Effector T Cells Promote Fibrosis in Corneal Transplantation Failure.

Purpose: To evaluate whether fibrosis contributes to corneal transplant failure and to determine whether effector CD4+ T cells, the key immune cells in corneal transplant rejection, play a direct role in fibrosis formation. Methods: Allogeneic corneal transplantation was performed in mice. Graft opacity was evaluated by slit-lamp biomicroscopy, and fibrosis was assessed by in vivo confocal microscopy. Expression of alpha-smooth muscle actin (α-SMA) in both accepted and failed grafts was assessed by real-time PCR and immunohistochemistry. Frequencies of graft-infiltrating CD4+ T cells, neutrophils, and macrophages were assessed using flow cytometry. In vitro, MK/T-1 corneal fibroblasts were co-cultured with activated CD4+CD25- effector T cells isolated from corneal transplant recipient mice, and α-SMA expression was quantified by real-time PCR and ELISA. Neutralizing antibody was used to evaluate the role of interferon gamma (IFN-γ) in promoting α-SMA expression. Results: The majority of failed grafts demonstrated clinical signs of fibrosis which became most evident at week 6 after corneal transplantation. Failed grafts showed higher expression of α-SMA as compared to accepted grafts. Flow cytometry analysis showed a significant increase in CD4+ T cells in failed grafts compared to accepted grafts. Co-culture of activated CD4+CD25- effector T cells with corneal fibroblasts led to an increase in α-SMA expression by fibroblasts. Inhibition of IFN-γ in culture significantly suppressed this increase in α-SMA expression as compared to immunoglobulin G control. Conclusions: Fibrosis contributes to graft opacity in corneal transplant failure and is mediated at least in part by effector CD4+ T cells via IFN-γ.

The Neuropeptide α-Melanocyte-Stimulating Hormone Prevents Persistent Corneal Edema following Injury.

Corneal endothelial cells (CEnCs) regulate corneal hydration and maintain tissue transparency through their barrier and pump function. However, these cells exhibit limited regenerative capacity following injury. Currently, corneal transplantation is the only established therapy for restoring endothelial function, and there are no pharmacologic interventions available for restoring endothelial function. This study investigated the efficacy of the neuropeptide α-melanocyte-stimulating hormone (α-MSH) in promoting endothelial regeneration during the critical window between ocular injury and the onset of endothelial decompensation using an established murine model of injury using transcorneal freezing. Local administration of α-MSH following injury prevented corneal edema and opacity, reduced leukocyte infiltration, and limited CEnC apoptosis while promoting their proliferation. These results suggest that α-MSH has a proregenerative and cytoprotective function on CEnCs and shows promise as a therapy for the prevention and management of corneal endothelial dysfunction.

Insights into mustard gas keratopathy- characterizing corneal layer-specific changes in mice exposed to nitrogen mustard.

Exposure to mustard agents, such as sulfur mustard (SM) and nitrogen mustard (NM), often results in ocular surface damage. This can lead to the emergence of various corneal disorders that are collectively referred to as mustard gas keratopathy (MGK). In this study, we aimed to develop a mouse model of MGK by using ocular NM exposure, and describe the subsequent structural changes analyzed across the different layers of the cornea. A 3 µL solution of 0.25 mg/mL or 5 mg/mL NM was applied to the center of the cornea via a 2-mm filter paper for 5 min. Mice were evaluated prior to and after exposure on days 1, 3, 7, 14, and 28 for 4 weeks using slit lamp examination with fluorescein staining. Anterior segment optical coherence tomography (AS-OCT) and in vivo confocal microscopy (IVCM) tracked changes in the epithelium, stroma, and endothelium of the cornea. Histologic evaluation was used to examine corneal cross-sections collected at the completion of follow-up. Following exposure, mice experienced central corneal epithelial erosion and thinning, accompanied by a decreased number of nerve branches in the subbasal plexus and increased activated keratocytes in the stroma in both dosages. The epithelium was recovered by day 3 in the low dose group, followed by exacerbated punctuate erosions alongside persistent corneal edema that arose and continued onward to four weeks post-exposure. The high dose group showed persistent epitheliopathy throughout the study. The endothelial cell density was reduced, more prominent in the high dose group, early after NM exposure, which persisted until the end of follow-up, along with increased polymegethism and pleomorphism. Microstructural changes in the central cornea at 4 weeks post-exposure included dysmorphic basal epithelial cells and reduced epithelial thickness, and in the limbal cornea included decreased cellular layers. We present a mouse model of MGK using NM that successfully replicates ocular injury caused by SM in humans who have been exposed to mustard gas.

