What is the pathophysiology of insulin resistance?

Updated: Jul 08, 2020
  • Author: Samuel T Olatunbosun, MD, FACP, FACE; Chief Editor: George T Griffing, MD  more...
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In insulin resistance, various clinical entities of this state are evident. The clinical heterogeneity can be explained, at least in part, on a biochemical basis. Insulin binds and acts mainly through the insulin receptor and also acts via the insulinlike growth factor–1 (IGF-1) receptor; cellular actions of insulin involve a wide variety of effects on postreceptor signaling pathways within target cells.

The b subunit of the insulin receptor is a tyrosine kinase, which is activated when insulin binds to the a subunit; the kinase activity autophosphorylates and mediates multiple actions of insulin. Ambient insulin levels, various physiologic and disease states, and drugs regulate insulin receptor concentration or affinity.

Insulin sensitivity and secretion are reciprocally related; thus, insulin resistance results in increased insulin secretion to maintain normal glucose and lipid homeostasis. [12, 13] The mathematical relation between sensitivity and secretion is curvilinear or hyperbolic. Several mediators are thought to signal the pancreatic B cells to respond to insulin resistance; failure of the signals or of the B cells to adapt adequately in relation to insulin sensitivity results in inappropriate insulin levels, impaired fasting glucose (IFG), impaired glucose tolerance (IGT), and type 2 diabetes.

These potential signaling mediators include glucose, free fatty acids, autonomic nerves, fat-derived hormones (eg, adiponectin), and the gut hormone glucagonlike peptide-1 (GLP-1). GLP-1 is an incretin hormone that stimulates insulin secretion, causes B-cell mitosis while inhibiting apoptosis, inhibits glucagon secretion, and delays gastric emptying with overall antidiabetic effects.

The mechanisms responsible for insulin resistance syndromes include genetic or primary target cell defects, autoantibodies to insulin, and accelerated insulin degradation. [14] Given that glucose and lipid metabolism largely depend on mitochondria to generate energy in cells, mitochondrial dysfunction may play an important role in the development of insulin resistance and associated complications. [15]

Obesity, the most common cause of insulin resistance, is associated with a decreased number of receptors and with postreceptor failure to activate tyrosine kinase. Although adiposity and insulin resistance are related, they are not necessarily synonymous, and each may make independent and different contributions to increasing the risk of cardiovascular disease. [16]  Moreover, "in obesity, inflammation, with increased accumulation and inflammatory polarization of immune cells, takes place in various tissues, including adipose tissue, skeletal muscle, liver, gut, pancreatic islet, and brain, and may contribute to obesity-linked metabolic dysfunctions, leading to insulin resistance and type 2 diabetes." [17]

Leptin and ghrelin are two hormones that have a major influence on energy balance. Leptin is a long-term regulator of energy balance, suppressing food intake and thereby inducing weight loss, while ghrelin is a fast-acting hormone, seemingly playing a role in meal initiation. Obese individuals tend to be leptin resistant; their circulating levels of the anorexigenic hormone leptin are increased, but the levels of the orexigenic hormone ghrelin are decreased. Potential exists for both hormones as drug targets. [18]

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