High Glycemic Index Metabolic Damage – a Pivotal Role of GIP and GLP-1
Authors: Andreas F.H. Pfeiffer, Farnaz Keyhani-Nejad
Journal: Trends in Endocrinology and Metabolism (2018)

The GI quantifies the widely variable increases in blood glucose after ingestion of different carbohydrates, with the concept that larger increases cause the development of cardiometabolic diseases. The metabolic effects of sugars depend primarily on the intestinal hormones GIP and GLP-1, which release insulin and regulate metabolic responses such as insulin resistance, adipose tissue subclinical inflammation, hepatic fat accumulation, and postprandial vascular responses. The GIP-releasing K cells are located in the proximal small intestine, while GLP-1 is released by more distally located L cells. Their responses to sugars depend on the site of resorption. GIP has mostly unfavorable, while GLP-1 has beneficial, metabolic and cardiovascular properties. The release of GIP therefore appears to be a primary mediator of the deleterious effects of sugars with a high glycemic index in metabolism. When glucose–fructose dimers are supplied as the slowly digestible, completely absorbable, low glycemic index (GI) sugar isomaltulose, the detrimental effects of high GI sucrose are avoided. This difference requires the presence of intact glucose-induced insulinotropic peptide receptor (GIPR) and is mediated by the rapid uptake of glucose and the stimulation of GIP release from K cells in the upper small intestine. GIP promotes lipogenesis, fatty liver, insulin resistance, and postprandial inflammation, and reduces fat oxidation in skeletal muscle, partly by hypothalamic interference with energy partitioning and epigenetic programming. GIP is similarly required for the detrimental metabolic effects of other high GI carbohydrates. We therefore propose that the release of GIP in the upper small intestine is an important determinant of the metabolic quality of carbohydrates. When glucose–fructose dimers are supplied as the slowly digestible, completely absorbable, low glycemic index (GI) sugar isomaltulose, the detrimental effects of high GI sucrose are avoided. This difference requires the presence of intact glucose-induced insulinotropic peptide receptor (GIPR) and is mediated by the rapid uptake of glucose and the stimulation of GIP release from K cells in the upper small intestine. GIP promotes lipogenesis, fatty liver, insulin resistance, and postprandial inflammation, and reduces fat oxidation in skeletal muscle, partly by hypothalamic interference with energy partitioning and epigenetic programming. GIP is similarly required for the detrimental metabolic effects of other high GI carbohydrates. We therefore propose that the release of GIP in the upper small intestine is an important determinant of the metabolic quality of carbohydrates. The glycemic index (GI) (see Glossary) remains a fervently debated concept regarding potential health benefits of the quality of the carbohydrates as defined by high or low GI of foods [1Sacks F.M. et al.Effects of high vs low glycemic index of dietary carbohydrate on cardiovascular disease risk factors and insulin sensitivity: the OmniCarb randomized clinical trial.JAMA. 2014; 312: 2531-2541Crossref PubMed Scopus (129) Google Scholar, 2Mirrahimi A. et al.Associations of glycemic index and load with coronary heart disease events: a systematic review and meta-analysis of prospective cohorts.J. Am. Heart Assoc. 2012; 1e000752Crossref PubMed Scopus (105) Google Scholar, 3Augustin L.S. et al.Glycemic index, glycemic load and glycemic response: an International Scientific Consensus Summit from the International Carbohydrate Quality Consortium (ICQC).Nutr. Metab. Cardiovasc. 