Cardiovascular Outcomes Among Patients with Acute Coronary Syndromes and Diabetes: Results from ACS QUIK Trial in India.

Background: Despite cardiovascular disease being the leading cause of death in India, limited data exist regarding the factors associated with outcomes in patients with diabetes who suffer acute myocardial infarction (AMI). Methods: We examined 21,374 patients with AMI enrolled in the ACS QUIK trial. We compared in-hospital and 30-day major adverse cardiac events including death, re-infarction, stroke, or major bleeding in those with and without diabetes. The associations between diabetes and cardiac outcomes were adjusted for presentation and in-hospital management using logistic regression. Results: Mean ± SD age was 60.1 ± 12.0 years, 24.3% were females, and 44.4% had diabetes. Those with diabetes were more likely to be older, female, hypertensive, and have higher Killip class but less likely to present with STEMI. Patients with diabetes had longer symptoms onset-to-arrival (median 225 vs 290 min; P < 0.001) and, in case of STEMI, longer door-to-balloon times (median, 75 vs 91 min; P < 0.001). Diabetes was independently associated with higher in-hospital death (adjusted odds ratio [aOR], 1.46; 95% CI, 1.12-1.89), in-hospital reinfarction (aOR, 1.52; 95% CI, 1.15-2.02), 30-day MACE (aOR, 1.33; 95% CI, 1.14-1.55) and 30-day death (aOR, 1.40; 95%CI, 1.16-1.69) but not 30-day stroke or 30-day major bleeding. Conclusion: Among patients presenting with AMI in Kerala, India, a considerable proportion has diabetes and are at increased risk for in-hospital and 30-day adverse cardiovascular outcomes. Increased awareness of the increased cardiovascular risk and attention to the implementation of established cardiovascular therapies are indicated for patients with diabetes in lower-middle-income countries who develop AMI. Clinical Trial registration: ClinicalTrials.gov Unique identifier: NCT02256658.

Overcoming Barriers to Diabetes Management in Young Adults with Type 1 Diabetes by Leveraging Telehealth: A Pilot Study.

OBJECTIVE: The LIFT-YA (leveraging intensive follow-up treatment in young adults) quality improvement program was developed to address clinical and social barriers in young adults (YA) with type 1 diabetes (T1D), using telehealth visits to promote clinic attendance and improve diabetes care. METHODS: LIFT-YA enrolled YA aged 18-30 with T1D and HbA1c >8% (64 mmol/mol) who had established adult care in our diabetes clinic. The 6-month, 7-visit hybrid program was facilitated by a case manager serving as the liaison between participants and the care team. The primary end-points were within-group and between-group changes from the baseline in HbA1c at the last visit and adoption of continuous glucose monitoring (CGM). RESULTS: Of the 57 eligible YA, 24 were enrolled and 33 were unable to participate (UTP). Thirteen of the enrolled participants attended at least 4/7 visits ("completers", C), whereas 11 were noncompleters (NC). HbA1c at the end of the program was significantly lower in the C versus UTP group [median -1.0; IQR (-0.6, -2.5) vs -0.25 (0.2, -1.0) in UTP; P < .05]. The percentage of CGM users significantly increased by 70% in the C group (P < .05), but did not change in the NC and UTP groups. Limited access to telehealth and the high cost of frequent visits were the main hurdles preventing enrollment into or completion of the program. CONCLUSIONS: The LIFT-YA pathway was associated with a significant HbA1c reduction and an increase in the adoption of CGM. Policy changes are necessary to expand access to LIFT-YA and other programs for high-risk YA with T1D in underserved communities and across all backgrounds.

Post-graduate medical education in the time of COVID-19: Not a remotely simple task.

