In order to study processes leading to hepatic insulin resistance, we cultured hepatoma cells in serum obtained from people with Type-2 diabetes [T2D]. We found that the dose response curve for insulin effects shifts to the right in cells grown for 2-3 weeks in serum from people with T2D. This effect represents a 10-fold loss of insulin sensitivity, perfectly mirroring the change in insulin sensitivity of hepatic glucose production in the human diabetic population. We propose that a blood borne factor mediates these effects.
Interestingly, there is a wide range of effects across the sera samples donated by the diabetic cohort which implies variation in the presence of the blood borne factor that causes this effect, indicating that the system could provide a mechanistic sub-classification of sera from T2D patients.
We further suggest that combining this assay with approaches to measure other key actions of insulin has the potential to improve the understanding of a major molecular cause of insulin resistance in a given donor sample by quantifying the resistance generating potential of blood at the individual level in multiple cell types. This could also provide a novel tool for stratifying volunteers in clinical trials.
Our over-arching ambition is therefore to develop combinations of assays/markers which predicate specific molecular forms of insulin resistance.
Objective of the Studentship
This studentship will examine the molecular basis of this effect and will address the following questions:
· What is the nature of the blood borne factor?
· Is the serum-mediated insulin resistance cell- and/or pathway-specific?
The identification of this factor offers possible utility in both developing new therapeutic targets for diabetes therapy and may provide the basis of a mechanistic sub-classification system using sera from T2D patients and those at risk of diabetes to aid participant selection in clinical trials and ultimately to personalise treatment of diabetes.
The student will gain expertise in basic cellular and molecular biology, with a clear focus on translational diabetes research – in particular for patient stratification. Both supervisors interact with many groups around the world via small and large meetings, exchanging ideas and reagents and fostering the growth of junior scientists. The student will contribute to this community engagement.
The approaches employed and questions being addressed place this student uniquely at the interface between basic science and clinical assessment. Our long-term goal is to ascertain whether the kinds of approaches we propose could be translated into a clinically relevant screening tool, so providing a clear translational bent to the work and encouraging the student to focus on real-world applications of basic research.
The student will be integrated into the SIPBS Postgraduate School and will benefit from the range of courses, training opportunities and progress assessment schemes already in place, supported by a team of two academic and peer mentors. The student will undertake a Postgraduate Certificate in Researcher Professional development (PgCertRPD) via the graduate program in SIPBS; this delivers an excellent wider-training focus for all our graduate students and provides a useful tangible outcome. Although based in Strathclyde the student will also spend time with Professor Calum Sutherland in Dundee exploiting the complementary skill sets of the two labs.
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