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The GI-concept (Box 1) proposes that a slower and lower increase in glucose reduces metabolic and cardiovascular disease [7Jenkins D.J. et al.Glycemic index: overview of implications in health and disease.Am. J. Clin. Nutr. 2002; 76: 266S-273SCrossref PubMed Google Scholar, 8Ludwig D.S. The glycemic index: physiological mechanisms relating to obesity, diabetes, and cardiovascular disease.JAMA. 2002; 287: 2414-2423Crossref PubMed Scopus (1237) Google Scholar, 9Brand-Miller J.C. et al.Glycemic index and obesity.Am. J. Clin. Nutr. 2002; 76: 281S-285SCrossref PubMed Google Scholar]. The exact reasons why a low GI is beneficial have remained somewhat elusive and the physiological mechanisms are not well defined. The most detailed model assumes that the greater increase in glucose and insulin with high GI foods is unfavorable, by inducing an exaggerated insulin response followed by delayed hypoglycemia and reactive increases in free fatty acids (FFAs), which increase triglycerides and low-density lipoprotein–cholesterol while decreasing high-density lipoprotein (HDL)–cholesterol. The greater insulin responses may increase body fat and weight and lead to insulin resistance and to exhaustion of endocrine pancreatic function and insulin release [8Ludwig D.S. The glycemic index: physiological mechanisms relating to obesity, diabetes, and cardiovascular disease.JAMA. 2002; 287: 2414-2423Crossref PubMed Scopus (1237) Google Scholar, 10Pawlak D.B. et al.Effects of dietary glycaemic index on adiposity, glucose homoeostasis, and plasma lipids in animals.Lancet. 2004; 364: 778-785Abstract Full Text Full Text PDF PubMed Scopus (248) Google Scholar].Box 1GI ConceptThe principle idea of the GI concept is that similar quantities of qualitatively different carbohydrates differ in their capacity to increase blood glucose. A slower and lower increase in glucose is proposed to be beneficial and to reduce metabolic and cardiovascular risks [3Augustin L.S. et al.Glycemic index, glycemic load and glycemic response: an International Scientific Consensus Summit from the International Carbohydrate Quality Consortium (ICQC).Nutr. Metab. Cardiovasc. Dis. 2015; 25: 795-815Abstract Full Text Full Text PDF PubMed Scopus (278) Google Scholar, 7Jenkins D.J. et al.Glycemic index: overview of implications in health and disease.Am. J. Clin. Nutr. 2002; 76: 266S-273SCrossref PubMed Google Scholar, 8Ludwig D.S. The glycemic index: physiological mechanisms relating to obesity, diabetes, and cardiovascular disease.JAMA. 2002; 287: 2414-2423Crossref PubMed Scopus (1237) Google Scholar, 9Brand-Miller J.C. et al.Glycemic index and obesity.Am. J. Clin. Nutr. 2002; 76: 281S-285SCrossref PubMed Google Scholar]. GI is defined as an increase in blood glucose after intake of 50 g of a carbohydrate over 120 min, using either glucose or white bread as the reference value [7Jenkins D.J. et al.Glycemic index: overview of implications in health and disease.Am. J. Clin. Nutr. 2002; 76: 266S-273SCrossref PubMed Google Scholar]. GI differs widely between different types of carbohydrates and their physical presentation. In general, sugar, white bread, and starchy vegetables have moderately high GI values compared to glucose while legumes, fruits and nonstarchy vegetables have low GI values. The same amount of whole grain will have a lower GI than the milled grains when consumed as flour, due to the slower disintegration of the whole grains in the gut. The same applies to pasta, which typically has a low GI. In mixed meals, other food components such as fat and protein slow gastric emptying and thereby retard the absorption and increase in blood sugar. In addition to the speed of digestion and absorption of a specific carbohydrate, the kinetics and quantity of insulin secretion, the inhibition of glucagon release, and gastric emptying directly determine postprandial glucose levels [3Augustin L.S. et al.Glycemic index, glycemic load and glycemic response: an International Scientific Consensus Summit from the International Carbohydrate Quality Consortium (ICQC).Nutr. Metab. Cardiovasc. Dis. 2015; 25: 795-815Abstract Full Text Full Text PDF PubMed Scopus (278) Google Scholar, 4Brand-Miller J.C. et al.Low vs high glycemic index diet.JAMA. 2015; 313: 1371-1372Crossref PubMed Scopus (9) Google Scholar, 7Jenkins D.J. et al.Glycemic index: overview of implications in health and disease.Am. J. Clin. Nutr. 2002; 76: 266S-273SCrossref PubMed Google Scholar, 8Ludwig D.S. The glycemic index: physiological mechanisms relating to obesity, diabetes, and cardiovascular disease.JAMA. 2002; 287: 2414-2423Crossref