{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,27]],"date-time":"2026-03-27T17:49:31Z","timestamp":1774633771038,"version":"3.50.1"},"reference-count":43,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,5,19]],"date-time":"2022-05-19T00:00:00Z","timestamp":1652918400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Nutr."],"abstract":"<jats:p>Glucagon (GCGN) plays a key role in glucose and amino acid (AA) metabolism by increasing hepatic glucose output. AA strongly stimulate GCGN secretion which regulates hepatic AA degradation by ureagenesis. Although increased fasting GCGN levels cause hyperglycemia GCGN has beneficial actions by stimulating hepatic lipolysis and improving insulin sensitivity through alanine induced activation of AMPK. Indeed, stimulating prandial GCGN secretion by isocaloric high protein diets (HPDs) strongly reduces intrahepatic lipids (IHLs) and improves glucose metabolism in type 2 diabetes mellitus (T2DM). Therefore, the role of GCGN and circulating AAs in metabolic improvements in 31 patients with T2DM consuming HPD was investigated. Six weeks HPD strongly coordinated GCGN and AA levels with IHL and insulin sensitivity as shown by significant correlations compared to baseline. Reduction of IHL during the intervention by 42% significantly improved insulin sensitivity [homeostatic model assessment for insulin resistance (HOMA-IR) or hyperinsulinemic euglycemic clamps] but not fasting GCGN or AA levels. By contrast, GCGN secretion in mixed meal tolerance tests (MMTTs) decreased depending on IHL reduction together with a selective reduction of GCGN-regulated alanine levels indicating greater GCGN sensitivity. HPD aligned glucose metabolism with GCGN actions. Meal stimulated, but not fasting GCGN, was related to reduced liver fat and improved insulin sensitivity. This supports the concept of GCGN-induced hepatic lipolysis and alanine- and ureagenesis-induced activation of AMPK by HPD.<\/jats:p>","DOI":"10.3389\/fnut.2022.808346","type":"journal-article","created":{"date-parts":[[2022,5,18]],"date-time":"2022-05-18T15:50:05Z","timestamp":1652889005000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":15,"title":["High Protein Diets Improve Liver Fat and Insulin Sensitivity by Prandial but Not Fasting Glucagon Secretion in Type 2 Diabetes"],"prefix":"10.3389","volume":"9","author":[{"given":"Jiudan","family":"Zhang","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Olga","family":"Pivovarova-Ramich","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stefan","family":"Kabisch","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mariya","family":"Markova","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Silke","family":"Hornemann","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stephanie","family":"Sucher","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sascha","family":"Rohn","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"J\u00fcrgen","family":"Machann","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andreas F. H.","family":"Pfeiffer","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2022,5,19]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"2160","DOI":"10.2337\/db11-0251","article-title":"Loss of inverse relationship between pulsatile insulin and glucagon secretion in patients with type 2 diabetes.","volume":"60","author":"Menge","year":"2011","journal-title":"Diabetes."},{"key":"B2","doi-asserted-by":"publisher","first-page":"41","DOI":"10.1016\/j.semcdb.2020.01.006","article-title":"Pancreatic alpha-cells \u2013 the unsung heroes in islet function.","volume":"103","author":"Wendt","year":"2020","journal-title":"Semin Cell Dev Biol."},{"key":"B3","doi-asserted-by":"publisher","first-page":"1372","DOI":"10.1007\/s00125-016-3965-9","article-title":"Glucagon is the key factor in the development of diabetes.","volume":"59","author":"Lee","year":"2016","journal-title":"Diabetologia."