Diabetes: Going the Distance

Aparna M. Bhagavat, MD, FACC

Insulin resistance and dysfunction of the pancreatic beta cells play a central role in patients with pre-diabetes, type 2 diabetes mellitus, and the metabolic syndrome. Although hyperinsulinemia is a primary feature of pre-diabetes, with the development of overt diabetes, insulin secretion starts declining. As this column has previously discussed weight loss as a crucial step in the treatment of type 2 diabetes mellitus, it is now time to examine the beta cells of the islets of Langerhans at the molecular level, to review the spectrum of hyperinsulinemia and eventual decreasing insulin levels. In addition to decreasing insulin level in overt diabetes, hyperglucagonemia is also a feature of type 2 diabetes mellitus.¹

Recent research has introduced new insights about beta cell function. Previous studies by Chang-Chen et al² have attributed beta cell failure or decreasing insulin secretion in overt diabetes to programmed cell death as a result of the body’s increasing requirement for insulin. In their article, Weir et al³ clearly depict the 5 stages of the evolution of diabetes. In stage 1, there is increased insulin secretion with increase in beta cell mass to maintain normoglycemia, with preservation of acute glucose-stimulated insulin secretion (GSIS). In stage 2, there is an increase in glucose level with loss of beta cell mass, with decreased GSIS. Stages 3 and 4 are stages in which glucose levels keep rising, with gradually decreasing insulin secretion and decreasing beta cell mass. Stage 5 consists of a significant decrease in beta cell mass with progression to ketosis. Paradoxically, however, another study⁴ has shown little or no significant change in beta cell mass, not enough to explain the insulin deficiency, thus suggesting some other probable mechanism for decreasing insulin levels.

Recent research by Talchai et al⁵ has proposed a different theory. Animal studies have demonstrated the role of a key transcription factor that differentiates the beta cells from other cells in the islets of Langerhans. This is a specific transcription factor: Forkhead transcription factor O1 (FoxO1) of the O subclass.⁶ In a euglycemic state,⁵ FoxO1 has little role to play; however, with increasing glucose and free fatty acid levels in the pre-diabetic stage, FoxO1 becomes active. FoxO1 moves from the cytoplasm to the nucleus⁵ to produce more insulin to meet the body’s demand. However, as this phase of hyperglycemia continues to full-blown diabetes, it has been shown that FoxO1 disappears altogether from the beta cells. Thus, Fox O1 is a marker of beta cell identity; loss of this transcription factor changes the very existence of beta cells, converting them into more of a progenitor/ stem cell capable of performing functions of other cells in the islets of Langerhans, such as producing glucagon, thus explaining the hyperglucagonemia noted in diabetes. These changed beta cells also lose their insulin encoding genes like glucose transporter 2, glucokinase, and major transcription factors. Studies in hyperglycemic stress-induced mice⁵ have also shown that there is a decrease in the pro-insulin-processing enzyme Pcsk 1 (proprotein convertase subtilisin/kexin type1). This leads to a vicious cycle of hyperglycemia, increased secretion of biologically inactive proinsulin, and reduced insulin secretion. With the disappearance of the Fox O1 factor, other markers of the endocrine progenitor cells like Neurogenin3, Oct4, Nanog, and L-Myc expression have been noted to increase.⁵ Thorel et al⁷ have also noted an inverse relation of FoxO1 and Neurogenin 3.

However, these beta cells that have lost their identity marker or transcription factor (FoxO1) do not die; in fact, they regress to their original or progenitor form, now capable of producing a variety of functions. This phenomenon of beta cell dedifferentiation has been labeled by Talchai et al⁵ as a “selfish” beta cell, thus also suggesting that the homeostatic mechanism of the endocrine islet cells is not perfect.⁸

A study by Al-Masri et al⁹ showed that FoxO1 has also been found in human fetal pancreas during 8 to 12 weeks of fetal life. When exposed to exogenous insulin, the fetal islet cells showed disappearance of the FoxO1 from the nucleus, suggesting that this factor has an important role to play in the development of beta cells during fetal life.

This basic science research in animal models has brought up several intriguing questions.¹⁰ Is this process true for humans as well, and if so, in what manner will it affect treatment strategy? Other questions may arise, such as, is FOXO1 activity reversible, once this transcription factor disappears from the beta cells; and does it reappear if euglycemia is restored? Or does it mean that once FOXO1 disappears, it cannot return—or that, once lost, beta cell identity is lost forever? Is there some other transcription factor that replaces FOXO1? It is known that with gastric bypass surgery or an intensive diet, exercise, and drug regimen, there is regression from stage 4 diabetes to stage 1 diabetes.³

Some other clinically relevant questions arise:

• Is there a window of opportunity prior to complete dedifferentiation and partial dysfunction or activation of the beta cells?

• How is exogenous insulin affecting these transcription factors, and how are our current treatment strategies affecting these transcription factors?

• Should our goal to correct hyperglycemia be targeted to reviving these dedifferentiated beta cells?

It would be interesting to monitor the studies that follow this exceptional article by Talchai et al.

References

1. Unger RH, Cherrington AD. Glucagonocentric restructuring of diabetes: a pathophysiologic and therapeutic makeover. J Clin Invest. 2012:122:4-12.

2. Chang-Chen KJ, Mullur R, Bernal-Mizrachi E. Rev Endocr Metab Disord. 2008;9:329-343.

3. Weir GC, Bonner-Weir S. Five stages of evolving beta cell dysfunction during progression to diabetes. Diabetes. 2004;53(suppl 3): S16-S21. 4. Rahier J, Goebbels RM, Henquin JC. Cellular composition of the human diabetic pancreas. Diabetologia. 1983:24:366-371.

5. Talchai C, Xuan S, Lin HV, Sussel L, Accili D. Pancreatic beta cell dedifferentiation as a mechanism of diabetic beta cell failure. Cell. 2012:150:1223-1234.

6. Buteau J, Accili D. Regulation of pancreatic beta cell function by the forkhead protein FoxO1. Diabetes Obes Metabolism. 2007;69(suppl 2):140-146.

7. Thorel F, Nepote V, Avril I, et al. Conversion of adult pancreatic alpha-cells to beta-cells after extreme beta-cell loss. Nature. 2010;464:114-115.

8. Accilli D, Ahrin B, Boitard C, Cerasi E, Henquin JC, Seino S. What ails the beta cell? Diabetes Obes Metab. 2010;12(suppl 2):1-3.

9. Al-Masri M, Krishnamurthy J, Li J, et al. Effect of forkhead box O1 (FOX01) on beta cell development in the human fetal pancreas. Diabetologia. 2010;53:699-711.

10. Dor Y, Glaser B. Beta-cell dedifferentiation and type 2 diabetes. N Engl J Med. 2013;368:572-573.