Comparative Effects of Proximal and Distal Small Intestinal Glucose Exposure on Glycemia, Incretin Hormone Secretion, and the Incretin Effect in Health and Type 2 Diabetes

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Aims The gastrointestinal tract, particularly the lower gut, may be key to the anti‐diabetic action of metformin. We evaluated whether administration of metformin into the distal, vs the proximal, small intestine would be more effective in lowering plasma glucose by stimulating glucagon‐like pepetide‐1 (GLP‐1) and/or slowing gastric emptying (GE) in type 2 diabetes (T2DM). Materials and methods Ten diet‐controlled T2DM patients were studied on three occasions. A transnasal catheter was positioned with proximal and distal infusion ports located 13 and 190 cm beyond the pylorus, respectively. Participants received infusions of (a) proximal + distal saline (control), (b) proximal metformin (1000 mg) + distal saline or (c) proximal saline + distal metformin (1000 mg) over 5 minutes, followed 60 minutes later by a glucose drink containing 50 g glucose and 150 mg 13C‐acetate. “Arterialized” venous blood and breath samples were collected over 3 hours for measurements of plasma glucose, GLP‐1, insulin and glucagon, and GE, respectively. Results Compared with control, both proximal and distal metformin reduced plasma glucose and augmented GLP‐1 responses to oral glucose comparably (P < 0.05 each), without affecting plasma insulin or glucagon. GE was slower after proximal metformin than after control (P < 0.05) and tended to be slower after distal metformin, without any difference between proximal and distal metformin. Conclusions In diet‐controlled T2DM patients, glucose‐lowering via a single dose of metformin administered to the upper and lower gut was comparable and was associated with stimulation of GLP‐1 and slowing of GE. These observations suggest that the site of gastrointestinal administration is not critical to the glucose‐lowering capacity of metformin.

Section: Discussionmentioning

confidence: 99%

Comparative effects of proximal and distal small intestinal administration of metformin on plasma glucose and glucagon‐like peptide‐1, and gastric emptying after oral glucose, in type 2 diabetes

Borg

Bound

Grivell

et al. 2018

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“…Surprisingly, exendin (9–39) was associated with an early, albeit modest, increase in plasma total GIP. Since GLP‐1 accounts for the slowing of gastric emptying and small intestinal transit, the so‐called “ileal brake”, antagonism of GLP‐1 may have resulted in an increase in the transit of fat within the proximal small intestine and therefore stimulated additional GIP secretion – our recent study in both healthy people and people with T2DM has shown that the distal small intestine is also capable of secreting GIP …”

Section: Discussionmentioning

confidence: 99%

“…Two people withdrew prior to the first study visit, and three withdrew before completing the study owing to intolerance of the nasoduodenal catheter (n = 2) or the intraduodenal fat infusion (n = 1, on the placebo/saline day). Accordingly, 15 participants (10 men and five women, mean age 68.8 ± 2.2 years, body mass index 30.2 ± 1.3 kg/m, glycated haemoglobin 49.3 ± 2.1 mmol/mol [6.7 ± 0.2%], and duration of known diabetes 6.6 ± 1.5 years) completed the study and were included in the final analysis. None had impaired liver or renal function, had diabetic microvascular complications, was a smoker, or was taking medication known to affect gastrointestinal function.…”

Section: Methodsmentioning

confidence: 99%

“…The incretin hormones glucose‐dependent insulinotropic polypeptide (GIP) and glucagon‐like peptide‐1 (GLP‐1) are secreted from the gut upon nutrient exposure and, while degraded rapidly by dipeptidyl peptidase 4 (DPP‐4), account for the substantially greater insulin response to enteral, compared to intravenous (i.v. ), glucose in healthy people . In type 2 diabetes (T2DM), the insulinotropic effect of GIP is markedly diminished, whereas that of GLP‐1 remains relatively intact .…”

Section: Introductionmentioning

confidence: 99%

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Role of endogenous glucagon‐like peptide‐1 enhanced by vildagliptin in the glycaemic and energy expenditure responses to intraduodenal fat infusion in type 2 diabetes

