Abstract
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.
Highlights
The development of new compounds in recent decades has substantially improved the pharmacotherapy of type 2 diabetes (T2D) by improving achievement of metabolic targets while mitigating specific side effects frequently observed in patients treated with traditional hypoglycemic drugs such as insulin and sulfonylureas
These results provide experimental evidence that both hyperstimulation and downregulation of IGF-1 receptor (IGF-1R) signaling may have a pathogenetic role in the onset and/or progression of neuronal disorders
A growing body of evidence indicates that several of the pleiotropic responses elicited by GLP-1RAs and SGLT-2is involve the activation of the Growth hormone (GH)/insulin-like growth factor-1 (IGF-1)/IGF-1R system
Summary
The development of new compounds in recent decades has substantially improved the pharmacotherapy of type 2 diabetes (T2D) by improving achievement of metabolic targets while mitigating specific side effects (e.g., weight gain, hypoglycemia) frequently observed in patients treated with traditional hypoglycemic drugs such as insulin and sulfonylureas. When the IGF-1R was knocked down in vitro, exendin-4 lost the ability to activate this pathway, suggesting that GLP-1 analogues may restore b-cell proliferation via autocrine or paracrine activation of IGF-1R [44] In concert, these results define a new scenario of action for incretin-based therapy that may involve the adipo-insular axis, linking the weight lowering competence with the sustained protection of b-cells from diabetogenic stressors. Lecher et al showed the absence of hypoglycemic episodes in the presence of higher concentrations of GLP-1 when administered continuously; in this study, the Authors showed that the counter-regulatory responses in terms of changes of GH circulating levels were unaffected by GLP-1 administration during 48 h of fasting, which lead to the exhaustion of liver glycogen stores, without apparent increased risk of hypoglycemia [52] Taken together, these data provide evidence that GLP-1RAs do not interfere with the overall counter-regulatory response to hypoglycemia both in healthy and metabolically unhealthy subjects, even though a small effect on GH secretion may be observed
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