The Role of Insulin Receptor Isoforms in Diabetes and Its Metabolic and Vascular Complications.

The insulin receptor (IR) presents by alternative splicing two isoforms: IRA and IRB. The differential physiological and pathological role of both isoforms is not completely known, and it is determinant the different binding affinity for insulin-like growth factor. IRB is more abundant in adult tissues and it exerts mainly the metabolic actions of insulin, whereas IRA is mainly expressed in fetal and prenatal period and exerts mitogenic actions. However, the change in the expression profile of both IR isoforms and its dysregulation are associated with the development of different pathologies, such as cancer, insulin resistance, diabetes, obesity, and atherosclerosis. In some of them, there is a significant increase of IRA/IRB ratio conferring a proliferative and migratory advantage to different cell types and favouring IGF-II actions with a sustained detriment in the metabolic effects of insulin. This review discussed specifically the role of IR isoforms as well as IGF-IR in diabetes and its associated complications as obesity and atherosclerosis. Future research with new IR modulators might be considered as possible targets to improve the treatment of diabetes and its associated complications.

Expression of insulin receptor (IR) A and B isoforms, IGF-IR, and IR/IGF-IR hybrid receptors in vascular smooth muscle cells and their role in cell migration in atherosclerosis.

BACKGROUND: Abnormal proliferation and migration of vascular smooth muscle cells (VSMCs) is a major contributor to the development of atherosclerotic process. In a previous work, we demonstrated that the insulin receptor isoform A (IRA) and its association with the insulin-like growth factor-I receptor (IGF-IR) confer a proliferative advantage to VSMCs. However, the role of IR and IGF-IR in VSMC migration remains poorly understood. METHODS: Wound healing assays were performed in VSMCs bearing IR (IRLoxP+/+ VSMCs), or not (IR-/- VSMCs), expressing IRA (IRA VSMCs) or expressing IRB (IRB VSMCs). To study the role of IR isoforms and IGF-IR in experimental atherosclerosis, we used ApoE-/- mice at 8, 12, 18 and 24 weeks of age. Finally, we analyzed the mRNA expression of total IR, IRB isoform, IGF-IR and IGFs by qRT-PCR in the medial layer of human aortas. RESULTS: IGF-I strongly induced migration of the four cell lines through IGF-IR. In contrast, insulin and IGF-II only caused a significant increase of IRA VSMC migration which might be favored by the formation of IRA/IGF-IR receptors. Additionally, a specific IGF-IR inhibitor, picropodophyllin, completely abolished insulin- and IGF-II-induced migration in IRB, but not in IRA VSMCs. A significant increase of IRA and IGF-IR, and VSMC migration were observed in fibrous plaques from 24-week-old ApoE-/- mice. Finally, we observed a marked increase of IGF-IR, IGF-I and IGF-II in media from fatty streaks as compared with both healthy aortas and fibrolipidic lesions, favoring the ability of medial VSMCs to migrate into the intima. CONCLUSIONS: Our data suggest that overexpression of IGF-IR or IRA isoform, as homodimers or as part of IRA/IGF-IR hybrid receptors, confers a stronger migratory capability to VSMCs as might occur in early stages of atherosclerotic process.

Updating experimental models of diabetic cardiomyopathy.

Diabetic cardiomyopathy entails a serious cardiac dysfunction induced by alterations in structure and contractility of the myocardium. This pathology is initiated by changes in energy substrates and occurs in the absence of atherothrombosis, hypertension, or other cardiomyopathies. Inflammation, hypertrophy, fibrosis, steatosis, and apoptosis in the myocardium have been studied in numerous diabetic experimental models in animals, mostly rodents. Type I and type II diabetes were induced by genetic manipulation, pancreatic toxins, and fat and sweet diets, and animals recapitulate the main features of human diabetes and related cardiomyopathy. In this review we update and discuss the main experimental models of diabetic cardiomyopathy, analysing the associated metabolic, structural, and functional abnormalities, and including current tools for detection of these responses. Also, novel experimental models based on genetic modifications of specific related genes have been discussed. The study of specific pathways or factors responsible for cardiac failures may be useful to design new pharmacological strategies for diabetic patients.

Factors involved in rosuvastatin induction of insulin sensitization in rats fed a high fat diet.

