Nutrition & GLP-1 Production

Nutrition & GLP-1 Production

The amount of nutrients in ingested food varies significantly between people and even within the same person throughout the day. The macronutrient composition of the diet affects glycemia and insulinemia. It also influences hunger and metabolic responses. One theory to explain the varied effects of macronutrients on these parameters is the modulation of GLP-1 secretion. Their catabolic byproducts secrete it. Among the breakdown products are monosaccharides, short-chain fatty acids, medium and long-chain fatty acids, amino acids, and peptides. These products of macronutrients bind to the receptors on L-cells in the intestine, resulting in the production of GLP-1.


GLP-1 secretion is undoubtedly related to meals. The plasma concentrations are relatively low while fasting. But they can be measured, and it has been shown that somatostatin can reduce fasting amounts in humans, indicating an actual basal secretion rate. Studies utilizing DPP-IV inhibitors, which raise the levels of intact endogenous GLP-1 between meals and when fasting, seem to support this as well. This effect would not have been achievable if the diet didn't affect GLP-1 production.

The quick increase in L-cell secretion following a meal is most noticeable when assessed with COOH-terminal assays. However, it is also frequently detectable using assays for the intact hormone. The response becomes apparent after 10 minutes. However, it happens after the "cephalic phase" stimulation of insulin secretion, indicating that GLP-1 (or GIP) release is unaffected by the neuronal, probably vagal, signals that trigger insulin secretion. There are numerous reasons to think that the GLP-1 response is caused by the actual presence of nutrients in the gut lumen and maybe by their interaction with the L-cell microvilli. Thus, after ileal installations of lipids or carbohydrates at levels that match "the physiological malabsorption" of these nutrients, people exhibit a rapid GLP-1 response.

The solution's osmolarity doesn't appear significant since hyperosmolar salt solutions have no effect. The meal reaction varies with meal size and is closely related to the rate at which the stomach empties. Minor intestine resections do not impact the reaction. However, the secretion of GLP-1 may be significantly increased in individuals with accelerated gastric emptying, such as those who have undergone gastrectomy or gastric bypass procedures for obesity. This excessive GLP-1 secretion may cause reactive hypoglycemia due to inappropriate insulin secretion in these patients.

Diet therapy is crucial as a primary diabetes treatment and a way to stimulate GLP-1, which works in conjunction with medication to improve glycemic control. This chapter will review nutrition, food, dietary habits, and a few strategies to stimulate GLP-1 secretion.

Effects of Carbohydrates on GLP-1 Secretion

Glucose is a strong trigger for the release of incretin hormones. The sodium-dependent glucose transporter is widely distributed in the intestine and the apical membranes of L and K cells. It is primarily responsible for facilitating intestinal glucose sensing. In addition to SGLT1, GLUT2 is necessary for glucose sensing and thus contributes to systemic glucose regulation. The artificial sweeteners do not cause the release of insulin, GLP-1, or GIP in humans, like glucose. Still, GLP-1 secretion in response to glucose may be mediated by the sweet taste receptors and SGLT1 and GLUT2.

While fructose, fucose, mannose, xylose, and lactose do not stimulate GLP-1 secretion, sugars like galactose, maltose, sucrose, and 3O-methyl-D-glucose and maltitol do. Although the exact mechanism of action is unknown, a slight variation in the molecular structures of sugars could change their ability to stimulate GLP-1.


After ingestion, enzymes break down digestible carbohydrates. Then these carbohydrates are mostly absorbed as glucose, with some fructose and galactose. Glucose absorption by enterocytes and glucose-induced GLP-1 secretion from L-cells appear to be mediated by the sodium-glucose transporter-1, a membrane transport protein produced in the small intestine.

Short-chain fatty acids and indigestible carbohydrates

Non-digestible carbohydrates undergo fermentation in the colon, producing varying levels of SCFAs depending on the kind of carbohydrate. Acetate, butyrate, and propionate

 are the most prevalent short-chain fatty acids. SCFAs are carboxylic acids with fewer than six carbons.

Dietary fiber and its metabolites, the SCFAs, appear to promote GLP-1 release from L-cells. They interact with the free fatty acid receptors 2 and 3. It has been demonstrated that physiological amounts of acetate and other short-chain fatty acids promote GLP-1 secretion in colonic cell cultures.