PubMed Scopus (1237) Google Scholar, 11Zeevi D. et al.Personalized nutrition by prediction of glycemic responses.Cell. 2015; 163: 1079-1094Abstract Full Text Full Text PDF PubMed Scopus (980) Google Scholar, 12Wolever T.M. et al.Measuring the glycemic index of foods: interlaboratory study.Am. J. Clin. Nutr. 2008; 87: 247S-257SCrossref PubMed Google Scholar]. Moreover, GI is highly circadian and increases in blood glucose for similar meals are two to three times greater in the evening as compared to the morning [13Kessler K. et al.The effect of diurnal distribution of carbohydrates and fat on glycaemic control in humans: a randomized controlled trial.Sci. Rep. 2017; 744170Crossref PubMed Scopus (24) Google Scholar]. The principle idea of the GI concept is that similar quantities of qualitatively different carbohydrates differ in their capacity to increase blood glucose. A slower and lower increase in glucose is proposed to be beneficial and to reduce metabolic and cardiovascular risks [3Augustin L.S. et al.Glycemic index, glycemic load and glycemic response: an International Scientific Consensus Summit from the International Carbohydrate Quality Consortium (ICQC).Nutr. Metab. Cardiovasc. Dis. 2015; 25: 795-815Abstract Full Text Full Text PDF PubMed Scopus (278) Google Scholar, 7Jenkins D.J. et al.Glycemic index: overview of implications in health and disease.Am. J. Clin. Nutr. 2002; 76: 266S-273SCrossref PubMed Google Scholar, 8Ludwig D.S. The glycemic index: physiological mechanisms relating to obesity, diabetes, and cardiovascular disease.JAMA. 2002; 287: 2414-2423Crossref PubMed Scopus (1237) Google Scholar, 9Brand-Miller J.C. et al.Glycemic index and obesity.Am. J. Clin. Nutr. 2002; 76: 281S-285SCrossref PubMed Google Scholar]. GI is defined as an increase in blood glucose after intake of 50 g of a carbohydrate over 120 min, using either glucose or white bread as the reference value [7Jenkins D.J. et al.Glycemic index: overview of implications in health and disease.Am. J. Clin. Nutr. 2002; 76: 266S-273SCrossref PubMed Google Scholar]. GI differs widely between different types of carbohydrates and their physical presentation. In general, sugar, white bread, and starchy vegetables have moderately high GI values compared to glucose while legumes, fruits and nonstarchy vegetables have low GI values. The same amount of whole grain will have a lower GI than the milled grains when consumed as flour, due to the slower disintegration of the whole grains in the gut. The same applies to pasta, which typically has a low GI. In mixed meals, other food components such as fat and protein slow gastric emptying and thereby retard the absorption and increase in blood sugar. In addition to the speed of digestion and absorption of a specific carbohydrate, the kinetics and quantity of insulin secretion, the inhibition of glucagon release, and gastric emptying directly determine postprandial glucose levels [3Augustin L.S. et al.Glycemic index, glycemic load and glycemic response: an International Scientific Consensus Summit from the International Carbohydrate Quality Consortium (ICQC).Nutr. Metab. Cardiovasc. Dis. 2015; 25: 795-815Abstract Full Text Full Text PDF PubMed Scopus (278) Google Scholar, 4Brand-Miller J.C. et al.Low vs high glycemic index diet.JAMA. 2015; 313: 1371-1372Crossref PubMed Scopus (9) Google Scholar, 7Jenkins D.J. et al.Glycemic index: overview of implications in health and disease.Am. J. Clin. Nutr. 2002; 76: 266S-273SCrossref PubMed Google Scholar, 8Ludwig D.S. The glycemic index: physiological mechanisms relating to obesity, diabetes, and cardiovascular disease.JAMA. 2002; 287: 2414-2423Crossref PubMed Scopus (1237) Google Scholar, 11Zeevi D. et al.Personalized nutrition by prediction of glycemic responses.Cell. 2015; 163: 1079-1094Abstract Full Text Full Text PDF PubMed Scopus (980) Google Scholar, 12Wolever T.M. et al.Measuring the glycemic index of foods: interlaboratory study.Am. J. Clin. Nutr. 2008; 87: 247S-257SCrossref PubMed Google Scholar]. Moreover, GI is highly circadian and increases in blood glucose for similar meals are two to three times greater in the evening as compared to the morning [13Kessler K. et al.The