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Background: The increasing prevalence of childhood obesity worldwide is leading to a decrease in the age of onset of obesity complications such as type 2 diabetes and its early manifestations, also described as glucose intolerance.

Objective: To investigate the prevalence of and identify risk factors associated with glucose intolerance in children with obesity, and to investigate pharmaceutical treatment with metformin for childhood obesity and glucose intolerance. 

Subjects: The study is based on paediatric obesity cohorts from three different countries: the Uppsala Longitudinal Study of Childhood Obesity (ULSCO) cohort, from which even participants for the Metformin Intervention in children with obesity (MINT) study were recruited, a Sri Lankan cohort consisting of 357 children with obesity, and the Beta-cell function in Juvenile Diabetes and Obesity (Beta-JUDO) cohort that includes subjects from ULSCO and Paracelsus Medical University Hospital (Salzburg, Austria).

Methods: Blood samples were collected after an overnight fast and glucose tolerance tests (OGTT) conducted. A parallel, three-armed, randomized, 6 months multi-center study, MINT, was conducted with an extended-release metformin formulation combined with lifestyle intervention (XR+L), an immediate-release metformin formulation combined with lifestyle intervention (IR+L), or lifestyle intervention alone (LA).

Results and conclusions: The total prevalence of all forms of glucose intolerance was high in all included study populations, but particularly in Swedish children and adolescents with obesity with 72%. The prevalence was lower at follow-up visits compared with baseline both in Uppsala and Salzburg patients. Risk factors for glucose intolerance included a family history of type 2 diabetes, Swedish origin (within the Swedish cohort) and higher educational status of the father for the Sri Lankan cohort. Elevated histamine-N-methyltransferase (HNMT) was identified as a potential risk factor among the markers associated with mast cell activity, showing significantly higher levels in patients with obesity than in controls and an independent association with fasting proinsulin. Metformin treatment led to a clinically significant BMI-SDS reduction in children and adolescents with obesity compared to lifestyle alone and was shown to be safe and generally well tolerated from the age of 7 years.