Thoughts on the progression of type 2 diabetes drug discovery

Abstract

Introduction: Type 2 diabetes is a growing epidemic in need of effective treatments. There has been research in recent years involving numerous drug therapies and targets. This article is a review of the progress thus far in type 2 diabetes drug discovery.

Areas covered: This editorial reviews type 2 diabetes drug discovery mainly over the past decade through a literature search of PubMed. Furthermore, the author reviews several avenues of research, including the expansion of knowledge for possible drug therapies involving the β-cell, such as targeting its proliferation, function and apoptosis. This knowledge has led to possible drug therapies in clinical trials, particularly insulin secretagogues that are glucose-dependent. Other areas of research in type 2 diabetes drug discovery discussed by the author relate to the new frontier of genome-wide association studies (GWAS), the challenges of oral insulin development and drug targets of inflammation. The author also reviews sirtuin activators and resveratrol, especially its relationship to insulin resistance.

Expert opinion: The progression of type 2 diabetes drug discovery holds much promise, but many agents are in the nascent stages of investigation and human trials proving efficacy are needed. Furthermore, basic science research into some of these agents may need to be further elucidated before clinical trials can be initiated.

Keywords:

• β-cells
• drug discovery
• genetics
• type 2 diabetes

1. Introduction

Type 2 diabetes drug therapy has evolved over the past two decades. Initially there were only the biguanide and the sulfonylurea classes, but developments in the past decade have seen much progress in type 2 diabetes drug treatments. Currently, drug classes such as thiazolidinediones, short-acting insulin secretagogues, sodium-glucose transporter 2 inhibitors and incretin-based therapies have added diversity to a disease in need of effective treatments. Insulin continues to be a mainstay therapy in advanced cases of type 2 diabetes. Analog insulin treatments such as glargine, lispro and aspart provide more predictable pharmacodynamic profiles compared to the earlier human insulin. Newer and more effective therapies for type 2 diabetes are always being researched and discovered. A focus of this editorial will be on reviewing current insights into type 2 diabetes drug discovery and its progress.

A more focused interest has been on improving β-cell proliferation in the natural course of type 2 diabetes. In this disease, insulin resistance at the cellular level within several organs prompts pancreatic β-cells to increase the production of insulin [1]. However, as peripheral insulin resistance continues, β-cell function fails and insulin production declines. There has been progress made on small-molecule inducers of β-cell proliferation [2]. One such inducer is WS6, which is a diarylamide, that impacts proliferation of the β-cell line R7T1 in mice [3]. WS6 was noted to decrease blood glucose, in vivo, in diabetic mice and was linked with an increase in β-cell mass of 50% after more than several weeks. Another sort of small-molecule inducer is a broader class of adenosine kinase inhibitors such as ABT-702 and 5-IT that have been noted to increase β-cell proliferation [4]. Similarly, NECA, an adenosine receptor agonist of the adenosine A_2A receptor, specific to β cells, is capable of exerting a proliferative effect on β cells. Subsequently, adenosine signaling pathway has been shown to be an important target to induce β-cell proliferation, and it also paves a way for possible drug therapies [5]. Promoting β-cell proliferation would not only be instrumental in disrupting the pathogenesis of advanced type 2 diabetes but also be important in stopping the underlying mechanism responsible for type 1 diabetes.

Just as β-cell proliferation is a key interest of drug discovery, there is an equal focus on attenuating β-cell apoptosis. This plays a key role in those type 2 diabetics who progress to eventual insulin use during the natural history of the disease. Glucolipotoxicity (collective term describing the possible harmful effect of hyperglycemia and free fatty acids) that induces death of β cells is proposed to play a central role in type 2 diabetes. Such toxicity increases oxidative stress and it hampers the ability of the endoplasmic reticulum to properly fold essential proteins [6]. Currently approved drugs such as metformin and pioglitazone are thought to protect β cells from glucolipotoxicity. However, the evidence in support of this idea is not definitive, because any agent that reduces hyperglycemia can indirectly reduce the effect of glucolipotoxicity [2]. However, an agent under investigation, glycogen synthase kinase 3β inhibitors, have shown some promise in preventing glucolipotoxicity-induced apoptosis of β cells in isolated rat islets [7]. This provides an added dimension in type 2 diabetes drug research where the toxicity of glucose on β cells can potentially be addressed directly.

Another area of research is ongoing investigations to discover drugs that improve β cells function. At present, there are the sulfonylurea and meglitinide drug classes approved to promote β-cell release of insulin. Both drug classes interact with sulfonylurea receptor 1, and they exert their effect on the β cells, regardless of the serum glucose levels. This obviously increases the risk of hypoglycemia. Therefore, an important aspect of secretagogue drug research is the discovery of agents that augment insulin release from the β cells based on the serum glucose, or in a glucose-dependent manner. Along this line, G-protein-coupled receptor signaling as a drug target may achieve this requirement. For instance, the activation of G-protein receptor 40 via an agonist of G-protein receptor 40 increases protein kinase C activity and this promotes glucose-dependent release of insulin from β cells [8]. A trial of this agent, TAK-845, have shown promising results in humans. As a result, this has the potential to circumvent the risk of hypoglycemia.

