The potential of glucagon-like peptide 1 to reverse high-fat, high-sugar diet-related metabolic damage

Abstract

Analogs of glucagon-like peptide 1 (GLP-1) are currently one of the best-in class pharmacotherapies to treat obesity and diabetes. Recently advanced biochemical engineering has led to the generation of series of unimolecular co-agonists at receptors for GLP-1 and glucagon or the glucose-dependent insulinotropic polypeptide. In studies from mouse models of obesity and insulin resistance to non-human primates to humans, these tailored molecules have shown to effectively improve several hallmarks of the metabolic syndrome, such as obesity, glucose intolerance and imbalances in cholesterol and lipid metabolism. The aim of this editorial is to briefly summarize the potential of this new class of GLP-1 based therapies for the treatment of the metabolic syndrome.

Keywords::

• diabetes
• GLP-1
• insulin resistance
• metabolic syndrome
• obesity

Obesity has reached global epidemic proportions and is a causal factor for the development of various chronic diseases such as diabetes, cardiovascular diseases and certain types of cancer. Obesity and its co-morbidities are an enormous burden on international healthcare systems. In the USA alone, it is estimated that 280,000 deaths per year are directly attributable to obesity [1]. In light of the growing socioeconomic burden of obesity and diabetes, new treatment options to combat the ‘diabesity' epidemic are urgently required. However, pharmacological treatment options to safely and efficiently lower body weight while improving glucose metabolism are scarce. Since the beginning of the 20th century, a series of weight lowering drugs have appeared on the market, but nearly all of them were discontinued after a short time due to limited efficacy or concern over adverse effects [2]. Whereas the history of anti-obesity pharmacotherapies is full of disappointments, hope is resting on recent advances in biochemical engineering, which has led to the generation of a series of long-acting analogs at the glucagon-like peptide 1 receptor (GLP-1R).

As a typical incretin, the gastrointestinal peptide hormone GLP-1 directly acts on the pancreatic islets to induce glucose-stimulated insulin secretion and to inhibit the release of glucagon. Beyond the classical role of GLP-1 to regulate glucose homeostasis, GLP-1 exerts a series of additional beneficial effects on system's metabolism. GLP-1 enhances β-cell proliferation and β-cell mass in rodents, has protective effects on the heart, increases insulin sensitivity in skeletal muscle, decreases hepatic gluconeogenesis and enhances weight loss through inhibition of food intake and delayed gastric emptying [3]. Postprandial GLP-1 secretion is further enhanced in rats and humans following bariatric surgery, such as after vertical sleeve gastrectomy or Roux-en-Y gastric bypass [4,5]. However, vertical sleeve gastrectomy equally improves body weight and glycemic control in GLP-1R knockout (ko) and wild-type mice, indicating that GLP-1 action is not required for the metabolic benefits induced by the surgery [6]. Nevertheless, a recent study in rats showed that the presurgical responsiveness to GLP-1-induced weight loss predicts the postsurgical efficacy on improvement of glycemic control [7]. Furthermore, GLP-1R agonism enhances the weight-lowering efficacy of adjustable gastric banding and suggests that GLP-1 therapy is a valuable adjunct to adjustable gastric banding to optimize the efficacy of this minimally invasive surgery [8]. Taken together, the evidence indicates that GLP-1 is an interesting target for pharmacological weight management. To date, several dipeptidyl peptidase-4-resistant, GLP-1 analogs, such as exenatide (Byetta^®; Eli Lilly & Co, Indianapolis, IN, USA) and liraglutide (Victoza^®; Novo Nordisk, Denmark) are approved for the treatment of diabetes by the US FDA. The efficacy of these GLP-1R agonists to improve glucose metabolism has been shown in numerous clinical studies (as reviewed in [3]). In humans, however, GLP-1R agonism confers a dose-dependent risk of causing nausea, which so far limits the potential of GLP-1 analogs for pharmacological weight management.

In 2009, new ground was broken in ‘diabesity' research with the intuitive biochemical engineering of a single peptide with nearly balanced co-agonism at the receptors for glucagon and GLP-1. Combining the glycemic and anorectic effects of GLP-1 with the lipolytic and thermogenic properties of glucagon into a single peptide enhanced the metabolic efficacy to reverse obesity [9]. Additionally, this co-agonist was engineered to have improved pharmacokinetics and a superior time-action as compared with the native hormones. Once-weekly treatment of diet-induced obese (DIO) mice with this newly designed GLP-1/glucagon co-agonist normalized body weight and glucose tolerance and improved liver steatosis with 4 weeks of treatment [9]. Body weight loss induced by the co-agonist was primarily due to decreased body fat mass and was the result of decreased food intake and increased energy expenditure, which is in line with GLP-1's anorectic effect and glucagon's thermogenic capacity. In line with glucagon's lipolytic effects, levels of phosphorylated hormone-sensitive lipase were further increased in the white adipose tissue. Notably, despite lower efficacy, the co-agonist also decreased body weight and fat mass in GLP-1R ko mice, thus emphasizing that glucagon action significantly contributes to the metabolic effects achieved by the co-agonist. Whereas subsequent studies evaluating the mechanistic underpinnings and translational value of this molecule are currently ongoing, a recent study indicates that this GLP-1/glucagon co-agonist improves leptin responsiveness in otherwise leptin-resistant DIO mice [10]. It is noteworthy that the GLP-1/glucagon co-agonist restored leptin action in DIO mice even under chronic exposure to a high-fat, high-sugar diet, a paradigm where other weight-lowering agents, such as exendin-4 or FGF21, failed to improve leptin sensitivity [11].

