Long-term health after malnutrition: the role of the pancreas

With current global changes in diet and lifestyle, even low- and middle-income countries are experiencing the 'double burden' of undernutrition and overweight. Both conditions can be found within communities, families and even individuals at different times over their life course. It is well established that malnutrition in pregnancy, resulting in an infant born with low birth weight, can increase the risk of diseases such as diabetes, heart disease and cancer in adulthood. However, the consequences of malnutrition after birth are much less studied. Severe acute malnutrition in childhood, indicated by extreme thinness, remains common in Africa and Asia. In addition, substantial numbers of adult patients with tuberculosis or HIV, diseases which are common in Africa and Asia, may become severely malnourished. We are interested in diabetes, which in Africa and Asia affects people at younger age and lower weight than in Europe. There is evidence from epidemiological studies that severe malnutrition in childhood and possibly in adulthood increases the risk of later diabetes but there is little information as to the mechanisms involved. We wish to focus on the pancreas which is a key organ in digestion and metabolic processes, especially in relation to diabetes. We will investigate pancreas size, microscopic structure, hormone and digestive enzyme production, and the body's response to these hormones among groups of people in Tanzania, Zambia, India and the Philippines. These groups have participated in the research team's previous studies of malnutrition and were severely malnourished before birth, as children, or as adults. They now live in places with a wide range of access to foods high and fat and sugar which could affect their risk of diabetes. We will use modern clinical methods to compare their pancreas function to that of never-malnourished controls at each site. We will use advanced statistical methods to understand the links between early malnutrition and later diabetes, taking into account the factors often associated with diabetes such as current overweight and high intakes of fat or sugar.

The research will lead to improved understanding of both the long-term consequences of malnutrition and the presentation and underlying metabolism of diabetes in Africa and Asia. Thus, it will lead to improved health care for both malnourished and diabetic people even if we find no important link between early malnutrition and later diabetes.

In Africa and Asia severe acute malnutrition (SAM) remains common while the prevalence of non-communicable diseases such as diabetes is rising. Diabetes may be found at younger age and lower body mass index (BMI) in Africa and Asia than in Europe. A development grant would enable us to obtain essential information to use in design of a larger study in which we will investigate whether there are causal links between SAM and diabetes. We will focus on exocrine and endocrine pancreas function. To do this we will follow up cohorts in Tanzania, Zambia, India and the Philippines who were recruited by members of the research team for prior studies related to SAM. The cohorts experienced malnutrition in utero, as children or as adults and are now adolescents or adults. Never-malnourished people are available as controls for all cohorts. We will investigate several aspects of pancreas structure and function: size by ultrasound, gross structure and microarchitecture by MRI, exocrine function by faecal elastase, endocrine function by production of and responses to hormones during oral glucose tolerance and arginine stimulation tests. The main marker of diabetes will be HbA1c. The effects of prior SAM on the pancreatic indicators will be analysed controlling for age, sex, age at SAM and its severity, current BMI and percent body fat, and dietary fat and sugar intake. Causal inference analyses will investigate pathways whereby prior SAM affects current pancreatic function and glucose metabolism.

The research will lead to improved understanding of both the long-term consequences of SAM and the phenotype and underlying metabolism of diabetes in Africa and Asia. Thus, it will lead to improved health care for both malnourished and diabetic people even if we find no important link between SAM and later diabetes.

Impacts at the development proposal stage are expected only for the research team and some clinicians and potential participants at each site. The research team will increase their knowledge of tools to assess diabetes, and the feasibility of these tools and of interventions to mitigate diabetes risk at the different sites. Local clinicians at each site will be able to work with the research team for mutual exchange of knowledge and good practice. Potential study participants will gain from discussion with the researchers about diabetes and how they can help prevent or manage it in their own lives.

If we proceed to a larger study, this will expand the benefits for researchers, clinicians and participants described above. All overseas sites are led by established researchers and there will be potential within a larger study to train postgraduate students and postdoctoral researchers under the combined supervision of local and UK collaborators. Areas of study could include metabolic nutrition, public health nutrition, epidemiology and medical statistics. Thus the study could have long term impact in diverse fields through these people's training.

The basic science information from a larger study will benefit academics and clinicians in several fields, as described under 'Academic beneficiaries'.

The impact of the larger study itself will depend on its results. If we find the pancreas mediates links between SAM and later diabetes, we will then conduct one or more trials of interventions suggested by the study results. If interventions prove efficacious, then we will work with local clinicians and government health officials to scale them up. The information will be important for health policy and planning, as affected countries experience increasing burdens of diabetes and related non-communicable diseases.

Even if we find no important links between prior SAM and diabetes, we will generate metabolic information about both these which can inform clinical practice globally. Furthermore, in that case, our study will be a definitive study which counterbalances previous work which has been suggestive of an association between SAM and later diabetes.