DIABETES AND ATHEROSCLEROSIS

Statistics published by the American Heart Association have shown that heart disease and stroke are the major causes of death among patients with diabetes. A growing emphasis on helping patients achieve tight glycemic control has reduced the risk of microvascular complications associated with diabetes, but it remains a challenge to reduce the risk of macrovascular complications, which account for half of all diabetes-related health care costs. The liver is a key contributor to the atherogenic process, primarily because of the release of atherogenic lipoproteins.

Insulin affects hepatic lipid metabolism and may promote an atherogenic profile, Dr Accili noted. While FoxO is important in the control of glucose production through its regulation of G6Pase, FoxO also regulates its opposing enzyme, glucokinase (GCK). Under normal physiologic conditions, as glucose flows in and out of the liver, plasma glucose levels are maintained within a narrow range by the interplay of the GCK:G6Pase ratio. GCK also has the ability to promote lipogenesis. In the absence of FoxO, neither of these mechanisms functions appropriately. Consequently, instead of glucose being released by the liver for use by other tissues as an energy source, it is converted into fat. Additional experimental work has also confirmed the strong relationship between GCK levels and the amount of triglycerides in the liver [Peter A et al. J Clin Endocrinol Metab. 2011].

Dr Accili explained that the intertwined nature of these processes has numerous implications. In patients with insulin resistance, as insulin levels increase to suppress HGP, they also promote GCK-dependent hepatic fat accumulation and triglyceride synthesis. Consequently, he proposed that an atherogenic lipoprotein profile is the price paid by the body to suppress HGP in the early stages of diabetes. He stressed that, at the clinical level, prevention of cardiovascular disease in T2DM must begin early, possibly even before the onset of fasting hyperglycemia. Trying to design a hepatic insulin sensitizer devoid of effects on lipoproteins will prove challenging.

WHY β CELLS FAIL

The intrinsic susceptibility for the functional exhaustion of β cells differentiates individuals who go on to develop T2DM from those who do not. Although insulin resistance has been considered to be pivotal in the development of T2DM in recent decades, it does not lead to T2DM unless there is also β-cell dysfunction, because healthy β cells can compensate for insulin resistance by increasing their number and the production of insulin [Kitamura T. Nat Rev Endocrinol. 2013]. β-cell failure is initially reversible, however, even after the onset of hyperglycemia. Dr Accili went on to emphasize 3 key islet abnormalities in T2DM:

• An impaired insulin response to a stimulus

• Reduced β-cell mass

• An inappropriate glucagon response

Dr Accili discussed the changes in FoxO1 activity in the β cell during the progression of diabetes, noting that, in early diabetes, FoxO1 is activated by moving into the nucleus, while in advanced stages of the disease, FoxO1 disappears from the β cell along with insulin. Research has also now shown that dedifferentiation, not cell death, is the main cause of β-cell failure in diabetes and that dedifferentiated β cells convert to non-β endocrine cells. FoxO1 is implicated in these mechanisms [Talchai C et al. Cell. 2012]. According to Dr Accili, hyperglycemia-induced loss of FoxO1 alters β-cell metabolic flexibility, and this metabolic inflexibility sets the stage for β-cell failure. He noted that, since data from a recently completed study [Kim-Muller JY et al. Cell Metab. 2014] have also demonstrated the occurrence of β-cell dedifferentiation in people with T2DM, the paradigm for new therapeutic approaches to T2DM should shift to one that aims to restore β-cell differentiation.

In his concluding remarks, Dr Accili described another interesting discovery from his laboratory—namely, that genetic removal of FoxO1 from endocrine progenitor cells in the gastrointestinal tract converts these gut cells into functional insulin-producing cells. Although this was initially seen in mice [Talchai C et al. Nat Genet. 2012], more recent work also demonstrated this mechanism in genetically engineered human cells [Bouchi R et al. Nat Commun. 2014]. Dr Accili added that, in addition to producing insulin, these cells release insulin in a physiologic-like manner. These findings highlight the potential to design drugs that can convert cells in the gut into insulin-producing cells, as a way to treat type 1 diabetes and possibly even T2DM.