effect of diurnal distribution of carbohydrates and fat on glycaemic control in humans: a randomized controlled trial.Sci. Rep. 2017; 744170Crossref PubMed Scopus (24) Google Scholar]. Postprandial increases in glucose differ dramatically between individuals, even to similar foods [11Zeevi D. et al.Personalized nutrition by prediction of glycemic responses.Cell. 2015; 163: 1079-1094Abstract Full Text Full Text PDF PubMed Scopus (980) Google Scholar], and are determined not only by the speed and quantity of insulin and glucagon secretion, but also by an array of variables including body composition, age, microbiome, fiber intake, and circadian changes in insulin sensitivity [11Zeevi D. et al.Personalized nutrition by prediction of glycemic responses.Cell. 2015; 163: 1079-1094Abstract Full Text Full Text PDF PubMed Scopus (980) Google Scholar, 12Wolever T.M. et al.Measuring the glycemic index of foods: interlaboratory study.Am. J. Clin. Nutr. 2008; 87: 247S-257SCrossref PubMed Google Scholar, 13Kessler K. et al.The effect of diurnal distribution of carbohydrates and fat on glycaemic control in humans: a randomized controlled trial.Sci. Rep. 2017; 744170Crossref PubMed Scopus (24) Google Scholar]. Foods with a low GI tend to contain more fibers and micronutrients that display potent health-promoting properties compared to more processed high-GI foods such as white bread or rice, thereby confounding the results of clinical intervention studies due to their content of non-starch food components affecting sugar and fat metabolism [14Weickert M.O. Pfeiffer A.F. Metabolic effects of dietary fiber consumption and prevention of diabetes.J. Nutr. 2008; 138: 439-442Crossref PubMed Scopus (413) Google Scholar, 15Weickert M.O. Pfeiffer A.F. Low-glycemic index vs high-cereal fiber diet in type 2 diabetes.JAMA. 2009; 301: 1538-1539Crossref PubMed Scopus (4) Google Scholar, 16Jenkins D.J. et al.Effect of a low-glycemic index or a high-cereal fiber diet on type 2 diabetes: a randomized trial.JAMA. 2008; 300: 2742-2753Crossref PubMed Scopus (287) Google Scholar]. Moreover, some sugars, such as fructose have a low GI but elicit additional metabolic effects on uric acid, liver fat, and blood pressure, which may further confound the outcomes [17Bray G.A. Potential health risks from beverages containing fructose found in sugar or high-fructose corn syrup.Diabetes Care. 2013; 36: 11-12Crossref PubMed Scopus (23) Google Scholar]. We propose a novel concept linking the GI to differential responses of the intestinal hormones GIP and glucagon-like peptide (GLP)-1, which are released in different segments of the small intestine (Box 2). In particular, a rapid and pronounced release of GIP in the proximal small intestine by high-GI carbohydrates is proposed to program metabolism for effective energy storage favoring fatty liver, insulin resistance, obesity, subclinical inflammation, and hypertriglyceridemia. This program may have been evolutionarily advantageous in times requiring rapid energy storage. Understanding the pathophysiological mechanisms of high-GI foods provides a basis for developing nutritional and therapeutic solutions.Box 2GIP and GLP-1GIP is released in the upper small intestine in response to food intake from enteroendocrine K cells [23Holst J.J. On the physiology of GIP and GLP-1.Horm. Metab. Res. 2004; 36: 747-754Crossref PubMed Scopus (168) Google Scholar, 25Buffa R. et al.Identification of the intestinal cell storing gastric inhibitory peptide.Histochemistry. 1975; 43: 249-255Crossref PubMed Scopus (83) Google Scholar]. GIP is an incretin hormone, which defines it as a gut hormone inducing the release of insulin from pancreatic islet β cells upon food intake but only if blood glucose is elevated [23Holst J.J. On the physiology of GIP and GLP-1.Horm. Metab. Res. 2004; 36: 747-754Crossref PubMed Scopus (168) Google Scholar, 24Nauck M.A. Meier J.J. The incretin effect in healthy individuals and those with type 2 diabetes: physiology, pathophysiology, and response to therapeutic interventions.Lancet Diabetes Endocrinol. 