Maintaining Effective Beta Cell Function in the Face of Metabolic Syndrome-Associated Glucolipotoxicity-Nutraceutical Options.

Mark F Mccarty,James J Dinicolantonio

doi:10.3390/healthcare10010003

Abstract

In people with metabolic syndrome, episodic exposure of pancreatic beta cells to elevated levels of both glucose and free fatty acids (FFAs)—or glucolipotoxicity—can induce a loss of glucose-stimulated insulin secretion (GSIS). This in turn can lead to a chronic state of glucolipotoxicity and a sustained loss of GSIS, ushering in type 2 diabetes. Loss of GSIS reflects a decline in beta cell glucokinase (GK) expression associated with decreased nuclear levels of the pancreatic and duodenal homeobox 1 (PDX1) factor that drives its transcription, along with that of Glut2 and insulin. Glucolipotoxicity-induced production of reactive oxygen species (ROS), stemming from both mitochondria and the NOX2 isoform of NADPH oxidase, drives an increase in c-Jun N-terminal kinase (JNK) activity that promotes nuclear export of PDX1, and impairs autocrine insulin signaling; the latter effect decreases PDX1 expression at the transcriptional level and up-regulates beta cell apoptosis. Conversely, the incretin hormone glucagon-like peptide-1 (GLP-1) promotes nuclear import of PDX1 via cAMP signaling. Nutraceuticals that quell an increase in beta cell ROS production, that amplify or mimic autocrine insulin signaling, or that boost GLP-1 production, should help to maintain GSIS and suppress beta cell apoptosis in the face of glucolipotoxicity, postponing or preventing onset of type 2 diabetes. Nutraceuticals with potential in this regard include the following: phycocyanobilin—an inhibitor of NOX2; agents promoting mitophagy and mitochondrial biogenesis, such as ferulic acid, lipoic acid, melatonin, berberine, and astaxanthin; myo-inositol and high-dose biotin, which promote phosphatidylinositol 3-kinase (PI3K)/Akt activation; and prebiotics/probiotics capable of boosting GLP-1 secretion. Complex supplements or functional foods providing a selection of these agents might be useful for diabetes prevention.

Highlights

In people with metabolic syndrome, episodic exposure of pancreatic beta cells to elevated levels of both glucose and free fatty acids (FFAs)—or glucolipotoxicity—can induce a loss of glucosestimulated insulin secretion (GSIS)
The episodic exposure of beta cells to elevated levels of both glucose and free fatty acids (FFAs)—a phenomenon known as “glucolipotoxicity”— may eventually induce a loss of beta cell capacity to respond to an acute increase of plasma glucose with an appropriate compensatory increase in insulin secretion [1,2,3,4]
The resulting exacerbation of beta cell glucolipotoxicity may progress to the point that fasting levels of glucose remain unduly elevated, at which point the patient is diagnosed with type 2 diabetes

Summary

A Key Role for Loss of PDX1 Activity and Glucokinase Expression Driven by ROS

This mechanism fails in beta cells experiencing excessive glucolipotoxicity owing to a maladaptive reduction in beta cell GK expression [5,6] (expression of the chief beta cell glucose transporter Glut falls, but this does not appear to be rate limiting for beta cell glycolytic activity). This effect likewise is induced by beta cell oxidant stress; likely, this reflects JNK-mediated phosphorylation of IRS-2, which is known to disrupt its interaction with the insulin receptor and promote its proteolytic degradation [30,31] The relationship of this phenomenon to PDX1 expression is as follows: appropriate Akt activity phosphorylates the forkhead box O1 (FOXO1) transcription factor, inducing its export from the nucleus [32]. CAMP-stimulated EPAC (exchange protein activated by cAMP) somehow promotes PDX1 expression [36] These considerations suggest that nutraceutical or dietary measures that lessen oxidant production by NOX2 or mitochondria, that suppress redox signaling, that reinforce signaling from the insulin receptor to Akt, or that boost intestinal production of GLP-1, could be expected to aid maintenance of GSIS and prevent apoptosis in beta cells challenged by glucolipotoxicity. The low proportion of total dietary fat provided as saturated fat in most vegan diets may provide protection in this regard by improving peripheral insulin sensitivity and lessening glucose/lipid overexposure [106]

Amplifying or Mimicking the Insulin Signal

Findings

Boosting Glucagon-Like Peptide-1 Production for Support of GSIS