Eight Weeks of Vitamin C Supplementation Restores the Lost Correlation between Serum Leptin and C-reactive Protein (CRP) in Patients with Type 2 Diabetes; A Randomized, Double-blind, Parallel-group, Placebo-controlled Clinical Trial.

OBJECTIVE: Inflammation is a well-described factor in the pathophysiology of type 2 diabetes mellitus (DM), which has been a suspect in the alteration of correlations between CRP and leptin in patients with type 2 DM. AIM: This study aimed to show the effect of vitamin C as an antioxidant on the correlation of the serum levels of C-reactive protein (CRP) and leptin in patients with type 2 DM. METHODS: We recruited 70 patients with longstanding T2DM and randomly assigned them into two groups; one received 500 mg/day of vitamin C, and the other received a placebo for eight weeks. Both groups were matched regarding baseline characteristics such as age, gender, weight, and diabetic medications. RESULTS: Out of 70 individuals, 57 participants were left in the study. After eight weeks of follow-up, leptin level was significantly increased in the Vitamin C group (MD = 3.48 change = 24%, p-value = 0.001) but did not change in the placebo group. Other markers such as Fasting plasma glucose, HbA1c, Creatinine, uric acid, Urea, cholesterol, HDL, LDL, TG, AST, ALT, insulin, and CRP did not significantly change in both groups (p value > 0.05). The significant changes in the leptin level among the vitamin C group also remained after controlling for age, BMI, Blood pressure (BP), Triglyceride (TG), and cholesterol. Also, the correlation between serum CRP and leptin became significant in the vitamin C group after eight weeks of follow-up but not in the placebo group. (rs = 0.730, p < 0.001 vs. rs = 0.286, p-value = 0.266 in placebo group). CONCLUSION: This study shows vitamin C can restore CRP-leptin correlation in patients with type 2 diabetes and increase serum leptin levels. More studies are needed to clarify the mechanism of this restoration. CLINICAL TRIAL REGISTRATION NUMBER: IRCT20160811029306N1.

The impact of donor diabetes on corneal transplant immunity.

Corneal transplantation is the most common form of solid tissue grafting, with an approximately 80% to 90% success rate. However, success rates may decline when donor tissues are derived from patients with a history of diabetes mellitus (DM). To evaluate the underlying immunopathologic processes that cause graft rejection, we used streptozotocin-induced type 1 DM (DM1) and transgenic Lepob/ob type 2 DM (DM2) diabetic murine models as donors and nondiabetic BALB/c as recipients. DM resulted in an increased frequency of corneal antigen-presenting cells (APCs) with an acquired immunostimulatory phenotype. Following transplantation, recipients that received either type of diabetic graft showed increased APC migration and T helper type 1 alloreactive cells, impaired functional regulatory T cells, and graft survival. Insulin treatment in streptozotocin-induced diabetic mice led to an increased tolerogenic profile of graft APC, lower T helper type 1 sensitization, and a higher frequency of functional regulatory T cells with high suppressive capacity, reflected in increased graft survival. We conclude that both DM1 and DM2 in donors can impact corneal APC functional phenotype, rendering the tissue more immunogenic and thereby increasing the risk of graft failure.

Insights into mustard gas keratopathy: Characterizing corneal layer-specific changes in mice exposed to nitrogen mustard.