2016; 4: 525-536Abstract Full Text Full Text PDF PubMed Scopus (152) Google Scholar]. GIP is released within minutes upon intake of glucose or rapidly digested carbohydrates such as saccharose or starch from milled flour, and is an important mediator of the early insulin response. GIP is also released by fat and protein but does not induce insulin release in the absence of increased blood glucose. In addition, GIP is an important regulator of postprandial metabolism by acting on receptors on many cell types including insulin producing beta cells, adipocytes, immune cells, endothelial cells, and neuronal cells, but not hepatocytes or striated muscle cells [38Rudovich N. et al.GIP receptor mRNA expression in different fat tissue depots in postmenopausal non-diabetic women.Regul. Pept. 2007; 142: 138-145Crossref PubMed Scopus (34) Google Scholar]. The whole-body genetic deletion of GIPR renders mice resistant to the development of obesity and insulin resistance in response to high-fat or high-GI diets [9Brand-Miller J.C. et al.Glycemic index and obesity.Am. J. Clin. Nutr. 2002; 76: 281S-285SCrossref PubMed Google Scholar, 55Miyawaki K. et al.Inhibition of gastric inhibitory polypeptide signaling prevents obesity.Nat. Med. 2002; 8: 738-742Crossref PubMed Scopus (677) Google Scholar]. GIPRs on pancreatic β cells become dysfunctional in chronic hyperglycemia and do not mediate insulin release in patients with type 2 diabetes, who show a delayed and prolonged insulin response to carbohydrates [22Vilsboll T. et al.Incretin secretion in relation to meal size and body weight in healthy subjects and people with type 1 and type 2 diabetes mellitus.J. Clin. Endocrinol. Metab. 2003; 88: 2706-2713Crossref PubMed Scopus (397) Google Scholar, 24Nauck M.A. Meier J.J. The incretin effect in healthy individuals and those with type 2 diabetes: physiology, pathophysiology, and response to therapeutic interventions.Lancet Diabetes Endocrinol. 2016; 4: 525-536Abstract Full Text Full Text PDF PubMed Scopus (152) Google Scholar]. Another well-characterized incretin hormone stimulating insulin release is GLP-1, which is released from L cells in the distal small intestine and colon upon food intake, particularly by foods that are not resorbed proximally. GLP-1 inhibits gastric emptying and reduces food intake and is a well-characterized principle in the treatment of type 2 diabetes [23Holst J.J. On the physiology of GIP and GLP-1.Horm. Metab. Res. 2004; 36: 747-754Crossref PubMed Scopus (168) Google Scholar, 24Nauck M.A. Meier J.J. The incretin effect in healthy individuals and those with type 2 diabetes: physiology, pathophysiology, and response to therapeutic interventions.Lancet Diabetes Endocrinol. 2016; 4: 525-536Abstract Full Text Full Text PDF PubMed Scopus (152) Google Scholar]. GLP-1 thus rather represents a signal to reduce food intake when digestive capacity is exceeded, such that undigested food reaches the distal small intestine. GIP is released in the upper small intestine in response to food intake from enteroendocrine K cells [23Holst J.J. On the physiology of GIP and GLP-1.Horm. Metab. Res. 2004; 36: 747-754Crossref PubMed Scopus (168) Google Scholar, 25Buffa R. et al.Identification of the intestinal cell storing gastric inhibitory peptide.Histochemistry. 1975; 43: 249-255Crossref PubMed Scopus (83) Google Scholar]. GIP is an incretin hormone, which defines it as a gut hormone inducing the release of insulin from pancreatic islet β cells upon food intake but only if blood glucose is elevated [23Holst J.J. On the physiology of GIP and GLP-1.Horm. Metab. Res. 2004; 36: 747-754Crossref PubMed Scopus (168) Google Scholar, 24Nauck M.A. Meier J.J. The incretin effect in healthy individuals and those with type 2 diabetes: physiology, pathophysiology, and response to therapeutic interventions.Lancet Diabetes Endocrinol. 