Project Title

EDCTP-GSK fellowship:The Role of Environmental Enteropathy on HIV-Associated Diabetes (REEHAD)

Project Objectives

The prevalence of diabetes is rising in SSA, particularly among HIV-infected people. Much of the diabetes seen in SSA is a variant form which may not be associated with the usual risk factors seen in high-income countries [8] so the best methods for treating it are unclear. Although diabetes in HIV is managed with conventional drugs like metformin as in HIV-uninfected patients, available data suggest that treatment with these drugs may not be sufficient. One study in the US found that diabetic HIV-infected patients on protease inhibitors had reduced response to metformin compared to HIV-uninfected patients, probably due to the effect of protease inhibitors in increasing insulin resistance[32]. Since HIV-infected patients on ART may develop excess abdominal adiposity and insulin resistance, particularly if they started ART when malnourished, as is the case for many HIV patients in Africa [33], many of them may not respond optimally to conventional anti-diabetic drugs like metformin. In addition, drugs like metformin which enhance insulin sensitivity may not be adequate if diabetes in HIV patients is partly due to inadequate insulin secretion. Hence alternative or complementary treatment approaches are urgently required to optimise treatment for HIV-infected patients with diabetes and other NCDs. This study will provide data on whether clinical trials evaluating efficacies of alternative or adjuvant treatments for diabetes available (or being evaluated) in other settings should be conducted in African HIV patients. If our study finds an important link between enteropathy and diabetes, future trials could test products including those suppressing inflammation and immune activation like 5-aminosalicylic acid, probiotics and prebiotics. If combined insulin deficiency and insulin resistance is causing diabetes, insulin treatment, GLP-1 agonists and, DPP-4 inhibitors are likely to be either superior or relevant add-ons to a metformin-based regimen and could be tested a

Host Organisation

EDCTP Project Call

Senior Fellowship (SF)

Study Design

Study aim To assess the role of enteropathy as a risk factor for diabetes among HIV-infected patients Specific objectives To assess associations between the following measures of gut dysfunction and diabetes as assessed by oral glucose tolerance test (OGTT) and haemoglobin A1c (HbA1c): enterocyte cell mass and function as assessed by plasma citrulline, GIP and GLP-1 and GLP-2 (all participants) local gut inflammation as assessed by fecal neopterin (all participants), MPO and AAT (subset) intestinal permeability as assessed by a 4-sugar test (all participants) bacterial translocation with consequent inflammation as assessed by CRP and AGP (all participants) and LBP and TNF-a receptor-1 (subset) fecal elastase, a measure of pancreatic function (subset). To assess the association between GLP-1 and GIP with insulin, insulin resistance (HOMA-IR), and b-cell function (HOMA-β) (all participants) To use causal inference analysis to investigate potential causal associations among the above measures of gut health and diabetes To evaluate the incretin effect in a subset of the participants.

Project Summary

Emerging data suggest that HIV-infected people have disproportionately higher risk of diabetes than HIV-uninfected people. Multiple factors may contribute to elevated diabetes risk including increased prevalence of conventional non-communicable diseases (NCDs) risk factors, use of some antiretroviral drugs regimens, and inflammation and immune activation secondary to environmental- and HIV-enteropathy. To date, enteropathy has been little studied in relation to HIV and diabetes in Sub-Saharan Africa. Enteropathy leads to systemic inflammation which may in turn result in insulin resistance and it may reduce secretion of incretins, the gut hormones which stimulate synthesis and secretion of insulin. Both mechanisms could potentially result in higher diabetes risk in HIV patients. Further research is required, for example, evaluation of romising products like immunosuppressants,glucagon-like peptide (GLP-1) agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors, in order to improve the treatment of diabetes in HIV patients. This study will investigate if enteropathy is associated with higher risk of diabetes in HIV patients using a cross-sectional study design. To implement it cost-efficiently, we will nest it to CICADA study; a Danida-funded cohort study investigating risk factors for diabetes (excluding enteropathy) among HIV-infected patients in Mwanza. CICADA has recruited 1945 patients during 2016/2017, and will follow up these patients during 2017/2018 and 2018/2019 by which point we expect about 1550 participants retained in the cohort. Data collection for the current study will coincide with the final CICADA follow-up. Data on demography, socioeconomic status, conventional NCDs risk factors, HIV and TB status, antiretroviral use history, anthropometry, body composition, lipid profile, CD4 count, C-reactive protein, alpha1-acid glycoprotein, insulin, and diabetes status will be retrieved from the CICADA database for the current study. Data on gut enteropathy biomarkers i.e plasma citrulline, GLP-1,glucagon like peptide-2 (GLP-2), glucose-dependent insulinotropic polypeptide (GIP), fecalmyeloperoxidase (MPO), neopterin, and alpha-1-antitrypsin, intestinal permeability (by 4-sugar test), lipopolysaccharide binding protein, tumour necrosis factor-a receptor, interleukin 6, and fecal elastase (as an indicator of pancreatic function) will be collected for the proposed study. Data will be entered in Cspro and managed and analysed in STATA. Both linear and logistic regression will be used to assess the associations between exposure variables (markers of enteropathy) and diabetes. In addition, causal inference techniques will be used to investigate associations between enteropathy biomarkers and diabetes. The project will support capacity building in health research for the applicant and 1 MSc and 1 PhD students.

Current Organisation

National Institute for Medical Research

Current Job Title

Principal Research Scientist

Biography

Publications