Detailed Background and Research Plan APP1066835 Detailed Background and Research Plan APP1066835 Rayner

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  • Detailed Background and Research Plan APP1066835 Rayner


    1. AIMS We propose a randomised, placebo-controlled trial of a twice daily 35g whey protein preload, taken before breakfast and dinner, to test the hypothesis that glycated haemoglobin (HbA1c) will be reduced by at least 0.5% compared to baseline at 12 weeks, in patients with type 2 diabetes who have relatively good glycaemic control (HbA1c ≤ 7.9%) on diet or metformin therapy alone. We will also test the secondary hypotheses that the whey preload:

    • Induces slowing of gastric emptying, stimulation of incretin hormones and insulin, and reduces appetite and glycaemia after a standardised meal, and that these effects are sustained over 12 weeks;

    • Induces greater reduction in HbA1c in subjects with more rapid gastric emptying at baseline;

    • Is not associated with weight gain, due to “compensation” for the increased protein load; and

    • Reduces HbA1c independently of changes in insulin resistance, weight, or body composition

    2. BACKGROUND If current trends are maintained in Australia, more than a third of the population will develop type 2 diabetes within their lifetime (1). Early intervention to prevent and limit progression of micro- and probably macro-vascular complications can be achieved with fastidious glycaemic control, albeit at the risk of weight gain and hypoglycaemia with insulin therapy (2). There is now increasing recognition of the importance of specifically lowering postprandial, rather than fasting or preprandial, glycaemia in patients with mildly or moderately elevated HbA1c – who make up a majority of type 2 patients in the community (3). The recently updated ADA/EASD guidelines for managing type 2 diabetes advocate an individualised approach, with dietary intervention and weight management the cornerstone of therapy, and the need to balance reduction in HbA1c with the risk of hypoglycaemia (4). Newer therapies, particularly the glucagon-like peptide-1 (GLP-1) agonists, are useful for targeting postprandial glycaemic excursions with minimal risk of hypoglycaemia and modest weight loss, but these are expensive, require subcutaneous injection, and cannot be tolerated by a substantial proportion of patients due to adverse effects, particularly nausea. Broadly effective nutritional strategies to reduce postprandial glycaemia are therefore highly attractive, and represent the greatest opportunity for optimising glycaemic control at affordable cost as the healthcare demands of our society escalate.

    Rationale for targeting postprandial glycaemic control Given that nutrients empty from the stomach in health in the range of 1 – 4 kcal/min (5; 6), and that people in modern societies generally consume three main meals per day, often with snacks in between, it is clear that most of the day is spent in the postprandial state, with only a few hours of true fasting before breakfast (7). The traditional focus on controlling “fasting” blood glucose in the management of type 2 diabetes is, therefore, often inappropriate. For the majority of type 2 patients, who have relatively good overall glycaemic control (in Australia, the median HbA1c in known type

    Reducing postprandial blood glucose excursions in type 2 diabetes is increasingly being recognised as fundamental to achieving good overall glycaemic control, as assessed by glycated haemoglobin. Our work has established that the rate of emptying of carbohydrates from the stomach, and the secretion of the gut peptides GLP-1 and GIP (“incretins”) that drive postprandial insulin stimulation, are critical determinants of postprandial glycaemia. We have developed the concept of giving macronutrient “preloads” in advance of a meal in type 2 diabetes, to limit postprandial glycaemia by initiating gut hormone secretion and slowing gastric emptying of the subsequent meal. In particular, we established that a whey protein preload substantially reduces postprandial glycaemia when given acutely in type 2 patients. If this magnitude of postprandial glucose lowering is maintained with sustained use, the preload strategy will represent an important advance in the dietary management of type 2 diabetes.

  • Detailed Background and Research Plan APP1066835 Rayner


    2 patients is 6.8% (3)), postprandial glycaemia predominates over fasting blood glucose in contributing to HbA1c, and a deterioration in postprandial glycaemic control precedes any substantial elevation of fasting blood glucose (8). Therapies that specifically target postprandial glycaemic excursions are therefore of fundamental importance in preventing the progression of diabetes and the emergence of micro- and macro-vascular complications, whose incidence is related closely to the HbA1c (2). This is not to say that the importance of controlling postprandial glycaemia is limited to “early” type 2 diabetes; there is increasing recognition that even insulin- treated patients benefit from the addition of an agent that targets postprandial blood glucose, such as a GLP-1 agonist, once basal insulin has provided control of fasting glycaemia (9; 10).

