Lipids and Glucose in Type 2 Diabetes
What is the cause and effect?
- Guenther Boden, MD1 and
- Markku Laakso, MD2
- 1Division of Endocrinology/Diabetes/Metabolism and the General Clinical Research Center, Temple University Hospital, Philadelphia, Pennsylvania
- 2Department of Medicine, University of Kuopio, Kuopio, Finland
- Address correspondencereprint requests to G. Boden, MD, Temple University Hospital, 3401 N. Broad St., Philadelphia, PA 19140. E-mail: bodengh{at}tuhs.temple.edu
- DAG, diacylglycerol
- FFA, free fatty acid
- IL, interleukin
- IRS, insulin receptor substrate
- NF, nuclear factor
- NHANES III, Third National Health and Nutrition Examination Survey
- PKC, protein kinase C
- PPAR, peroxisome proliferator–activated receptor
- TNF, tumor necrosis factor
- TZD, thiazolidinedione
Historically, type 2 diabetes was considered to revolve around a glucose-insulin axis. The foundations for this thinking were probably laid down by two momentous discoveries in diabetes research. According to popular legend, Oskar Minkowski noticed that urine from his pancreatectomized dogs attracted an inordinate number of flies. He is then alleged to have tasted the urine and noted its sweetness. From this observation came the supposition that the pancreas produced a substance that controlled sugar concentration, and diabetes occurred in the absence of this substance. The second landmark was the discovery by Frederick Banting that insulin was the active element from the pancreas. As a consequence of these two discoveries, the concept that the glucose-insulin relationship was the central element of fuel metabolism gained a firm hold. Diabetes has since been considered to be a disorder primarily associated with abnormal glucose metabolism. This notion is given credence by the considerable amount of data indicating that the chronic elevation of plasma glucose causes many of the microvascular complications of diabetes.
In 1992, McGarry (1) asked what would have happened if Minkowski had lacked a sense of taste but had a good nose. If that had been the case, he may have smelled acetone, and this may have led him to the conclusion that removal of the pancreas affects fatty acid metabolism. If this had happened, our understanding of the pathogenesis of type 2 diabetes may have developed along a different route and led us more quickly to our current awareness that obesity, or more accurately, the products of excess adipose tissue, precede the perturbations of glucose metabolism.
It is now apparent that elevation of plasma free fatty acids (FFAs) plays a pivotal role in the development of type 2 diabetes by causing insulin resistance. Type 2 diabetes develops because pancreatic β-cells …