Exposure to mustard agents, such as sulfur mustard (SM) and nitrogen mustard (NM), often results in ocular surface damage. This can lead to the emergence of various corneal disorders that are collectively referred to as mustard gas keratopathy (MGK). In this study, we aimed to develop a mouse model of MGK by using ocular NM exposure, and describe the subsequent structural changes analyzed across the different layers of the cornea. A 3 µL solution of 0.25 mg/mL NM was applied to the center of the cornea via a 2-mm filter paper for 5 min. Mice were evaluated prior to and after exposure on days 1 and 3, and weekly for 4 weeks using slit lamp examination with fluorescein staining. Anterior segment optical coherence tomography (AS-OCT) and in vivo confocal microscopy (IVCM) tracked changes in the epithelium, stroma, and endothelium of the cornea. Histologic evaluation and immunostaining were used to examine corneal cross-sections collected at the completion of follow-up. A biphasic ocular injury was observed in mice exposed to NM, most prominent in the corneal epithelium and anterior stroma. Following exposure, mice experienced central corneal epithelial erosions and thinning, accompanied by a decreased number of nerve branches in the subbasal plexus and increased activated keratocytes in the stroma. The epithelium was recovered by day 3, followed by exacerbated punctuate erosions alongside persistent stromal edema that arose and continued onward to four weeks post-exposure. The endothelial cell density was reduced on the first day after NM exposure, which persisted until the end of follow-up, along with increased polymegethism and pleomorphism. Microstructural changes in the central cornea at this time included dysmorphic basal epithelial cells, and in the limbal cornea included decreased cellular layers and p63+ area, along with increased DNA oxidization. We present a mouse model of MGK using NM that successfully replicates ocular injury caused by SM in humans who have been exposed to mustard gas. Our research suggests DNA oxidation contributes to the long-term effects of nitrogen mustard on limbal stem cells.

Descemet Stripping Only Technique for Corneal Endothelial Damage in Mice.

PURPOSE: Descemet stripping only is an emerging surgical technique used to remove central Descemet membrane and corneal endothelial cells in patients with corneal endothelial disease. Here, we describe a murine model of this procedure to help facilitate basic science investigation and evaluation of postoperative outcomes using this surgical technique. METHODS: Slitlamp biomicroscopy, central corneal thickness assessment (by optical coherence tomography), and immunohistochemistry were used to assess the model through 7 weeks of follow-up. RESULTS: Complete removal of the endothelium and Descemet membrane was confirmed by slitlamp biomicroscopy and by histology. Central corneal thickness peaked at day 1 postinjury and then declined over the course of 2 weeks to a stable level of persistent edema. Seven weeks postinjury, immunohistochemical staining for ZO-1 showed the area of Descemet stripping was fully covered by enlarged and dysmorphic corneal endothelial cell. No significant ocular complications were appreciated through the end of the follow-up. CONCLUSIONS: We demonstrate the feasibility of and provide detailed instructions for a murine model of Descemet stripping only. This model provides a potential in vivo platform to investigate the mechanisms and biology of this emerging surgical procedure.

A Novel Murine Model of Endothelial Keratoplasty.

PURPOSE: The purpose of this study was to establish a murine model of endothelial keratoplasty. METHODS: Endothelial keratoplasty (EK) was performed using C57BL/6 donor and BALB/c recipient mice. The central endothelium and Descemet membrane were removed from the recipient cornea, and a 1.5-mm posterior lamellar donor graft was made adherent to the recipient cornea with a small amount of viscoelastic. Mice were followed through slitlamp microscopy postoperatively, and OCT was used to assess the cornea and anterior chamber and measure central corneal thickness. Histology and immunohistochemistry were performed to confirm graft adherence and endothelial cell morphology. RESULTS: Successfully attached EK grafts were visualized in all transplanted animals. Histology and immunostaining confirmed proper graft orientation and adherence, as well as the presence of donor endothelium on transplanted grafts. We observed maximal corneal edema in all animals at day 1 postoperatively which gradually subsided. EK graft survival was 97% at 8 weeks. CONCLUSIONS: In this study, we describe a novel murine model for EK which we anticipate will enable detailed investigation into the cellular and molecular mechanisms involved in EK pathobiology.

Immune regulation of the ocular surface.

Despite constant exposure to various environmental stimuli, the ocular surface remains intact and uninflamed while maintaining the transparency of the cornea and its visual function. This 'immune privilege' of the ocular surface is not simply a result of the physical barrier function of the mucosal lining but, more importantly, is actively maintained through a variety of immunoregulatory mechanisms that prevent the disruption of immune homeostasis. In this review, we focus on essential molecular and cellular players that promote immune quiescence in steady-state conditions and suppress inflammation in disease-states. Specifically, we examine the interactions between the ocular surface and its local draining lymphoid compartment, by encompassing the corneal epithelium, corneal nerves and cornea-resident myeloid cells, conjunctival goblet cells, and regulatory T cells (Treg) in the context of ocular surface autoimmune inflammation (dry eye disease) and alloimmunity (corneal transplantation). A better understanding of the immunoregulatory mechanisms will facilitate the development of novel, targeted immunomodulatory strategies for a broad range of ocular surface inflammatory disorders.