Consuming non-digestible carbohydrates is the primary method for raising colonic SCFA levels in people. Overall, research findings point to a few mechanisms that relate the beneficial effects of fermentable fiber on calorie intake, weight gain, and blood glucose via an elevated GLP-1 release. Fermentable fiber and SCFAs produced by their intestinal fermentation boost GLP-1 production. It is done by up-regulating proglucagon expression. These also result in the over-expression of prohormone convertase 1. This enzyme is responsible for cleaving proglucagon.

Consuming fermentable fiber is also associated with increased L cells in the proximal colon, which offers another rationale for the elevated GLP-1 synthesis and release. Increased expression of the transcription factors neuregenin-3 and neuro-D, essential for intestinal stem cells to differentiate into enteroendocrine cells, is also linked to increased L-cells.

The biological mechanisms underlying insulin production in the islets and the stimulation of GLP-1 release from L-cells are the same, at least in part. The closure of ATP-sensitive KATP channels and consequent membrane depolarization boost GLP-1 production in intestinal cells in a dose-dependent manner. Voltage-dependent channels must open due to glucose-induced membrane depolarization. The opening of these channels is needed for exocytosis and the release of GLP-1 into the bloodstream.

The release of GLP-1 from the cells is coordinated in a calcium-dependent manner requiring cellular machinery similar to that in b-cells, which occurs downstream of glucose-mediated membrane depolarization. It has been shown that fructose stimulates the release of GLP-1 in rats, mice, humans, and GLUTag cells. Compared to an identical dosage of glucose, fructose is a far less effective GLP-1 secretagogue when administered orally. Similar results have been observed in people following intragastric infusion of glucose and fructose at sweetness-matched dosages.

Uncertainty surrounds the potential contribution of intestine sweet-taste receptors to glucose-stimulated GLP-1 production. Sucralose, an artificial sweetener, and glucose increase GLP-1 secretion in isolated murine and human L-cell cultures. In contrast, glucose's stimulation of GLP-1 secretion is decreased in mice lacking a-gustducin, a crucial component of the sweet-taste receptor. In contrast, sucralose does not affect GLP-1 secretion in primary L-cell cultures. The artificial sweetener infusion does not impact healthy adult volunteers' glucose-stimulated GLP-1 secretion.



GLP-1 release mediated by proteins

As the most satiating macronutrient, protein is frequently linked to weight loss, possibly due to the stimulation of appetite-controlling hormones like GLP-1 by protein. Studies comparing protein administration with human carbohydrates and fat disproved the conventional wisdom that carbohydrates and fat were the most effective GLP-1-release stimulants.

Proteins, Amino Acids and GLP-1

Calcium sensing receptor, GPRC6A, and peptide transporter 1 (PEPT1), all highly expressed in L cells, are implicated in the release of GLP-1. L-arginine improves glucose clearance and functions as an insulin secretagogue by raising GLP-1 levels. Like how glutamine increases GLP-1 secretion in murine GLUTag cells, Na+-coupled amino acid transporters are believed to be crucial for GLP-1 production. Amino acids cause the release of GLP-1 through calcium-sensing receptors and PEPT1 receptors. These amino acids include glutamine, phenylalanine, tryptophan, asparagine, arginine, and the dipeptide glycine-sarcosine.

Direct comparison of isocaloric macronutrients

GLP-1 release after consuming macronutrients matched in terms of calories and volume has only been compared in a few studies. The effects of high-protein versus high-fat meals on the production of GLP-1 were evaluated in 12 healthy males. These subjects consumed milk and egg protein at a rate of 2 g/kg on one occasion and 0.88 g/kg of oleic acid on the other (volume- and calorie-matched). Following both meals, GLP-1 rose proportionately but did not differ in magnitude under the two circumstances (Reference 1).

Another study evaluated the amount of GLP-1 released in 18 healthy-weight women after consuming maltodextrin (45 g) against whey protein. A trend toward higher GLP-1 was seen after the whey protein test meal. Additionally, the acute effects of 3 isocaloric(375 kcal) test meals high in protein (352 g grilled turkey), fat (84 mL double cream), and carbohydrate (100 g glucose) led to similar peak GLP-1 levels, though at different times (Reference 2).

The three macronutrients were consumed in various forms, which may have impacted stomach emptying and subsequent delivery to the intestine. These studies support that consuming specific macronutrients generally causes more GLP-1 secretion.

Meals with a lot of protein, fat, or carbohydrates

A more practical approach would consider how several macronutrients included in the usual diet interact with one another. Males were given isocaloric pasta and dessert meals. These meals were heavy in fat (65%), carbohydrate (66%), or protein (65%), with the remaining energy requirement shared equally between the other two macronutrients. The subjects were ten healthy, normal-weight, and ten overweight males.

