Amino Acid-stimulated Insulin Secretion: a Path Forward in Type 2 Diabetes

Overview

Journal Amino Acids

Specialty Biochemistry

Date 2023 Nov 15

PMID 37966501

Authors

Jelena Kolic

WenQing Grace Sun

James D Johnson

Nicola Guess

Affiliations

Soon will be listed here.

Abstract

Qualitative and quantitatively appropriate insulin secretion is essential for optimal control of blood glucose. Beta-cells of the pancreas produce and secrete insulin in response to glucose and non-glucose stimuli including amino acids. In this manuscript, we review the literature on amino acid-stimulated insulin secretion in oral and intravenous in vivo studies, in addition to the in vitro literature, and describe areas of consensus and gaps in understanding. We find promising evidence that the synergism of amino acid-stimulated insulin secretion could be exploited to develop novel therapeutics, but that a systematic approach to investigating these lines of evidence is lacking. We highlight evidence that supports the relative preservation of amino acid-stimulated insulin secretion compared to glucose-stimulated insulin secretion in type 2 diabetes, and make the case for the therapeutic potential of amino acids. Finally, we make recommendations for research and describe the potential clinical utility of nutrient-based treatments for type 2 diabetes including remission services.

Citing Articles

Biphasic glucose-stimulated insulin secretion over decades: a journey from measurements and modeling to mechanistic insights.

Peng X, Wang K, Chen L Life Metab. 2025; 4(1):loae038.

PMID: 39872989 PMC: 11770817. DOI: 10.1093/lifemeta/loae038.

Free amino acids accelerate the time-dependent inactivation of rat liver nucleotide pyrophosphatase/phosphodiesterase Enpp3 elicited by EDTA.

Romero A, Cumplido-Laso G, Fernandez A, Moreno J, Canales J, Ferreira R Amino Acids. 2024; 57(1):1.

PMID: 39641818 PMC: 11624235. DOI: 10.1007/s00726-024-03431-4.

Dietary protein, amino acids and type 2 diabetes mellitus: a short review.

Mensink M Front Nutr. 2024; 11:1445981.

PMID: 39114126 PMC: 11305142. DOI: 10.3389/fnut.2024.1445981.

Cell identity dynamics and insight into insulin secretagogues when employing stem cell-derived islets for disease modeling.

Wang C, Abadpour S, Aizenshtadt A, Dalmao-Fernandez A, Hoyem M, Wilhelmsen I Front Bioeng Biotechnol. 2024; 12:1392575.

PMID: 38933536 PMC: 11199790. DOI: 10.3389/fbioe.2024.1392575.

References

Anello M, Ucciardello V, Piro S, Patane G, Frittitta L, Calabrese V . Chronic exposure to high leucine impairs glucose-induced insulin release by lowering the ATP-to-ADP ratio. Am J Physiol Endocrinol Metab. 2001; 281(5):E1082-7. DOI: 10.1152/ajpendo.2001.281.5.E1082. View

Berger S, Vongaraya N . Insulin response to ingested protein in diabetes. Diabetes. 1966; 15(5):303-6. DOI: 10.2337/diab.15.5.303. View

Blachier F, Boutry C, Bos C, Tome D . Metabolism and functions of L-glutamate in the epithelial cells of the small and large intestines. Am J Clin Nutr. 2009; 90(3):814S-821S. DOI: 10.3945/ajcn.2009.27462S. View

Bolea S, Pertusa J, Martin F, Sanchez-Andres J, Soria B . Regulation of pancreatic beta-cell electrical activity and insulin release by physiological amino acid concentrations. Pflugers Arch. 1997; 433(6):699-704. DOI: 10.1007/s004240050334. View

Branstrom R, Efendic S, Berggren P, Larsson O . Direct inhibition of the pancreatic beta-cell ATP-regulated potassium channel by alpha-ketoisocaproate. J Biol Chem. 1998; 273(23):14113-8. DOI: 10.1074/jbc.273.23.14113. View

Brennan L, Shine A, Hewage C, Paul G Malthouse J, Brindle K, McClenaghan N . A nuclear magnetic resonance-based demonstration of substantial oxidative L-alanine metabolism and L-alanine-enhanced glucose metabolism in a clonal pancreatic beta-cell line: metabolism of L-alanine is important to the regulation of insulin.... Diabetes. 2002; 51(6):1714-21. DOI: 10.2337/diabetes.51.6.1714. View