The COVID-19 pandemic has stimulated a rapid shift towards telemedicine, which has had tremendous repercussions on all domains of the healthcare ecosystem. The effects of the transition to telemedicine on post-graduate medical education and on patient care provided by trainees have not been fully elucidated. Focusing on the multifaceted scope of endocrinology teaching clinics, the experience garnered by endocrinology fellows, preceptors, and patients through the adoption of virtual visits has shed new light on relevant challenges that require specific attention. First, we identified a divergent trend in glycated hemoglobin in people with type 1 diabetes according to their use of continuous glucose monitoring (CGM). Second, the patient's perspective highlighted positive aspects, including expanded options for clinical care, but also limitations in communication with clinicians for people without access to videoconferencing tools or EHR-based portals. Finally, regarding medical training evaluation and skills-based learning, academic centers, professional organizations, and clinical educators should develop new teaching curricula suitable for a telemedicine-based environment. While simultaneously facing numerous pressures, fellows can potentially spearhead new models of care delivery and innovative approaches to clinical education leveraging telemedicine.

Pancreas transplantation perceptions and practice: Results from a national US survey.

BACKGROUND: Due to a substantial decline in pancreas transplantation (PT) across the United States over the past 15 years, we sought to understand the perceptions and practices of US PT programs. METHODS: Surveys were sent to members of the American Society of Transplantation Surgeons and the American Society of Transplantation by email and professional society postings between August 2019 and November 2019. RESULTS: One hundred twenty three responses were recorded from 56 unique programs. Program characteristics were obtained from the Scientific Registry of Transplant Recipients. Respondents were transplant surgeons (71%), transplant nephrologists (17%), trainees (9%), and allied professionals (3%). Programs were defined according to annual volume as: low (<5 PT/year), intermediate (6-20), or high (>20). High-volume programs reported that these factors were most important for increased PT: expansion of recipient selection, more aggressive donor utilization, and hiring of PT program-specific personnel. At both the program and national level, the vast majority (82% and 79%, respectively) felt the number of PTs currently performed are not in balance with patients' needs. CONCLUSIONS: Overall, programs reported that the option of PT is not offered adequately to diabetic patients and that strategies to maintain higher PT volume are most evident at intermediate, and especially, high-volume programs.

Influence of Cinnamon on Glycemic Control in Individuals With Prediabetes: A Randomized Controlled Trial.

CONTEXT: The identification of adjunct safe, durable, and cost-effective approaches to reduce the progression from prediabetes to type 2 diabetes (T2D) is a clinically relevant, unmet goal. It is unknown whether cinnamon's glucose-lowering properties can be leveraged in individuals with prediabetes. OBJECTIVE: The objective of this work is to investigate the effects of cinnamon on measures of glucose homeostasis in prediabetes. DESIGN SETTING PARTICIPANTS AND INTERVENTION: This double-blind, placebo-controlled, clinical trial randomly assigned adult individuals meeting any criteria for prediabetes to receive cinnamon 500 mg or placebo thrice daily (n = 27/group). Participants were enrolled and followed at 2 academic centers for 12 weeks. MAIN OUTCOME MEASURES: Primary outcome was the between-group difference in fasting plasma glucose (FPG) at 12 weeks from baseline. Secondary end points included the change in 2-hour PG of the oral glucose tolerance test (OGTT), and the change in the PG area under the curve (AUC) derived from the OGTT. RESULTS: From a similar baseline, FPG rose after 12 weeks with placebo but remained stable with cinnamon, leading to a mean between-group difference of 5 mg/dL (P < .05). When compared to the respective baseline, cinnamon, but not placebo, resulted in a significant decrease of the AUC PG (P < .001) and of the 2-hour PG of the OGTT (P < .05). There were no serious adverse events in either study group. CONCLUSIONS: In individuals with prediabetes, 12 weeks of cinnamon supplementation improved FPG and glucose tolerance, with a favorable safety profile. Longer and larger studies should address cinnamon's effects on the rate of progression from prediabetes to T2D.

Purine Metabolite Signatures and Type 2 Diabetes: Innocent Bystanders or Actionable Items?

