Metformin regulates the incretin receptor axis via a pathway dependent on peroxisome proliferator-activated receptor-α in mice

Maida, Adriano; Lamont, Benjamin J.; Cao, Xiemin; Drucker, Daniel J.

doi:10.1007/s00125-010-1937-z

Cited by 272 publications

(256 citation statements)

References 34 publications

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“…Additional studies will be required to determine whether metformin can increase incretin receptor expression in human beta cells and thereby bolster incretin action in a meaningful way. Although there are undoubtedly more details to unravel regarding the mechanisms of action of metformin, the work by Maida et al [10] extends previous findings to indicate that metformin can be regarded as an enhancer of GLP-1 secretion and possibly as a GLP-1 sensitiser, beyond its known biological functions (Fig. 1).…”

Section: Ampk Amp-activated Protein Kinase Dpp-4mentioning

confidence: 52%

“…Yet, contrary to these findings, metformin does not directly inhibit DPP-4 activity in vitro [9,14,16]. Maida et al [10] also found that metformin at doses exhibiting GLP-1-increasing effects exerted no effect on plasma DPP-4 activity in mice. Furthermore, metformin increased plasma GLP-1 levels in rats genetically lacking DPP-4 [9].…”

Section: Ampk Amp-activated Protein Kinase Dpp-4mentioning

confidence: 87%

“…Interestingly, there have been a few reports suggesting a direct interaction between metformin and the incretin axis [7][8][9]. In this regard, the article by Maida et al published in this issue of Diabetologia [10] provides new insights into the biological actions of metformin that improve glucose homeostasis.…”

Section: Ampk Amp-activated Protein Kinase Dpp-4mentioning

confidence: 99%

“…Maida et al [10] reported that metformin acutely and selectively increased plasma levels of GLP-1 in mice, even in the absence of concomitant oral glucose administration, while it did not increase plasma levels of the other incretin hormone, glucose-dependent insulinotropic polypeptide (GIP), or, curiously, peptide YY, a gastrointestinal hormone co-localised with GLP-1 in L cells. Therefore, the action of metformin on the gut endocrine system may be L cellspecific and, more precisely, GLP-1-specific.…”

Section: Ampk Amp-activated Protein Kinase Dpp-4mentioning

confidence: 99%

“…Interestingly, Maida et al [10] showed that metformin enhanced the expression of the genes encoding the receptors for both GIP and GLP-1 (Gipr and Glp1r, respectively) in mouse islets and also increased the effects of GIP and GLP-1 on insulin secretion from beta cells. While most of the actions of metformin appear to be mediated by cellular activation of AMP-activated protein kinase (AMPK), their findings indicate that the effects on incretin receptor expression in beta cells appear to be independent of AMPK, but, rather, are mediated by peroxisome proliferator-activated receptor α (PPARα), as metformin failed to induce expression of the gene encoding the incretin receptor in islets from Pparα knockout mice [10]. A PPARα-dependent mechanism was also found to regulate the expression of the Gipr in beta cells by glucose and fat [22].…”

Section: Ampk Amp-activated Protein Kinase Dpp-4mentioning

confidence: 99%

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New aspects of an old drug: metformin as a glucagon-like peptide 1 (GLP-1) enhancer and sensitiser

Cho

Kieffer

2010

Diabetologia

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The two major deficits in type 2 diabetes, insulin resistance and impaired beta cell function, are often treated with metformin and incretin-based drugs, respectively. However, there may be unappreciated benefits of this combination of therapies. In this issue of Diabetologia, Maida et al. (doi:10.1007Maida et al. (doi:10. /s00125-010-1937 report that metformin acutely increases plasma levels of glucagon-like peptide 1 (GLP-1) in mice. Moreover, they show that metformin enhances the expression of the genes encoding the receptors for both GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) in mouse islets and also increases the effects of GIP and GLP-1 on insulin secretion from beta cells. Interestingly, these incretin-sensitising effects of metformin appear to be mediated by a peroxisome proliferator-activated receptor α-dependent pathway, as opposed to the more commonly ascribed pathway of metformin action involving AMP-activated protein kinase. These provocative findings by Maida et al. extend our understanding of the mechanism of action of metformin and provide further insights into the benefits of combining metformin with incretin-based drugs to combat diabetes.

