ABOVE: Transmission electron microscope micrograph of a beta cell, with insulin granules in blue, mitochondria in green, and the nucleus in purple. © ISTOCK.COM, JOSE LUIS CALVO MARTIN & JOSE ENRIQUE GARCIA-MAURIÑO MUZQUIZ

Between the 1950s and 1980s, various studies reported the prevalence of diabetes with distinctive features in young people with a history of nutritional deficiency in low- and middle-income countries. The reports motivated the World Health Organization (WHO) to create the category “malnutrition-related diabetes mellitus.” But in 1999, the same agency removed it as an official category, based on what it said was a lack of evidence “that diabetes can be caused by malnutrition or protein deficiency per se.” 

A clinical study published May 27 in Diabetes Care now argues that malnutrition-related diabetes mellitus is indeed a distinct type of diabetes, and that studying it as such may improve how it is treated. By studying a small sample of diabetic and healthy males from South India, the authors concluded that diabetic patients with a body mass index (BMI) of 19 kg/m2 or below with a history of malnutrition have a defect in insulin secretion—a feature previously suspected in these diabetic lean populations. 

Suzanne Filteau, a nutritionist with a public health focus at the London School of Hygiene and Tropical Medicine who was not involved in the work, says it was “very carefully conducted.” Its findings, she adds, are consistent with observations that previous studies had hinted at but lacked the resources to look at—namely that in low- and middle-income countries, there is “a problem of diabetes amongst lean people [that] is more related to lack of insulin production rather than insulin resistance, and therefore we need to reconsider how we treat these people.”

Based on the current figures on the prevalence of diabetes and on epidemiologic studies, “we estimate [there are] probably about 80 million people” worldwide currently suffering from malnutrition-related diabetes, says Meredith Hawkins, director of the Global Diabetes Institute of Albert Einstein College of Medicine and one of the leaders of the new study. She says that the potentially high prevalence of this type of diabetes in various regions, along with the fact that the WHO had removed it as an official category of diabetes, motivated her to study its metabolic profile in detail. 

Hawkins and her colleagues teamed up with researchers at the Christian Medical College, Vellore, in India, and recruited South Indian males between 19 and 45 years old to participate in the study. They chose a male-only cohort partly because this disease is known to affect mostly men. The team selected 73 individuals who fell into five categories: two groups without diabetes (lean and overweight) and three groups previously diagnosed with diabetes and classified by the team into either type 1, type 2, or low BMI diabetes. 

The type 1 and 2 patients had consistently been diagnosed with those forms, Hawkins explains. The low BMI diabetic individuals were defined according to the criteria set by the WHO in 1985, including having a BMI equal to or below 19 kg/m2 and a history of low birth weight or episodes of malnutrition since childhood. This low BMI group also underwent immunogenetic analyses to rule out other types of diabetes, including all currently known types of maturity-onset diabetes of the young and type 1 itself.

An insulin secretion problem

The team characterized each group’s insulin secretion and resistance. The metabolic profiles of the patients with type 1 and type 2 diabetes were in line with what is currently known for both categories. Namely, in type 1 diabetes, an autoimmune reaction destroys individuals’ insulin-producing beta cells in the pancreas, resulting in little to no insulin secretion. Meanwhile, in type 2 diabetes, the main issue is insulin resistance, meaning that receptors on cells in the muscle, fat, and liver respond poorly to insulin. Type 2 patients also have an insulin secretion problem, but it’s much milder than in those with type 1. 

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By assessing insulin production over the first three hours after a meal, the team found that patients with diabetes and low BMI had significantly lower insulin secretion than those with type 2 diabetes, but higher than those with type 1. On the other hand, insulin resistance was on the whole significantly lower in the lean diabetes patients than in type 2 diabetes. A few of these lean participants were as insulin resistant as those in type 2 patients, though, “and maybe, if we studied hundreds of [them], we would start to see subgroups,” says Hawkins. But for these lean diabetes subjects, the major problem was insulin secretion, not insulin resistance, she notes. 

The research team hypothesizes that this secretion failure may result from decreased beta cell mass, a feature that has been associated with maternal low-protein diets in mice. Weanling rats fed with a low protein diet also show a marked defect in insulin secretion. While low protein intake may be the main culprit in impaired beta cell function in malnourished diabetic populations, Hawkins explains that other nutritional deficiencies could also play a role. For example, “a lot of micronutrients like zinc can be extremely important in improving insulin secretion and improving beta cell function,” she says.   

Current challenges and those ahead 

Viswanathan Mohan, a diabetologist and director of the Madras Diabetes Research Foundation in Chennai, India, who did not participate in this study, says that the observations in it are interesting, but he is skeptical that the diabetes described by Hawkins and colleagues falls outside recognized categories. Some of these cases could be a subtype of type 2, he says, as it is difficult to distinguish malnutrition-related diabetes from other kinds of diabetes without a molecular marker. Before labeling this type of diabetes and reviving the past classification, it will be important to have a genetic, biochemical, or hormonal marker to diagnose it, Mohan argues, adding that the new study motivates the search for such a marker.

University of Rwanda endocrinologist Charlotte Bavuma, who was not involved in the study, says it provides insight into the physiopathology of an unrecognized but real type of diabetes—and that it may be going undetected because it is being confused with other types. For example, along with her colleagues, she recently conducted a study in Rwanda that pointed to a higher prevalence of type 1 diabetes compared with type 2. This is “not normal,” she says, and may indicate that many of the identified type 1 cases were in fact the malnutrition-related diabetes. 

Although Bavuma and Filteau note that it is difficult to extrapolate the new study’s results to other populations, given the small and single-sex sample size, they say these findings bring insight that could help improve the management of diabetes in lean individuals with a history of malnutrition. According to Hawkins, these patients might, for instance, be candidates for treatment with “safer drugs than insulin.” They could still receive tiny doses of it, but not enough to cause their blood sugar to drop to dangerous levels, she notes, adding that “pills to improve insulin secretion,” currently available for people with type 2, may be among the feasible treatments for this population.

Hawkins says she hopes this clinical study, along with epidemiological studies over the past few decades, will help to prompt the official recognition of malnutrition-related diabetes again, which would facilitate further research and awareness of it. Bavuma agrees that this is needed, as the current lack of recognition affects clinical management of the disease, she says. Prevention and treatment guidelines are mainly based on type 1 and type 2 diabetes, she notes. As a clinician, explaining patients’ condition to them is thus challenging. Patients may learn about common risk factors for diabetes, such as obesity and a sedentary lifestyle, she says, but educational materials don’t provide an explanation and preventive measures for their condition. The messages to prevent and treat “diabetes are not covering such population,” Bavuma concludes.