Xie

Wang

Jones

et al. 2019

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Aim To evaluate the effects of the dipeptidyl peptidase‐4 (DPP‐4) inhibitor vildagliptin on glycaemic and energy expenditure responses during intraduodenal fat infusion, as well as the contribution of endogenous glucagon‐like peptide‐1 (GLP‐1) signalling, in people with type 2 diabetes (T2DM). Methods A total of 15 people with T2DM managed by diet and/or metformin (glycated haemoglobin 49.3 ± 2.1 mmol/mol) were studied on three occasions (two with vildagliptin and one with placebo) in a double‐blind, randomized, crossover fashion. On each day, vildagliptin 50 mg or placebo was given orally, followed by intravenous exendin (9–39) 600 pmol/kg/min, on one of the two vildagliptin treatment days, or 0.9% saline over 180 minutes. At between 0 and 120 minutes, a fat emulsion was infused intraduodenally at 2 kcal/min. Energy expenditure, plasma glucose and glucose‐regulatory hormones were evaluated. Results Intraduodenal fat increased plasma GLP‐1 and glucose‐dependent insulinotropic polypeptide (GIP), insulin and glucagon, and energy expenditure, and decreased plasma glucose (all P < 0.05). On the two intravenous saline days, plasma glucose and glucagon were lower, plasma intact GLP‐1 was higher (all P < 0.05), and energy expenditure tended to be lower after vildagliptin (P = 0.08) than placebo. On the two vildagliptin days, plasma glucose, glucagon and GLP‐1 (both total and intact), and energy expenditure were higher during intravenous exendin (9–39) than saline (all P < 0.05). Conclusions In well‐controlled T2DM during intraduodenal fat infusion, vildagliptin lowered plasma glucose and glucagon, and tended to decrease energy expenditure, effects that were mediated by endogenous GLP‐1.

“…A recent study reported that metformin induced GLP‐1 secretion ex vivo in human gut mucosa, suggesting the potential for metformin to stimulate GLP‐1 secretion directly . If this were the case, infusing metformin into the distal small intestine, where GLP‐1‐releasing L‐cells are abundant, would be anticipated to enhance GLP‐1 secretion (as is evident with other GLP‐1 stimuli, such as glucose); however, there was no difference in the effects of metformin (1 g) administered into the ileum compared to metformin administered into the duodenum on GLP‐1 secretion, gastric emptying or the glycaemic response to oral glucose in patients with T2DM (Figure ) . These observations suggest that stimulation of GLP‐1 secretion by metformin is mediated by indirect mechanisms.…”

Section: Gastrointestinal Effects Of Metformin: Role Of Gut Peptidesmentioning

confidence: 99%

Mechanism of glucose‐lowering by metformin in type 2 diabetes: Role of bile acids

Sansome

Xie

Veedfald

et al. 2019

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Type 2 diabetes mellitus (T2DM) is an increasingly prevalent chronic condition, characterized by abnormally elevated blood glucose concentrations and, as a consequence, increased risk of micro‐ and macrovascular complications. Metformin is usually the first‐line glucose‐lowering medication in T2DM; however, despite being used for more than 60 years, the mechanism underlying the glucose‐lowering action of metformin remains incompletely understood. Although metformin reduces hepatic glucose production, there is persuasive evidence that the gastrointestinal tract is crucial in mediating this effect, particularly via secretion of the incretin hormone glucagon‐like peptide 1 (GLP‐1). It is now well recognized that bile acids, in addition to their established function in fat digestion and absorption, are important regulators of glucose metabolism. Exposure of the small and large intestine to bile acids induces GLP‐1 secretion, modulates the composition of the gut microbiota, and reduces postprandial blood glucose excursions in humans with and without T2DM. Metformin reduces intestinal bile acid resorption substantially, such that intraluminal bile acids may, at least in part, account for its glucose‐lowering effect. The present review focuses on the conceptual shift in our understanding as to how metformin lowers blood glucose in T2DM, with a particular emphasis on the role of intestinal bile acids.