Therapies for type 2 diabetes: lowering HbA1c and associated cardiovascular risk factors

<p>Abstract</p> <p>Objectives</p> <p>To summarize data supporting the effects of antidiabetes agents on glucose control and cardiovascular risk factors in patients with type 2 diabetes.</p> <p>Methods</p> <p>Studies reporting on the effects of antidiabetes agents on glycemic control, body weight, lipid levels, and blood pressure parameters are reviewed and summarized for the purpose of selecting optimal therapeutic regimens for patients with type 2 diabetes.</p> <p>Results</p> <p>National guidelines recommend the aggressive management of cardiovascular risk factors in patients with type 2 diabetes, including weight loss and achieving lipid and blood pressure treatment goals. All antidiabetes pharmacotherapies lower glucose; however, effects on cardiovascular risk factors vary greatly among agents. While thiazolidinediones, sulfonylureas, and insulin are associated with weight gain, dipeptidyl peptidase-4 inhibitors are considered weight neutral and metformin can be weight neutral or associated with a small weight loss. Glucagon-like peptide-1 receptor agonists and amylinomimetics (e.g. pramlintide) result in weight loss. Additionally, metformin, thiazolidinediones, insulin, and glucagon-like peptide-1 receptor agonists have demonstrated beneficial effects on lipid and blood pressure parameters.</p> <p>Conclusion</p> <p>Management of the cardiovascular risk factors experienced by patients with type 2 diabetes requires a multidisciplinary approach with implementation of treatment strategies to achieve not only glycemic goals but to improve and/or correct the underlying cardiovascular risk factors.</p

The central role of vascular extracellular matrix and basement membrane remodeling in metabolic syndrome and type 2 diabetes: the matrix preloaded

The vascular endothelial basement membrane and extra cellular matrix is a compilation of different macromolecules organized by physical entanglements, opposing ionic charges, chemical covalent bonding, and cross-linking into a biomechanically active polymer. These matrices provide a gel-like form and scaffolding structure with regional tensile strength provided by collagens, elasticity by elastins, adhesiveness by structural glycoproteins, compressibility by proteoglycans – hyaluronans, and communicability by a family of integrins, which exchanges information between cells and between cells and the extracellular matrix of vascular tissues. Each component of the extracellular matrix and specifically the capillary basement membrane possesses unique structural properties and interactions with one another, which determine the separate and combined roles in the multiple diabetic complications or diabetic opathies. Metabolic syndrome, prediabetes, type 2 diabetes mellitus, and their parallel companion (atheroscleropathy) are associated with multiple metabolic toxicities and chronic injurious stimuli. The adaptable quality of a matrix or form genetically preloaded with the necessary information to communicate and respond to an ever-changing environment, which supports the interstitium, capillary and arterial vessel wall is individually examined

Ultrastructure study of the transgenic REN2 rat aorta – part 2: media, external elastic lamina, and adventitia

BackgroundThe renin-angiotensin-aldosterone system (RAAS) plays an important role in the development and progression of vascular stiffness, hypertension and accelerated atherosclerosis, which are associated with the metabolic syndrome (MetS) and type 2 diabetes mellitus. In addition to the intima, RAAS plays an important role in vascular media and adventitial remodeling. Methods Descending thoracic aortas of young male transgenic heterozygous (mRen2) 27 (Ren2) rats were utilized for ultrastructural study. This lean model of hypertension, insulin resistance, and oxidative stress harbors the mouse renin gene and is known to have increased aortic tissue levels of angiotensin II, angiotensin type 1 receptors, and elevated plasma aldosterone levels. ResultsUltrastructural observations substantiate known and novel findings in the tunica media, internal and external elastic lamina, and tunica adventitia, which includes: increased media collagen - proteoglycan matrix expansion, increased secretory and proliferative activity and migration of vascular smooth muscle cells (VSMCs) into a newly developing subendothelial neointima, increased VSMC caveolae, mitochondria degeneration, apoptosis; and lipid retention at the elastin lamellar interface. Openings in the external elastic lamina allow pericyte-to-VSMC contacts. The tunica adventitia exhibits stromal pericyte hyperplasia with actively synthetic phenotype and pericyte-pericyte connections. ConclusionWhile these studies only represent a single snapshot in time, they provide an evaluation of early abnormal ultrastructural vascular remodeling in Ren-2 models of the conduit-elastic thoracic aorta

