Metformin Improves Peripheral Insulin Sensitivity in Youth With Type 1 Diabetes

Cree‐Green, Melanie; Bergman, Bryan C.; Cengiz, Eda; Fox, Larry A.; Hannon, Tamara S.; Miller, Kellee M.; Nathan, Brandon M.; Pyle, Laura; Kahn, Darcy E.; Tansey, Michael; Tichy, Eileen; Tsalikian, Eva; Libman, Ingrid; Nadeau, Kristen J.

doi:10.1210/jc.2019-00129

Cited by 77 publications

(103 citation statements)

References 46 publications

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“…1). There is clear evidence of elevated left ventricular mass, abnormal cardiac geometry and impaired diastolic function, reduced cardiopulmonary fitness, abnormal limb blood flow, arterial stiffness and higher blood pressure, as well as renal hyperfiltration, in both diabetes types compared with peers without diabetes with a similar BMI [24,[48][49][50][51][52][53][54][55][56][57][58][59]. However, some comorbidities including low HDL-cholesterol and elevated triacylglycerol, hepatic fat [54] and liver transaminases [60], and non-alcoholic steatohepatitis (NASH) [61] are not typically present in youth with type 1 diabetes, especially in those with a normal BMI.…”

Section: Comorbidities and Complicationsmentioning

confidence: 99%

“…A recent meta-analysis of 13 randomised controlled metformin trials in type 1 diabetes found significant improvements in BMI and reductions in insulin requirements, total cholesterol and LDL-cholesterol [77], but little or no decrease in HbA 1c . Short-term paediatric data suggest similar metabolic improvements in youth [78,79], along with improvements in insulin sensitivity [53] and vascular health on imaging [79], but data on long-term benefits of metformin in type 1 diabetes are currently lacking.…”

Section: Treatmentmentioning

confidence: 99%

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The changing face of paediatric diabetes

Shah

Nadeau

2020

Diabetologia

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The purpose of this review is to provide an update on the changing face of paediatric type 1 diabetes and type 2 diabetes. Paediatric diabetes is on the rise, with extensive research dedicated to understanding its pathophysiology, comorbidities and complications. As obesity continues to increase among all youth, differentiating between type 1 diabetes and type 2 diabetes has become increasingly difficult but remains important for optimising treatment, anticipating complications and predicting disease risk. Novel treatments are emerging, with the ultimate goal being to achieve glycaemic control, limit weight gain, improve quality of life and reduce comorbidities. In this review, we focus on updates regarding the epidemiology, clinical presentation, comorbidities and complications of paediatric type 1 diabetes and type 2 diabetes and conclude with current and emerging treatments.

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Section: Comorbidities and Complicationsmentioning

confidence: 99%

Section: Treatmentmentioning

confidence: 99%

The changing face of paediatric diabetes

Shah

Nadeau

2020

Diabetologia

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“…2. Lower daily insulin dose improved whole-body and peripheral insulin resistance in adolescents with T1D who were overweight/obese [76]. 3.…”

Section: Pediatric T1dmentioning

confidence: 99%

“…Improvement in HbA1c level in adolescents with T1D [79,80]. In contrast, some trials did not observe improvement in HbA1c [76,81], or glycemic control. As expected, there was an increased gastrointestinal adverse event in overweight adolescents with T1D [81].…”

Section: Pediatric T1dmentioning

confidence: 99%

New Insight into Metformin Mechanism of Action and Clinical Application

Yan¹,

Kover²,

Moore³

2020

Metformin [Working Title]