PURPOSE OF REVIEW: This article reviews evidence linking cardiometabolic conditions with changes in purine metabolites, including increased serum uric acid (sUA), and discusses intervention studies that investigated the therapeutic relevance of these associations. RECENT FINDINGS: Metabolic and epidemiological findings support a correlation between sUA and circulating levels of other purines with insulin resistance (IR) and risk factors for cardiovascular disease (CVD). In addition, increased activity of xanthine oxidoreductase (XOR), the rate-limiting enzyme for UA production, has been detected in tissues targeted by obesity. Yet, inhibition of XOR in pre-clinical and clinical studies generally failed to support a causal role for excess sUA in IR and CVD. The lack of efficacy of XOR inhibitors strongly suggests that UA is a marker of, rather than a direct contributory factor for, cardiometabolic diseases. Validation of the function of other purines will require a paradigm shift, from a "UA-centric" view to a more granular assessment of the entire purine network and its interaction with other pathways.

Dexamethasone and perioperative blood glucose in patients undergoing total joint arthroplasty: A retrospective study.

STUDY OBJECTIVE: Perioperative dexamethasone is commonly used to prevent nausea. It can also increase blood glucose levels, and recent concern about its blood glucose-elevating effect in humans has been raised. This study aimed to demonstrate relationships between dexamethasone administration and elevated perioperative blood glucose in patients undergoing total joint arthroplasty. DESIGN: Retrospective study. SETTING: Academic, orthopedic hospital. PATIENTS: A total of 625 patients (18-99years) who underwent total hip or total knee arthroplasty with an ASA ≤3 were included in the study. INTERVENTIONS: Patients who received dexamethasone perioperatively were compared to those who did not receive dexamethasone. MEASUREMENTS: The primary outcome, which was any postoperative glucose >200mg/dl, was compared between groups using multiple logistic regression. Demographic information, intraoperative information, incidence of postoperative nausea and vomiting, white blood cell count, medication use, and length of stay were also collected. MAIN RESULTS: Perioperative dexamethasone (median [1st quartile, 3rd quartile] dose=4 [4, 8] mg) was administered to 76% of patients. Only 5.6% (95% CI: 3.8-7.5) of patients had postoperative glucose levels >200mg/dl. After covariate adjustment, there was no evidence of a difference in odds of experiencing postoperative glucose levels >200mg/dl (odds ratio [95% CI]: 0.76 [0.28-2.07]; P=0.594) and maximum glucose levels (P=0.518) between groups. Dexamethasone-treated patients had greater changes in white blood cell count between baseline and postoperative days 0-1. There was no evidence of a difference in wound healing and length of stay between groups. CONCLUSIONS: There was no evidence of an association between perioperative dexamethasone administration and the odds of having postoperative glucose levels >200mg/dl or higher maximum glucose levels. However, these findings may not be generalizable to patients having different baseline characteristics or procedures.

Insulin receptor activation with transmembrane domain ligands.

Complementary surfaces are buried when peptide hormones, growth factors, or cytokines bind and activate cellular receptors. Although these extended surfaces provide high affinity and specificity to the interactions, they also present great challenges to the design of small molecules that might either mimic or antagonize the process. We show that the insulin receptor (IR) and downstream signals can be activated by targeting a site outside of its ligand-binding domain. A 24-residue peptide having the IR transmembrane (TM) domain sequence activates IR, but not related growth factor receptors, through specific interactions with the receptor TM domain. Like insulin-dependent activation, IR-TM requires that IR have a competent ATP-binding site and kinase activation loop. IR-TM also activates mutated receptors from patients with severe insulin resistance, which do not respond to insulin. These results show that IR can be activated through a pathway that bypasses its canonical ligand-binding domain.

The multifaceted role of profilin-1 in adipose tissue inflammation and glucose homeostasis.