Cardiac Insulin Resistance and MicroRNA Modulators

Cardiac insulin resistance is a metabolic and functional disorder that is often associated with obesity and/or the cardiorenal metabolic syndrome (CRS), and this disorder may be accentuated by chronic alcohol consumption. In conditions of over-nutrition, increased insulin (INS) and angiotensin II (Ang II) activate mammalian target for rapamycin (mTOR)/p70 S6 kinase (S6K1) signaling, whereas chronic alcohol consumption inhibits mTOR/S6K1 activation in cardiac tissue. Although excessive activation of mTOR/S6K1 induces cardiac INS resistance via serine phosphorylation of INS receptor substrates (IRS-1/2), it also renders cardioprotection via increased Ang II receptor 2 (AT2R) upregulation and adaptive hypertrophy. In the INS-resistant and hyperinsulinemic Zucker obese (ZO) rat, a rodent model for CRS, activation of mTOR/S6K1signaling in cardiac tissue is regulated by protective feed-back mechanisms involving mTOR↔AT2R signaling loop and profile changes of microRNA that target S6K1. Such regulation may play a role in attenuating progressive heart failure. Conversely, alcohol-mediated inhibition of mTOR/S6K1, down-regulation of INS receptor and growth-inhibitory mir-200 family, and upregulation of mir-212 that promotes fetal gene program may exacerbate CRS-related cardiomyopathy

Relation between Childhood Obesity and Adult Cardiovascular Risk

The incidence of overweight and obesity is rising at an alarming pace in the pediatric population, just as in the adult population. The adult comorbidities associated with this risk factor are well-recognized and are being further elucidated continually. Additionally, we are gradually developing a better understanding of the risks of overweight and obesity among children while they are still young. However, there is now a growing body of evidence showing that childhood obesity not only leads all too frequently to adult obesity, but is in itself a risk factor for cardiometabolic syndrome and resultant cardiovascular risk in adulthood. If current trends continue, the problem of pediatric overweight and obesity will become of unmanageable proportions once these individuals reach adulthood. Future research efforts toward understanding this complex problem will need to focus on those overweight and obese children who later went on to change their metabolic course and become normal-weight adults

Vascular ossification – calcification in metabolic syndrome, type 2 diabetes mellitus, chronic kidney disease, and calciphylaxis – calcific uremic arteriolopathy: the emerging role of sodium thiosulfate

BACKGROUND: Vascular calcification is associated with metabolic syndrome, diabetes, hypertension, atherosclerosis, chronic kidney disease, and end stage renal disease. Each of the above contributes to an accelerated and premature demise primarily due to cardiovascular disease. The above conditions are associated with multiple metabolic toxicities resulting in an increase in reactive oxygen species to the arterial vessel wall, which results in a response to injury wound healing (remodeling). The endothelium seems to be at the very center of these disease processes, acting as the first line of defense against these multiple metabolic toxicities and the first to encounter their damaging effects to the arterial vessel wall. RESULTS: The pathobiomolecular mechanisms of vascular calcification are presented in order to provide the clinician – researcher a database of knowledge to assist in the clinical management of these high-risk patients and examine newer therapies. Calciphylaxis is associated with medial arteriolar vascular calcification and results in ischemic subcutaneous necrosis with vulnerable skin ulcerations and high mortality. Recently, this clinical syndrome (once thought to be rare) is presenting with increasing frequency. Consequently, newer therapeutic modalities need to be explored. Intravenous sodium thiosulfate is currently used as an antidote for the treatment of cyanide poisioning and prevention of toxicities of cisplatin cancer therapies. It is used as a food and medicinal preservative and topically used as an antifungal medication. CONCLUSION: A discussion of sodium thiosulfate's dual role as a potent antioxidant and chelator of calcium is presented in order to better understand its role as an emerging novel therapy for the clinical syndrome of calciphylaxis and its complications