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Section: Ampk Amp-activated Protein Kinase Dpp-4mentioning

confidence: 52%

Section: Ampk Amp-activated Protein Kinase Dpp-4mentioning

confidence: 87%

Section: Ampk Amp-activated Protein Kinase Dpp-4mentioning

confidence: 99%

Section: Ampk Amp-activated Protein Kinase Dpp-4mentioning

confidence: 99%

Section: Ampk Amp-activated Protein Kinase Dpp-4mentioning

confidence: 99%

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New aspects of an old drug: metformin as a glucagon-like peptide 1 (GLP-1) enhancer and sensitiser

Cho

Kieffer

2010

Diabetologia

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Hyperglycemia induces NF‐κB activation and MCP‐1 expression via downregulating GLP‐1R expression in rat mesangial cells: inhibition by metformin

Kang

Zeng

Zhang

et al. 2019

Cell Biology International

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Hyperglycemia impairs glucagon‐like peptide‐1 receptor (GLP‐1R) signaling in multiple cell types and thereby potentially attenuates the therapeutic effects of GLP‐1R agonists. We hypothesized that the downregulation of GLP‐1R by hyperglycemia might reduce the renal‐protective effects of GLP‐1R agonists in diabetic nephropathy (DN). In this study, we examined the effects of high glucose on the expression of GLP‐1R and its signaling pathways in the HBZY‐1 rat mesangial cell line. We found that high glucose reduced GLP‐1R messenger RNA (mRNA) levels in HBZY‐1 cells and in the renal cortex in db/db mice comparing with control groups. In consistence, GLP‐1R agonist exendin‐4 induced CREB phosphorylation was attenuated by high glucose but not low glucose treatment, which is paralleled with abrogated anti‐inflammatory functions in HBZY‐1 cells linked with nuclear factor‐κB (NF‐κB) activation. In consistence, GLP‐1R inhibition aggravated the high glucose‐induced activation of NF‐κB and MCP‐1 protein levels in cultured HBZY‐1 cells while overexpression of GLP‐1R opposite effects. We further proved that metformin restored high glucose‐inhibited GLP‐1R mRNA expression and decreased high glucose evoked inflammation in HBZY‐1 cells. On the basis of these findings, we conclude that high glucose lowers GLP‐1R expression and leads to inflammatory responses in mesangial cells, which can be reversed by metformin. These data support the rationale of combinative therapy of metformin with GLP‐1R agonists in DN.

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Glucagon‐like Peptide‐2 and the Regulation of Intestinal Growth and Function

Brubaker

2018

Comprehensive Physiology

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Glucagon-like peptide-2 (GLP-2) is an intestinally derived hormone that enhances intestinal growth, digestion, absorption, barrier function, and blood flow in healthy animals as well as preventing damage and improving repair in preclinical models of enteritis and colitis and following massive small bowel resection. These beneficial effects of GLP-2 on the intestinal tract are largely recapitulated in humans with intestinal failure. The high-specificity of this peptide for the intestinal tract and the development of degradation-resistant, long-acting GLP-2 receptor agonists have rapidly led to clinical implementation of GLP-2-based therapy for the treatment of patients with short bowel syndrome, with few reported side effects. This comprehensive review covers the biology of GLP-2, from the control of proglucagon gene expression and the posttranslational processing of proglucagon to liberate GLP-2 to the regulation of GLP-2 secretion from the intestinal L cell, and from the mechanism of action of GLP-2 through its highly localized receptor to the biological activities of GLP-2 in the intestine and other restricted locations in the body, under physiological conditions as well as in animal models of intestinal disease and in patients with short bowel syndrome. Collectively, the history of GLP-2 serves as a remarkable bench-to-bedside story of translational medicine. © 2017 American Physiological Society. Compr Physiol 8:1185-1210, 2018.

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Metformin regulates the incretin receptor axis via a pathway dependent on peroxisome proliferator-activated receptor-α in mice

Cited by 272 publications

References 34 publications

New aspects of an old drug: metformin as a glucagon-like peptide 1 (GLP-1) enhancer and sensitiser

New aspects of an old drug: metformin as a glucagon-like peptide 1 (GLP-1) enhancer and sensitiser

Hyperglycemia induces NF‐κB activation and MCP‐1 expression via downregulating GLP‐1R expression in rat mesangial cells: inhibition by metformin

Glucagon‐like Peptide‐2 and the Regulation of Intestinal Growth and Function

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