Despite no variations in GLP-1 concentrations after each meal, satiety was highest after the high-protein meal (Reference 3).

Instead, this can be explained by the higher release of PYY3-36  in high-protein conditions compared to high-fat and high-carbohydrate. PYY3-36 is the active version of an L-cell-derived hormone.

An analogous experimental design involved measuring the gut hormone responses of 8 healthy volunteers after eating pancake breakfasts, with 60% of the energy coming from protein, fat, or carbohydrate. The high protein means resulted in the highest levels of GLP-1 secretion, but this did not result in appreciable differences in subsequent food consumption.

After eating the meals with increasing protein consumption, mean GLP-1 concentrations increased dose-dependently. With increasing protein load, higher protein delivery to more distant gut sections may have contributed to this dose-dependent rise in GLP-1.

More extended periods seem to prolong the short-term effects of high-protein meals on GLP-1 secretion and hunger. For instance, in a study, 12 healthy women received either a high-protein diet (30% energy from protein, 40% from carbs, and 30% from fat) or an adequate protein diet (10% energy from protein, 60% from carbs, and 30% from fat) for four days. On day 4 of each diet, GLP-1 was measured for 24 hours. After the high-protein diet compared to the adequate-protein diet, GLP-1 was considerably higher 15 minutes after dinner and tended to be higher following breakfast.

These studies show that a (mixed-macronutrient) diet with a high relative protein composition can stimulate GLP-1 release more than diets with high carbohydrates or fat in healthy and overweight adults.

Form and Type of Protein

It is essential to consider protein type and shape when discussing GLP-1 release, given that nutrition transport and sensing are essential processes that control gut hormone secretion.

Liquid Meals Compared to Solid Meals

It is commonly known that liquid meals cause the stomach to empty more quickly than solid ones. Therefore, instant nutrient delivery (after a liquid as opposed to a solid meal) could shorten the window for intestinal absorption. Liquid meals expose nutrients to more distal portions of the colon, thereby increasing GLP-1 release. A study involved six healthy males and females matched for energy content and volume (52% energy from carbohydrates, 34% from fat, and 15% from protein). GLP-1 release was considerably higher after a mixed macronutrient drink than after a solid meal. (Reference 4)

A similar study found that GLP-1 increased more after a liquid-mixed meal (345 kcal) than after a solid-mixed meal (362 kcal). The subjects were six people who had recently undergone surgical or medicinal weight loss within a year. (Reference 5)

Following RYGB surgery, similar results were also seen in a larger trial with 32 individuals. (Reference 6)

Despite no variations in gastric pouch emptying times between liquid and solid meals, GLP-1 was higher after a mixed macronutrient liquid than a solid meal (matched for nutritional composition and energy content). This shows that the changes in GLP-1 after solid and liquid meals may be due to other factors like osmolarity. Studies comparing the release of GLP-1 after consuming matched protein meals in solid and liquid forms are necessary to determine whether certain macronutrients influence the effects of meal shape.

Casein, in comparison to whey

Most milk protein comprises whey and casein proteins, which comprise 20% and 80%. Previous studies have not definitively determined which protein is more satiating than the other. However, whey has been thought to be more satiating in the short term (180 min) due to faster gastric emptying after whey ingestion. Casein is more satiating in the long term (> 180 min). Given these variations, GLP-1 responses have been inconsistent.

Eight healthy ladies and one healthy male took casein protein as a 48-g liquid preload on one occasion and whey protein on the other. Compared to casein after 90 minutes, the GLP-1 was 65% higher after the whey protein preload. Despite this, given the slower rate of GI transit following casein consumption, a longer measurement interval could have been more appropriate. (Reference 7)

Other sources of protein

Other protein sources, such as gluten, soy, and cod, increase GLP-1 production. However, the strength of these effects doesn't seem to vary significantly depending on the source. This seems true for people with average healthy weight, overweight or obese, and type 2 diabetes. In conclusion, the data point to a more considerable GLP-1 secretion after consuming liquid mixed meals instead of solid ones (matched for food composition and caloric amount). Casein and whey show equivalent GLP-1 responses when the stomach empties at similar rates. Finally, the size of the GLP-1 responses induced by soy and gluten consumption is comparable to that of whey and casein. Identifying the ideal circumstances for protein-mediated GLP-1 release may be possible by isolating particular amino acids or peptides (available after digestion or absorption).