BACKGROUND AND AIM: To investigate whether rosuvastatin can improve insulin sensitivity in overweight rats having a high fat diet (HFD). The potential mechanisms involved in this action were evaluated, including SIRT-1, other factors involved in glucose metabolism and stress signaling pathways. METHODS AND RESULTS: Male Wistar rats (n = 30) were divided into three groups: (i) rats fed a standard diet (3.5% fat); (ii) rats fed a HFD (33.5% fat); and (iii) rats fed a HFD and treated with rosuvastatin (15 mg/kg/day). Evolution: 7 weeks. HFD rats showed increased body, epididymal and lumbar adipose tissue weights. Plasma levels of cholesterol, triglycerides, VLDL, glucose and insulin and leptin/adiponectin ratio were higher in HFD rats, and rosuvastatin treatment reduced them. SIRT-1, p53, PGC-1α, PPAR-γ and GLUT-4 protein levels in white adipose tissue (WAT) were lower, and JNK was higher in HFD rats compared to controls. Rosuvastatin treatment normalized expression of these mediators. Endothelium-dependent relaxation was reduced in mesenteric rings from HFD rats compared to controls and rosuvastatin enhanced it in HFD rats. CONCLUSION: Rosuvastatin treatment reduced insulin resistance without affecting body weight or WAT loss in HFD rats. Reduction of leptin and JNK, and enhancement of SIRT-1, p53, PGC-1α, PPAR-γ and GLUT-4 expression in WAT could contribute to insulin sensitization. Normalization of SIRT-1 expression in WAT could be considered a key novel mechanism that aids in explaining the beneficial effects of rosuvastatin on the amelioration of glucose metabolism and the arrangement of multiple signaling pathways participating in insulin resistance in overweight HFD rats.

El tratamiento con dosis altas de atorvastatina disminuye la inflamación en la aterosclerosis carotídea humana / High-dose atorvastatin therapy reduces inflammation in human carotid atherosclerosis

Introducción. Las estatinas mejoran la estabilidad de la placa al disminuir la actividad inflamatoria. Hemos analizado el efecto de un ciclo corto de tratamiento con altas dosis de atorvastatina sobre la inflamación de la placa de ateroma carotídea humana. Materiales y métodos. Veinte pacientes programados para endarterectomía carotídea electiva, y sin tratamiento previo con estatinas, fueron asignados aleatoriamente en el momento de la indicación quirúrgica para recibir atorvastatina 80 mg/día (n = 11) o no estatinas (n = 9) hasta el día de la cirugía (1 mes). En las placas extraídas durante la endarterectomía se analizaban el infiltrado de macrófagos, y la expresión de MCP-1 (monocyte chemoattractant protein-1) y ciclooxigenasa-2 (COX-2) por inmunohistoquímica. La activación de NF-kB se estudió con la técnica de Southwestern. Resultados. La atorvastatina disminuyó las concentraciones de colesterol total (118 ± 10 frente a 191 ± 10 mg/dl; p = 0,016) y de lipoproteínas de baja densidad (LDL) (63 ± 9 frente a 125 ± 9 mg/dl; p = 0,038), mientras que no hubo cambios en el grupo control. Los triglicéridos y las lipoproteínas de alta densidad (HDL) no variaron significativamente en ningún grupo. Las placas ateroscleróticas del grupo de atorvastatina presentaron una reducción significativa del infiltrado de macrófagos (2,5 ± 1% frente a 9,3 ± 2,4%; p < 0,05), y de la expresión de MCP-1 (11 ± 1% frente a 24 ± 4%; p < 0,05) y COX-2 (16 ± 2,3% frente a 34 ± 4,4%; p < 0,05). El número de núcleos con actividad de NF-kB era menor en las placas de los pacientes que recibieron atorvastatina que en los que no recibieron tratamiento (5.706 ± 1.260 frente a 8.063 ± 1.308; p < 0,05). Conclusiones. El tratamiento intensivo con atorvastatina disminuye la inflamación en las placas de aterosclerosis carotídea humana en sólo 1 mes (AU)

Introduction. Statins improve plaque stability by diminishing inflammatory activity. We analyzed the effect of short-term high-dose atorvastatin on plaque inflammation in human carotid atherosclerosis. Materials and methods. Twenty patients scheduled to undergo elective carotid endarterectomy without previous statin treatment were randomized at the time of surgical indication to receive either atorvastatin 80 mg/day (n = 11) or no statins (n = 9) until surgery (1 month later). Atherosclerotic plaques were analyzed by immunohistochemistry to investigate macrophage infiltrate, and expression of monocyte chemoattractant protein-1 (MCP-1) and cyclooxygenase-2 (COX-2). In addition, nuclear factor-kB (NF-kB) activity was studied by Southwestern histochemistry. Results. Atorvastatin decreased serum levels of total cholesterol (118 ± 10 versus 191 ± 10 mg/dl; p = 0.016) and low-density lipoprotein (63 ± 9 versus 125 ± 9 mg/dl; p = 0.038), while no changes were noted in the control group. Triglycerides and high-density lipoprotein showed no significant changes in either of the two groups. Carotid atherosclerotic plaques from the atorvastatin group demonstrated a significant reduction in macrophage infiltration (2.5 ± 1% versus 9.3 ± 2.4%; p < 0.05) and expression of MCP-1 (11 ± 1% versus 24 ± 4%; p < 0.05) and COX-2 (16 ± 2.3% versus 34 ± 4.4%; p < 0.05). The number of nuclei active for NF-kB was lower in plaques from patients that received atorvastatin than in those from the non-treated group (5,706 ± 1,260 versus 8063 ± 1,308; p < 0.05). Conclusions. Intensive atorvastatin therapy decreases inflammatory activity in human carotid atherosclerotic plaques in as little as 1 month (AU)