nutrients Review Potential for Gut Peptide-Based Therapy in Postprandial Hypotension Malcolm J. Borg 1, Cong Xie 1 , Christopher K. Rayner 1, Michael Horowitz 1,2, Karen L. Jones 1,2 and Tongzhi Wu 1,2,* 1 Adelaide Medical School and Centre of Research Excellence in Translating Nutritional Science to Good Health, The University of Adelaide, Adelaide 5000, Australia; [email protected] (M.J.B.); [email protected] (C.X.); [email protected] (C.K.R.); [email protected] (M.H.); [email protected] (K.L.J.) 2 Endocrine and Metabolic Unit, Royal Adelaide Hospital, Adelaide 5000, Australia * Correspondence: [email protected]; Tel.: +61-8-8313-6535 Abstract: Postprandial hypotension (PPH) is an important and under-recognised disorder resulting from inadequate compensatory cardiovascular responses to meal-induced splanchnic blood pool- ing. Current approaches to management are suboptimal. Recent studies have established that the cardiovascular response to a meal is modulated profoundly by gastrointestinal factors, including the type and caloric content of ingested meals, rate of gastric emptying, and small intestinal transit and absorption of nutrients. The small intestine represents the major site of nutrient-gut interactions and associated neurohormonal responses, including secretion of glucagon-like peptide-1, glucose- dependent insulinotropic peptide and somatostatin, which exert pleotropic actions relevant to the postprandial haemodynamic profile. This review summarises knowledge relating to the role of these gut peptides in the cardiovascular response to a meal and their potential application to the management of PPH. Keywords: postprandial hypotension; glucagon-like peptide-1; glucose-dependent insulinotropic Citation: Borg, M.J.; Xie, C.; Rayner, polypeptide; somatostatin; diabetes mellitus; autonomic failure C.K.; Horowitz, M.; Jones, K.L.; Wu, T. Potential for Gut Peptide-Based Therapy in Postprandial Hypotension. Nutrients 2021, 13, 2826. 1. Introduction https://doi.org/10.3390/nu13082826 Postprandial hypotension (PPH) is defined as a fall in systolic blood pressure (SBP) of ≥20 mmHg, or a decrease to ≤90 mmHg if normotensive at baseline, within 2 h of a Academic Editor: Ghassan Bkaily meal [1]. It is under-recognised, despite occurring frequently in the elderly (prevalence ~20–30%) and individuals with type 2 diabetes mellitus (T2D) (~40%) and chronic neu- Received: 17 July 2021 rological disorders, such as Parkinson’s disease (40–100%) [1]. PPH is associated with Accepted: 14 August 2021 Published: 17 August 2021 substantially increased morbidity and mortality, and predisposes to syncope, falls, angina, transient ischaemic attacks and stroke [2]. The pathophysiology underlying PPH remains incompletely understood, but emerging evidence has revealed the fundamental role of Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in gastrointestinal function in the regulation of cardiovascular responses to a meal [1], partic- published maps and institutional affil- ularly the secretion and action of gut-derived peptides including glucagon-like peptide-1 iations. (GLP-1) [3], glucose-dependent insulinotropic polypeptide (GIP) [4,5] and somatostatin [6]. Indeed, therapeutic strategies that modulate gastrointestinal hormone secretion or sig- nalling have been shown to influence postprandial blood pressure substantially, although few, if any, studies have assessed whether the available therapies have a sustained effect on postprandial blood pressure or can prevent complications of PPH [1]. This review discusses Copyright: © 2021 by the authors. the relevance of gastrointestinal function to the regulation of postprandial blood pressure, Licensee MDPI, Basel, Switzerland. This article is an open access article with an emphasis on the role of gut peptides in the pathophysiology and management distributed under the terms and of PPH. conditions of the Creative Commons 2. Gastrointestinal Regulation of Postprandial Blood Pressure Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ The onset of PPH reflects inadequate cardiovascular compensation to meal-induced 4.0/). splanchnic blood pooling, which results from complex interactions between ingested nutri- Nutrients 2021, 13, 2826. https://doi.org/10.3390/nu13082826 https://www.mdpi.com/journal/nutrients Nutrients 2021, 13, x FOR PEER REVIEW 2 of 14 2. Gastrointestinal Regulation of Postprandial Blood Pressure Nutrients 2021, 13, 2826 2 of 14 The onset of PPH reflects inadequate cardiovascular compensation to meal-induced splanchnic blood pooling, which results from complex interactions between ingested nu- trients and the gastrointestinal tract. There is now compelling evidence that gastrointesti- nalents factors, and including the