A role for foregut tyrosine metabolism in glucose tolerance

Abstract

Objective We 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. Methods To 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. Results We 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. Conclusions We 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.

Dopamine regulates pancreatic glucagon and insulin secretion via adrenergic and dopaminergic receptors

“…Functionally, we show that α-cells produce both L-DOPA and DA de novo and significantly boost DA production in response to exogenous L-DOPA supplementation. In contrast, both in vitro and in vivo studies suggest that β-cells synthesize little L-DOPA de novo but instead rely on uptake of precursors from the peripheral circulation to drive DA production 6,7,9,33,34,59 . Remarkably, after meals, blood L-DOPA and DA levels increase >50-fold in humans and rodents [67][68][69][70][71] , allowing β-cells to tune DA synthesis and signaling to meal size 7 .…”

“…We employed a CRISPR-Cas9-mediated approach to delete endogenous α 2A -adrenergic receptor expression in INS-1E cells. Since INS-1E cells are rat-derived, we used the mRNA sequence encoding rat α 2A -adrenergic receptor as a template to generate guide RNA (gRNA) to disrupt the promoter region of the Adra2a gene (gRNA sequence: 5′-GCAGCCGGATGCCGGCAATA-3′, positions [57][58][59][60][61][62][63][64][65][66][67][68][69][70][71][72][73][74][75][76]. We then generated a construct containing the Adra2a gRNA sequence along with cDNA sequences encoding Cas9 and GFP (pENTR-Adra2a-sgRNA-Cas9-GFP).…”

Towards resolving the enigma of the dichotomy of resveratrol: cis- and trans-resveratrol have opposite effects on TyrRS-regulated PARP1 activation

“…Recent studies demonstrated that chronic administration of L-tyrosine inhibited the activity of complex I, II-III, and IV in the striatum, which can be prevented by antioxidant treatment [413,414]. Consistently, oral supplementation of L-tyrosine impairs glucose uptake and insulin secretion in rats [415], and the capacity to detoxify excess L-tyrosine is an essential life trait for the blood-sucking arthropods [416,417]. Quite interestingly, L-tyrosine was negatively correlated with hypothalamic transcriptional levels of Drd5, a dopamine receptor expressed in the limbic regions of the brain [418] that not only activates memory formation [419] but also evokes anti-tumor effects through autophagy induction [420].…”

Mendelian Randomization Study on Amino Acid Metabolism Suggests Tyrosine as Causal Trait for Type 2 Diabetes

“…Whether dietary supplementation of tyrosine is able to modulate glucose tolerance is studied within an ongoing clinical trial [ 47 ]. A recent study in rodents showed that beta cell function is affected by oral tyrosine administration and postulated dopamine and L-DOPA derived from nutritional tyrosine as anti-incretin candidates [ 48 ]. On the one hand, high blood levels of tyrosine may result in high L-DOPA and dopamine levels and therefore strengthen the anti-incretin effect.…”