    The gastrointestinal tract as a key determinant of postprandial glycaemia It should not be surprising that the gastrointestinal tract, which is responsible for storing ingested nutrients in the stomach and regulating their delivery to the small intestine at a controlled rate to optimise digestion and absorption, plays a central role in determining postprandial glycaemic excursions (11). When nutrients interact with the small intestine, they generate feedback that slows further gastric emptying and suppresses appetite, via both neural and hormonal mechanisms. The latter include cholecystokinin (CCK), peptide YY (PYY), and GLP-1. The small and large intestine also secrete peptides that account for the “incretin effect” – the phenomenon by which insulin secretion is at least doubled when glucose is given by the enteral route when compared to an isoglycaemic intravenous glucose infusion (12; 13). The two known incretins are glucose- dependent insulinotropic polypeptide (GIP) and GLP-1. It is only in recent years, with the advent of incretin-based therapy for type 2 diabetes (ie. GLP-1 agonists and DPP-4 inhibitors), that the role of the gut in postprandial glycaemic control has been widely appreciated. Such therapies have focussed on GLP-1, since it retains much of its activity on type 2 diabetes, unlike GIP (14).

    GLP-1 agonists are appealing for the management of postprandial glycaemia in type 2 diabetes because they stimulate insulin secretion and suppress glucagon in a glucose-dependent manner (ie. mainly when the blood glucose concentration is elevated above normal fasting values), so carry little risk of hypoglycaemia, and they are also associated with modest weight loss. However, their predominant action to lower postprandial blood glucose is to slow gastric emptying, and their efficacy is relatively less in patients who already have abnormally slow emptying at baseline (15). Due to their expense, the need for regular subcutaneous injections, and the high prevalence of adverse effects such as nausea, GLP-1 agonists are not appropriate for the majority of patients with type 2 diabetes. Initial reports that patients with longstanding diabetes have impaired GLP-1 secretion after mixed meals (16; 17) did not take differences in gastric emptying into account, and have not been confirmed subsequently (18). We have reported that type 2 patients controlled with diet or metformin alone have intact GLP-1 secretion in response to an intraduodenal glucose challenge (19), supporting the concept that dietary approaches to enhance the stimulation of endogenous GLP-1 and other gut peptides may be a useful strategy in the management of type 2 diabetes. Harnessing nutrient-gut interactions to improve postprandial glycaemia – development of the “preload” concept Nutritional therapies to improve glycaemic control in type 2 diabetes, such as adopting low carbohydrate, low glycaemic index, or high protein diets, have generally had relatively modest benefits over sustained periods, probably largely due to the need to adhere to relatively rigid restrictions (20). Our approach differs, in that the only prescribed element of the diet is the “preload”, which acts by stimulating nutrient-gut interactions in order to optimise metabolism of the subsequent meal. In recent years we have undertaken a series of acute physiological studies in patients with type 2 diabetes that have allowed us to refine this concept.

    We initially evaluated the effects of a fat preload, given the potency of fat for stimulating GLP-1 and slowing gastric emptying (21; 22). A preload of 30 mL olive oil was consumed 30 min before a

  • Detailed Background and Research Plan APP1066835 Rayner


    high carbohydrate potato meal in diet-controlled type 2 patients (mean HbA1c 6.2% ± standard error 0.3 %) (23). This preload substantially slowed the emptying of the subsequent meal (Fig. 1), with a corresponding delay in the postprandial glycaemic excursion (Fig. 2) – effects which were much greater than when the same amount of oil was consumed with the meal, indicating the importance of timing of the preload. The fat preload stimulated an enhanced endogenous GLP-1 response, but insulin secretion was suppressed rather than increased, due to the delay in entry of carbohydrate to the small intestine, and the fact that the insulinotropic effect of GLP-1 is glucose- dependent and blood glucose was < 10 mmol/L when GLP-1 peaked. As a result, the decrease in the magnitude of the postprandial blood glucose excursion was modest, without a signifi