High Glycemic Index Metabolic Damage – a Pivotal Role of GIP and GLP-1 Andreas F.H. Pfeiffer, Farnaz Keyhani-Nejad  Trends in Endocrinology & Metabolism  Volume 29, Issue 5, Pages 289-299 (May 2018) DOI: 10.1016/j.tem.2018.03.003 Copyright © 2018 The Authors Terms and Conditions

Figure 1 Effect of 50g Oral Sucrose Compared to Isomaltulose on Levels of Plasma Glucose (A), Serum Insulin (B), GIP (C), and GLP-1 (D) in 15 Healthy Humans (Aged 38.1±12.9 Years, Body Mass Index 25.1±5.02kg/m2). The data show typical responses to sucrose and isomaltulose corresponding to published data. Sucrose induces larger increases of glucose and insulin than isomaltulose does, although both are completely resorbed in the small intestine. The increase in GIP is due to the rapid cleavage and uptake of glucose in the upper small intestine where the GIP-releasing K cells are located, which in parallel induce insulin secretion within 15min, while isomaltulose is cleaved slowly and resorbed in the distal small intestine resulting in a bypass of K cells and stimulation of L cells, which release GLP-1. Abbreviations: GIP, glucose-induced insulinotropic peptide; GLP-1, glucagon-like peptide 1; iAUC, integrated Area Under Curve. Trends in Endocrinology & Metabolism 2018 29, 289-299DOI: (10.1016/j.tem.2018.03.003) Copyright © 2018 The Authors Terms and Conditions

Figure 2 Oral Sucrose and Isomaltulose Tolerance Tests in Mice Show Profiles That Are Similar to Those in Humans. The sugars were administered by gavage. Plasma levels of (A) glucose (B) insulin and (C) GIP. Mixed meal tests in mice with 40% isomaltulose as compared to 40% sucrose in food composed of 40% fat and 20% protein and 40% sucrose/isomaltulose. Responses of (D) glucose (E) insulin, and (F) GIP (adapted from [36]). Glucose responses did not differ between sucrose and isomaltulose in mixed meal tests due to the additive effects of fat and protein on gastric emptying and insulin responses were even enhanced with isomaltulose. However the differential effect on GIP was maintained, which may be explained by the slow cleavage and bypass of the K-cells also in mixed meals (adapted from [35]). Abbreviation: GIP, glucose-induced insulinotropic peptide. Trends in Endocrinology & Metabolism 2018 29, 289-299DOI: (10.1016/j.tem.2018.03.003) Copyright © 2018 The Authors Terms and Conditions

Figure 3 Nutrition with a Low GI Over 6 Month Lowers the Inflammation Marker CRP Over 24 Weeks. In this pan-European study (Diet, Obesity, and Genes, DiOGENES) obese humans first lost 11kg weight using low-calorie diets from week −8 to week 0, which reduced CRP as expected. The participants then received HGI or LGI diets in combination with HP or LP content in weight-stable conditions. Diets with a low GI resulted in a further decrease of CRP (n=487) irrespective of the protein content, supporting the notion that the GI modulates nutritionally induced subclinical inflammation (adapted from [55]). Abbreviations: GIP, glucose-induced insulinotropic peptide; HGI, high glycemic index; HP, high protein; hsCRP, highly sensitive C-reactive protein; LGI, low glycemic index; LP, low protein. Trends in Endocrinology & Metabolism 2018 29, 289-299DOI: (10.1016/j.tem.2018.03.003) Copyright © 2018 The Authors Terms and Conditions

Figure 4 Key Figure: Summary of GIP Actions Regulating Metabolism in Response to High-GI Food Intake The release of GIP is triggered in the upper small intestine by rapidly absorbed high-GI carbohydrates and stimulates insulin release. GIP further acts on the brain to increase NPY release and decrease activity. It alters energy metabolism by interfering with the activity of the central AKT–mTOR pathway, resulting in decreased fat oxidation in muscle and fatty liver. GIP further increases adipose tissue postprandial inflammation and induces chemokines to recruit inflammatory cells. Abbreviations: CNS, central nervous system; GI, glycemic index; GIP, glucose-induced insulinotropic peptide; mTOR, mammalian target of rapamycin; NPY, neuropeptide Y. Trends in Endocrinology & Metabolism 2018 29, 289-299DOI: (10.1016/j.tem.2018.03.003) Copyright © 2018 The Authors Terms and Conditions