The Neuropeptide Alpha-Melanocyte-Stimulating Hormone Is Critical for Corneal Endothelial Cell Protection and Graft Survival after Transplantation.

Corneal transplantation is the most common form of tissue transplantation. The success of corneal transplantation mainly relies on the integrity of corneal endothelial cells (CEnCs), which maintain tissue transparency by pumping out excess water from the cornea. After transplantation, the rate of CEnC loss far exceeds that seen with normal aging, which can threaten sight. The underlying mechanisms are poorly understood. Alpha-melanocyte-stimulating hormone (α-MSH) is a neuropeptide that is constitutively found in the aqueous humor with both cytoprotective and immunomodulatory effects. The curent study found high expression of melanocortin 1 receptor (MC1R), the receptor for α-MSH, on CEnCs. The effect of α-MSH/MC1R signaling on endothelial function and allograft survival in vitro and in vivo was investigated using MC1R signaling-deficient mice (Mc1re/e mice with a nonfunctional MC1R). Herein, the results indicate that in addition to its well-known immunomodulatory effect, α-MSH has cytoprotective effects on CEnCs after corneal transplantation, and the loss of MC1R signaling significantly decreases long-term graft survival in vivo. In conclusion, α-MSH/MC1R signaling is critical for CEnC function and graft survival after corneal transplantation.

Pigment Epithelium-Derived Factor Enhances the Suppressive Phenotype of Regulatory T Cells in a Murine Model of Dry Eye Disease.

Pigment epithelium-derived factor (PEDF) is a widely expressed 50-kDa glycoprotein belonging to the serine protease inhibitor family, with well-established anti-inflammatory functions. Recently, we demonstrated the immunoregulatory role played by PEDF in dry eye disease (DED) by suppressing the maturation of antigen-presenting cells at the ocular surface following exposure to the desiccating stress. In this study, we evaluated the effect of PEDF on the immunosuppressive characteristics of regulatory T cells (Tregs), which are functionally impaired in DED. In the presence of PEDF, the in vitro cultures prevented proinflammatory cytokine (associated with type 17 helper T cells)-induced loss of frequency and suppressive phenotype of Tregs derived from normal mice. Similarly, PEDF maintained the in vitro frequency and enhanced the suppressive phenotype of Tregs derived from DED mice. On systemically treating DED mice with PEDF, moderately higher frequencies and significantly enhanced suppressive function of Tregs were observed in the draining lymphoid tissues, leading to the efficacious amelioration of the disease. Our results demonstrate that PEDF promotes the suppressive capability of Tregs and attenuates their type 17 helper T-cell-mediated dysfunction in DED, thereby playing a role in the suppression of DED.

Barriers to initiation of insulin therapy in poorly controlled type 2 diabetes based on self-determination theory.

BACKGROUND: Proper glycaemic control can slow progression of diabetes complications. One of the main causes of poor glycaemic control is delayed initiation of insulin therapy. AIMS: To explain the reasons for delayed insulin initiation based on a behavioural model using patients' innate psychological needs. METHODS: We enrolled 151 patients with type 2 diabetes who had indications for insulin therapy. Thirty general practitioners (GPs) were included as care providers. Patients were studied by questionnaires evaluating components of self determination theory, such as competency, relatedness and autonomy. We also evaluated patients' attitudes towards insulin therapy using the Insulin Treatment Appraisal Scale questionnaire. GPs' attitudes towards insulin therapy were assessed with a different questionnaire. RESULTS: Competency of patients was scored as acceptable (14.44/20). Relatedness score was low at around 15.63/30. The findings suggested that the patients' intrinsic motivation was less than their extrinsic motivation (8.41/15 vs 15.03/20). The main barrier to insulin therapy on the patients' side was rejection of severity of illness (67.5%). According to GPs, low compliance (96.7%) was the main cause of delayed insulin prescription. CONCLUSIONS: We observed that patients do not have a proper understanding about their illness. Due to the low score of relatedness as a representative of patients and care providers' relationship, we highlight the importance of educating both about insulin therapy and how they can have the most effective relationship in this process.

