Expression and function of the insulin receptor in normal and osteoarthritic human chondrocytes: modulation of anabolic gene expression, glucose transport and GLUT-1 content by insulin

Abstract

Human chondrocytes express functional InsR that respond to physiologic insulin concentrations. The InsR seems to be more abundant in normal than in OA chondrocytes, but these still respond to physiologic insulin concentrations, although some responses are impaired while others appear fully activated. Understanding the mechanisms that regulate the expression and function of the InsR in normal and OA chondrocytes can disclose new targets for the development of innovative therapies for OA.

Hyperglycemia and Hyperinsulinemia-Like Conditions Independently Induce Inflammatory Responses in Human Chondrocytes

“…In summary, the results presented here, along with the pro-catabolic and anti-anabolic effects that we and others reported previously [11,12], further support the hypothesis that hyperglycemia per se can drive cartilage damage and OA, in agreement with in vivo studies that showed increased joint damage associated with a more intense inflammatory response in animal models of DM2 [13,14]. Moreover, the results obtained also indicate that hyperinsulinemia, which is characteristic of DM2 and metabolic syndrome, can also by itself contribute to activate an inflammatory state in human chondrocytes that can accelerate OA development and progression.…”

“…Insulin is essential for maintenance of glucose homeostasis and for proper maintenance of the energetic balance, but also contributes to maintain anabolic processes in several tissues, including cartilage, as it was shown to induce anabolic and inhibit catabolic responses in adult chondrocytes and cartilage explant cultures from various species [12,26]. In DM2 and the metabolic syndrome, hyperinsulinemia occurs as an attempt at maintaining glucose homeostasis, at least while pancreatic β cells remain functional.…”

“…Only a few studies have been conducted so far to identify direct effects of high glucose in articular chondrocytes, collectively indicating that hyperglycemia-like glucose concentrations favor catabolic processes and impair anabolic responses [9][10][11][12][13], especially in chondrocytes from OA/aged articular cartilage [11,12]. Moreover, high glucose has also been shown to directly induce the expression of interleukin (IL)-6 and cyclooxygenase 2 [13], two important inflammatory mediators, as well as to potentiate the same inflammatory responses induced by interleukin-1β (IL-1β) [14].…”

Diabetes-Associated Osteoarthritis: A Syntropy?

“…Доставка глюкозы в хон-дроциты осуществляется белками-транспортера-ми GLUT-1 (основной транспортер) и GLUT-3 без участия инсулина. Хондроциты здоровых людей, даже при высоком внеклеточном содер-жании глюкозы (30 мм), экспрессируют неболь-шое количество GLUT-1, в результате чего кон-центрация глюкозы внутри клетки существенно не увеличивается [60,64]. Показано, что хондро-циты больных ОА in vitro при тех же уровнях вне-клеточной глюкозы накапливают ее в большей концентрации за счет увеличения экспрессии GLUT-1 [59].…”

Potentials and Limitations of Bile Acids and Probiotics in Diabetes Mellitus

“…GLUT-2 (mainly in beta-cells) and GLUT-4 (mainly in skeletal muscles) are the dominant glucose transporters. In general, insulin activates to become fully functional pores that are able to transport glucose molecules into tissues (Rosa et al 2011;Stuart et al 2009). The pancreas produces large quantities of insulin which it stores in intracellular secretary granules ).…”