Lipids and Glucose in Type 2 Diabetes: What About the β-Cell and the Mitochondria?
Response to Eldor and Raz
- 1Temple University Health Science Center, General Clinical Research Center, Philadelphia, Pennsylvania
- 2Kuopio University Hospital, Kuopio, Finland
- Address correspondence to Dr. Guenther Boden, MD, Temple University Health Science Center, General Clinical Research Center, North Broad St., 4W, Philadelphia, PA 19140. E-mail: guenther.boden{at}tuhs.temple.edu
Response to Eldor and Raz
Drs. Eldor and Raz (1) assert that “high levels of FFAs [free fatty acids] have a detrimental effect on β-cell survival and insulin secretion.” We agree, but only in relation to patients who have dysfunctional β-cells, i.e., patients with pre-diabetes, impaired glucose tolerance, or type 2 diabetes (2–5). On the other hand, in people with normally functioning β-cells, there is much evidence that FFAs, rather than impairing, actually augment insulin secretion. For instance, several groups have recently shown that in healthy individuals, elevation of plasma FFAs, for as long as 96 h, potentiated glucose-stimulated insulin secretion (2,6–8). Moreover, lowering plasma FFA levels, rather than improving insulin secretion, has been shown to actually decrease insulin secretion (9,10). Thus, there is currently little evidence to support the concept of FFA-induced β-cell lipotoxicity in normal human subjects. Moreover, the concept of β-cell lipotoxicity would be difficult to reconcile with the observation that >50% of obese people with chronically elevated FFA levels never develop type 2 diabetes during their lifetime, despite the fact that most of them are insulin resistant.
Drs. Eldor and Raz also state that lipotoxicity-induced mitochondrial damage is a “core process in the pathogenesis of type 2 diabetes.” We agree that there is mitochondrial dysfunction in patients with pre-diabetes as well as in patients with diabetes. It is not known, however, whether this is a primary or secondary defect. Moreover, whereas it is possible, perhaps even likely, that high fatty acid levels contribute to mitochondrial dysfunction, to our knowledge, there are presently no human data to support this assertion.
Footnotes
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