Serum HSP70 level in patients with endometrial cancer with and without diabetes.

Diabetes mellitus (DM) is associated with an increased risk of endometrial carcinoma (EC). Heat shock proteins have a role in the modulation of both diseases. The aim of this study was to investigate extracellular HSP70 (eHSP70) level alternations in patients with two different types of EC (endometrioid and non-endometrioid) with and without type 2 diabetes. In a case-control study, 88 participants were enrolled in four groups including: 18 EC patients with DM, 19 EC patients without DM, 29 patients with DM, and 22 healthy individuals. Blood samples were taken before surgery in cancer patients. Estradiol, eHSP70, sex hormone-binding globulin (SHBG), FBS, and HbA1c were assessed. Serum HSP70 level was higher in patients with diabetes (52.24 ± 14.2 ng/ml) compared to healthy controls (39.04 ± 6.96) (p < .05). It was lower in EC (26.05 ± 12.28) compared to healthy controls (39.04 ± 6.96) (p < .05). eHSP70 was also lower in endometrioid-type carcinoma (22.57 ± 11) compared to non-endometrioid type (31.55 ± 12.38) (p < .05). Further analysis showed increased levels of eHSP70 in patients having both endometrioid-type carcinoma and diabetes (27.23 ± 11.41) compared to the same patients without DM (17.08 ± 7.78) (p < .05). Presence of diabetes in patients with endometrioid type carcinoma resulted in an increase in eHSP70 approaching the level of eHSP70 in patients with non-endometrioid histology.

Determinants of glycemic control: Phase 2 analysis from nationwide diabetes report of National Program for Prevention and Control of Diabetes (NPPCD-2018).

BACKGROUND: Diabetes is one of the leading causes of morbidity and mortality worldwide, especially among middle and low income nations. Many diabetic complications and comorbidities are attributable to poor glycemic control. The aim of this study was to update and extend the national diabetes reports on the status of comorbidities, diabetes care and complications in Iran. Moreover, we investigated the risk factors of poor glycemic control in the Iranian population. METHODS: National database of 99,651 patients with diabetes who attended university-affiliated clinics between April 1, 2017 and February 30, 2018 was used to carry out a cross-sectional study. Stepwise backward selection logistic regression model was used to examine the associated factors of glycemic control. RESULTS: In this study 73.0% and 56.5% of the enrolled population with diabetes, had hypertension and hyperlipidemia, respectively. The prevalence of patients who received education for nutrition therapy or diabetes self-management was 16.3% and 23.3% respectively. Poor glycemic control was associated with male gender (OR=1.06, p=0.001), obesity (OR=1.03, p=0.05), duration of diabetes (OR=1.018, p<0.001), smoking (OR=1.08, p=0.041), hypertension (OR=1.53, p<0.001), hyperlipidemia (OR=1.15, p<0.001), insulin therapy (OR=1.26, p<0.001) and combination of insulin and oral anti-diabetic agents compared to oral anti-diabetic agents alone (OR=2.36, p<0.001). CONCLUSION: We demonstrated that the prevalence of diabetes comorbidities is high in Iranian population and that a great proportion of Iranian patients with diabetes had not reached the goal of glycemic control. Our findings provide a starting point from which to investigate the obstacles that prevent patients with diabetes from reaching metabolic targets.

Smoking and Diabetes Control in Adults With Type 1 and Type 2 Diabetes: A Nationwide Study From the 2018 National Program for Prevention and Control of Diabetes of Iran.