Amino Acids

As discussed earlier, individual amino acids can trigger GLP-1 release. Studies have shown that glutamine, phenylalanine, arginine, and tryptophan are some of the most potent examples.

In a trial, healthy, normal-weight men received intraduodenal infusions of L-tryptophan (0.15 kcal/min), L-phenylalanine (0.45 kcal/min), and L-glutamine (0.45 kcal/min) for 90 minutes before a buffet-style test meal. Due to poor tolerance of higher doses, the rate of L-tryptophan infusion was lower. Although the reduction in food intake after L-tryptophan treatment was more significant after L-phenylalanine and L-glutamine administration, GLP-1 was comparable across amino acids.

Intriguingly, delivery of L-arginine and L-tryptophan to the vascular system led to 2.9- and 2.7-fold increases in GLP-1 secretion relative to baseline. This suggests that absorptive and postabsorptive processes are involved in amino acid-mediated GLP-1 secretion. (Reference 8)

Future nutritional therapies could explore the possibility of combining different amino acids or peptides to promote GLP-1 secretion.

Final Words on Proteins and GLP-1

Evidence suggests that proteins fed alone are more or less effective than other isolated macronutrients for promoting GLP-1 production. However, it may be more beneficial to increase GLP-1 secretion by consuming mixed meals with high compared to low relative protein composition. Protein feeding or administration alone is sufficient to increase gut hormone release. Figuring out which amino acids are most effective at triggering this process could help develop protein forms or supplements targeting increased gut hormone availability.




Lipids and GLP-1

Docosahexaenoic acid (DHA), monounsaturated fatty acids, and linolenic acid are potent stimulators for producing GLP-1 from L cells. Several G protein-coupled receptors (GPRs), including GPR40, GPR43, GPR119, and GPR120, serve as critical fat sensors. Free fatty acid receptors (FFAR 1/3) are crucial in triggering the release of GLP-1. While GPR120 has limited involvement in the control of incretin secretion, GPR40 and GPR119 work together to modulate the triglyceride (TG)-induced release of incretins.

These experimental results suggest that GLP-1 is released in response to many variables, including different foods. However, it is unclear what kind of diet successfully increases GLP-1 secretion.

Fatty Acids

Acetate, butyrate, and propionate are three short-chain fatty acids (SCFAs) produced by fermentation-resistant starch that raise GLP-1 levels.

Free fatty acids

Triglycerides, which consist of a glycerol molecule and three fatty acids, make up the majority of dietary lipids. After the intake, triglycerides are hydrolyzed by lipases and emulsified by bile salts in the duodenum. Enterocytes then absorb them as glycerol and free fatty acids.

Free fatty acids, such as unsaturated long-chain fatty acids, are effective stimulators of GLP-1 secretion through interactions with free fatty acid receptors. When a substance binds to these receptors, phospholipase C is activated. This enzyme triggers calcium release from the endoplasmic reticulum into the cytoplasm. Unsaturated long-chain fatty acids have been found to boost the production of GLP-1.

Thomsen and colleagues were the first to examine GLP-1 responses in healthy individuals or adults with T2D after a meal containing olive oil (Reference 9). The consumption of the meal, including olive oil, led to increased postprandial GLP-1 blood concentrations compared to a meal containing butter, which is heavy in saturated fatty acids. However, neither the blood concentrations of insulin nor blood glucose showed any discernible acute differences.

A second study found that consuming an olive oil-rich diet for a longer time enhanced GLP-1 production. It also increased insulin secreted in response to glucose and better glucose tolerance at the 36-day mark. Similar outcomes were observed when consumption of a diet high in monounsaturated fatty acids (MUFAs) from olive oil for 50 days boosted GLP-1 blood concentrations, reduced weight gain, and enhanced insulin sensitivity. (Reference 10)

Studies revealed that consuming an olive oil-rich Mediterranean diet for 28 days led to noticeably greater postprandial GLP-1 blood concentrations in people with abdominal obesity and insulin resistance. Consuming the Mediterranean diet increased insulin sensitivity compared to a diet high in saturated fatty acids. This may have contributed to the observed decline in insulin secretion, fasting, and postprandial blood glucose levels. The colonic delivery of the PUFA -linolenic acid abruptly elevated GLP-1 and insulin blood concentrations.