Spurred by the observation that the GLP-1/glucagon co-agonist exerts beneficial effects beyond what is achieved by the native hormones, other single-molecule co-agonists were generated that combine the beneficial effects of GLP-1 with those of the glucose-dependent insulinotropic polypeptide (GIP) [12]. This nearly balanced dual incretin co-agonist potently corrected several hallmarks of the metabolic syndrome, such as obesity, hyperglycemia and dyslipidemia in rodent models of diet-induced obesity, insulin resistance and Type 2 diabetes. Improvement of glycemic control was thereby achieved through enhanced insulinotropic efficacy, which translated from rodent models of obesity and diabetes to non-human primates to humans. Notably, in contrast to the GLP-1 analog exendin-4, this ‘twincretin' did not cause gastric discomfort, and no major adverse effects were reported in the clinical studies [12].

Building on these achievements, an even more advanced biomolecule was recently generated, one which still comprises GLP-1 as a peptide backbone, but which is covalently linked to the nuclear receptor hormone estrogen [13]. Whereas estrogen exerts a variety of beneficial effects on energy metabolism, such as inhibition of food intake, stimulation of energy expenditure and improvement of insulin sensitivity (as reviewed in [14]), the oncogenic potential and gynecological action of estrogen limits its pharmacological use in weight management. Thus, a tremendous achievement was gained by the generation of a stable GLP-1/estrogen hybrid, which selectively delivers the estrogen into those cells that express the GLP-1R and simultaneously prevents the estrogen from acting on cells that do not express GLP-1R, including breast and uterine tissue. In DIO mice, this stable GLP-1/estrogen hybrid potently corrected obesity, insulin resistance and abnormalities in cholesterol and lipid metabolism. Subsequent studies in CNS-specific GLP-1R ko mice showed that this hybrid affects systems metabolism primarily via CNS neurocircuits. Accordingly, the stable conjugate was unable to promote weight loss in CNS-specific GLP-1R ko mice and treatment of wild-type mice with this hybrid increased expression of proopiomelanocortin in the arcuate nucleus to a greater extent as treatment with GLP-1 or estrogen alone. Notably, the stable GLP-1/estrogen hybrid showed no off-target effects in GLP-1-negative tissues, as assessed by uterus weight and MCF-7 xenograft studies. As GLP-1R is predominantly expressed in tissues implicated in energy metabolism control, namely, the brain, the pancreas and the intestine, but not in tissues where estrogen confers unwanted adverse effects, such as the uterus and breast tissue, this strategy sheds new light on the potential of estrogen in the treatment of the metabolic syndrome. This strategy also advances the potential development of safe, efficient and cell-specific novel pharmacotherapies in general. Further studies are needed to clarify whether and to what extent these studies translate into humans and whether they prove safe for inducing sustained weight loss in large study cohorts and over longer time periods. However, within only a few years, this new class of biomolecules has significantly advanced our knowledge about pharmacotherapies and has re-primed our understanding about how to best target metabolic diseases. These molecules emphasize the principle that novel highly active peptides that simultaneously target multiple signaling pathways can be designed to safely and efficiently improve systemic metabolism, thus paving the way for a new area in obesity and diabetes research. Without doubt, extension of these principles to include more endocrine factors implicated in systems metabolism and transfer of these strategies to other disease models, such as cancer, cachexia or cardiovascular diseases, might lead to an enormous boom in the development of novel pharmacotherapies in the near future. Notably, several recent studies reported that GLP-1-based therapies may confer an increased risk for the development of pancreatitis [15,16] and expansion of the endocrine and exocrine pancreas [17]. These studies prompted the EMA Committee for Medical Products for Human Use to review all available non-clinical and clinical data and in a press release on 26 July 2013, the EMA Committee for Medical Products for Human Use announced that there is no evidence regarding an increased risk of pancreatic adverse effects associated with the use of GLP-1-based therapies (EMA/463027/2013).

Financial & competing interests disclosure

Within the scope of an academic cooperation, the author's laboratory received financial support to conduct the studies mentioned in this article from the patent holders of the molecules involved. The author has no direct financial disclosure in relation to this paper. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.