OBJECTIVES: Smoking is among the top leading causes of morbidity and mortality worldwide. To date, studies on the association between smoking and diabetes complications and metabolic control have shown conflicting results. In this study, we aimed to assess the association of smoking with micro- and macrovascular complications of diabetes and lipid and glycemic indices. METHODS: We used the National Program for Prevention and Control of Diabetes of Iran database of 99,651 adult patients with diabetes across Iran. Multiple logistic regression models were used to examine the association between smoking and diabetes complications including cardiovascular disease, neuropathy, nephropathy and retinopathy. This association was adjusted for age, sex, duration of diabetes, glycated hemoglobin (A1C), hypertension, hyperlipidemia, medication, obesity and type of diabetes. RESULTS: Smoking was associated with cardiovascular disease, nephropathy, retinopathy and neuropathy (odds ratios [ORs] for patients with type 1 diabetes were 1.51, 2.29, 2.70 and 2.40, respectively; for patients with type 2 diabetes, ORs were 1.27, 1.21, 1.51 and 1.70, respectively; all with p values <0.001). Among patients with type 1 diabetes, smoking was significantly (p<0.05) associated with A1C (OR, 2.12), 2-h postglucose level (OR, 1.30), triglycerides (OR, 1.48) and high-density lipoprotein (HDL) control (OR, 1.34). Among patients with type 2 diabetes, smoking was significantly associated with A1C (OR, 1.09) and HDL control (OR, 1.21). CONCLUSIONS: Smoking was associated with multiple diabetes complications including cardiovascular disease, neuropathy, nephropathy and retinopathy and worse A1C and HDL control in both patients with type 1 and type 2 diabetes. It was also associated with worse 2-h postglucose level and triglyceride control among patients with type 1 diabetes. Our findings signify that national programs for smoking prevention and cessation may be beneficial to diabetes control in Iran.

Comparison of primary versus secondary prevention of cardiovascular disease in patients with type2 diabetes: Focus on achievement of ABC goals.

BACKGROUND: Primary and secondary prevention of cardiovascular disease is of utmost importance in the management of patients with diabetes. OBJECTIVES: We studied a group of Iranian patients with type2 diabetes to provide an overview of the current status of secondary prevention of cardiovascular disease in the Middle East. METHODS: This is a cross-sectional study of 2029 Patients with type2 diabetes including 323 patients with coronary artery disease (CAD) were recruited. Achievement of goals in HbA1c (A), blood pressure (B) and LDL-cholesterol(C) was assessed. RESULTS: The study showed 25.3% of CAD positive patients achieved HbA1c <7% compared to 30% in CAD negative patients. The achievement of blood pressure ≤140/90 mmHg was 53.2% and 52.8% in CAD positive and CAD negative patients respectively. There was no difference in the achievement of all three ABC goals between the two groups (p = 0.733). After logistic regression analysis, history of hypertension had the highest odds ratio for CAD. CONCLUSION: Although ABC control has an important impact on the prevention of cardiovascular outcomes, the ideal goal needs further efforts to be achieved.

Loss of Inverse Association between Framingham Risk Score and Estimated Glomerular Filtration Rate in Moderate to Severe Diabetic Kidney Disease.

BACKGROUND: We investigated the association of estimated glomerular filtration rate (eGFR) with Framingham risk score (FRS), and actual cardiovascular disease (CVD) in patients with type 2 diabetes (T2DM). We also assessed improvement in FRS for prediction of CVD after inclusion of eGFR and albuminuria. METHODS: A total of 571 patients with T2DM and mean age 55 were divided into 2 groups based on the presence of CVD. Participants without CVD were then divided into three groups according to FRS. CVD is defined as an episode of CCU admission, Myocardial infarction, history of coronary artery bypass graft surgery or percutaneous intervention. FRS is calculated using the Wilson 1998 Circulation equation, which includes age, sex, high blood pressure, smoking, high-density lipoprotein (HDL), total cholesterol and diabetes as components to assess CVD risk in 10 years. RESULTS: An inverse adjusted association between eGFR and prevalent CVD was confirmed by multiple logistic regression analysis (OR = 0.84, 95% CI: 0.74, 0.94, P = 0.03). We observed every 10 mL/min/1.73 m2 decrease in eGFR is related to 3% increase in FRS in patients without chronic kidney disease (CKD) (coefficient = -0.03, P < 0.001). The association between FRS and GFR and also CVD and eGFR were not significant in patients with CKD (P = 0.12; P = 0.17, respectively). Predictive values for FRS components with and without considering eGFR and albuminuria were calculated (0.74 and 0.75, respectively). CONCLUSION: Inclusion of eGFR and albuminuria in the FRS formula did not improve the predictive value of the model. We showed an inverse association between eGFR and FRS in early stages of diabetic kidney disease, which was lost in patients with CKD.

Association of extracellular heat shock protein 70 and insulin resistance in type 2 diabetes; independent of obesity and C-reactive protein.

