partly due to its antioxidative properties. The novel algal strain may be a useful tool as an alternative medicine for skin and joint inflammatory disorders.

[A case of adult intussusception in the transverse colon with an advanced ileal Peutz-Jeghers type polyp associated with cancer].

A man in his thirties was admitted to the hospital because of upper abdominal pain. Computed tomography showed intussusception in the ascending and transverse colon. After spontaneous discontinuation, endoscopy revealed a 25-mm 0-I tumor in the ileum. An emergency operation was performed the next day due to intussusception recurrence. The tumor was hyperplastic intestinal epithelium with dendritic smooth muscle fascicles and partly cancerous. The patient had no clinical features of Peutz-Jeghers syndrome. Therefore, the patient was diagnosed with Peutz-Jeghers type polyps based on pathological findings. This case is considered to be a rare case of intussusception in the transverse colon due to Peutz-Jeghers type polyp with canceration.

Oral administration of spa-derived green alga improves insulin resistance in overweight subjects: Mechanistic insights from fructose-fed rats.

Advanced glycation end products (AGEs) and their receptor (RAGE) system evoke inflammatory reactions and insulin resistance in adipocytes. Spa-derived green alga Mucidosphaerium sp. (MS) had anti-inflammatory properties in vitro. We examined here whether and how MS could ameliorate insulin resistance in fructose-rich diet-fed rats, and conducted a randomized, double blind, placebo-controlled trial to investigate the effects of MS on insulin resistance in overweight subjects. Oral administration of MS for 8 weeks significantly decreased random blood glucose, and fasting insulin, oxidative stress levels, and improved homeostasis model assessment of insulin resistance (HOMA-IR) values in fructose-fed rats, which were associated with the reduction of AGEs, RAGE, 8-hydroxy-2'-deoxy-guanosine, NADPH oxidase activity, macrophage and lymphocyte infiltration, monocyte chemoattractant protein-1 (MCP-1) expression, and adipocyte size in the adipose tissues as well as restoration of adiponectin levels. MS decreased the AGE-induced NADPH oxidase activity, ROS generation, MCP-1 and RAGE gene expression, and lipid accumulation in differentiated adipocytes, while it restored the decrease in adiponectin mRNA levels. An anti-oxidant, N-acetylcysteine mimicked the effects of MS on ROS generation, RAGE gene expression, and lipid accumulation. Oral intake of MS for 12 weeks significantly decreased systolic and diastolic blood pressure, fasting plasma glucose, fasting insulin, HOMA-IR, HDL-cholesterol and creatinine in overweight subjects. Baseline-adjusted diastolic blood pressure, fasting plasma glucose, fasting insulin, and HOMA-IR values were significantly lower in MS treatment group than in placebo. Our present findings suggest that MS may improve insulin resistance by blocking the AGE-RAGE-oxidative stress axis in the adipose tissues.

Two-hour postload plasma glucose and pigment epithelium-derived factor levels are markers of coronary artery inflammation in type 2 diabetic patients.

BACKGROUND: We have previously found that pioglitazone attenuates inflammation in the left main trunk of coronary artery (LMT), evaluated as target-to-background ratio (TBR) by 18F-fluorodeoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT) in patients with impaired glucose tolerance or type 2 diabetes. OBJECTIVES: We assessed which clinical variables could predict the change in TBR in the LMT after 4-month add-on therapy with oral hypoglycemic agents (OHAs). METHODS: A total of 38 type 2 diabetic patients with carotid atherosclerosis who had already received OHAs except for pioglitazone was enrolled. At baseline and 4 months after add-on therapy with pioglitazone or glimepiride, all patients underwent 75 g oral glucose tolerance test, blood chemistry analysis, and FDG-PET/CT. RESULTS: Fasting plasma glucose, 30-, 60-, 90-, 120-minutes postload plasma glucose, HbA1c, and LMT-TBR values were significantly decreased by add-on therapy, whereas high-density lipoprotein-cholesterol and adiponectin levels were increased. Increased serum levels of pigment epithelium-derived factor (PEDF), a marker of insulin resistance and non-use of aspirin at baseline could predict the favorable response of LMT-TBR to add-on therapy. Moreover, Δ120-minutes postload plasma glucose and ΔPEDF were independent correlates of ΔLMT-TBR. CONCLUSIONS: Our present study suggests that 120-minutes postload plasma glucose and PEDF values may be markers and potential therapeutic targets of coronary artery inflammation in type 2 diabetic patients. CLINICAL TRIAL REGISTRATION: URL: http://clinicaltrials.gov . Unique identifier: NCT00722631. New markers for diabetes and CAD is on the horizon! Two-hour postload plasma glucose and pigment epithelium derived factor are markers of coronary artery inflammation in type 2 diabetic patients.

GIP as a Potential Therapeutic Target for Atherosclerotic Cardiovascular Disease-A Systematic Review.

Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are gut hormones that are secreted from enteroendocrine L cells and K cells in response to digested nutrients, respectively. They are also referred to incretin for their ability to stimulate insulin secretion from pancreatic beta cells in a glucose-dependent manner. Furthermore, GLP-1 exerts anorexic effects via its actions in the central nervous system. Since native incretin is rapidly inactivated by dipeptidyl peptidase-4 (DPP-4), DPP-resistant GLP-1 receptor agonists (GLP-1RAs), and DPP-4 inhibitors are currently used for the treatment of type 2 diabetes as incretin-based therapy. These new-class agents have superiority to classical oral hypoglycemic agents such as sulfonylureas because of their low risks for hypoglycemia and body weight gain. In addition, a number of preclinical studies have shown the cardioprotective properties of incretin-based therapy, whose findings are further supported by several randomized clinical trials. Indeed, GLP-1RA has been significantly shown to reduce the risk of cardiovascular and renal events in patients with type 2 diabetes. However, the role of GIP in cardiovascular disease remains to be elucidated. Recently, pharmacological doses of GIP receptor agonists (GIPRAs) have been found to exert anti-obesity effects in animal models. These observations suggest that combination therapy of GLP-1R and GIPR may induce superior metabolic and anti-diabetic effects compared with each agonist individually. Clinical trials with GLP-1R/GIPR dual agonists are ongoing in diabetic patients. Therefore, in this review, we summarize the cardiovascular effects of GIP and GIPRAs in cell culture systems, animal models, and humans.

Glyceraldehyde-Derived Pyridinium Evokes Renal Tubular Cell Damage via RAGE Interaction.

Glyceraldehyde-derived advanced glycation end products (glycer-AGEs) contribute to proximal tubulopathy in diabetes. However, what glycer-AGE structure could evoke tubular cell damage remains unknown. We first examined if deleterious effects of glycer-AGEs on reactive oxygen species (ROS) generation in proximal tubular cells were blocked by DNA-aptamer that could bind to glyceraldehyde-derived pyridinium (GLAP) (GLAP-aptamer), and then investigated whether and how GLAP caused proximal tubular cell injury. GLAP-aptamer and AGE-aptamer raised against glycer-AGEs were prepared using a systemic evolution of ligands by exponential enrichment. The binding affinity of GLAP-aptamer to glycer-AGEs was measured with a bio-layer interferometry. ROS generation was evaluated using fluorescent probes. Gene expression was analyzed by reverse transcription-polymerase chain reaction (RT-PCR). GLAP-aptamer bound to glycer-AGEs with a dissociation constant of 7.7 × 10-5 M. GLAP-aptamer, glycer-AGE-aptamer, or antibodies directed against receptor for glycer-AGEs (RAGE) completely prevented glycer-AGE- or GLAP-induced increase in ROS generation, MCP-1, PAI-1, or RAGE gene expression in tubular cells. Our present results suggest that GLAP is one of the structurally distinct glycer-AGEs, which may mediate oxidative stress and inflammatory reactions in glycer-AGE-exposed tubular cells. Blockade of the interaction of GLAP-RAGE by GLAP-aptamer may be a therapeutic target for proximal tubulopathy in diabetic nephropathy.

AGE-RAGE Axis Stimulates Oxidized LDL Uptake into Macrophages through Cyclin-Dependent Kinase 5-CD36 Pathway via Oxidative Stress Generation.

Advanced glycation end products (AGEs) are localized in macrophage-derived foam cells within atherosclerotic lesions, which could be associated with the increased risk of atherosclerotic cardiovascular disease under diabetic conditions. Although foam cell formation of macrophages has been shown to be enhanced by AGEs, the underlying molecular mechanism remains unclear. Since cyclin-dependent kinase 5 (Cdk5) is reported to modulate inflammatory responses in macrophages, we investigated whether Cdk5 could be involved in AGE-induced CD36 gene expression and foam cell formation of macrophages. AGEs significantly increased Dil-oxidized low-density lipoprotein (ox-LDL) uptake, and Cdk5 and CD36 gene expression in U937 human macrophages, all of which were inhibited by DNA aptamer raised against RAGE (RAGE-aptamer). Cdk5 and CD36 gene expression levels were correlated with each other. An antioxidant, N-acetyl-l-cysteine, mimicked the effects of RAGE-aptamer on AGE-exposed U937 cells. A selective inhibitor of Cdk5, (R)-DRF053, attenuated the AGE-induced Dil-ox-LDL uptake and CD36 gene expression, whereas anti-CD36 antibody inhibited the Dil-ox-LDL uptake but not Cdk5 gene expression. The present study suggests that AGEs may stimulate ox-LDL uptake into macrophages through the Cdk5-CD36 pathway via RAGE-mediated oxidative stress.