2016; 4: 525-536Abstract Full Text Full Text PDF PubMed Scopus (152) Google Scholar]. GIP is released within minutes upon intake of glucose or rapidly digested carbohydrates such as saccharose or starch from milled flour, and is an important mediator of the early insulin response. GIP is also released by fat and protein but does not induce insulin release in the absence of increased blood glucose. In addition, GIP is an important regulator of postprandial metabolism by acting on receptors on many cell types including insulin producing beta cells, adipocytes, immune cells, endothelial cells, and neuronal cells, but not hepatocytes or striated muscle cells [38Rudovich N. et al.GIP receptor mRNA expression in different fat tissue depots in postmenopausal non-diabetic women.Regul. Pept. 2007; 142: 138-145Crossref PubMed Scopus (34) Google Scholar]. The whole-body genetic deletion of GIPR renders mice resistant to the development of obesity and insulin resistance in response to high-fat or high-GI diets [9Brand-Miller J.C. et al.Glycemic index and obesity.Am. J. Clin. Nutr. 2002; 76: 281S-285SCrossref PubMed Google Scholar, 55Miyawaki K. et al.Inhibition of gastric inhibitory polypeptide signaling prevents obesity.Nat. Med. 2002; 8: 738-742Crossref PubMed Scopus (677) Google Scholar]. GIPRs on pancreatic β cells become dysfunctional in chronic hyperglycemia and do not mediate insulin release in patients with type 2 diabetes, who show a delayed and prolonged insulin response to carbohydrates [22Vilsboll T. et al.Incretin secretion in relation to meal size and body weight in healthy subjects and people with type 1 and type 2 diabetes mellitus.J. Clin. Endocrinol. Metab. 2003; 88: 2706-2713Crossref PubMed Scopus (397) Google Scholar, 24Nauck M.A. Meier J.J. The incretin effect in healthy individuals and those with type 2 diabetes: physiology, pathophysiology, and response to therapeutic interventions.Lancet Diabetes Endocrinol. 2016; 4: 525-536Abstract Full Text Full Text PDF PubMed Scopus (152) Google Scholar]. Another well-characterized incretin hormone stimulating insulin release is GLP-1, which is released from L cells in the distal small intestine and colon upon food intake, particularly by foods that are not resorbed proximally. GLP-1 inhibits gastric emptying and reduces food intake and is a well-characterized principle in the treatment of type 2 diabetes [23Holst J.J. On the physiology of GIP and GLP-1.Horm. Metab. Res. 2004; 36: 747-754Crossref PubMed Scopus (168) Google Scholar, 24Nauck M.A. Meier J.J. The incretin effect in healthy individuals and those with type 2 diabetes: physiology, pathophysiology, and response to therapeutic interventions.Lancet Diabetes Endocrinol. 2016; 4: 525-536Abstract Full Text Full Text PDF PubMed Scopus (152) Google Scholar]. GLP-1 thus rather represents a signal to reduce food intake when digestive capacity is exceeded, such that undigested food reaches the distal small intestine. Foods that have similar composition but differ in GI are required to investigate the physiological impact of the GI under weight-stable conditions in an unambiguous manner. The prototype of such a food is provided by isomaltulose (marketed under the brand name Palatinose), which consists of a glucose–fructose dimer similar to sucrose. However, the two sugars are linked by an α1,2-glycosidic bond in sucrose and by an α1,6-glycosidic bond in isomaltulose. The α1,2 bond is rapidly cleaved by the intestinal glucosidases while the α,1,6 bond is cleaved slowly, resulting in a delayed but complete uptake in the small intestine, which has also been confirmed in human ileostomy patients [18Holub I. et al.Novel findings on the metabolic effects of the low glycaemic carbohydrate isomaltulose (Palatinose).Br. J. Nutr. 2010; 103: 1730-1737Crossref PubMed Scopus (80) Google Scholar]. The complete uptake in the small intestine is important to distinguish effects on the GI from those caused by changes in gut microbiota that occur when the sugar reaches the large intestine and alters the composition of the microbiome, which affects postprandial glucose responses [11Zeevi D. et al.Personalized nutrition by prediction of glycemic responses.Cell. 2015; 163: 1079-1094Abstract Full Text Full Text PDF PubMed Scopus (980) Google Scholar]. Intake of isomaltulose results in a slow and delayed increase of blood sugar and insulin and reduced peak concentrations as compared to sucrose, resulting in apparently better glucose tolerance [18Holub I. et al.Novel findings on the metabolic effects of the low glycaemic carbohydrate isomaltulose (Palatinose).Br. J. Nutr. 2010; 103: 1730-1737Crossref