Insulin Resistance
Insulin resistance is the decreased ability of insulin to regulate blood sugar in the body due to decreased sensitivity of tissues to insulin signaling. This condition impacts more than 25% of the US population and is thought to be a major contributing factor to Pre-Diabetes, to Type 2 Diabetes Mellitus (T2DM), and to the Metabolic Syndrome.
Insulin is a key factor in the control of carbohydrate, lipid, and protein metabolism, as well as in regulation of certain hormones. Insulin action has profound effects on cell growth, vascular health, and many other functions in the body. Insulin secretion by the b cells in the pancreas is carefully regulated, and its actions are primarily mediated through the insulin receptor. Consequently, derangements in insulin signaling at the level of the receptor or its signaling pathway have widespread and devastating effects on many organs and tissues.
Insulin resistance is commonly identified clinically as a decrease in the effectiveness of insulin to control plasma glucose in the body and is often associated with weight gain, decreased physical activity, and aging. Insulin resistance is a key feature of Pre-Diabetes, which can predate dysregulation of blood sugar, and is often associated with an array of complications, demonstrating the widespread impact of insulin signaling. Insulin resistance is a progressive disorder characterized by increasing demand for insulin, which if coupled with an inability of the cells that make insulin (pancreatic b cells) to keep up with demand, plays a major role in the appearance and progression of Type 2 Diabetes Mellitus (T2DM).
Beyond glucose regulation, an important and often overlooked aspect of insulin resistance is the impact on the many other normal effects of insulin, which impact metabolism of lipids, regulation of hormones, cell growth, and vascular health. Disruptions in these physiological processes due to insulin resistance may contribute to a number of other significant diseases including cardiovascular disease, Polycystic Ovarian Syndrome (PCOS) and cancer.
Therapeutic approaches to insulin resistance have focused on weight loss and increased physical activity, which can have substantial benefit to improve insulin sensitivity and improve glucose abnormalities. Activation of PPARg by the thiazolidinediones (TZDs) represents a pharmacologic intervention that has been shown to significantly impact insulin resistance and has been demonstrated to slow and perhaps even prevent the progression of T2DM. Coupled with these benefits in glucose regulation, treatment of IR has also been shown to ameliorate several associated disorders, such as hyperinsulinemia, hypertension, dyslipidemia, and PCOS.
The only currently available therapeutic agents to activate PPARg belong to the TZD class. However, this class has been associated with dose proportional fluid retention and weight gain, which has limited their clinical utility. INT131, belonging to a novel non-TZD class, acts through selective modulation of PPARg offering the potential for potent insulin sensitizing activity without the TZD associated fluid retention, weight gain, and other side effects.