gastrointestinal meal composition, tract. There the israte now of compellingnutrient delivery evidence to the that small gastrointestinal intestine (i.e.,factors, gastric including emptying), meal nutrient composition, absorption, the rate the of specific nutrient region delivery of the to the small small intestine intestine ex- (i.e., gastric emptying), nutrient absorption, the specific region of the small intestine exposed to posed to nutrients, and the consequent neurohormonal responses, are integral to the post- nutrients, and the consequent neurohormonal responses, are integral to the postprandial prandial blood pressure response (Figure 1) [1]. blood pressure response (Figure1)[1]. Figure 1. Proposed model by which the gut modulates the postprandial haemodynamic response. The composition of the meal ingested, rate of small intestinal nutrient exposure and subsequent Figureabsorption 1. Proposed of nutrients, model by region which of smallthe gut intestine modulates exposed the postprandial to nutrients and haemodynamic neurohormonal response. responses Theall composition affect postprandial of the meal haemodynamics, ingested, rate with of sm theall potential intestinal to nutrient influence exposure the blood and pressure subsequent response absorptionto a meal. of Gutnutrients, peptides, region notably of small GLP-1 intestin [7],e GIP exposed [8] and to somatostatin nutrients and [ 9neurohormonal], may have profound responses effects all affect postprandial haemodynamics, with the potential to influence the blood pressure response on postprandial haemodynamic responses. to a meal. Gut peptides, notably GLP-1 [7], GIP [8] and somatostatin [9], may have profound effects on postprandialCarbohydrate, haemodynamic fat and responses. protein have all been shown to induce variable haemodynamic responses. For example, in hypertensive older individuals, oral carbohydrate, but not fat or Carbohydrate, fat and protein have all been shown to induce variable haemodynamic protein, reduced mean blood pressure [10]. In “healthy” older individuals, intraduodenal responses. For example, in hypertensive older individuals, oral carbohydrate, but not fat administration of glucose (3 kcal/min) led to a more rapid decline in SBP when compared or protein, reduced mean blood pressure [10]. In “healthy” older individuals, intraduode- with intraduodenal isocaloric fat and protein [11], and the increase in superior mesenteric nalartery administration blood flow, of glucose a surrogate (3 kcal/min) measure led of to splanchnic a more rapid blood decline pooling, in SBP inresponse when com- to in- paredtraduodenal with intraduodenal protein was isocaloric less when fat compared and protein with [11], glucose and the and increase fat [11]. in In superior individuals mes- with entericT2D, artery intraduodenal blood flow, infusion a surrogate of glucose measure (2 kcal/min), of splanchnic but not blood lipid, pooling, reduced diastolicin response blood to intraduodenalpressure (DBP) protein [12]. The was variable less when haemodynamic compared with responses glucose to and macronutrients fat [11]. In individu- may reflect als differenceswith T2D, intraduodenal in neurohormonal infusion profiles; of glucose for example, (2 kcal/min), fat, relative but not to lipid, isocaloric reduced glucose, dias- is a tolicmore blood potent pressure stimulus (DBP) for [12]. secretion The variable of the twohaemodynamic incretin hormones, responses GLP-1 to macronutrients and GIP [12,13 ]. may reflectThe differences rate of nutrient in neurohormonal delivery into theprofiles small; for intestine example, is tightly fat, relative controlled to isocaloric by gastric glucose,emptying, is a more which potent exhibits stimulus substantial for secr inter-individual,etion of the two incretin but much hormones, less intra-individual, GLP-1 and GIPvariation [12,13]. [14]. Along with the observation that gastric emptying predicts postprandial glucose excursions [14], changes in postprandial blood pressure have also been found to be related to the rate of gastric emptying. There is now compelling evidence that gastric emptying represents a major determinant of the blood pressure response to a meal, such that the postprandial fall in SBP is greater when gastric emptying is relatively more rapid [15,16], reflecting enhanced small intestinal nutrient interaction and splanchnic blood pooling [17]. However, the relationship between gastric emptying and postprandial blood Nutrients 2021, 13, 2826 3 of 14 pressure does not appear to be linear; in healthy older individuals, the fall in blood pressure increased with escalating rates of intraduodenal glucose infusion between 1–2 kcal/min but did not differ between 2 and 3 kcal/min [17].