The persistent need for insulin sensitizers and other disease-modifying anti-diabetic drugs

Abstract

Despite significant advances in diabetes care since the introductions of insulin and metformin, disease burden continues to grow. Large gaps in standard of care remain, and no robustly disease-modifying pharmacotherapy exists. Substantial research has been directed towards beta cell preservation and regeneration with no translational success, while little drug discovery or development is aimed at the other major cause of diabetes, namely, insulin resistance. Given the absence of convincing evidence that human beta cells can be regenerated, the diabetes community must broaden its focus to include new therapeutic strategies to limit, and reverse, insulin resistance.

Keywords::

• beta cells
• glucose
• insulin
• resistance
• thiazolidinediones

The disease of diabetes is diagnosed when circulating glucose levels rise above the range normally found in the blood. Despite serving as a critical energy source for the brain, muscle and kidneys as well as the liver’s ‘feedstock’ to produce fuel for other organs, glucose at persistently high concentrations is toxic to key cell types in the body. Approximately 5% of the world’s 7 billion population suffers from diabetes, and every year 1% of the sufferers die from its sequelae [101]. Diabetic pathophysiology is caused by a combination of reduced responses of the liver and peripheral tissues to insulin and a reduced ability of the pancreas to produce insulin. Diabetic pathophysiology can become disabling and even life-threatening because it is concentrated in the circulatory and nervous systems, thereby resulting in heart disease; chronic kidney disease and kidney failure; peripheral artery disease; neuropathies leading to ulcerations, infections and amputation; and retinopathies triggering loss of vision.

A healthy diet and active lifestyle reduce the risk of developing diabetes, and if diagnosed diabetics can delay the need for pharmacotherapy. Most diabetics, however, will eventually require medication to manage their hyperglycemia. Since the discovery and mass marketing of insulin, the biomedical community has advanced the diagnosis and treatment of diabetes and its complications to the point that a detailed algorithm for the guidance of patient care exists [1].

The first pharmacotherapy encountered in the algorithm is metformin, a 40-year-old drug that reduces liver glucose output through lowering de novo glucose production, thus reducing hyperglycemia while also lowering triglycerides. Metformin also facilitates postreceptor insulin transport and often weight loss, contributing to an overall improved metabolic status [2,3]. If inadequate control of blood glucose levels persists, patients and their physicians will escalate through the algorithm to two- and three-drug combinations until reaching the last resort of injecting insulin. The choice of which class and drug to employ depends on a number of patient-specific factors around efficacy, tolerability and costs, but thankfully thiazolidinediones (TZDs), DPP4 inhibitors, GLP1 receptor agonists and insulin itself are all deployed with some success in patients when lifestyle change and metformin no longer suffice.

While such progress during one generation of patients must be considered a success, substantial gaps in the standard of care remain. At its most basic level of conception, diabetes generally results from insulin resistance in the periphery, thereby necessitating increased insulin production by the pancreas to maintain normal circulating glucose levels. This process usually progresses to the point of β-cell failure which, when summed over all islets in the pancreas, leads to inadequate insulin production to overcome peripheral resistance. The subsequent incomplete peripheral glucose disposal leaves circulating glucose levels elevated, precipitating eventual diagnosis of disease and emergence of its comorbidities, which are often ultimately fatal.

Despite the simplicity of this intellectual framework, modern drug discovery has not resulted in agents that substantially reverse the molecular or cellular origins of either insulin resistance or loss of functional β-cell mass. Sulfonylureas, DPP4 inhibitors and GLP1 receptor agonists act primarily to elevate insulin secretion beyond that driven by sensors in the pancreas, in either glucose-independent or glucose-dependent fashions, respectively [4]. Nonclinical data supporting β-cell protection by stimulation of the GPL1 axis have been generated [5], and while the high level of research directed toward the goal of β-cell preservation and regeneration must be acknowledged, no convincing data exist supporting β-cell preservation in patients whose GLP1 axis is stimulated pharmacologically. Moreover, drugs in the later stages of clinical development or recently approved, such as GPR40 modulators or SGLT2 inhibitors [6,7], do not stimulate the modification or reversal of disease through either insulin sensitization or preservation of functional β-cell mass.

