Long-term health after Severe Acute Malnutrition in children and adults: the role of the Pancreas - SAMPA

Whilst there is an increasing prevalence of overweight and obesity worldwide, malnutrition remains common. In addition, malnutrition, overweight, and infections often interact. 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 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 the evidence is piecemeal and there is little information as to the mechanisms involved. It is thus difficult to determine what treatments or preventative strategies are appropriate.

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 malnourished before birth, as children, or as adults. They now live in places with a wide range of access to foods high in 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 age, current overweight and infection.

The project will have a substantial training component so that staff at all sites can be trained in assessment methods for nutritional status including body fat and lean content, diabetes, and pancreas function and in statistical methods. We will work with local clinicians and patient support groups to ensure that results of the project are taken up and used locally. We also plan to conduct workshops with the child participants to help them understand aspects of the science in which they are involved.

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

In Africa and Asia acute malnutrition (MALN) 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. We wish to investigate whether postnatal MALN is associated with later exocrine and endocrine pancreas function and structure. We will follow up our cohorts in Tanzania, Zambia, India and the Philippines whom we previously recruited for studies related to MALN. The cohorts experienced MALN 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, gross structure and microarchitecture by MRI, calcification by X-ray, exocrine function by faecal elastase and plasma lipase, endocrine function by oral glucose tolerance tests (OGTT). We will do in-depth hormonal analyses in subsets of adult participants with repeated blood samples during OGTT and intravenous GTT to investigate the role of incretins, and the relative contribution to glucose dysregulation of decreased insulin production and increased insulin resistance. We will analyse proinsulin/insulin ratio in archived samples from one cohort to investigate the time course of abnormalities preceding overt diabetes. We will conduct univariable statistical analyses and multivariable models guided by a conceptual framework. We will investigate whether sex, age, BMI and dietary pattern are modifiers of the MALN-outcome links. Even if we find no important link between MALN and later glucose metabolism, the research will improve understanding of both the long-term consequences of MALN and the phenotype of glucose dysregulation in Africa and Asia. It will thus lead to improved health care for people with malnutrition and those with diabetes.

Local clinicians at each site will be able to work with the research team for mutual exchange of knowledge and good practice. Study participants will gain from discussion with the researchers about diabetes and how they can help prevent or manage it in their own lives.

Academics and clinicians in several fields globally will learn from the study findings, as described under 'Academic beneficiaries'. They will then be able to take the results in various directions which will have impact beyond the study team's expertise. In addition, the study investigators will benefit by linking the African and Asian researchers who have so far being working separately on related clinical and nutritional conditions.

All overseas sites are led by established researchers and this project will maximise the value of the existing cohorts, whilst supporting opportunities for further add-on studies, including cost-effective metabolomic research, from planned archiving of samples with appropriate protocols. There will be potential within the 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.

If our project shows that insulin insufficiency is a bigger factor than insulin resistance in variant diabetes seen in Africa and Asia, then metformin might not be the optimal pharmacological treatment, and glucose dysregulation may be less modifiable or reversible by lifestyle changes, e.g. in diet. If abnormalities are due to insufficient stimulation from gut incretins, then future treatments may include GLP-1 receptor agonists. If MALN is associated with long-lasting exocrine dysfunction, provision of supplementary enzymes may improve overall nutritional status.

If we find that prior MALN is associated with later diabetes, we will then conduct one or more trials of interventions (pharmacological or lifestyle modification) suggested by the study results. If MALN is associated and interacts with dietary patterns, then interventions for early prevention and monitoring for early diagnosis would improve health of previously malnourished people. 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 MALN 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 MALN and later diabetes.