Defining the molecular and physiological mechanisms of pancreatic islet dysfunction which lead to type 2 diabetes

The growing prevalence of Type 2 diabetes (T2D) worldwide represents a massive challenge to global health in the decades to come, and novel strategies for the prevention and the treatment of this condition are urgently required.

It is widely accepted that T2D results from a failure of the insulin-producing pancreatic beta-cells to respond adequately to demands for increased insulin production resulting from age- and obesity-related insulin resistance. However, the reasons for that failure remain poorly understood: it is not known for example how far this is the consequence of problems within the beta-cells themselves as opposed to the impact of external influences.

Many of the treatments currently available for T2D are designed to bolster insulin release from the pancreas but they are only partially effective in most patients. The hope is that a better understanding of the processes responsible for the failing beta-cell performance will open the door to more powerful options for treatment.

Historically, much of the work to define these processes has relied on studies conducted in a variety of animal and cellular models of diabetes. Whilst studies in such models have generated many useful insights, the relevance to the human situation can always be questioned. The use of suboptimal models may go some way to explaining the high failure rates seen when new, promising drugs are first tested in man.

The present study is motivated by the view that the solution lies, at least in part, in the extended use of human subjects in diabetes research. Our research integrates several novel research opportunities and strategies, and aims to deliver insights that are of direct relevance to the mechanisms driving development of T2D in man.

The specific question we seek to answer is this: "What are the molecular and physiological mechanisms of pancreatic islet dysfunction which lead to type 2 diabetes?". Our research plan involved four main steps
- First, we will exploit data from a number of massive genetic studies that are currently underway to identify sets of DNA sequence differences ("DNA variants") that are clearly associated with individual predisposition to T2D and/or related traits;
- Second, we will select a subset of those diabetes-associated DNA variants that we can show exert their diabetes-effect via defective insulin production from the pancreatic islets. We will use studies of human subjects and of recently-available human-derived pancreatic cell-lines to achieve this;
- Third, and at the core of the program, we will recruit healthy human volunteers from a pool of at least 12,000 individuals who have agreed to participate in studies such as these. We will select volunteers who carry the DNA variants of interest, and individuals with similar characteristics who do not, and will conduct detailed tests of physiology designed to tease out subtle metabolic differences beween the two groups.
- Finally, we will perform further rounds of studies involving both human subjects and human-derived cells to define the mechanisms through which those DNA variants are acting, and how altered gene function is modifying an individual's risk of T2D.

By delivering an improved understanding of the processes involved in T2D-associated islet dysfunction, this research will pave the way for development of novel drugs acting against high-quality targets that have been validated, from the perspectives of both therapeutic potential and side-effect profile, in human subjects. The work may also lead to identification of new markers of islet function that have clinical value in monitoring of disease progression, prediction of disease risk and evaluating treatment response.

This research program will be challenging to implement, but it represents a powerful strategy for delivering the precise biological insights that form an essential part of a principled and systematic effort to reduce the impact of T2D on global health.

Our research strategy has four components:

(i) to identify risk variants causal for T2D and informative for islet function, we will leverage large-scale (>100,000 individuals) genome-wide association, next-generation sequencing and targeted genotyping studies;

(ii) to prioritise amongst T2D-associated variants for those causing islet dysfunction we will (a) interrogate quantitative trait data ("epidemiological physiology"); and (b) exploit cellular and molecular studies in human islets and human beta-cell lines to confirm the islet phenotype and distinguish islet-autonomous transcript effects from those driven by external factors (e.g. incretins);

(iii) we will then use large genotype-based recall samples (Oxford Biobank and EXTEND primarily) to perform intensive physiological phenotyping in human volunteers comparing those carrying variant alleles of interest with matched controls. We will perform tests that target specific components of islet response and function. Initial efforts will be targeted to variants at ARAP1 and G6PC2 with additional signals considered in subsequent years;

(iv) finally, we will deepen understanding of the basis of T2D-associated islet dysfunction by further rounds of cellular, epidemiological and physiological analyses. The approaches to be taken will be transcript- and variant-specific but will involve further interrogation of human beta-cell lines, and patient-derived induced pluripotent stem cells (iPSCs); population scale targeted resequencing; and biomarker analyses.

This proposal implements the vision that, by combining powerful approaches for the characterisation of human pancreatic islet function - sequence-based human genetics and genomics, the first authentic human beta-cell lines, the ability to perform detailed physiological analysis in cohorts consented for genotype-based recall - we have a singular opportunity to characterise processes key to the development of T2D.

The principal beneficiaries of the research will be:
i) industry and biotechnology companies, in a position to exploit the improved biological understanding we seek to provide to develop novel products and services (see below);
ii) academics in the fields outlined in the "academic beneficiaries" section;
iii) the public sector (NHS, policy-makers), in the event that the research generates translational advances that provide more cost-effective means of managing diabetes;
iv) the wider public, if those translational advances provide more acceptable, more effective strategies for the treatment and prevention of those conditions.

The academic benefits will be manifest through:
i) the generation of new knowledge related to diabetes pathogenesis, which has the potential to contribute to amelioration of the social, economic and personal costs of the "epidemic" of global diabetes;
ii) the development of research models, alleles and targets of value for academic research;
iii) bolstering of research in human integrative physiology (given concerns about declining expertise);
iv) improved training of researchers in the specific areas of research activity, and in the development of cross-disciplinary expertise.

The broader economic and social impact will be manifest through:
i) economic benefits to pharma and biotechnology companies (including "spin-outs" with potential for attracting "inwards" investment) able to exploit actionable translational opportunities with respect to the development of novel therapeutic approaches that build on the validated targets we provide. Given the scale of the global problem and the inadequacy of current therapeutic and preventative options, the opportunities for wealth creation are substantial;
ii) improved effectiveness of public services if the biological insights result in better ways of treating and preventing T2D and related conditions (novel treatments, better diagnostics, improved strategies for stratifying risk and response to interventions);
iii) transformation of public policy if the research leads, over time, to improved public health strategies for the prevention of T2D;
iv) improved health outcomes (less diabetes-related morbidity and mortality, fewer diabetes complications) if the work leads to effective clinical translation, resulting in further personal, social and economic benefits.

It is important to be transparent about the timelines for effective clinical translation: too often expectations in this regard are unrealistic. In practice, the time from "new biology" to "novel treatment" involves years of biological validation, target characterisation, lead molecule optimisation, and clinical evaluation. As is well-known, substantial attrition is typical at each stage. On the positive side:
i) the massive unmet clinical need and the scale of the global problem with respect to diabetes will support investments that would not be economic for other diseases;
ii) repurposing of existing drugs can enable much shorter intervals to therapeutic implementation; further, we have recently shown (with the validation of novel biomarkers for monogenic forms of diabetes) that it is possible to move rapidly from genetic discovery to clinical utility, at least where biomarkers are concerned;
iii) the human focus of the research means targets which emerge are already validated in man: exploration of the whole body effects of perturbations of interest (including potential "on-target" side-effects) through human genetic and physiological studies should thereby minimise attrition during development;
iv) we are well-equipped, via the Target Discovery Institute in Oxford, to initiate high-throughput screens for potential small molecule modulators of this pathway, and to do so in parallel with some of the biological validation described here, thereby expediting progress.