Profilin-1 (pfn) is a small ubiquitous protein that can bind to: (1) G-actin, (2) phosphatidylinositol 4,5-bisphosphate, and (3) a heterogeneous group of proteins harboring poly-l-proline stretches. Through these interactions, pfn integrates signaling from a diverse array of extracellular cues with actin cytoskeleton dynamics. Cumulating evidence indicates that changes in pfn levels are associated and may play a pathogenic role in such inflammatory diseases as atherosclerosis and glomerulonephritis. We recently demonstrated that high fat diet (HFD) increases pfn expression in the white adipose tissue (WAT), but not in the liver or the muscle. Pfn heterozygote mice (PfnHet) were protected against HFD-induced glucose intolerance, and WAT and systemic inflammation, when compared to pfn wild-type mice. In addition to blunted accumulation of macrophages and reduced "pro-inflammatory" cytokines, the WAT of PfnHet exhibited preserved frequency of regulatory T cells. These findings suggest that pfn levels in WAT-both adipocytes and hematopoietic-derived cells-can modulate immune homeostasis within the WAT and glucose tolerance systemically. Here, we review the interaction of pfn with his diverse array of binding partners and discuss mechanisms that may underlie the effects of pfn dosage on insulin sensitivity and metabolic inflammation.

Profilin-1 haploinsufficiency protects against obesity-associated glucose intolerance and preserves adipose tissue immune homeostasis.

Metabolic inflammation may contribute to the pathogenesis of obesity and its comorbidities, including type 2 diabetes and cardiovascular disease. Previously, we showed that the actin-binding protein profilin-1 (pfn) plays a role in atherogenesis because pfn heterozygote mice (PfnHet) exhibited a significant reduction in atherosclerotic lesion burden and vascular inflammation. In the current study, we tested whether pfn haploinsufficiency would also limit diet-induced adipose tissue inflammation and insulin resistance (IR). First, we found that a high-fat diet (HFD) upregulated pfn expression in epididymal and subcutaneous white adipose tissue (WAT) but not in the liver or muscle of C57BL/6 mice compared with normal chow. Pfn expression in WAT correlated with F4/80, an established marker for mature macrophages. Of note, HFD elevated pfn protein levels in both stromal vascular cells and adipocytes of WAT. We also found that PfnHet were significantly protected from HFD-induced glucose intolerance observed in pfn wild-type mice. With HFD, PfnHet displayed blunted expression of systemic and WAT proinflammatory cytokines and decreased accumulation of adipose tissue macrophages, which were also preferentially biased toward an M2-like phenotype; this correlated with preserved frequency of regulatory T cells. Taken together, the findings indicate that pfn haploinsufficiency protects against diet-induced IR and inflammation by modulating WAT immune homeostasis.

Metabolic syndrome, insulin resistance, and roles of inflammation--mechanisms and therapeutic targets.

Obesity and its comorbidities, including type 2 diabetes mellitus and cardiovascular disease, are associated with a state of chronic low-grade inflammation that can be detected both systemically and within specific tissues. Areas of active investigation focus on the molecular bases of metabolic inflammation and potential pathogenic roles in insulin resistance, diabetes, and cardiovascular disease. An increased accumulation of macrophages occurring in obese adipose tissue has emerged as a key process in metabolic inflammation. Recent studies have also begun to unravel the heterogeneity of adipose tissue macrophages, and their physical and functional interactions with adipocytes, endothelial cells, and other immune cells within the adipose tissue microenvironment. Translating the information gathered from experimental models of insulin resistance and diabetes into meaningful therapeutic interventions is a tantalizing goal with long-term global health implications. In this context, ongoing clinical studies are testing the effects of targeting inflammation systemically on metabolic and cardiovascular outcomes.

Profilin-1 is expressed in human atherosclerotic plaques and induces atherogenic effects on vascular smooth muscle cells.