Ironically, it is two older classes of drugs, TZDs and metformin, which lessen resistance to insulin’s actions to partition nutrients into tissue. However, their disease-modifying effects are limited. Metformin’s actions beyond the liver are weak, and it reduces peripheral insulin resistance only indirectly through creating an improved physiological environment. Accordingly, metformin should be considering insulin sensitizing only to the same extent as pharmacologic antiobesity strategies, bariatric surgery and other methods of weight loss and metabolic improvement. In contrast, TZDs provide clear improvements in insulin resistance and glucose disposal in human disease and its models [8]. Unfortunately, TZD monotherapy in frank diabetes only improves glucose disposal rates by 20–30%, whereas type II diabetics typically display glucose disposal rates of one-half to one-third of those of normal or impaired glucose tolerance subjects [9]. TZDs can be more effective in prediabetes and early type 2 diabetes, as demonstrated in the DPP [10], TRIPOD and PIPOD [11], DREAM [12] and ADOPT [13] trials, as well as when combined with metformin [14] and GLP1 [15]. Based on these clinical facts, this editorial posits that insufficient attention has been paid by both researchers and drug discoverers to the problem – and potential – of poorly treated insulin resistance and requests a renewed focus on this critical half of the root cause of diabetes.

Whole-body resistance to the actions of insulin can be framed as defects in lineage- and pathway-specific biology. Insulin resistance manifests in lowered insulin-stimulated synthesis of triglycerides from fatty acids; reduced inhibition of fatty acid release from triglycerides and adipocytes; partial loss of insulin-stimulated synthesis of hepatic glycogen, hepatic glucose uptake and storage; reduced inhibition of hepatic gluconeogenesis and concomitant loss of amino acid sparing induced by insulin; and diminished insulin-stimulated glucose uptake and glycogen synthesis in skeletal muscle. Binding of insulin to insulin receptors on the surface of adipocytes, hepatocytes and myocytes induces conformational changes in the receptor that trigger tyrosine kinase activity, which stimulates several signaling cascades activating both the PI3K and MAP kinase pathways. The downstream consequences of PI3K pathway stimulation include regulation of glucose transporter GLUT4 and GSK3 activation, resulting in glucose uptake by cells and glycogen synthesis and reduced gluconeogenesis. MAP kinase pathway activation triggers gene expression involved in growth regulation and mitogenic signaling [16].

As TZD treatment is the only clinically validated avenue to even partially normalize insulin resistance in diabetes, it is logical to begin the search for new strategies for insulin sensitization in this biological space. TZDs act through the PPARγ transcription factor, which is predominantly expressed in the adipocyte and also in the macrophage and hepatocyte. While liver and especially skeletal muscle are major tissues of insulin-dependent glucose homeostasis, Sugii et al. demonstrated several years ago that adipose-specific overexpression of PPARγ was sufficient to improve whole-body insulin sensitivity and had a comparable effect to TZD treatment [17]. Thus, understanding the molecular mechanism of this clinically validated insulin sensitization pathway in the adipose depot may provide new therapeutic targets for insulin sensitizer research and drug discovery. Since changes in PPARγ activity in adipocytes can have effects on glucose homeostasis in liver and muscle [17], it is conceivable that release of adipose-derived hormones or alteration of fatty acid metabolism and release from adipose tissue through PPARγ action may contribute to whole-body insulin sensitization [18], suggesting that a systems biology characterization of differential changes along these dimensions in diseased versus normal subjects resistant to the actions of TZDs on glucose disposal may highlight correlations that suggest therapeutic hypotheses and potential targets for testing and drug discovery efforts.

More remarkably, despite clinical validation for insulin sensitization by TZDs, a class of drugs whose target is a well-studied member of a large superfamily of transcription factors, the specific genes and transcriptional programs driving improvements in insulin sensitization by TZDs remain poorly defined. Sugii et al. noted the gene expression changes in liver, muscle, adipose and macrophages, but again therapeutic hypotheses and potential targets for testing and drug discovery efforts may be best generated through a broader campaign of pathway biology investigation of a range of PPARγ activation, either genetically or with a panel of partial agonists. Such targets and pathways may be intrinsically ‘metabolic’, or may include the effects of resident immune and inflammatory cells on adipose, liver and muscle physiology. Interestingly, compounds that minimize classical activation of PPARγ stimulate sufficient metabolic improvements to be tested in clinical trials [19], suggesting that insulin sensitization strategies avoiding PPARγ entirely may be successful.

In conclusion, despite the current prevalence and increasing incidence and disease burden of diabetes, clear gaps in the standard of care remain. In particular, no substantially disease-modifying pharmacotherapy exists, and no obvious candidates for this role are present in late-stage clinical development pipelines. While the goal of β-cell preservation and regeneration has attracted significant research efforts and resources, the equally important goal of normalizing tissue response to glucose sensor–reactor units appears less funded with the resources of scientists’ efforts, money and time. Accordingly, the diabetes community must broaden its future focus to include new therapeutic strategies to treat, and finally completely reverse, insulin resistance in peripheral tissue, particularly in adipose tissue with its resident population of inflammatory cells and demonstrated trans effect on other insulin-responsive tissues. Only then will the physician’s toolkit be capable of providing the optimum combination of treatment options for diabetic patients.

Financial & competing interests disclosure

The author is an employee of Takeda Pharmaceuticals. 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.