Despite few studies on intracellular heat shock protein70, the clinical association between insulin resistance and extracellular heat shock protein70 (eHSP70) is not well studied. In the current study, we examined the association between homeostatic model assessment-insulin resistance (HOMA-IR) and eHSP70 in patients with type 2 diabetes (T2DM) and healthy controls. A total of 145 patients with T2DM and 41 matched healthy controls were selected. Patients and controls were divided based on waist circumference (WC) to two groups, and eHSP70 was compared between them. The association between HOMA-IR and eHSP70 was examined using regression models adjusted for age, high-sensitive C-reactive protein (hs-CRP), and central obesity as confounding factors. While eHSP70 and hs-CRP were significantly correlated with HOMA-IR in patients with T2DM (p = 0.032, 0.025, respectively), there was no correlation between eHSP70 and HOMA-IR in the control group. Extracellular HSP70 and hs-CRP were not correlated in healthy controls. But a significant association appeared between eHSP70 and hs-CRP in patients with T2DM (p = 0.05). Both BMI and WC were not correlated with eHSP70 in both groups. Extracellular HSP70 was positively associated with HOMA-IR in patients with T2DM, independent from hs-CRP and obesity. We also showed eHSP70 levels remained unchanged through increase in BMI or WC in patients with T2D and in healthy controls. Our findings suggest that eHSP70 may contribute to the pathogenesis of T2DM by increasing insulin resistance.

Ambulatory blood pressure monitoring and diabetes complications: Targeting morning blood pressure surge and nocturnal dipping.

Ambulatory blood pressure monitoring (ABPM) correlates more closely to organ damages than clinic blood pressure (BP). In the current study we aimed to investigate the association between micro- and macrovascular complications of diabetes and both diurnal and nocturnal variability in BP.A total of 192 patients with type 2 diabetes (T2DM) who had complete data on ABPM were selected. BP categories were defined based on 2017 ACC/American Heart Association BP guideline. The cross-sectional association between different BP phenotypes and diabetes complications including cardiovascular disease (CVD), nephropathy, retinopathy, and neuropathy was assessed using multiple logistic regression models adjusted for age, sex, body mass index, hypertension (HTN), hemoglobin A1c, fasting blood glucose (FBG), triglyceride (TG), high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and total cholesterol.Approximately 48.9% of participants with T2DM had 24-hour HTN. The prevalence of daytime, nighttime, and clinic HTN were 35.9%, 96.3%, and 53.1%, respectively. Approximately 54.2% of participants had nondipping nocturnal pattern and 28.6% were risers. Nondipping nocturnal BP was associated with CVD, neuropathy, and retinopathy (P = .05, .05, and .014, respectively). Sleep trough morning blood pressure surge (MBPS) was associated with neuropathy (P = .023). Neuropathy was also associated with other components of MBPS (P < .05).We demonstrated that diabetic neuropathy was associated with all the components of MBPS and abnormal dipping status. Our results indicated loss of nocturnal BP dipping but not MBPS as a risk factor for CVD and retinopathy in patients with T2DM. Our findings once again highlighted the importance of ambulatory BP monitoring and targeted antihypertensive therapy directed toward to restore normal circadian BP in patients with T2DM.

Pulse pressure and diabetes treatments: Blood pressure and pulse pressure difference among glucose lowering modality groups in type 2 diabetes.

Type 2 diabetes is associated with higher pulse pressure. In this study, we assessed and compared effects of classic diabetes treatments on pulse pressure (PP), systolic blood pressure (SBP), and diastolic blood pressure (DBP) in patients with type 2 diabetes.In a retrospective cohort study, 718 non-hypertensive patients with type 2 diabetes were selected and divided into 4 groups including metformin, insulin, glibenclamide+metformin, and metformin+insulin. They were followed for 4 consecutive visits lasting about 45.5 months. Effects of drug regimens on pulse and blood pressure over time were assessed separately and compared in regression models with generalized estimating equation method and were adjusted for age, duration of diabetes, sex, smoking, and body mass index (BMI).Studied groups had no significant change in PP, SBP, and DBP over time. No significant difference in PP and DBP among studied groups was observed (PP:P = 0.090; DBP:P = 0.063). Pairwise comparisons of PP, SBP, and DBP showed no statistically significant contrast between any 2 studied groups. Interactions of time and treatment were not different among groups.Our results demonstrate patients using metformin got higher PP and SBP over time. Averagely, pulse and blood pressure among groups were not different. Trends of variation in pulse and blood pressure were not different among studied diabetes treatments.