Metformin is an effective agent with a good safety profile that is widely used as a first-line treatment for type 2 diabetes, yet its mechanisms of action and variability in terms of efficacy and side effects remain poorly understood. Although the liver is recognised as a major site of metformin pharmacodynamics, recent evidence also implicates the gut as an important site of action. Metformin has a number of actions within the gut. It increases intestinal glucose uptake and lactate production, increases GLP-1 concentrations and the bile acid pool within the intestine, and alters the microbiome. A novel delayed-release preparation of metformin has recently been shown to improve glycaemic control to a similar extent to immediate-release metformin, but with less systemic exposure. We believe that metformin response and tolerance is intrinsically linked with the gut. This review examines the passage of metformin through the gut, and how this can affect the efficacy of metformin treatment in the individual, and contribute to the side effects associated with metformin intolerance.

BackgroundA syndrome of young‐onset diabetes mellitus associated with microcephaly, epilepsy and intellectual disability caused by mutations in the tRNA methyltransferase 10 homologue A (TRMT10A) gene has recently been described.Case reportWe report two siblings from the fourth family reported to have diabetes mellitus as a result of a TRMT10A mutation. A homozygous nonsense mutation p.Glu27Ter in TRMT10A was identified using targeted next‐generation sequencing and confirmed by PCR/Sanger sequencing. Diabetes was diagnosed while the subjects were in their 20s and was characterized by insulin resistance. Epilepsy and intellectual disability were features in common. Mild microcephaly was present at birth but their final head circumferences were normal.ConclusionOur report provides independent confirmation of the role of TRMT10A mutations in this syndrome and expands its phenotypic description. TRMT10A sequencing should be considered in children or adults with young‐onset diabetes who have a history of intellectual disability, microcephaly and epilepsy. This report also shows the advantages of using a targeted panel to identify previously unsuspected monogenic diabetes among young‐onset non‐insulin‐dependent diabetes in the absence of obesity and autoimmunity.

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