High-protein meals and foods are promoted for their beneficial effects on satiety, weight loss and glucose homeostasis. However, the mechanisms involved and the long-term benefits of such diets are still debated. We here review how the characterisation of intestinal gluconeogenesis (IGN) sheds new light on the mechanisms by which protein diets exert their beneficial effects on health. The small intestine is the third organ (in addition to the liver and kidney) contributing to endogenous glucose production via gluconeogenesis. The particularity of glucose produced by the intestine is that it is detected in the portal vein and initiates a nervous signal to the hypothalamic nuclei regulating energy homeostasis. In this context, we demonstrated that protein diets initiate their satiety effects indirectly via IGN and portal glucose sensing. This induction results in the activation of brain areas involved in the regulation of food intake. The μ-opioid-antagonistic properties of protein digests, exerted in the portal vein, are a key link between IGN induction and protein-enriched diet in the control of satiety. From our results, IGN can be proposed as a mandatory link between nutrient sensing and the regulation of whole-body homeostasis. The use of specific mouse models targeting IGN should allow us to identify several metabolic functions that could be controlled by protein diets. This will lead to the characterisation of the mechanisms by which protein diets improve whole-body homeostasis. These data could be the basis of novel nutritional strategies targeting the serious metabolic consequences of both obesity and diabetes.

Animal studies indicate that the composition of gut microbiota may be involved in the progression of insulin resistance to type 2 diabetes. Probiotics and/or prebiotics could be a promising approach to improve insulin sensitivity by favourably modifying the composition of the gut microbial community, reducing intestinal endotoxin concentrations and decreasing energy harvest. The aim of the present review was to investigate the effects of probiotics, prebiotics and synbiotics (a combination of probiotics and prebiotics) on insulin resistance in human clinical trials and to discuss the potential mechanisms whereby probiotics and prebiotics improve glucose metabolism. The anti-diabetic effects of probiotics include reducing pro-inflammatory cytokines via a NF-κB pathway, reduced intestinal permeability, and lowered oxidative stress. SCFA play a key role in glucose homeostasis through multiple potential mechanisms of action. Activation of G-protein-coupled receptors on L-cells by SCFA promotes the release of glucagon-like peptide-1 and peptide YY resulting in increased insulin and decreased glucagon secretion, and suppressed appetite. SCFA can decrease intestinal permeability and decrease circulating endotoxins, lowering inflammation and oxidative stress. SCFA may also have anti-lipolytic activities in adipocytes and improve insulin sensitivity via GLUT4 through the up-regulation of 5'-AMP-activated protein kinase signalling in muscle and liver tissues. Resistant starch and synbiotics appear to have favourable anti-diabetic effects. However, there are few human interventions. Further well-designed human clinical studies are required to develop recommendations for the prevention of type 2 diabetes with pro- and prebiotics.

The recent availability of high-throughput nucleic acid sequencing technologies has rapidly advanced approaches to analysing the role of the gut microbiome in governance of human health, including gut health, and also metabolic, cardiovascular and mental health, inter alia. Recent scientific studies suggest that energy intake (EI) perturbations at the population level cannot account for the current obesity epidemic, and significant work is investigating the potential role of the microbiome, and in particular its metabolic products, notably SCFA, predominantly acetate, propionate and butyrate, the last of which is an energy source for the epithelium of the large intestine. The energy yield from dietary residues may be a significant factor influencing energy balance. This review posits that the contribution towards EI is governed by EI diet composition (not just fibre), the composition of the microbiome and by the levels of physical activity. Furthermore, we hypothesise that these factors do not exist in a steady state, but rather are dynamic, with both short- and medium-term effects on appetite regulation. We suggest that the existing modelling strategies for bacterial dynamics, specifically for growth in chemostat culture, are of utility in understanding the dynamic interplay of diet, activity and microbiomic organisation. Such approaches may be informative in optimising the application of dietary and microbial therapy to promote health.