BACKGROUND: Profilin-1 is an ubiquitous actin binding protein. Under pathological conditions such as diabetes, profilin-1 levels are increased in the vascular endothelium. We recently demonstrated that profilin-1 overexpression triggers indicators of endothelial dysfunction downstream of LDL signaling, and that attenuated expression of profilin-1 confers protection from atherosclerosis in vivo. METHODOLOGY: Here we monitored profilin-1 expression in human atherosclerotic plaques by immunofluorescent staining. The effects of recombinant profilin-1 on atherogenic signaling pathways and cellular responses such as DNA synthesis (BrdU-incorporation) and chemotaxis (modified Boyden-chamber) were evaluated in cultured rat aortic and human coronary vascular smooth muscle cells (VSMCs). Furthermore, the correlation between profilin-1 serum levels and the degree of atherosclerosis was assessed in humans. PRINCIPAL FINDINGS: In coronary arteries from patients with coronary heart disease, we found markedly enhanced profilin expression in atherosclerotic plaques compared to the normal vessel wall. Stimulation of rat aortic and human coronary VSMCs with recombinant profilin-1 (10(-6) M) in vitro led to activation of intracellular signaling cascades such as phosphorylation of Erk1/2, p70(S6) kinase and PI3K/Akt within 10 minutes. Furthermore, profilin-1 concentration-dependently induced DNA-synthesis and migration of both rat and human VSMCs, respectively. Inhibition of PI3K (Wortmannin, LY294002) or Src-family kinases (SU6656, PP2), but not PLCγ (U73122), completely abolished profilin-induced cell cycle progression, whereas PI3K inhibition partially reduced the chemotactic response. Finally, we found that profilin-1 serum levels were significantly elevated in patients with severe atherosclerosis in humans (p<0.001 vs. no atherosclerosis or control group). CONCLUSIONS: Profilin-1 expression is significantly enhanced in human atherosclerotic plaques compared to the normal vessel wall, and the serum levels of profilin-1 correlate with the degree of atherosclerosis in humans. The atherogenic effects exerted by profilin-1 on VSMCs suggest an auto-/paracrine role within the plaque. These data indicate that profilin-1 might critically contribute to atherogenesis and may represent a novel therapeutic target.

Oxysterol and diabetes activate STAT3 and control endothelial expression of profilin-1 via OSBP1.

Endothelial dysfunction plays a central role in diabetic vascular disease, but its molecular bases are not completely defined. We showed previously that the actin-binding protein proflin-1 was increased in the diabetic endothelium and that attenuated expression of profilin-1 protected against atherosclerosis. Also 7-ketocholesterol up-regulated profilin-1 in endothelial cells via transcriptional mechanisms. The present study addressed the pathways responsible for profilin-1 gene expression in 7-ketocholesterol-stimulated endothelial cells and in the diabetic aorta. In luciferase reporter assays, the response to 7-ketocholesterol within the 5'-flanking region of profilin-1 was dependent on a single STAT response element. In aortic endothelial cells, 7-ketocholesterol enhanced STAT3 activation, which required JAK2 and tyrosine 394 phosphorylation of oxysterol-binding protein-1. These changes were recapitulated in the aorta of diabetic rats. Also 7-ketocholesterol in cultured endothelial cells and diabetes in the aorta elicited the recruitment of STAT3 and relevant coregulatory factors to the oxysterol-responsive region of the profilin-1 promoter. These events were required for profilin-1 up-regulation. These studies identify a previously unrecognized oxysterol-binding protein-mediated mode of activation of STAT3 that controls the expression of the proatherogenic protein profilin-1 in response to 7-ketocholesterol and the diabetic milieu.

Attenuated expression of profilin-1 confers protection from atherosclerosis in the LDL receptor null mouse.

