Natural history of meal-induced changes in blood pressure, gastric emptying and incretin hormone secretion and approaches to the management of postprandial hypotension

Abstract

This thesis presents a series of clinical research studies focusing on postprandial blood pressure (BP), glycaemic and incretin hormone responses in healthy ageing. The studies address the underlying pathophysiology, natural history, and approaches to management, of postprandial hypotension (PPH), longitudinal changes in and relationship between postprandial plasma levels of the incretin hormones, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). PPH, usually defined as a fall in systolic BP of greater than, or equal to, 20 mmHg within 2 h of a meal occurs frequently, particularly in older people and those with type 2 diabetes (T2D). PPH increases the incidence of falls, syncope, cerebrovascular disease, angina, and has been associated with a higher risk of cardiovascular mortality even when it is asymptomatic. After a meal, there is a substantial increase in splanchnic blood flow, leading to a reduction of blood volume returning to the heart. PPH occurs when compensatory responses are inadequate to maintain BP. Multiple factors are involved in the pathophysiology of PPH, including small intestinal nutrient delivery, changes in autonomic function, the release of gastrointestinal hormones and changes in splanchnic blood flow. Chapter 1, 2 and 3 are structured as narrative reviews which aim to provide a comprehensive background to the studies. Chapter 1 summarises ‘up-to-date’ knowledge relating to PPH, including the prevalence, clinical relevance, pathophysiology and approaches to management. Chapter 2 is a brief review of the physiology of gastric emptying, which is pivotal to the pathophysiology of PPH, while Chapter 3 focusses on the interrelated relationship between gastric emptying and glycaemia. In healthy older subjects and patients with T2D, there is a correlation between the magnitude of fall in BP induced by glucose with the rate of gastric emptying of glucose, so that relatively more rapid gastric emptying is associated with a greater fall in BP. Cross-sectional studies indicate that healthy ageing is associated with a modest slowing of gastric emptying, however, there is limited information about longitudinal changes in gastric emptying in a healthy, ageing population and no studies which have evaluated the natural history of the fall in BP induced by glucose with ageing. In the study described in Chapter 4, longitudinal changes in the BP response to, and gastric emptying of, glucose were evaluated in 33 healthy older people at an initial study and after 5.8 ± 0.1yr. BP, heart rate (HR) and gastric emptying (using a stable isotope breath test technique) were assessed concurrently after participants consumed a 300mL drink containing 75g glucose and 150mg C13-acetate. PPH is under-recognised, but common. Following health concerns about excessive consumption of sugar, there has been an increasing trend to use low- or non-nutritive sweeteners as an alternative. Due to the lack of literature in this area, a systematic review described in Chapter 5 was conducted to identify important gaps in information relevant to the effects of different types of sweeteners on postprandial BP. While all macronutrients reduce BP comparably, the hypotensive responses to fat and protein occur slightly later than the response to glucose in healthy older people, probably reflecting the more prolonged time for digestion. Moreover, xylose, a poorly absorbed pentose sugar, empties from the stomach at a comparable rate to glucose, but has no effect on BP in healthy older subjects, as is also the case for fructose. The effect of artificial sweeteners, such as sucralose, on postprandial BP, was unknown. In the study described in Chapter 6, the effects of intraduodenal (ID) infusion of sucralose and glucose versus saline, on BP and HR, superior mesenteric artery (SMA) blood flow and blood glucose, were assessed in healthy older individuals. Current management of PPH is suboptimal. Acarbose is known to attenuate the fall in systolic BP induced by oral sucrose in healthy older adults, associated with slowing of gastric emptying and enhanced release of GLP-1. Gastric distension with water at a volume as low as 300 mL mitigates the fall in BP in response to ID glucose. In the study described in Chapter 7, the effects of gastric distension and acarbose, either alone or in combination, on BP, glycaemia and SMA flow after oral sucrose were assessed in healthy older people. A whey protein/guar preload has been shown to reduce postprandial glycaemia in T2D, an effect suggested to be mediated by slowing of gastric emptying. However, the latter has only been assessed using a stable isotope breath test technique, which cannot discriminate between slowing of gastric emptying and a delay in small intestinal absorption. This preload also has potential for use in the management of postprandial hypotension. In the study reported in Chapter 8, the effects of a guar/whey protein preload on gastric emptying (using scintigraphy), glucose absorption, glycaemic/insulinaemic and BP responses to an oral glucose load, were evaluated in healthy older people. The rate of gastric emptying is a major determinant of the glycaemic response to carbohydratecontaining meals in healthy subjects, as well as individuals with T2D. Gastric emptying also influences the release of incretin hormones, GLP-1 and GIP, which impact postprandial glycaemic excursions. It is not known whether baseline and/or nutrient-stimulated GLP-1 or GIP levels are predictable within an individual or affected by ageing. The study described in Chapter 9 re-evaluated a cohort of healthy older subjects after an interval of ~ 5.9 years and determined changes in fasting and glucose-stimulated plasma GLP-1 and GIP concentrations and their relationships with gastric emptying. The incretin hormones, GLP-1 and GIP, are secreted following intestinal macronutrient exposure - GIP primarily from the proximal small intestine and GLP-1 from the more distal small intestine and colon. Their relative importance to the incretin effect in health has been contentious, although recent studies employing a specific GIP antagonist now indicate that GIP has the dominant role. It is uncertain whether there is a relationship between GIP and GLP-1 secretion. The study described in Chapter 10 evaluates the relationship between GIP and GLP-1 responses to a 75g oral glucose load in older individuals with either normal (NGT) or impaired glucose tolerance (IGT).