The Effects of Macronutrient and Micronutrient Diet Manipulation on Human Insulin Sensitivity

Abstract

Insulin resistance leading to diabetes is currently at pandemic levels. The associated costs to society and burden on health providers are incalculable. Aside from type 2 diabetes and cardiovascular disease, it is now clear that insulin resistance (and resultant hyperinsulinism) is implicit with the pathogenesis of a wide range of other diseases, including cancers, and neurodegenerative and infectious diseases. Dietary manipulation as part of lifestyle modification is recognised as a fundamental way to prevent obesity and type 2 diabetes. However, as yet, there is no consensus on the best dietary interventions to improve glucose homeostasis or the long-term risk of developing type 2 diabetes. The objectives of this thesis are: i) to understand the mechanisms through which insulin resistance causes disease; ii) to review the current knowledge on dietary macro- and micronutrients that can be manipulated to improve insulin sensitivity; and iii) to add to this knowledge base through novel investigations. Literature review indicates that reducing dietary free sugars and increasing dietary fibre consumption are the most important dietary manipulations to improve insulin sensitivity. With respect to dietary fibre, there is no existing literature examining the impact of supplemented fibre alone on insulin sensitivity in adolescents. Hence, the first aim was to investigate if psyllium (a purified source of fibre) alone could improve insulin sensitivity in adolescents. To accomplish this, we conducted a participant-blinded, randomized, placebo-controlled, crossover trial in 47 adolescents, supplemented with 6 g/day of psyllium fibre for 6 weeks. 45 subjects completed the study, and compliance was very high: 87% of participants took >80% of prescribed capsules. At baseline, 44% of subjects were overweight or obese but none had impaired glucose tolerance. However, this was a negative study; there was no improvement in insulin sensitivity. Nevertheless, there was a 4% reduction in android to gynoid fat ratio (p=0.019), as well as a 0.12 mmol/l (6%) reduction in LDL cholesterol (p=0.042). The effect of dietary micronutrient manipulation on insulin sensitivity is a new and exciting area of research, with considerable commercial interest from a burgeoning nutraceutical industry. However, the existing data are often confusing, conflicting, or of poor quality. Nevertheless, there are several traditional remedies rich in unique micronutrients that hold some promise, many of which are polyphenols. A published commentary contained in this thesis describes the various difficulties when trying to assess the effects of polyphenols on insulin sensitivity, namely the heterogeneity of the raw product, diverse inter- and intra-individual responses, and lack of robust data. Taking into account these difficulties, a systematic step-wise research program was embarked upon, aiming to investigate the effects of unique olive plant polyphenols (oleuropein and hydroxytyrosol) on insulin sensitivity. The first step was to establish the bioavailability of olive leaf polyphenols at different doses (lower and higher) and formulations (liquid or capsule) when ingested as olive leaf extract (OLE). Nine volunteers (5 males) aged 42.8 ± 7.4 years were randomized to receive either capsulated or liquid OLE as a single lower (51.1 mg oleuropein, 9.7 mg hydroxytyrosol) or higher (76.6 mg oleuropein, 14.5 mg hydroxytyrosol) dose, and then the opposite strength (but same formulation) a week later. Conjugated metabolites of hydroxytyrosol were the primary metabolites recovered in plasma and urine after OLE ingestion, and we showed plasma concentrations approached those used in in-vitro experiments. However, as predicted, there was wide inter-individual variation, with plasma time-course, peak concentrations, and area under the curve all influenced by preparation, dose, and gender. With the knowledge that olive polyphenols are absorbed when ingested as OLE, we conducted a clinical trial investigating the effects of OLE supplementation on insulin sensitivity. In a randomized, placebo-controlled, double-blind, crossover trial, 46 participants (aged 46.4 ± 5.5 years and with BMI 28.0 ± 2.0 kg/m2) received capsules with OLE or placebo for 12 weeks. All participants took >96% of prescribed capsules. OLE supplementation was associated with a 15% improvement in insulin sensitivity (p=0.024) compared to placebo. There was also a 28% improvement in pancreatic β-cell responsiveness (p=0.013). Translating practical research results such as these to the general population has many obstacles. Nevertheless, the results from our studies provide an important contribution to our understanding of important dietary supplements and their effects on insulin sensitivity and other cardiovascular risk factors, which can be applied at both an individual and population level.