Origin of the Hypothesis
The theory that inflammation may be involved in the pathogenesis of type 2 diabetes is not new. The first indication of this pathophysiological connection can be traced to Ebstein who, >100 years ago, reported in the German scientific literature that high doses of salycilate improved glycosuria in diabetic patients. This idea was then forgotten until a group of epidemiologists in the mid-1990s discussed the possibility that diabetes and atherosclerosis, an inflammatory condition in its own right, have common antecedents (the "common soil hypothesis" ). But it was the 1998 publication "Is Type II Diabetes Mellitus a Disease of the Innate Immune System?" by Pickup and Crook that finally laid out a more specific pathophysiological hypothesis. Based on the observation that the dyslipidemia common to people with type 2 diabetes (high triglycerides and low HDL cholesterol) is also a feature of experimental and naturally occurring acute-phase reactions, Pickup and Crook proposed that in individuals with an innately hypersensitive acute-phase response, long-term lifestyle and environmental stressors, such as nutrition, produce disease (type 2 diabetes) instead of repair.
Pickup and Crook explained that the innate immune system, a rapid first-line defense system based on nonlymphoid tissue, is primarily responsible for the acute-phase response, a self-limiting process induced by a variety of stressors (infection, tissue injury, and malignancy) causing a number of cells (macrophages, adipocytes, and endothelial cells) to secrete cytokines (interleukin [IL]-1, IL-6, and tumor necrosis factor-α [TNF-α]), which act on the liver to synthesize acute-phase proteins (fibrinogen, C-reactive protein, serum amyloid A, and others). Due to its self-limiting nature, the acute-phase response is aimed at restoring the homeostasis disturbed by an acute stressor. However, in response to chronic stressors, the system may become allostatic, i.e., the sustained effort to acutely battle challenges may ultimately result in an overload of the system resources. Eventually when the allostatic load exceeds these resources, the system breaks down.
While brilliant, Pickup and Crook's theory had a few shortcomings. It was based primarily on cross-sectional observations, and, although it predicted that the most likely chronic stressors are nutritional ones, it did not explain how this could result in increased secretion of cytokines by multiple cell types and gave no molecular explanation as to how these cytokines could inhibit insulin action in peripheral tissues and/or glucose-stimulated insulin secretion in the pancreas.
Diabetes. 2005;54(4):917-927. © 2005 American Diabetes Association, Inc.
Cite this: A Burning Question - Medscape - Apr 01, 2005.