Editorial: The Role of Medicinal Chemistry in Treating Obesity, Diabetes and Metabolic Syndrome
Article first published online: 25 MAR 2013
Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Special Issue: Obesity, Diabetes and Metabolic Syndrome
Volume 8, Issue 4, pages 535–537, April 2013
How to Cite
Ortúzar, N. (2013), Editorial: The Role of Medicinal Chemistry in Treating Obesity, Diabetes and Metabolic Syndrome. ChemMedChem, 8: 535–537. doi: 10.1002/cmdc.201300012
- Issue published online: 25 MAR 2013
- Article first published online: 25 MAR 2013
In today′s world, obesity, diabetes and metabolic syndrome are major global health issues, and collectively, their impact on human health is severe. These disorders are highly related and interlinked through various factors, both environmental and physiological.
Arguably, the current prevalence of type 2 diabetes can be largely attributed to the increased incidence of obesity. Obesity has become a major public health concern in recent years, with the number of obese individuals increasing in almost all areas worldwide. As the prevalence of obesity increases, so too do the comorbidities of type 2 diabetes, cardiovascular disease, and other associated diseases. Obesity has a dramatic effect on the quality of life and decreases typical life expectancy. With this in mind, it is unsurprising that significant research efforts are currently underway to find new means of preventing and controlling obesity.
While the most common cause of obesity is generally considered to be disparity between daily intake and expenditure of energy, it can also arise through malfunction of the endocrine system caused by genetic defects or environmental factors. Typically, the first approach of clinicians when treating obese individuals is to recommend lifestyle changes (diet, exercise, etc.), and in extreme cases, surgery. There is also the option of pharmaceutical intervention, which is where the medicinal chemist steps in. Examples of currently available therapeutics include orlistat (tetrahydrolipstatin), which promotes weight loss by inhibiting gastrointestinal lipase, the recently approved lorcaserin (APD-356), a serotonergic agent that acts in the brain leading to appetite suppression, and phentermine, which promotes weight loss through adrenal gland stimulation leading to norepinephrine release and appetite suppression—interestingly, phentermine can be administered alone or, since recent approval, in combination (Qsymia™) with topiramate, an anticonvulsant drug that also causes weight loss. Rimonabant, a CB1 agonist that was briefly approved for the treatment of obesity but was subsequently withdrawn from the market due to side effects caused by action in the brain, is a cautionary tale; current research looking at CB1 agonists as anorectic agents focuses on peripherally expressed receptors. New agents acting against novel targets in the treatment of obesity are also emerging, such as angiopoietin-like proteins, adipokines, and modulators of lipid metabolic enzymes and recQ-mediated genome instability 1 (RMI1).
Obesity significantly increases the risk of developing type 2 diabetes, and given the prevalence of obesity, it comes as little surprise that, according to the World Health Organization, 347 million people worldwide are currently diabetic, with 80 % of those living in middle and low income countries. If incident rates of diabetes continue as expected, by 2030 the number of individuals with diabetes will have doubled since 2005.
Diabetes mellitus is a chronic disease caused by the body′s inability to either produce (type 1) or respond (type 2) to insulin, leading to high blood glucose levels and the associated symptoms such as increased hunger, thirst and frequent urination. Left untreated, diabetes can cause neuropathy, blindness due to retina damage, kidney disease, heart disease, and stroke. The management of type 1 diabetes involves the administration of insulin or synthetic insulin analogues, usually by injection, to control blood glucose levels as the pancreatic β cells have either been destroyed or are dysfunctional and thus unable to generate endogenous insulin. In type 2 diabetes, insulin is sometimes used but more often than not, oral agents are administered to control blood glucose levels. It is here that the medicinal chemist plays a role, with the standard treatment involving agents that either increase pancreatic secretion of, or cellular sensitivity to, insulin. The first line drug is metformin, a biguanide that acts to suppress hepatic glucose production. Metformin is hypothesized to act as an adenosine monophophate (AMP)-activated protein kinase (AMPK) agonist, although the mechanism of action has yet to be fully elucidated.
When metformin fails, additional agents are prescribed, including sulfonylureas (e.g., glipizide, glimepiride and glyburide) and meglitinides (e.g., repaglinide and nateglinide) that act via ATP-dependent K+ channels on the membrane of pancreatic β cells to increase the secretion of insulin, α-glucosidase inhibitors (e.g., acarbose and miglitol) that prevent the metabolism of dietary carbohydrates, and peroxisome proliferator-activated receptor (PPAR) agonists such as rosiglitazone and pioglitazone, both members of the thiazolidinedione class of antidiabetic agents. This latter class has had serious side effects associated with their use; adverse cardiovascular effects led to the withdrawal of rosiglitazone, and pioglitazone is currently being investigated for potential cancer-promoting effects. In addition to these more established drug classes, newer agents are available to type 2 diabetics including dipeptidyl peptidase-4 (DPP4) inhibitors saxagliptin, sitagliptin and linagliptin that decrease glucagon and blood glucose levels, dapagliflozin, a first-in-class sodium-glucose linked transporter (SGLT)-2 inhibitor recently approved in Europe, and liraglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist administered via injection for the treatment of type 2 diabetes with off-label use in obesity. Unfortunately, none of the agents currently approved for the treatment of type 2 diabetes prevent disease progression. Ultimately, oral treatment fails and patients need to be treated with insulin.
Despite a strong arsenal available for the management of diabetes, improved therapeutics are continually needed to eliminate side effects associated with chronic use and improve the options available to patients, particularly those with complications such as related or unrelated conditions. Investigations continue into the identification of new agents acting against known targets, such as aleglitazar, a PPARα/γ agonist with fuel storage and insulin-sensitizing effects (γ) and fuel burning and lipid modulating effects (α). Recent research has also uncovered novel targets for the development of antidiabetic agents. For some of these novel targets, the therapeutic rationale remains the same, such as increasing insulin sensitivity (glycogen synthase kinase 3 (GSK3) and protein tyrosine phosphatase-1B (PTP-1B)), inhibiting gluconeogenesis (dehydrogenase kinase (PDH)), or increasing insulin production/secretion (GLP-1 and other gut hormone receptors). Other novel targets currently under investigation involve new approaches to modulating blood glucose levels and treating diabetes: for example, targets involved in fatty acid metabolism, such as carnitine palmitoyltransferase (CPT) I and II, those that offer alternative routes for glucose excretion, like SGLT, modulating energy expenditure (β(3)-adrenoceptor), or inhibition of lipolysis.
Metabolic syndrome is a collection of conditions, including high blood pressure, increased blood glucose levels and abnormal cholesterol levels, that together significantly increase the individual′s risk of developing a more serious condition, such as diabetes, heart disease or stroke. Unsurprisingly, many of the targets described for the treatment of obesity and/or diabetes are also indicated and under investigation for the treatment of metabolic syndrome, for example, bile acid receptors, such as farnesoid X receptor (FXR) and GPBAR1 (TGR5).
What is clear is that as our understanding of the intricate system of metabolic control deepens, the points at which we are able to intervene therapeutically become more numerous. While it is highly unlikely that a single drug will be able to prove curative in any of these diseases, it seems probable that we will be able to modulate several targets with distinct but related pharmacology to give patients controlled blood glucose levels, stabilized weight or access to a more healthy body mass index, and through this, decreased risk of complications associated with these disorders. In short, improved therapeutic agents are the key to improved prognosis for patients—the end goal of any pharmaceutical endeavor.
Dr. Natalia Ortúzar Editor-in-Chief ChemMedChem