A role for foregut tyrosine metabolism in glucose tolerance

Judith Korner,Gary W Cline,Mark Slifstein,Pasquale Barba,Gina R Rayat,Gerardo Febres,Rudolph L Leibel,Antonella Maffei,Paul E Harris

doi:10.1016/j.molmet.2019.02.008

Abstract

ObjectiveWe hypothesized that DA and L-DOPA derived from nutritional tyrosine and the resultant observed postprandial plasma excursions of L-DOPA and DA might affect glucose tolerance via their ability to be taken-up by beta cells and inhibit glucose-stimulated β-cell insulin secretion. MethodsTo investigate a possible circuit between meal-stimulated 3,4-dihydroxy-L-phenylalanine (L-DOPA) and dopamine (DA) production in the GI tract and pancreatic β-cells, we: 1) mapped GI mucosal expression of tyrosine hydroxylase (TH) and aromatic amino acid decarboxylase (AADC); 2) measured L-DOPA and DA content of GI mucosal tissues following meal challenges with different L-tyrosine (TYR) content, 3) determined whether meal TYR content impacts plasma insulin and glucose excursions; and 4) characterized postprandial plasma excursions of L-DOPA and DA in response to meal tyrosine content in rodents and a population of bariatric surgery patients. Next, we characterized: 1) the metabolic transformation of TYR and L-DOPA into DA in vitro using purified islet tissue; 2) the metabolic transformation of orally administrated stable isotope labeled TYR into pancreatic DA, and 3) using a nuclear medicine technique, we studied endocrine beta cells in situ release and binding of DA in response to a glucose challenge. ResultsWe demonstrate in rodents that intestinal content and circulatory concentrations L-DOPA and DA, plasma glucose and insulin are responsive to the tyrosine (TYR) content of a test meal. Intestinal expression of two enzymes, Tyrosine hydroxylase (TH) and Aromatic Amino acid Decarboxylase (AADC), essential to the transformation of TYR to DA was mapped and the metabolism of metabolism of TYR to DA was traced in human islets and a rodent beta cell line in vitro and from gut to the pancreas in vivo. Lastly, we show that β cells secrete and bind DA in situ in response to glucose stimulation. ConclusionsWe provide proof-of-principle evidence for the existence of a novel postprandial circuit of glucose homeostasis dependent on nutritional tyrosine. DA and L-DOPA derived from nutritional tyrosine may serve to defend against hypoglycemia via inhibition of glucose-stimulated β-cell insulin secretion as proposed by the anti-incretin hypothesis.

Highlights

Pancreatic b-cells integrate several different external signals to finetune the release of insulin and accurately regulate blood glucose levels commensurate with metabolic demand
GI tissue content of L-DOPA and DA is responsive to the tyrosine content of the mixed meal stimulus Using immunohistochemistry with previously validated antibodies, we studied the expression of TH and AADC in the foregut of the rat (Supplemental Materials, Figure S1)
We set out to provide proof of principle that DA and L-DOPA derived from nutritional tyrosine might be involved in the defense against hypoglycemia as postulated by anti incretin hypothesis

Summary

Introduction

Pancreatic b-cells integrate several different external signals to finetune the release of insulin and accurately regulate blood glucose levels commensurate with metabolic demand. Net insulin production and glucose homeostasis are regulated by a number of other molecules as well, including several gut-derived peptide hormones (e.g. GLP-1) and a number of classical neurotransmitters (e.g. epinephrine). Many of these molecules function as amplifying agents (“incretins”) that, they have little or no effect alone, enhance the signals generated by the b-cell glucose sensing apparatus (reviewed in [2]). The kinetics of DA and L-DOPA excursions coincide with postprandial GLP-1 levels observed after a mixed meal tolerance test (MMTT) administered to Lewis rats [8] Both L-DOPA and DA inhibit glucose-stimulated insulin secretion (GSIS)

Methods

Results

Conclusion