Casperson S, Sheffield-Moore M, Hewlings S, Paddon-Jones D . Leucine supplementation chronically improves muscle protein synthesis in older adults consuming the RDA for protein. Clin Nutr. 2012; 31(4):512-9. PMC: 3640444. DOI: 10.1016/j.clnu.2012.01.005. View

Corless M, Kiely A, McClenaghan N, Flatt P, Newsholme P . Glutamine regulates expression of key transcription factor, signal transduction, metabolic gene, and protein expression in a clonal pancreatic beta-cell line. J Endocrinol. 2006; 190(3):719-27. DOI: 10.1677/joe.1.06892. View

Dawson-Hughes B, Harris S, Rasmussen H, Dallal G . Comparative effects of oral aromatic and branched-chain amino acids on urine calcium excretion in humans. Osteoporos Int. 2007; 18(7):955-61. DOI: 10.1007/s00198-006-0320-x. View

10.

Del Prato S, Tiengo A . The importance of first-phase insulin secretion: implications for the therapy of type 2 diabetes mellitus. Diabetes Metab Res Rev. 2001; 17(3):164-74. DOI: 10.1002/dmrr.198. View

11.

Del Prato S, Leonetti F, Simonson D, Sheehan P, Matsuda M, DeFronzo R . Effect of sustained physiologic hyperinsulinaemia and hyperglycaemia on insulin secretion and insulin sensitivity in man. Diabetologia. 1994; 37(10):1025-35. DOI: 10.1007/BF00400466. View

12.

Dunne M, Yule D, Gallacher D, Petersen O . Effects of alanine on insulin-secreting cells: patch-clamp and single cell intracellular Ca2+ measurements. Biochim Biophys Acta. 1990; 1055(2):157-64. DOI: 10.1016/0167-4889(90)90116-u. View

13.

Efendic S, Lins P, Cerasi E . Potentiation and inhibition of insulin release in man following priming with glucose and with arginine--effect of somatostatin. Acta Endocrinol (Copenh). 1979; 90(2):259-71. DOI: 10.1530/acta.0.0900259. View

14.

Fasching P, Ratheiser K, Nowotny P, Uurzemann S, Parzer S, Waldhausl W . Insulin production following intravenous glucose, arginine, and valine: different pattern in patients with impaired glucose tolerance and non-insulin-dependent diabetes mellitus. Metabolism. 1994; 43(3):385-9. DOI: 10.1016/0026-0495(94)90109-0. View

15.

Fitch W, King J . Plasma amino acid, glucose, and insulin responses to moderate-protein and high-protein test meals in pregnant, nonpregnant, and gestational diabetic women. Am J Clin Nutr. 1987; 46(2):243-9. DOI: 10.1093/ajcn/46.2.243. View

16.

FLOYD Jr J, FAJANS S, CONN J, Knopf R, Rull J . Stimulation of insulin secretion by amino acids. J Clin Invest. 1966; 45(9):1487-502. PMC: 292828. DOI: 10.1172/JCI105456. View

17.

FLOYD Jr J, FAJANS S, Pek S, Thiffault C, Knopf R, CONN J . Synergistic effect of certain amino acid pairs upon insulin secretion in man. Diabetes. 1970; 19(2):102-8. DOI: 10.2337/diab.19.2.102. View

18.

Gannon M, Nuttall F . Amino acid ingestion and glucose metabolism--a review. IUBMB Life. 2010; 62(9):660-8. DOI: 10.1002/iub.375. View

19.

Gannon M, Nuttall J, Damberg G, Gupta V, Nuttall F . Effect of protein ingestion on the glucose appearance rate in people with type 2 diabetes. J Clin Endocrinol Metab. 2001; 86(3):1040-7. DOI: 10.1210/jcem.86.3.7263. View

20.

Gannon M, Hoover H, Nuttall F . Further decrease in glycated hemoglobin following ingestion of a LoBAG30 diet for 10 weeks compared to 5 weeks in people with untreated type 2 diabetes. Nutr Metab (Lond). 2010; 7:64. PMC: 2923629. DOI: 10.1186/1743-7075-7-64. View