},{"key":"B4","doi-asserted-by":"publisher","first-page":"696","DOI":"10.1210\/en.2016-1748","article-title":"Insulin and glucagon: partners for life.","volume":"158","author":"Holst","year":"2017","journal-title":"Endocrinology."},{"key":"B5","doi-asserted-by":"publisher","first-page":"532","DOI":"10.2337\/dbi19-0004","article-title":"Repositioning glucagon action in the physiology and pharmacology of diabetes.","volume":"69","author":"Finan","year":"2020","journal-title":"Diabetes."},{"key":"B6","doi-asserted-by":"publisher","first-page":"2305","DOI":"10.1172\/JCI105916","article-title":"Characterization of response of circulating glucagon to intraduodenal and intravenous administration of amino acids.","volume":"47","author":"Ohneda","year":"1968","journal-title":"J Clin Invest."},{"key":"B7","doi-asserted-by":"publisher","first-page":"785","DOI":"10.1172\/jci111272","article-title":"Effects of glucagon on plasma amino acids.","volume":"73","author":"Boden","year":"1984","journal-title":"J Clin Invest."},{"key":"B8","doi-asserted-by":"publisher","first-page":"212","DOI":"10.1111\/j.1432-0436.1987.tb00171.x","article-title":"Induction of the five urea-cycle enzymes by glucagon in cultured foetal rat hepatocytes.","volume":"35","author":"Husson","year":"1987","journal-title":"Differentiation."},{"key":"B9","doi-asserted-by":"publisher","first-page":"811","DOI":"10.1056\/NEJM196910092811503","article-title":"Plasma amino acid levels and insulin secretion in obesity.","volume":"281","author":"Felig","year":"1969","journal-title":"N Engl J Med."},{"key":"B10","doi-asserted-by":"publisher","first-page":"1353","DOI":"10.1210\/er.2018-00251","article-title":"The liver\u2013\u03b1-cell axis and type 2 diabetes.","volume":"40","author":"Wewer Albrechtsen","year":"2019","journal-title":"Endocr Rev."},{"key":"B11","doi-asserted-by":"publisher","first-page":"E93","DOI":"10.1152\/ajpendo.00198.2017","article-title":"Disruption of glucagon receptor signaling causes hyperaminoacidemia exposing a possible liver-alpha-cell axis.","volume":"314","author":"Galsgaard","year":"2018","journal-title":"Am J Physiol Endocrinol Metab."},{"key":"B12","doi-asserted-by":"publisher","first-page":"671","DOI":"10.1007\/s00125-017-4535-5","article-title":"Evidence of a liver\u2013alpha cell axis in humans: hepatic insulin resistance attenuates relationship between fasting plasma glucagon and glucagonotropic amino acids.","volume":"61","author":"Wewer Albrechtsen","year":"2018","journal-title":"Diabetologia."},{"key":"B13","doi-asserted-by":"publisher","first-page":"2608","DOI":"10.1111\/dom.13440","article-title":"Efficacy and safety of the glucagon receptor antagonist PF-06291874: a 12-week, randomized, dose-response study in patients with type 2 diabetes mellitus on background metformin therapy.","volume":"20","author":"Kazierad","year":"2018","journal-title":"Diabetes Obes Metab."},{"key":"B14","doi-asserted-by":"publisher","first-page":"1373","DOI":"10.1080\/13543784.2017.1395020","article-title":"Investigational glucagon receptor antagonists in phase I and II clinical trials for diabetes.","volume":"26","author":"Scheen","year":"2017","journal-title":"Expert Opin Investig Drugs."},{"key":"B15","doi-asserted-by":"publisher","first-page":"542","DOI":"10.2337\/dbi19-0021","article-title":"A primary role for \u03b1-Cells as amino acid sensors.","volume":"69","author":"Dean","year":"2020","journal-title":"Diabetes."},{"key":"B16","doi-asserted-by":"publisher","first-page":"1367","DOI":"10.1007\/s00125-016-3950-3","article-title":"Glucagon action in the brain.","volume":"59","author":"Abraham","year":"2016","journal-title":"Diabetologia."},{"key":"B17","doi-asserted-by":"publisher","first-page":"e126742","DOI":"10.1172\/jci.insight.126742","article-title":"\u03b2 Cell tone is defined by proglucagon peptides through cAMP signaling.","volume":"4","author":"Capozzi","year":"2019","journal-title":"JCI Insight."},{"key":"B18","doi-asserted-by":"crossref","first-page":"e129954","DOI":"10.1172\/jci.insight.129954","article-title":"Glucagon lowers glycemia when \u03b2 cells are active.","volume":"4","author":"Capozzi","year":"2019","journal-title":"JCI Insight."