Growth hormone directly favors hepatic ketogenesis in persons with prediabetes or type 2 diabetes mellitus treated with empagliflozin

Rocha, Aline Franco da; Pereira, Paulo Sérgio; Calefi, Gabriela Simonetti; Marquezine, Guilherme Figueiredo; Morimoto, Helena Kaminami; Mazzuco, Tânia Longo; Faria, Eliana Cotta de; Urbano, Mariana Ragassi; Carrilho, A.J.F.

doi:10.1007/s12020-021-02730-0

Cited by 5 publications

(6 citation statements)

References 17 publications

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“…In particular, the administration of empagliflozin in individuals with prediabetes or diabetes was associated with the amelioration of glycemia and insulin sensitivity and with increased β-hydroxybutyrate (BHB) levels. However, when empagliflozin was administered with pegvisomant, a GH receptor antagonist, BHB levels were restored to baseline; thus, it was suggested that SGLT-2i therapy may promote ketogenesis by inducing GH ( 93 ). Therefore, diabetic patients with acromegaly could be treated with SGLT-2i, albeit caution is required for patients with uncontrolled disease.…”

Section: Sglt-2 Inhibitorsmentioning

confidence: 99%

Mini Review: Effect of GLP-1 Receptor Agonists and SGLT-2 Inhibitors on the Growth Hormone/IGF Axis

et al. 2022

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Accumulating evidence supports the early use of glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium glucose transporter-2 inhibitors (SGLT-2is) for the treatment of type 2 diabetes. Indeed, these compounds exert numerous pleiotropic actions that favorably affect metabolism and diabetes comorbidities, showing an additional effect beyond glucose control. Although a substantial amount of knowledge has been generated regarding the mechanism of action of both drug classes, much remains to be understood. Growth hormone (GH) is an important driver for multiple endocrine responses involving changes in glucose and lipid metabolism, and affects several tissues and organs (e.g., bone, heart). It acts directly on several target tissues, including skeletal muscle and bone, but several effects are mediated indirectly by circulating (liver-derived) or locally produced IGF-1. In consideration of the multiple metabolic and cardiovascular effects seen in subjects treated with GLP-1RAs and SGLT-2is (e.g., reduction of hyperglycemia, weight loss, free/fat mass and bone remodeling, anti-atherosclerosis, natriuresis), it is reasonable to speculate that GH and IGF-1 may play a about a relevant role in this context. This narrative mini-review aims to describe the involvement of the GH/IGF-1/IGF-1R axis in either mediating or responding to the effects of each of the two drug classes.

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Section: Sglt-2 Inhibitorsmentioning

confidence: 99%

Mini Review: Effect of GLP-1 Receptor Agonists and SGLT-2 Inhibitors on the Growth Hormone/IGF Axis

et al. 2022

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“…55 However, stress hormones are also involved in ketogenic processes. [78][79][80] In fact, these stress hormones are well-known potent inducers of ketogenesis via stimulating FFA release and lipolysis, thereby supporting hepatic ketogenesis. [78][79][80][81] Lipoprotein lipase activity increased promptly after a rise in stress hormone concentration and, thereafter, circulating FFAs and ketone bodies increased.…”

Section: Stress Hormonesmentioning

confidence: 99%

“…[78][79][80] In fact, these stress hormones are well-known potent inducers of ketogenesis via stimulating FFA release and lipolysis, thereby supporting hepatic ketogenesis. [78][79][80][81] Lipoprotein lipase activity increased promptly after a rise in stress hormone concentration and, thereafter, circulating FFAs and ketone bodies increased. 65,66 Therefore, SGLT2 inhibition could indirectly increase ketogenesis via stress hormones (Figure 4).…”

Section: Stress Hormonesmentioning

confidence: 99%

“…These hormones, also known as stress hormones, are primarily released in an attempt to regain glucose homeostasis by increasing the level of circulating glucose 55 . However, stress hormones are also involved in ketogenic processes 78–80 . In fact, these stress hormones are well‐known potent inducers of ketogenesis via stimulating FFA release and lipolysis, thereby supporting hepatic ketogenesis 78–81 .…”

Section: Pathophysiology Of Sglt2i‐induced Acidosismentioning

confidence: 99%

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New insights into cellular links between sodium–glucose cotransporter‐2 inhibitors and ketogenesis

Yaribeygi

Maleki

Butler

et al. 2022

J of Cellular Biochemistry

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Sodium-glucose cotransporter-2 inhibitors (SGLT2is) are a newly developed class of highly effective antidiabetic therapies that normalize hyperglycemia via urinary glucose excretion. However, they may be accompanied by certain side effects that negatively impact their therapeutic benefits. SGLT2is induce a metabolic shift from glucose to fatty acids and thus increase lipolysis which, in turn, induces ketogenesis. The complete pathways linking SGLT2is to ketoacidosis have not yet been fully elucidated, though much is now known.Therefore, in this mechanistic study, we present the current knowledge and shed light upon the possible cellular pathways involved. A deeper understanding of the possible links between SGLT2is and ketogenesis could help to prevent adverse side effects in diabetic patients treated with these drugs.

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“…This is based on a study in prediabetic/diabetic patients where treatment with the sodium-glucose cotransporter 2 (SGLT2) inhibitor, empagliflozin, leads to an increase in β-hydroxybutyrate levels associated with a decrease in insulin/glucagon ratio, as well as glucose and NEFA levels, when studied after a meal where the primary source of NEFA is from the diet. When patients are co-treated with empagliflozin and pegvisomant, the rise in β-hydroxybutyrate is blocked, without significantly impacting the other endpoints [170]. In addition, hepatic β-hydroxybutyrate levels are reduced in aHepGHRkd mice in the post-absorptive state, independent of changes in glucose and NEFA levels, or the evidence of enhanced hepatic insulin signaling [59].…”

Section: Ketogenesismentioning

confidence: 99%

Towards Understanding the Direct and Indirect Actions of Growth Hormone in Controlling Hepatocyte Carbohydrate and Lipid Metabolism

Vázquez‐Borrego

Río-Moreno

Kineman

2021

Cells

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Growth hormone (GH) is critical for achieving normal structural growth. In addition, GH plays an important role in regulating metabolic function. GH acts through its GH receptor (GHR) to modulate the production and function of insulin-like growth factor 1 (IGF1) and insulin. GH, IGF1, and insulin act on multiple tissues to coordinate metabolic control in a context-specific manner. This review will specifically focus on our current understanding of the direct and indirect actions of GH to control liver (hepatocyte) carbohydrate and lipid metabolism in the context of normal fasting (sleep) and feeding (wake) cycles and in response to prolonged nutrient deprivation and excess. Caveats and challenges related to the model systems used and areas that require further investigation towards a clearer understanding of the role GH plays in metabolic health and disease are discussed.

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Growth hormone directly favors hepatic ketogenesis in persons with prediabetes or type 2 diabetes mellitus treated with empagliflozin

Cited by 5 publications

References 17 publications

Mini Review: Effect of GLP-1 Receptor Agonists and SGLT-2 Inhibitors on the Growth Hormone/IGF Axis

Mini Review: Effect of GLP-1 Receptor Agonists and SGLT-2 Inhibitors on the Growth Hormone/IGF Axis

New insights into cellular links between sodium–glucose cotransporter‐2 inhibitors and ketogenesis

Towards Understanding the Direct and Indirect Actions of Growth Hormone in Controlling Hepatocyte Carbohydrate and Lipid Metabolism

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