An important interest of type 2 diabetes drug discovery is slowing the progression of type 2 diabetes and its related comorbidities by targeting inflammation. There are many proposed anti-inflammatory agents currently being studied, and the targets of some of these agents are ILs. ILs, in particular IL-1β, are cytokines that have been shown to promote insulin resistance in type 2 diabetes [9]. One such drug anakinra, a human recombinant IL-1 receptor antagonist, approved in the US for rheumatoid arthritis, reduced hyperglycemia and decreased markers of inflammation in a proof-of-concept study [10]. To the contrary, clinical studies have shown that TNF antagonism had a statistically insignificant effect on improving insulin sensitivity in obese diabetics [11]. However, further preclinical and clinical studies elucidating the effect of TNF antagonists are needed within the realm of diabetes.

Other potential drug targets such as activation of a deacetylase, known as sirtuins, essential in metabolism and inflammation, may improve hyperglycemia through multiple mechanisms. Specifically, sirtuin1, which plays a necessary role during caloric restriction, regulates important metabolic function for inflammation, insulin release and gluconeogenesis [12]. Insulin resistance also correlates with low sirtuin 1 gene expression, and sirtuin 1 gene expression was negatively correlated with carotid atherosclerosis [13]. Sirtuin activators may have a possible role in improving insulin sensitivity. Resveratrol, a polyphenol found in certain plants, has shown promise in improving insulin signaling for insulin-resistant mice [14]. Insulin resistance as a target of treatment for type 2 diabetes has the potential to ameliorate the underlying pathology of type 2 diabetes and indirectly halts the decline of β-cell function.

Human genetics is an important dimension of diabetes drug discovery that holds many possibilities. Specifically genome-wide association studies (GWAS) have shown numerous mutations in genetic loci associated with type 2 diabetes [15]. For example, zinc transporter 8, encoded by the gene SLC30A8, has been noted to be important in insulin secretion, where a mutation in this gene protects individuals from developing type 2 diabetes [16]. Subsequently, because of this knowledge, there has been much interest in designing drugs that alter zinc transporter 8 [17]. Bioinformatics overall, particularly in search of genetic mutations, can aid in drug development, when dealing with so many potential genetic sequences implicated in type 2 diabetes.

Finally among the largest challenges in diabetes therapy, remains a more convenient means of insulin delivery. Ever since its discovery, insulin is delivered via subcutaneous injection and there is an obvious barrier for many patients to accept this mode of administration. Recent advances in insulin therapeutics have yielded inhaled insulin as a therapy, and there are attempts at developing a formulation of insulin administered orally. However major obstacles remain in the development of oral insulin, because oral insulin is subject to enzymatic degradation and poor gastrointestinal (GI) absorption. Advances in nanoparticles and permeation enhancers have provided an avenue for further progress in this area, but much work still remains [18].

2. Expert opinion

Type 2 diabetes drug discovery is an area that approaches the problem on many fronts and has seen many advances in the past decade (Figure 1). Increasing knowledge about the β-cell has expanded potential therapeutic options and preserving β cells are considered a strong cornerstone to effective drug treatments. The most exciting part of β-cell-centered research is the investigations revolving around improving β-cell function. Finding an insulin secretagogue that augments insulin release dependent on the ambient glucose goes a long way in finding a smart agent that avoids the complication of hypoglycemia.

Figure 1. Illustration of type 2 diabetes drug discovery: a challenge with many fronts.

An area that is often not researched is the interplay of glucagon in diabetes and potential drug targets addressing the exaggerated glucagon response postprandially in diabetics. Currently approved drugs such as GLP-1 agonists attempt to address this issue; however, searching for other gut peptides that play similar roles would expand the field of potential therapies.

Research thus far in drugs targeting inflammatory markers in diabetes such as IL hold promise in preventing many of devastating microvascular complications of diabetes. However, drugs that simply target hyperglycemia, through other means, may indirectly target inflammatory markers, because hyperglycemia plays a critical role in microvascular comorbidities.

The greatest promise remains in the field of human genetics, and GWAS can unlock possible drug targets that have never been considered in the past. The innate challenge of this approach is finding targets that benefit a majority of those afflicted with type 2 diabetes. This area is the future of type 2 diabetes drug discovery, but tailoring resources in the proper channels will be a major long-term challenge. GWAS may not establish direct cause and effect but can put forth avenues of research not considered before. Along the same line, oral insulin remains an elusive yet worthy goal with hurdles mostly revolving around GI absorption, but at the rate of research in this domain it is reasonable to see significant advances in the coming years. The progression of type 2 diabetes drug discovery holds much promise, but many agents are in the nascent stages and human trials proving efficacy are needed. However, basic science research into some of these agents may need to be further elucidated before clinical trials can be initiated. Finally from the perspective of a clinician, the ultimate goal in the field of type 2 diabetes drug discovery will always be finding therapies that are safe, convenient and ultimately effective. Most importantly, therapies that safely reduce or eliminate the burden of type 2 diabetes on the patient will ultimately prove to be the most efficacious.

Declaration of interest

The author has no 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. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents, received or pending, or royalties.

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