A novel nutritional approach to the management of type 2 diabetes: effects of nutritional preloads on postprandial blood glucose and gastric emptying in type 2 diabetes mellitus

Abstract

This thesis focuses on the impact of dietary protein and fibre preloads on postprandial blood glucose and gastric emptying in type 2 diabetes mellitus. Key themes relate to: 1) The longitudinal evaluation of gastric emptying in type 2 diabetes 2) The evaluation of gastric emptying as measured by means of a ¹³C-octanoic acid breath test in older adults with type 2 diabetes 3) The evaluation of the acute effects of low dose ‘preloads’ of whey and guar, given alone or in combination before a meal, on postprandial glycaemia, GLP-1, insulin, and gastric emptying 4) The evaluation of the effects of 12 weeks’ treatment with a whey/guar preload on gastric emptying, postprandial glycaemia, and glycated haemoglobin (HbA1c), in type 2 diabetes. It is well established that the rate of gastric emptying plays a major role in determining the early postprandial glycaemic response, and that interventions that slow gastric emptying can reduce postprandial glycaemic excursions in type 2 diabetes. Gastric emptying is regulated by inhibitory feedback arising from the interaction of nutrients with the small intestine, mediated in part by the secretion of gut hormones. Gastric emptying is often disordered in people with type 2 diabetes; the emptying of solids and/or nutrient liquids is abnormally delayed in up to 30-50% with patients with longstanding type 2 diabetes, while gastric emptying may be accelerated in ‘early’ type 2 diabetes, although this has not been a consistent observation. Dietary strategies that slow gastric emptying, such as the use of ‘preloads’ (small quantities of macronutrient given in advance of the main meal), represent an appealing approach to reducing postprandial glycaemia. However, if modulating the rate of gastric emptying is to be developed further as a therapeutic strategy for postprandial glycaemic control, additional information is required about the natural history of gastric emptying in these patients. In the study reported in Chapter 2, I explored how the rate of gastric emptying changed over an interval of some 14 years in a group of patients with type 2 diabetes. The intra-individual variation of gastric emptying in health is modest, so that emptying is highly reproducible, although there is substantial inter-individual variation. Studies from tertiary referral centres involving patients with longstanding (typically 8-12 years) type 2 diabetes, relatively poor glycaemic control (HbA1c >8.5%), and a high prevalence of microvascular complications, indicate that 30-50% have abnormally delayed emptying of solids and/or nutrient liquids, whether studied by scintigraphy or stable isotope breath test, while a few have rapid emptying. Conversely, patients with ‘early’ type 2 diabetes (< 2 years) and/or an absence of autonomic neuropathy have been reported to have abnormally rapid emptying for solids and/or liquids, although this has not been observed in all series. Gastric emptying has a profound impact on control of glycaemia in type 2 diabetes, such that more rapid emptying of a glucose drink is associated with a higher blood glucose response. Scintigraphy is the gold standard technique used to quantify gastric emptying, but requires exposure of patients to ionising radiation and access to specialised equipment and personnel to undertake the assessment. An alternative method of measuring gastric emptying is by means of a stable isotope breath test, which can be used in an office-based setting, and has been validated against scintigraphy in both health and type 2 diabetes. There is also conflicting information regarding the effect of ageing on gastric emptying, with reports that emptying is either slowed, accelerated, or unchanged when compared to the young. When assessing the effects of type 2 diabetes on gastric emptying, it is important to select an age-matched healthy control group, particularly since type 2 diabetes cohorts tend to be older than the general population. In the study reported in Chapter 3, I evaluated the rate of gastric emptying using a ¹³C-octanoic acid breath test in community-based patients with type 2 diabetes, and compared this with age-matched healthy controls. Nutritional strategies to reduce postprandial glycaemia are attractive, and represent the greatest opportunity for optimising glycaemic control at an affordable cost as the healthcare demands of society escalate. Both the rate of gastric emptying, and the actions of the incretin hormones, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), are major determinants of postprandial glycaemic excursions. In type 2 diabetes, the insulinotropic effect of GIP is diminished, whereas GLP-1 retains its capacity to stimulate insulin secretion, and also slows gastric emptying and suppresses glucagon secretion and energy intake. Stimulation of GLP-1 secretion is appealing in the management of type 2 diabetes. Whey protein, a by-product of the cheese-making process, can reduce postprandial glycaemia when taken with, or before, a meal, through interrelated mechanisms including enhancement of insulin and gut hormone secretion, slowing of gastric emptying, and reductions in appetite and energy consumption. Guar gum is a viscous soluble fibre, and when given with a meal, can decrease postprandial glycaemic excursions by slowing gastric emptying and inhibiting small intestinal absorption of glucose, associated with reduced, rather than increased plasma insulin levels, as well as attenuation of plasma GLP-1. Accordingly, combining both guar gum and whey protein in a dietary supplement may be advantageous. However, the relative contribution of whey and guar to glucose-lowering and slowing of gastric emptying when used alone, and whether their actions are additive or synergistic when given together, are uncertain. In the study reported in Chapter 4, I evaluated the comparative acute effects of whey protein and guar gum preloads, either alone or in combination, on postprandial glycaemia, GLP-1, insulin, and gastric emptying in type 2 diabetes. For the majority of people with type 2 diabetes who have relatively good overall glycaemic control (HbA1c ≤ 7.9%), postprandial glycaemia predominates over fasting blood glucose in contributing to HbA1c. Indeed, a ‘target’ HbA1c of ≤ 7% is difficult to achieve without minimizing postprandial glycaemic excursions. We have previously established that acute administration of high doses of whey protein preloads (50g) slows gastric emptying of the subsequent meal. An acute study in subjects with type 2 or pre-diabetes reported a preload incorporating low-dose whey (17g) together with guar (5g) slows gastric emptying and reduces postprandial glycaemia. However, it remains to be determined if a ‘pre-load’ strategy to reduce glycaemia are sustained with long-term use. Similarly, while a pre-load slows gastric emptying acutely, it is unknown whether this effect is sustained with daily pre-load administration. Moreover, whey supplements incur a substantial energy burden, so it is also important to determine if patients compensate by adjusting their overall intake with long-term use. In the study reported in Chapter 5, I evaluated the effects of a twice daily low dose whey/guar preload taken 15 minutes before breakfast and dinner over 12 weeks, in 79 patients with type 2 diabetes and relatively good glycaemic control treated with diet or metformin only, on HbA1c, gastric emptying, postprandial glycaemia and body weight and composition, in a single-blind, randomized, placebo-controlled trial.