tolazamide (Tolinase brand has been discontinued.)

Title: tolazamide (Tolinase brand has been discontinued.)
Category: Medications
Created: 3/2/2005 12:00:00 AM
Last Editorial Review: 9/23/2016 12:00:00 AM

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Avandamet (rosiglitazone/metformin)

Title: Avandamet (rosiglitazone/metformin)
Category: Medications
Created: 3/2/2005 12:00:00 AM
Last Editorial Review: 9/21/2016 12:00:00 AM

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Actos (pioglitazone)

Title: Actos (pioglitazone)
Category: Medications
Created: 11/28/1999 12:00:00 AM
Last Editorial Review: 9/20/2016 12:00:00 AM

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Decreased Satellite Cell Number and Function in Humans and Mice With Type 1 Diabetes Is the Result of Altered Notch Signaling

Type 1 diabetes (T1D) negatively influences skeletal muscle health; however, its effect on muscle satellite cells (SCs) remains largely unknown. SCs from samples from rodents (Akita) and human subjects with T1D were examined to discern differences in SC density and functionality compared with samples from their respective control subjects. Examination of the Notch pathway was undertaken to investigate its role in changes to SC functionality. Compared with controls, Akita mice demonstrated increased muscle damage after eccentric exercise along with a decline in SC density and myogenic capacity. Quantification of components of the Notch signaling pathway revealed a persistent activation of Notch signaling in Akita SCs, which could be reversed with the Notch inhibitor DAPT. Similar to Akita samples, skeletal muscle from human subjects with T1D displayed a significant reduction in SC content, and the Notch ligand, DLL1, was significantly increased compared with control subjects, supporting the dysregulated Notch pathway observed in Akita muscles. These data indicate that persistent activation in Notch signaling impairs SC functionality in the T1D muscle, resulting in a decline in SC content. Given the vital role played by the SC in muscle growth and maintenance, these findings suggest that impairments in SC capacities play a primary role in the skeletal muscle myopathy that characterizes T1D.

Source Diabetes Pathophysiology http://ift.tt/2cVbGk0

DNA Damage and the Activation of the p53 Pathway Mediate Alterations in Metabolic and Secretory Functions of Adipocytes

Activation of the p53 pathway in adipose tissue contributes to insulin resistance associated with obesity. However, the mechanisms of p53 activation and the effect on adipocyte functions are still elusive. Here we found a higher level of DNA oxidation and a reduction in telomere length in adipose tissue of mice fed a high-fat diet and an increase in DNA damage and activation of the p53 pathway in adipocytes. Interestingly, hallmarks of chronic DNA damage are visible at the onset of obesity. Furthermore, injection of lean mice with doxorubicin, a DNA damage-inducing drug, increased the expression of chemokines in adipose tissue and promoted its infiltration by proinflammatory macrophages and neutrophils together with adipocyte insulin resistance. In vitro, DNA damage in adipocytes increased the expression of chemokines and triggered the production of chemotactic factors for macrophages and neutrophils. Insulin signaling and effect on glucose uptake and Glut4 translocation were decreased, and lipolysis was increased. These events were prevented by p53 inhibition, whereas its activation by nutlin-3 reproduced the DNA damage-induced adverse effects. This study reveals that DNA damage in obese adipocytes could trigger p53-dependent signals involved in alteration of adipocyte metabolism and secretory function leading to adipose tissue inflammation, adipocyte dysfunction, and insulin resistance.

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Lack of miR-133a Decreases Contractility of Diabetic Hearts: A Role for Novel Cross Talk Between Tyrosine Aminotransferase and Tyrosine Hydroxylase

MicroRNAs (miRNAs) have a fundamental role in diabetic heart failure. The cardioprotective miRNA-133a (miR-133a) is downregulated, and contractility is decreased in diabetic hearts. Norepinephrine (NE) is a key catecholamine that stimulates contractility by activating β-adrenergic receptors (β-AR). NE is synthesized from tyrosine by the rate-limiting enzyme, tyrosine hydroxylase (TH), and tyrosine is catabolized by tyrosine aminotransferase (TAT). However, the cross talk/link between TAT and TH in the heart is unclear. To determine whether miR-133a plays a role in the cross talk between TH and TAT and regulates contractility by influencing NE biosynthesis and/or β-AR levels in diabetic hearts, Sprague-Dawley rats and miR-133a transgenic (miR-133aTg) mice were injected with streptozotocin to induce diabetes. The diabetic rats were then treated with miR-133a mimic or scrambled miRNA. Our results revealed that miR-133a mimic treatment improved the contractility of the diabetic rat’s heart concomitant with upregulation of TH, cardiac NE, β-AR, and downregulation of TAT and plasma levels of NE. In miR-133aTg mice, cardiac-specific miR-133a overexpression prevented upregulation of TAT and suppression of TH in the heart after streptozotocin was administered. Moreover, miR-133a overexpression in CATH.a neuronal cells suppressed TAT with concomitant upregulation of TH, whereas knockdown and overexpression of TAT demonstrated that TAT inhibited TH. Luciferase reporter assay confirmed that miR-133a targets TAT. In conclusion, miR-133a controls the contractility of diabetic hearts by targeting TAT, regulating NE biosynthesis, and consequently, β-AR and cardiac function.

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High-Density Lipoproteins Rescue Diabetes-Impaired Angiogenesis via Scavenger Receptor Class B Type I

Disordered neovascularization and impaired wound healing are important contributors to diabetic vascular complications. We recently showed that high-density lipoproteins (HDLs) enhance ischemia-mediated neovascularization, and mounting evidence suggests HDL have antidiabetic properties. We therefore hypothesized that HDL rescue diabetes-impaired neovascularization. Streptozotocin-induced diabetic mice had reduced blood flow recovery and neovessel formation in a hindlimb ischemia model compared with nondiabetic mice. Reconstituted HDL (rHDL) infusions in diabetic mice restored blood flow recovery and capillary density to nondiabetic levels. Topical rHDL application rescued diabetes-impaired wound closure, wound angiogenesis, and capillary density. In vitro, rHDL increased key mediators involved in hypoxia-inducible factor-1α (HIF-1α) stabilization, including the phosphoinositide 3-kinase/Akt pathway, Siah1, and Siah2, and suppressed the prolyl hydroxylases (PHD) 2 and PHD3. rHDL rescued high glucose–induced impairment of tubulogenesis and vascular endothelial growth factor (VEGF) A protein production, a finding associated with enhanced phosphorylation of proangiogenic mediators VEGF receptor 2 and endothelial nitric oxide synthase. Siah1/2 small interfering RNA knockdown confirmed the importance of HIF-1α stability in mediating rHDL action. Lentiviral short hairpin RNA knockdown of scavenger receptor class B type I (SR-BI) in vitro and SR-BI^–/– diabetic mice in vivo attenuated rHDL rescue of diabetes-impaired angiogenesis, indicating a key role for SR-BI. These findings provide a greater understanding of the vascular biological effects of HDL, with potential therapeutic implications for diabetic vascular complications.

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