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Diabetes Care 28:986-987, 2005
© 2005 by the American Diabetes Association, Inc.

Letters: Comments and Responses

Lipids and Glucose in Type 2 Diabetes: What About the ß-Cell and the Mitochondria?

Response to Eldor and Raz

Guenther Boden, MD1 and Markku Laakso, MD2

1 Temple University Health Science Center, General Clinical Research Center, Philadelphia, Pennsylvania
2 Kuopio 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

Drs. Eldor and Raz (1) assert that "high levels of FFAs [free fatty acids] have a detrimental effect on ß-cell survival and insulin secretion." We agree, but only in relation to patients who have dysfunctional ß-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 ß-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 ß-cell lipotoxicity in normal human subjects. Moreover, the concept of ß-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.

References

  1. Eldor R, Raz I: Lipids and glucose in type 2 diabetes: what about the ß-cell and the mitochondria? (Letter). Diabetes Care 28:985–986, 2005
  2. Kashyap S, Belfort R, Gastaldelli A, Pratipanawatr T, Berria R, Pratipanawatr W, Bajaj M, Mandarino L, DeFronzo R, Cusi K: A sustained increase in plasma free fatty acids impairs insulin secretion in nondiabetic subjects genetically predisposed to develop type 2 diabetes. Diabetes 52:2461–2474, 2003[Abstract/Free Full Text]
  3. Storgaard H, Jensen CB, Vaag AA, Volund A, Madsbad S: Insulin secretion after short- and long-term low grade free fatty acid infusion in men with increased risk of developing type 2 diabetes. Metabolism 52:885–894, 2003[Medline]
  4. Stefan N, Stumvoll M, Bogardus C, Tataranni PA: Elevated plasma nonesterified fatty acids are associated with deterioration of acute insulin response in IGT but not NGT. Am J Physiol Endocrinol Metab 284:E1156–E1161, 2003[Abstract/Free Full Text]
  5. Boden G, Chen X: Effects of fatty acids and ketone bodies on basal insulin secretion in type 2 diabetes. Diabetes 48:577–583, 1999[Abstract]
  6. Boden G, Chen X, Rosner J, Barton M: Effects of a 48-h fat infusion on insulin secretion and glucose utilization. Diabetes 44:1239–1242, 1995[Abstract]
  7. Jensen CB, Storgarrd H, Holst JJ, Dela F, Madsbad S, Vaag AA: Insulin secretion and cellular glucose metabolism after prolonged low-grade intralipid infusion in young men. J Clin Endocrinol Metab 88:2775–2783, 2003[Abstract/Free Full Text]
  8. Carpentier A, Giacca A, Lewis GF: Effect of increased plasma non-esterified fatty acids (NEFAs) on arginine-stimulated insulin secretion in obese humans. Diabetologia 44:1989–1997, 2001[Medline]
  9. Dobbins RL, Chester MW, Daniels MB, McGarry JD, Stein DT: Circulating fatty acids are essential for efficient glucose-stimulated insulin secretion after prolonged fasting in humans. Diabetes 47:1613–1618, 1998[Abstract]
  10. Boden G, Chen X, Iqbal N: Acute lowering of plasma fatty acids lowers basal insulin secretion in diabetic and nondiabetic subjects. Diabetes 47:1609–1612, 1998[Abstract]

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