Long-term dosing of alpha-linolenic acid has also been demonstrated to promote beta-cell proliferation and increase GLP-1 blood concentrations. The authors proposed that the rise in GLP-1 concentrations mediated the increased beta-cell proliferation. The raised GLP-1 secretion was caused by ingesting alpha-linolenic acid because GLP-1 has been proven to increase neogenesis and decrease the apoptosis of pancreatic cells.

According to a recent study, alpha-linolenic acid sources like fish oil and flax seed oil raised receptor expression while lowering the expression of the pro-inflammatory tumor necrosis factor.

Together, these studies suggest that diets higher in MUFAs or omega-3 polyunsaturated fatty acids (PUFAs) than in saturated fatty acids (SFAs), with similar energy contents, may increase GLP-1 secretion from L-cells. This GLP-1 may mediate the rise in insulin secretion, increased insulin sensitivity, increased -cell proliferation, and improved glucose tolerance seen in animal models and humans.



Mixed-nutrient foods

Contrary to single nutrients and foods with only one nutrient (such as oil), complex diets with various nutrients are more common. Clinical guidelines advise consuming carbohydrates from high-fiber foods such as vegetables, fruit, legumes, and whole grains for T2D management while lowering dietary SFA intake and boosting MUFA and omega-3 PUFA intake. They have variously been linked to an increase in GLP-1 production.

Many scientists have examined how high-fiber grain products, which bind to SGLT-1, FFAR2, and FFAR3, could increase GLP-1 secretion. In this regard, two recent studies evaluated the hunger responses of healthy young adults to isoenergetic breakfasts, including low-fiber ready-to-eat cereals or high-fiber oatmeal. Oatmeal (66.8 g) boosted fullness and decreased hunger, the urge to eat, and perceived prospective food intake compared to ready-to-eat breakfast cereals. Additionally, oatmeal reduced the amount of energy consumed in the subsequent meal. Compared to low-fiber breakfast cereals (control group, 0.5 g/day of fiber from the cereal), daily consumption of a high wheat-fiber breakfast cereal (test group, 24 g/day of fiber from the cereal) for a year significantly increased colonic SCFAs production as well as GLP-1 blood concentrations. More precisely, acetate and butyrate plasma concentrations were already noticeably elevated in the test group 9 months into the intervention. (Reference 11)

Nilsson and colleagues showed that eating high-fiber bread made from barley kernels for three days was linked to higher postprandial PYY and fasting GLP-1 blood concentrations in healthy persons. In healthy people, these alterations in GI peptide concentrations were linked to increased insulin sensitivity and reduced postprandial blood glucose levels. The scientists' discovery of elevated blood SCFAs and breath hydrogen concentrations suggests that elevated SCFAs pro- mediated the beneficial benefits of the barley kernel bread. (Reference 12)

Dietary Fibers in the colon.

A high-carb meal has been demonstrated to improve postprandial glycemic responses when high protein, MUFA, and fiber foods are added, such as almonds (30.0 to 90.0 g) or pistachios (28.0 to 85.0 g). This effect is dose-dependent.

Researchers have also discovered a decrease in insulin secretion after short-term and long-term almond eating in healthy persons and adults with hyperlipidemia. Similarly, persons with T2D experienced a reduction in body mass index, systolic blood pressure, and C-reactive protein blood concentrations after consuming 50.0 g of pistachios every day for 12 weeks. Consuming peanuts (42.5 g) or peanut butter (42.5 g) as part of a typical breakfast meal boosted postprandial insulin blood concentrations. It lowered postprandial glucose levels in obese women.

Additionally, after a typical lunch meal, peanut butter dramatically reduced postprandial blood glucose concentrations and increased postprandial PYY blood concentrations. Since L-cells emit GLP-1 and PYY, it is conceivable that peanut butter may promote GLP-1 secretion.

It has also been demonstrated that eating 2 to 3 MUFA and protein-rich eggs for breakfast or lunch can reduce emotional postprandial hunger. In addition, eating a breakfast consisting of fruit or cereal rather than a bagel resulted in lower postprandial blood glucose levels, less appetite, and lower calorie intake the next day. After eating eggs, men also expressed greater subjective satisfaction.

Although GLP-1 blood levels were not assessed in these investigations, researchers discovered that adults who consumed an egg-based breakfast had significantly higher postprandial blood levels of PYY. A high-carbohydrate, isocaloric meal can be made more satisfying and satiating by including avocado (50 to 90 g), which is rich in fiber and MUFAs.

Back to blog