Atherosclerosis-related events are a major cause of morbidity and death worldwide, but the mechanisms underlying atherogenesis are not fully understood. We showed in previous studies that the actin-binding protein profilin-1 (pfn) was upregulated in atherosclerotic plaques and in endothelial cells (ECs) treated with oxidized low-density lipoproteins (oxLDL). The present study addressed the role of pfn in atheroma formation. To this end, mice with heterozygous deficiency of pfn, Pfn(+/-), were crossed with Ldlr(-/-) mice. After 2 months under a 1.25% cholesterol atherogenic diet, Pfn(+/-)Ldlr(-/-) (PfnHet) exhibited a significant reduction in lesion burden compared with Ldlr(-/-) control mice (PfnWT), whereas total cholesterol and triglyceride levels were similar in the 2 groups. Relevant atheroprotective changes were identified in PfnHet. When compared with PfnWT, aortas from PfnHet mice showed preserved endothelial nitric oxide synthase (eNOS) activation and nitric oxide (NO)-dependent signaling, and reduced vascular cell adhesion molecule (VCAM)-1 expression and macrophage accumulation at lesion-prone sites. Similarly, knockdown of pfn in cultured aortic ECs was protective against endothelial dysfunction triggered by oxLDL. Finally, bone marrow-derived macrophages from PfnHet showed blunted internalization of oxLDL and oxLDL-induced inflammation. These studies demonstrate that pfn levels modulate processes critical for early atheroma formation and suggest that pfn heterozygosity confers atheroprotection through combined endothelial- and macrophage-dependent mechanisms.

Development of diabetic nephropathy in the Milan normotensive strain, but not in the Milan hypertensive strain: possible permissive role of hemodynamics.

BACKGROUND: Rats of the Milan normotensive strain develop spontaneous glomerulosclerosis, whereas those of the Milan hypertensive strain are resistant to renal disease, possibly due to intrarenal artery hypertrophy protecting from systemic hypertension. To assess the role of hemodynamic versus metabolic factors in diabetic nephropathy, we investigated whether streptozotocin-induced diabetes accelerates glomerulosclerosis in Milan normotensive and/or removes (the hemodynamic) protection in Milan hypertensive rats by reducing preglomerular vascular resistance. METHODS: Diabetic and nondiabetic Milan normotensive, hypertensive, and progenitor Wistar rats were followed for 6 months for the assessment of renal function and structure. RESULTS: Proteinuria increased in nondiabetic and diabetic normotensive and, to a lesser extent, in diabetic Wistar, but not hypertensive rats. Serum creatinine increased and creatinine clearance decreased in nondiabetic and diabetic normotensive rats at 6 months. At 1.5 months, diabetic normotensive, but not hypertensive rats showed increased glomerular filtration rate and filtration fraction, suggesting glomerular hypertension. Diabetic nephropathy was detected in diabetic normotensive and Wistar, but not hypertensive rats. Glomerular extracellular matrix and TGF-beta mRNA levels increased with diabetes (and age) in normotensive, but not hypertensive rats. Arterioles and interlobular arteries showed increased media thickness in hypertensive versus normotensive rats, with diabetes reducing it only in the normotensive. CONCLUSION: These data show that Milan hypertensive rats are not susceptible to diabetic nephropathy, at variance with glomerulosclerosis-prone Milan normotensive rats, thus indicating the importance of genetic background. Our study suggests that the nature of this (genetic) protection might be hemodynamic, with intrarenal artery hypertrophy preventing diabetes-induced loss of autoregulation.

Heat shock protein 90alpha-dependent translocation of annexin II to the surface of endothelial cells modulates plasmin activity in the diabetic rat aorta.

The goals of this article were (1) to identify cell surface proteins whose expression was regulated by diabetes and (2) to assess their contribution to diabetic complications. We purified heat shock protein 90alpha (Hsp90alpha) from the membrane fraction of high glucose-treated endothelial cells (ECs) as a binding partner for a diabetes-specific phage. Further investigation revealed that high glucose elevated cell surface Hsp90alpha in cultured cells, and that diabetes increased the amount of Hsp90alpha on the luminal surface of the aorta. We also found that high glucose or diabetes promoted the association of Hsp90alpha with annexin II and increased the expression of annexin II on the surface of aortic ECs. Finally, plasmin activity was increased by high glucose or diabetes, and this change was partially reversed with an annexin II antibody. These findings reveal a novel glucose-regulated interaction between Hsp90alpha and annexin II, and raise the possibility that increased expression of annexin II, which promotes the generation of plasmin, is linked to clotting abnormalities associated with the diabetic state.