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Metformin is the first-line medication for Type 2 diabetes (T2D) treatment, and it is the only US FDA approved oral antidiabetic medication for pediatric patients with T2D 10 years and older. Metformin is also used to treat polycystic ovary syndrome (PCOS), another condition with underlying insulin resistance. The clinical applications of metformin are continuing to expand into other fields including cancer, aging, cardiovascular diseases, and neurodegenerative diseases. Metformin modulates multiple biological pathways. Its novel properties and effects continue to evolve; however, its molecular mechanism of action remains incompletely understood. In this chapter, we focus on the recent translational research and clinical data on the molecular action of metformin and the evidence linking the effects of metformin on insulin resistance, prediabetes, diabetes, aging, cancer, PCOS, cardiovascular diseases, and neurodegenerative diseases. Metformin 2 Mechanisms of actionThe potential mechanisms of metformin action involve several pathways. The AMPK-pathway plays an important role in metformin actions [2, 3]. Metformin inhibits the mitochondrial respiratory chain (complex I), which increases the AMP to ATP ratio, leading to the phosphorylation of AMP-activated protein kinase (AMPK) at Thr-172. We have demonstrated that metformin treatment increases protein level of phosphorylated AMPK in high-glucose-treated endothelial cells [4]. The phosphorylated AMPK subsequently phosphorylates multiple downstream effectors to regulate cellular metabolism and energy homeostasis [5]. These downstream effectors include thioredoxin interacting protein (TXNIP) and TBC1D1, a RAB-GTPase activating protein and a member of the tre-2/BUB2/cdc1 domain family. Phosphorylated TXNIP and TBC1D1 increase the plasma membrane localization of glucose transporter 1 (GLUT1) and GLUT4, respectively [6, 7], and regulate glycogen synthases (GYS1 and GYS2) to prevent the storage of glycogen [8]. Some actions of metformin have been found to be AMPK-independent [9].In diabetic mice, metformin has an effect on gut microbiota by inducing a profound shift in the gut microbial community profile, resulting in an increase in the Akkermansia spp. population [10] and cAMP-induced agmatine production [11], which may decrease absorption of glucose from the gastrointestinal tract and increase lipid metabolism respectively. In addition, metformin decreases insulin-induced suppression of fatty acid oxidation and lowers lipid content of hepatic cells [12].New Insight into Metformin Mechanism of Action and Clinical Application DOI: http://dx.doi.org/10.5772/intechopen.91148 association with insulin resistance. Metformin decreases the level of circulating branched-chain amino acids and reduces insulin resistance in a high-fat diet mouse model [22]. Metformin treatment lowers plasma ADMA which is associated with improved glycemic control in patients with T2D [23].Recent studies indicate that phosphatidylinositol-3-kinase/protein kinase B protein (PI3K/PKB, also known as ...

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“…Given increasing support for the role of specific diets in the promotion of a pro-inflammatory state that is associated with T1DM (Vaarala 2011, Knip et al 2012, van Bussel et al 2013 and ENDO (Saguyod et al 2018, it is prudent to consider dietary changes, which can significantly impact the intestinal microbiota, for management of co-morbid ENDO and T1DM (Henschel et al 2018). Similarly, the use of metformin for targeting co-morbid T1DM and ENDO may have value, given recent evidence for its efficacy in reducing T1DM (Bjornstad et al 2018, Cree-Green et al 2019 and hindering the progression of ENDO lesions and associated signaling pathways (Takemura et al 2007, Yilmaz et al 2010. Additionally, therapies that reduce inflammation could prove beneficial, given the pro-inflammatory status of T1DM and ENDO.…”

Section: Potential Therapeutic Complications In Co-morbid T1dm and Endomentioning

confidence: 99%

Co-morbidity of type 1 diabetes and endometriosis: bringing a new paradigm into focus

Simmen

Brown

Quick

et al. 2019

Journal of Endocrinology

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Type 1 diabetes mellitus and endometriosis separately affect millions of women worldwide. Reproductive-age women diagnosed with type 1 diabetes may also suffer from endometriosis, but the asymptomatic pre-clinical period of highly variable duration for each condition can lead to challenges in the timely recognition of co-morbid disease onset and misdiagnosis. While knowledge of the pathogenesis of each condition has grown substantially, co-morbid endometriosis and type 1 diabetes has not been widely considered and much less addressed. This review discusses the molecular rationale for the likelihood of their co-existence, and prospects for improvements in therapeutic strategies and reduced complications, if this paradigm is included as a significant variable in disease management.

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Metformin Improves Peripheral Insulin Sensitivity in Youth With Type 1 Diabetes

Cited by 77 publications

References 46 publications

The changing face of paediatric diabetes

The changing face of paediatric diabetes

New Insight into Metformin Mechanism of Action and Clinical Application

Co-morbidity of type 1 diabetes and endometriosis: bringing a new paradigm into focus

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