Long-term Health After Severe Acute Malnutrition in Children and Adults: the Role of the Pancreas

Whilst there is an increasing prevalence of overweight and obesity worldwide, malnutrition remains common. In addition, malnutrition, overweight, and infections often interact. The consequences of malnutrition after birth are little studied. Severe acute malnutrition in childhood remains common in Africa and Asia and many adult patients with tuberculosis or HIV, diseases which are common in Africa and Asia, may become malnourished. The investigators are interested in diabetes, which in Africa and Asia affects people at younger age and lower weight than in Europe. There is evidence that severe postnatal malnutrition 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.

The investigators wish to focus on the pancreas which is a key organ in digestion and metabolic processes, especially in relation to diabetes. They 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. The investigators will compare their pancreas function to that of never-malnourished controls at each site. The investigators 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.

Even if the investigators 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.

Prenatal growth retardation is associated with increased risk of adult chronic non-communicable diseases (NCDs) including diabetes. However, there is limited information regarding how postnatal malnutrition, in childhood or adulthood, affects these risks. The question of long-term effects of postnatal malnutrition is of increasing importance, because, with improved care, more children survive severe acute malnutrition and, amongst adults, drug treatments for infections, e.g. HIV and tuberculosis which frequently cause or are associated with malnutrition (MALN), have improved patient survival. Our project will focus on the role of the pancreas in the long-term consequences of MALN since both its endocrine and exocrine functions are critical for nutrition and NCDs. There is evidence that pancreatic functions may not recover fully after childhood or adult MALN and that the phenotype of diabetes in countries with prevalent MALN differs from that in high-income countries.

Overall hypothesis:

Severe malnutrition (MALN) at any age has medium- and long-term detrimental effects on endocrine and exocrine pancreatic function and structure.

Study design and population: Cross-sectional observational study recruiting a total of 3700 participants from previous/ongoing observational cohorts in: Zambia (1 adult (N=300) and 1 adolescent cohort (N=180)), Tanzania (1 adult cohort (N=1400)), Philippines (2 adult cohorts N=600/N=420), India (1 adolescent low birth weight cohort N=800))

Specific objective 1: To determine if MALN earlier in life is associated with abnormalities of pancreas structure and function.

Hypothesis 1: Prior MALN is associated with later abnormal pancreatic structure and endocrine and exocrine function.

Approach: The investigators will follow up individuals from the above cohorts in which there are participants, all now adolescents or adults, who suffered from MALN at different stages earlier in life as well as age- and sex-matched individuals who have never been malnourished as a comparison. The researchers will assess in those with and without prior MALN:

1. blood glucose, insulin and C-peptide during an oral glucose tolerance test (OGTT)
2. haemoglobin A1c (HbA1c)
3. faecal elastase and plasma lipase as exocrine pancreas markers
4. pancreas size and architecture using ultrasound and computed tomography (CT) (subset)

Specific objective 2: To investigate whether pancreatic abnormalities in participants with prior MALN and diabetes are compatible with a previously prescribed entity of fibro-calculous diabetes.

Hypothesis 2: Prior MALN is associated with pancreatic calcifications and is common in those with diabetes.

Approach: The investigators will conduct CT scans to investigate pancreatic calcification among non-pregnant adult study participants.

Specific objective 3: To investigate the relative importance of decreased insulin production or increased insulin resistance in MALN associated with concurrent infections in African and Asian adult populations.

Hypothesis 3: The abnormal glucose regulation seen after MALN and infection is associated with relative insulin deficiency with or without insulin resistance.

Approach: This hypothesis will be investigated within the Tanzanian cohort and one Filipino adult cohort, both of whom had MALN associated with infection. 20 men and 20 women will be selected from each of two groups (MALN and non-MALN) in each cohort based on whether or not in our prior research they were recorded as experiencing MALN. In these participants the investigators will:

1. Measure in blood samples collected at 0, 15, 30, 45, 60, 90 and 120 minutes during an OGTT: glucose, insulin, C-peptide (all time points), the incretins gastric inhibitory polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) and glucagon at 0, 30, 60, 90 and 120 minutes, and proinsulin and trypsinogen at baseline only;
2. Conduct intravenous glucose tolerance tests (IVGTT) and measure in blood samples collected at -10, -1, 2, 4, 6, 8, 10 minutes: glucose, insulin, and C-peptide.

Specific objective 4: To investigate whether a prior abnormal pro-insulin / insulin ratio is associated with diabetes in adults infected with HIV or previously with tuberculosis.

Hypothesis 4: An abnormal pro-insulin/insulin ratio is associated with later development of diabetes in adults who had MALN and infection.

Approach: For participants from the CICADA, Tanzania, cohort the reasearch team has fasting plasma samples stored from prior follow-ups up to 10 years earlier. Glucose has already been measured in these samples as well as insulin in some samples. The investigators will measure insulin in the remaining stored samples and proinsulin in all to investigate whether prior proinsulin / insulin ratio is associated with subsequent diabetes.

Eligibility Criteria:
Inclusion Criteria:

* member of one of the 6 included cohorts
* informed consent (for children, informed assent and consent of guardian)

Exclusion Criteria:

* lack of consent
* pregnant women and chidlren will be excluded from CT scans and interavenous glucose tolerance tests