Outcomes in children of women with type 2 diabetes exposed to metformin versus placebo during pregnancy (MiTy Kids): a 24-month follow-up of the MiTy randomised controlled trial

Feig, Denice S.; Sanchez, Johanna; Murphy, Kellie; Asztalos, Elizabeth; Zinman, Bernard; Fantus, I. George; Lipscombe, Lorraine L.; Armson, Anthony; Barrett, Jon; Donovan, Lois; Karanicolas, Paul J.; Tobin, Siobhan; Mangoff, Kathryn; Klein, Gail; Jiang, Yidi; Tomlinson, George; Hamilton, Jill; Feig, DS; Galper, A; Cleave, Barbara; Strom, Michele; Poolman, K; Fong, Debbie; Viguiliouk, Effie; Legault, Laurent; Boutin, L; Ho, J; Virtanen, Heidi; Zahedi, Afshan; Szwiega, Krystyna; Coolen, Jillian; Dias, R. Palma; Sellers, Elizabeth; Fletcher, B; Bourrier, L; Haqq, Andrea M.; Rylance, Heather; Hadjiyannakis, S; Courtney, J; McManus, Ruth; Halperin, Ilana; Miller, David; Coles, Karen; Simmons, David; Nema, Jodie; Weisnagel, S. John; Dubé, MC; Chanoine, Jean‐Pierre; Kwan, J; Hd, McIntyre; Laurie, Josephine; Maguire, Frances B; Soper, J; Bridger, T; Houlden, Robyn L.; Breen, Adriana; McLean, Mark; Duke, A; Hendon, Susan; Sigmund, Allison

doi:10.1016/s2213-8587(23)00004-9

Cited by 25 publications

(18 citation statements)

References 28 publications

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“…Metformin inhibits the intestinal absorption of dietary glucose in rodents and minipigs [42][43][44] and patients with T2DM 45 . This finding was confirmed by PET-CT imaging showing accumulation of 18 F-labelled fluorodeoxyglucose (FDG), a non-metabolizable glucose analogue, in the intestinal lumen of Goto-Kakizaki diabetic rats treated with a single oral dose of metformin 46 . The inhibition of intestinal glucose absorption resulted from the transient decrease in the abundance of sodium-glucose transporter 1 (SGLT1) at the apical membrane of enterocytes in the jejunum.…”

Section: Metformin Target Organsmentioning

confidence: 73%

“…Taking advantage of newly developed 18 F-FDG PET-MRI techniques, a dose-dependent metformin-induced accumulation of 18 F-FDG was demonstrated in both the intestinal wall and the luminal space of the ileum and the colon of participants with T2DM receiving metformin 50,51 , which suggests that metformin also promotes the release of glucose from enterocytes into the intraluminal space. In addition, after acute oral administration of 18 F-FDG and metformin in HFD-fed mice, 18 F-FDG PET showed reduced transepithelial glucose transport from the proximal small intestine lumen into the circulation 52 .…”

Section: Boxmentioning

confidence: 99%

Section: Boxmentioning

confidence: 99%

“…Based on observations in patients with T2DM receiving metformin, PET-CT imaging after intravenous administration of 18 F-FDG, which enters enterocytes via basolateral GLUT2, showed that increased glucose uptake from the circulation into the gastrointestinal system contributes to the glucose-lowering effect of the drug and the improvement in glycaemic control 37,48,49 . Similarly, 18 F-FDG PET-CT imaging in mice fed a high-fat diet (HFD) confirmed that metformin-induced basolateral intestinal glucose uptake is accompanied by an improvement in glucose tolerance, which occurs in a dose-dependent manner 37 . Taking advantage of newly developed 18 F-FDG PET-MRI techniques, a dose-dependent metformin-induced accumulation of 18 F-FDG was demonstrated in both the intestinal wall and the luminal space of the ileum and the colon of participants with T2DM receiving metformin 50,51 , which suggests that metformin also promotes the release of glucose from enterocytes into the intraluminal space.…”

Section: Boxmentioning

confidence: 99%

“…While in utero exposure to metformin was considered safe, some studies have found higher occurrence of small for gestational age birthweight and increased risk of childhood obesity 17 . However, reassuring data were provided in a long-term follow-up study showing similar anthropometrics in children exposed or not to metformin in utero 18 .…”

Section: Introductionmentioning

confidence: 99%

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Metformin: update on mechanisms of action and repurposing potential

2023

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Currently, metformin is the first-line medication to treat type 2 diabetes mellitus (T2DM) in most guidelines and is used daily by >200 million patients. Surprisingly, the mechanisms underlying its therapeutic action are complex and are still not fully understood. Early evidence highlighted the liver as the major organ involved in the effect of metformin on reducing blood levels of glucose. However, increasing evidence points towards other sites of action that might also have an important role, including the gastrointestinal tract, the gut microbial communities and the tissue-resident immune cells. At the molecular level, it seems that the mechanisms of action vary depending on the dose of metformin used and duration of treatment. Initial studies have shown that metformin targets hepatic mitochondria; however, the identification of a novel target at low concentrations of metformin at the lysosome surface might reveal a new mechanism of action. Based on the efficacy and safety records in T2DM, attention has been given to the repurposing of metformin as part of adjunct therapy for the treatment of cancer, age-related diseases, inflammatory diseases and COVID-19. In this Review, we highlight the latest advances in our understanding of the mechanisms of action of metformin and discuss potential emerging novel therapeutic uses.

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Section: Metformin Target Organsmentioning

confidence: 73%

Section: Boxmentioning

confidence: 99%

Section: Boxmentioning

confidence: 99%

Section: Boxmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Metformin: update on mechanisms of action and repurposing potential

2023

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Metformin for Diabetes in Pregnancy

Feig

2023

JAMA

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An unwelcome inheritance: childhood obesity after diabetes in pregnancy

Meek

2023

Diabetologia

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Diabetes in pregnancy affects 20 million women per year and is associated with increased risk of obesity in offspring, leading to insulin resistance and cardiometabolic disease. Despite the substantial public health ramifications, relatively little is known about the pathophysiological mechanisms underlying obesity in these high-risk children, which creates a barrier to successful intervention. While maternal glucose itself is undeniably a major stimulus upon intrauterine growth, the degree of offspring hyperinsulinism and disturbed lipid metabolism in mothers and offspring are also likely to be implicated in the disease process. The aim of this review is to summarise current understanding of the pathophysiology of childhood obesity after intrauterine exposure to maternal hyperglycaemia and to highlight possible opportunities for intervention. I present here a new unified hypothesis for the pathophysiology of childhood obesity in infants born to mothers with diabetes, which involves self-perpetuating twin cycles of pancreatic beta cell hyperfunction and altered lipid metabolism, both acutely and chronically upregulated by intrauterine exposure to maternal hyperglycaemia. Graphical Abstract

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Outcomes in children of women with type 2 diabetes exposed to metformin versus placebo during pregnancy (MiTy Kids): a 24-month follow-up of the MiTy randomised controlled trial

Cited by 25 publications

References 28 publications

Metformin: update on mechanisms of action and repurposing potential

Metformin: update on mechanisms of action and repurposing potential

Metformin for Diabetes in Pregnancy

An unwelcome inheritance: childhood obesity after diabetes in pregnancy

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