},{"key":"B19","doi-asserted-by":"publisher","first-page":"571.e","DOI":"10.1053\/j.gastro.2016.10.007","article-title":"Isocaloric diets high in animal or plant protein reduce liver fat and inflammation in individuals with type 2 diabetes.","volume":"152","author":"Markova","year":"2017","journal-title":"Gastroenterology."},{"key":"B20","doi-asserted-by":"publisher","first-page":"944","DOI":"10.1111\/dom.12901","article-title":"Comparison of the effects of diets high in animal or plant protein on metabolic and cardiovascular markers in type 2 diabetes: a randomized clinical trial.","volume":"19","author":"Sucher","year":"2017","journal-title":"Diabetes Obes Metab."},{"key":"B21","doi-asserted-by":"publisher","first-page":"279","DOI":"10.1093\/ajcn\/nqy100","article-title":"Rate of appearance of amino acids after a meal regulates insulin and glucagon secretion in patients with type 2 diabetes: a randomized clinical trial.","volume":"108","author":"Markova","year":"2018","journal-title":"Am J Clin Nutr."},{"key":"B22","doi-asserted-by":"publisher","first-page":"862","DOI":"10.1016\/j.clnu.2019.03.019","article-title":"Effects of plant and animal high protein diets on immune-inflammatory biomarkers: a 6-week intervention trial.","volume":"39","author":"Markova","year":"2020","journal-title":"Clin Nutr."},{"key":"B23","doi-asserted-by":"publisher","first-page":"101397","DOI":"10.1016\/j.redox.2019.101397","article-title":"Effects of diets high in animal or plant protein on oxidative stress in individuals with type 2 diabetes: a randomized clinical trial.","volume":"29","author":"Pivovarova-Ramich","year":"2020","journal-title":"Redox Biol."},{"key":"B24","doi-asserted-by":"publisher","first-page":"279","DOI":"10.1038\/s41586-020-2074-6","article-title":"Glucagon stimulates gluconeogenesis by INSP3R1-mediated hepatic lipolysis.","volume":"579","author":"Perry","year":"2020","journal-title":"Nature."},{"key":"B25","doi-asserted-by":"publisher","first-page":"412","DOI":"10.1007\/bf00280883","article-title":"Homeostasis model assessment: insulin resistance and ?-cell function from fasting plasma glucose and insulin concentrations in man.","volume":"28","author":"Matthews","year":"1985","journal-title":"Diabetologia."},{"key":"B26","doi-asserted-by":"publisher","first-page":"1462","DOI":"10.2337\/diacare.22.9.1462","article-title":"Insulin sensitivity indices obtained from oral glucose tolerance testing: comparison with the euglycemic insulin clamp.","volume":"22","author":"Matsuda","year":"1999","journal-title":"Diabetes Care."},{"key":"B27","doi-asserted-by":"publisher","first-page":"512","DOI":"10.1007\/s00125-020-05334-x","article-title":"The liver-alpha cell axis associates with liver fat and insulin resistance: a validation study in women with non-steatotic liver fat levels.","volume":"64","author":"Gar","year":"2021","journal-title":"Diabetologia"},{"key":"B28","doi-asserted-by":"publisher","first-page":"1398","DOI":"10.1210\/clinem\/dgab019","article-title":"Impaired suppression of glucagon in obese subjects parallels decline in insulin sensitivity and beta-cell function.","volume":"106","author":"Chen","year":"2021","journal-title":"J Clin Endocrinol Metab."},{"key":"B29","doi-asserted-by":"publisher","first-page":"939","DOI":"10.2337\/db18-1138","article-title":"Postprandial aminogenic insulin and glucagon secretion can stimulate glucose flux in humans.","volume":"68","author":"Ang","year":"2019","journal-title":"Diabetes."},{"key":"B30","doi-asserted-by":"publisher","first-page":"805","DOI":"10.1016\/0026-0495(74)90114-0","article-title":"Effect of glucagon on amino acid and nitrogen metabolism in fasting man.","volume":"23","author":"Aoki","year":"1974","journal-title":"Metabolism."},{"key":"B31","doi-asserted-by":"publisher","first-page":"394","DOI":"10.1038\/s42255-021-00369-9","article-title":"Liver alanine catabolism promotes skeletal muscle atrophy and hyperglycaemia in type 2 diabetes.","volume":"3","author":"Okun","year":"2021","journal-title":"Nat Metab."