PubMed Scopus (80) Google Scholar, 19Kawai K. et al.Changes in blood glucose and insulin after an oral palatinose administration in normal subjects.Endocrinol. Jpn. 1985; 32: 933-936Crossref PubMed Scopus (73) Google Scholar, 20Keyhani-Nejad F. et al.Effects of palatinose and sucrose intake on glucose metabolism and incretin secretion in subjects with type 2 diabetes.Diabetes Care. 2016; 39: e38-e39Crossref PubMed Scopus (16) Google Scholar]. Indeed, using isomaltulose, it is possible to show distinct roles of the GI regarding intestinal hormone responses of incretins and other hormones, insulin sensitivity, hepatic lipid accumulation and fatty liver, and inflammatory responses. A closer understanding is achieved by taking the intestinal hormone responses into account and by determining the responses of humans to postprandial elevations of these hormones. Administration of 50 g isomaltulose results in smaller peak increases in glucose than sucrose in healthy individuals [18Holub I. et al.Novel findings on the metabolic effects of the low glycaemic carbohydrate isomaltulose (Palatinose).Br. J. Nutr. 2010; 103: 1730-1737Crossref PubMed Scopus (80) Google Scholar, 19Kawai K. et al.Changes in blood glucose and insulin after an oral palatinose administration in normal subjects.Endocrinol. Jpn. 1985; 32: 933-936Crossref PubMed Scopus (73) Google Scholar] (Figure 1) and in people with type 2 diabetes [20Keyhani-Nejad F. et al.Effects of palatinose and sucrose intake on glucose metabolism and incretin secretion in subjects with type 2 diabetes.Diabetes Care. 2016; 39: e38-e39Crossref PubMed Scopus (16) Google Scholar]. In parallel, there is a smaller peak and total increase in insulin [19Kawai K. et al.Changes in blood glucose and insulin after an oral palatinose administration in normal subjects.Endocrinol. Jpn. 1985; 32: 933-936Crossref PubMed Scopus (73) Google Scholar]. This is surprising in view of the similar amount of glucose and fructose being absorbed by the organism with either sugar, and indicates an improved insulin action or insulin-independent disposal of glucose. Insulin secretion is partly determined by the intestinal incretins GIP and GLP-1 [21Vilsboll T. et al.Both GLP-1 and GIP are insulinotropic at basal and postprandial glucose levels and contribute nearly equally to the incretin effect of a meal in healthy subjects.Regul. Pept. 2003; 114: 115-121Crossref PubMed Scopus (327) Google Scholar, 22Vilsboll T. et al.Incretin secretion in relation to meal size and body weight in healthy subjects and people with type 1 and type 2 diabetes mellitus.J. Clin. Endocrinol. Metab. 2003; 88: 2706-2713Crossref PubMed Scopus (397) Google Scholar, 23Holst J.J. On the physiology of GIP and GLP-1.Horm. Metab. Res. 2004; 36: 747-754Crossref PubMed Scopus (168) Google Scholar, 24Nauck M.A. Meier J.J. The incretin effect in healthy individuals and those with type 2 diabetes: physiology, pathophysiology, and response to therapeutic interventions.Lancet Diabetes Endocrinol. 2016; 4: 525-536Abstract Full Text Full Text PDF PubMed Scopus (152) Google Scholar]. GIP is produced by K cells, which are predominantly located in the upper small intestine [25Buffa R. et al.Identification of the intestinal cell storing gastric inhibitory peptide.Histochemistry. 1975; 43: 249-255Crossref PubMed Scopus (83) Google Scholar], while the GLP-1-producing L cells are located in the more distal small intestine and in the colon [23Holst J.J. On the physiology of GIP and GLP-1.Horm. Metab. Res. 2004; 36: 747-754Crossref PubMed Scopus (168) Google Scholar]. Therefore, it is reasonable to assume that the faster digestion of sucrose and uptake of glucose results in stimulation of the more proximal K cells, while the slowly cleaved isomaltulose may bypass these proximal K cells and therefore release little GIP. Indeed, GIP is rapidly released by sucrose, reaching peak concentrations after 15 min, which coincides and correlates with the early insulin secretion in healthy humans (Figure 1). By contrast, there is little increase in GIP after ingestion of isomaltulose, consistent with bypass of the proximal K cells, and accordingly, little early increase in insulin [