Retinal Redox Stress and Remodeling in Cardiometabolic Syndrome and Diabetes

Diabetic retinopathy (DR) is a significant cause of global blindness; a major cause of blindness in the United States in people aged between 20–74. There is emerging evidence that retinopathy is initiated and propagated by multiple metabolic toxicities associated with excess production of reactive oxygen species (ROS). The four traditional metabolic pathways involved in the development of DR include: increased polyol pathway flux, advanced glycation end-product formation, activation of protein kinase Cisoforms and hexosamine pathway flux. These pathways individually and synergisticallycontribute to redox stress with excess ROS resulting in retinal tissue injury resulting in significant microvascular blood retinal barrier remodeling. The toxicity of hyperinsulinemia, hyperglycemia, hypertension, dyslipidemia, increased cytokines and growth factors, in conjunction with redox stress, contribute to the development and progression of DR. Redox stress contributes to the development and progression of abnormalities of endothelial cells and pericytes in DR. This review focuses on the ultrastructural observations of the blood retinal barrier including the relationship between the endothelial cell and pericyte remodeling in young nine week old Zucker obese (fa/ fa) rat model of obesity; cardiometabolic syndrome, and the 20 week old alloxan induced diabetic porcine model. Preventing or delaying the blindness associated with these intersecting abnormal metabolic pathways may be approached through strategies targeted to reduction of tissue inflammation and oxidative—redox stress. Understanding these abnormal metabolic pathways and the accompanying redox stress and remodeling mayprovide both the clinician and researcher a new concept of approaching this complicated disease proces

Nebivolol, a beta adrenergic receptor antagonist blocks angiotensin II-mediated signaling in heart [abstract]

We recently showed that Nebivolol, a [beta]-adrenergic receptor (AR) antagonist attenuates myocardial oxidative stress and promotes insulin metabolic signaling in 9 week old Zucker obese (ZO) insulin resistant rats. Here, we demonstrate that Nebivolol suppresses angiotensin II type I receptor (AT1R)-mediated signaling in ZO hearts as well as in HL-1 cardiomyocytes

Ultrastructural Islet Study of Early Fibrosis in the Ren2 Rat Model of Hypertension Emerging Role of the Islet Pancreatic Pericyte-Stellate Cell

Type 2 diabetes mellitus is a multifactorial disease with polygenic and environmental stressors resulting in multiple metabolic toxicities and islet oxidative stress. We have integrated the role of the islet renin-angiotensin system (RAS) in the pathogenesis of early islet fibrosis utilizing the transgenic (mRen2)27 rodent model of hypertension and tissue RAS overexpression. The Ren2 pancreatic islet tissue was evaluated with transmission electron microscopy to study both early cellular and extracellular matrix remodeling. Major remodeling differences in the Ren2 model were found to be located within the islet exocrine interface, including deposition of early fibrillar-banded collagen (fibrosis) and cellular remodeling of the pericyte suggesting proliferation, migration, hypertrophy and activation as compared to the Sprague Dawley controls.This research was supported by the investigator initiated grants NIH (R01 HL73101-01A1), the Veterans Affairs Merit System (0018) grant and Novartis Pharmaceuticals. Male transgenic Ren2 rats and male Sprague-Dawley controls were kindly provided by Dr. Carlos M. Ferrario, Wake Forest University School of Medicine, Winston-Salem, North Carolina through the Transgenic Core Facility supported in part by NIH grant HL-51952

High Glucose-enhanced Acetylcholine Stimulated CGMP Masks Impaired Vascular Reactivity in Tail Arteries from Short-Term Hyperglycemic Rats

Impaired vascular endothelium-dependent relaxation and augmented contractile responses have been reported in several models of long-term hyperglycemia. However, the effects of short-term ambient hyperglycemia are poorly understood. Since oxidative stress has been implicated as a contributor to impaired vascular function, we investigated the following