Targeting the brain to restore normoglycaemia
المؤلف:
Holt, Richard IG, and Allan Flyvbjerg
المصدر:
Textbook of diabetes (2024)
الجزء والصفحة:
6th ed , page 137-139
2025-11-03
60
Brain- directed treatments have been identified over the past decade that can return elevated plasma glucose levels to the normal range in rodent models of both type 1 diabetes and type 2 diabetes. For the most part, these interventions (i) target the mediobasal hypo thalamus; (ii) rely primarily on insulin- independent glucose- lowering mechanisms; and (iii) reset the BDLG to normal, rather than simply lowering glucose levels in a transient manner.
Several members of the fibroblast growth factor (FGF) family of peptides elicit potent glucose- lowering actions in rat and mouse models of type 2 diabetes following central administration.
Initially, studies focused on two hormones in this family, FGF- 21 and FGF- 19, which are secreted primarily from the liver and intestine, respectively. Although each has distinct physiological functions, pharmacological administration of either peptide can normalize blood glucose levels in multiple rodent models of type 2 diabetes. Although these effects were originally proposed to be mediated via peripheral mechanisms, they were subsequently shown to be mediated primarily in the brain.
Meanwhile, the growth factor FGF- 1 elicits a more a durable anti- diabetes action. Like FGF- 19 and FGF- 21, this effect was first reported following systemic administration, but was subsequently found to be highly effective following intracerebroventricular FGF- 1 injection at a dose too low to have systemic effects. What distinguishes FGF- 1 from any other pharmaceutical treatments of type 2 diabetes, however, is that a single intracerebroventricular injection can normalize glycaemia for weeks to even months in rodent models of type 2 diabetes, despite having no sustained effect on food intake, body weight, or body adiposity (Figure 1). Cellular mechanisms underlying the hypothalamic response to FGF- 1 appear to involve glia–neuron interactions that increase melanocortin signaling and are accompanied by reversal of maladaptive changes in the extracellular matrix. Whether these findings will translate to more effective treatment strategies for human type 2 diabetes awaits additional study. A key final point related to central actions of FGF1 (as well as leptin) in diabetic animals is that beyond simply lowering elevated plasma glucose levels, these interventions appear to restore the BDLG to normal.
Fig1. Sustained blood glucose lowering by central fibroblast growth factor (FGF)- 1 treatment in a mouse model of type 2 diabetes. A single intracerebroventricular injection of human (hFGF1) or mouse (mFGF1) at a dose of 3 μg induces sustained diabetes remission in diabetic Lepob/ob mice. Source: Adapted with permission from Morton et al. 2015.
Current and future anti- diabetes drugs that target central pathways
Anti- diabetes agents in current use can act on tissues ranging from the pancreas to muscle, adipose tissue, liver, kidney, and gut, with some also acting in the brain (Table 1). Perhaps the most clear- cut example of the latter is the dopamine agonist bromocriptine, which acts centrally to suppress hepatic glucose production and improve insulin resistance. The amylin analogue pramlintide is another centrally acting anti-diabetes drug that elicits a distinctly different set of effects via its receptor expressed by hindbrain neurons. These include reduced food intake and weight loss, decreased gastric emptying, and inhibition of glucagon secretion. While neither bromocriptine nor pramlintide is particularly effective or is in wide use, both offer proof- of- concept evidence that the brain can be targeted to treat diabetes in humans, although drugs that target both brain and periphery are currently far more efficacious.
Table1. Glucose- lowering agents and their site of action with specific reference to central effects.
Among these are synthetic GLP- 1 receptor agonists, which are currently among the most potent anti- diabetes medications. Long- acting GLP- 1 receptor agonists can be administered on a weekly basis and are especially effective in lowering HbA1c; unlike insulin, they do so without weight gain (and often induce weight loss) and with minimal risk of hypoglycaemia. GLP- 1 receptors on pancreatic β cells are a key target for these drugs, activation of which augments glucose- induced insulin secretion. In addition, these agents can impact brain function in multiple ways. Activation of GLP- 1 receptors on vagal afferent fibres supplying the gastrointestinal tract induces satiety while reducing gastric emptying, and activation of hindbrain GLP- 1 receptors can amplify this effect, with the combination leading to significant weight loss. Some POMC neurons also express GLP- 1 receptors and increase firing rate, leading to increased melanocortin signalling in response to GLP- 1 stimulation. Whether these or other CNS effects promote glucose lowering independently of effects on food intake and weight is presently unknown.
Recent progress in this area includes the development and clinical testing of unimolecular dual- and tri- agonist compounds that com bine GLP- 1 with glucagon and/or gastric inhibitory peptide (GIP) into a single, long- acting peptide suitable for systemic administration. One of these compounds recently received licensing approval for type 2 diabetes treatment. The dual agonist tirzepatide exerts glucose- lowering and weight loss effects that are more potent than other non- surgical options. Like GLP- 1 receptor agonists, these drugs mediate their beneficial effects via actions on both pancreatic β cells and the peripheral and central nervous system.
Another recent development relates to metformin, a first- line drug for type 2 diabetes, with anti- diabetes effects that appear to involve a subset of hindbrain neurons. This inference is based on evidence that metformin induces expression of growth and differentiation factor- 15 (GDF- 15, also known as MIC- 1), a potent endogenous inhibitor of feeding that can be secreted by several cell types and tissues, typically in response to cellular stress. The central effects of GDF- 15 are mediated via the binding to its receptor, GFRAL, expressed uniquely by neurons in the area postrema and nucleus of the solitary tract. Although the metformin- induced increase of circulating GDF- 15 levels is modest (and below that needed to cause pronounced anorexia), the finding that in mice metformin’s anti- diabetes effect is abrogated by GFRAL deletion implies a requirement for GDF- 15 and its action in the brain. As more is learned about the brain’s role in glucose homeostasis and diabetes pathogenesis, successful targeting of the brain to improve diabetes management seems likely.
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