},{"key":"B32","doi-asserted-by":"publisher","first-page":"E3423","DOI":"10.1073\/pnas.1606022113","article-title":"Argininosuccinate synthetase regulates hepatic AMPK linking protein catabolism and ureagenesis to hepatic lipid metabolism.","volume":"113","author":"Madiraju","year":"2016","journal-title":"Proc Natl Acad Sci USA."},{"key":"B33","doi-asserted-by":"publisher","first-page":"179","DOI":"10.1016\/0026-0495(73)90269-2","article-title":"The glucose-alanine cycle.","volume":"22","author":"Felig","year":"1973","journal-title":"Metabolism."},{"key":"B34","doi-asserted-by":"publisher","first-page":"4671","DOI":"10.1172\/JCI129913","article-title":"Regulation of hepatic mitochondrial oxidation by glucose-alanine cycling during starvation in humans.","volume":"129","author":"Petersen","year":"2019","journal-title":"J Clin Invest."},{"key":"B35","doi-asserted-by":"publisher","first-page":"61","DOI":"10.1016\/j.molmet.2018.08.002","article-title":"l-Alanine activates hepatic AMP-activated protein kinase and modulates systemic glucose metabolism.","volume":"17","author":"De Sousa-Coelho","year":"2018","journal-title":"Mol Metab."},{"key":"B36","doi-asserted-by":"publisher","first-page":"102217","DOI":"10.1016\/j.isci.2021.102217","article-title":"Trans-omic analysis reveals obesity-associated dysregulation of inter-organ metabolic cycles between the liver and skeletal muscle.","volume":"24","author":"Egami","year":"2021","journal-title":"IScience."},{"key":"B37","doi-asserted-by":"crossref","first-page":"905","DOI":"10.1016\/j.jhep.2018.06.023","article-title":"Urea cycle dysregulation in non-alcoholic fatty liver disease.","volume":"69","author":"De Chiara","year":"2018","journal-title":"J Hepatol."},{"key":"B38","doi-asserted-by":"publisher","first-page":"267","DOI":"10.1016\/j.clnu.2011.02.009","article-title":"Insulin resistance of amino acid and protein metabolism in type 2 diabetes.","volume":"30","author":"Tessari","year":"2011","journal-title":"Clin Nutr."},{"key":"B39","doi-asserted-by":"publisher","first-page":"F2","DOI":"10.1152\/ajprenal.00614.2014","article-title":"Protein- and diabetes-induced glomerular hyperfiltration: role of glucagon, vasopressin, and urea.","volume":"309","author":"Bankir","year":"2015","journal-title":"Am J Physiol Renal Physiol."},{"key":"B40","doi-asserted-by":"publisher","first-page":"249","DOI":"10.1016\/j.jcjd.2020.08.108","article-title":"Association of glucagon with obesity, glycemic control and renal function in adults with type 2 diabetes mellitus.","volume":"45","author":"Hamasaki","year":"2021","journal-title":"Can J Diabetes."},{"key":"B41","doi-asserted-by":"publisher","first-page":"119","DOI":"10.1016\/j.diabres.2018.10.004","article-title":"Glucagon revisited: coordinated actions on the liver and kidney.","volume":"146","author":"Bankir","year":"2018","journal-title":"Diabetes Res Clin Pract."},{"key":"B42","doi-asserted-by":"publisher","first-page":"365","DOI":"10.3390\/nu12020365","article-title":"The effects of different quantities and qualities of protein intake in people with diabetes mellitus.","volume":"12","author":"Pfeiffer","year":"2020","journal-title":"Nutrients."},{"key":"B43","first-page":"CD002181","article-title":"Protein restriction for diabetic renal disease.","volume":"200","author":"Robertson","year":"2007","journal-title":"Cochrane Database Syst Rev."}],"container-title":["Frontiers in Nutrition"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnut.2022.808346\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,5,18]],"date-time":"2022-05-18T15:50:09Z","timestamp":1652889009000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnut.2022.808346\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,5,19]]},"references-count":43,"alternative-id":["10.3389\/fnut.2022.808346"],"URL":"https:\/\/doi.org\/10.3389\/fnut.2022.808346","relation":{},"ISSN":["2296-861X"],"issn-type":[{"value":"2296-861X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,5,19]]},"article-number":"808346"}}