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Diabetes drugs that protect pancreatic β cells

Akira Nakatsuma

Kagawa School of Pharmaceutical Sciences, Tokushima Bunri University, Japan

Yoshimitsu Kiriyama

Kagawa School of Pharmaceutical Sciences, Tokushima Bunri University, Japan

Katsuhito Kino

Kagawa School of Pharmaceutical Sciences, Tokushima Bunri University, Japan

Masaki Ninomiya

Kagawa School of Pharmaceutical Sciences, Tokushima Bunri University, Japan

E-mail : m-nino@kph.bunri-u.ac.jp

DOI: 10.15761/IMM.1000189.

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Abstract

 Many drugs, such as sulfourea, rapid-acting insulin secretagogues, biguanides, thiazolidines, alpha-glucosidase inhibitors, sodium glucose cotransporter 2 inhibitors, and dipeptidyl peptidase-4 inhibitors, have been developed for treating diabetes orally. Currently, it is possible to choose from these drugs to specifically treat the condition of the individual patient. However, blood glucose control of most oral diabetes drugs gradually diminishes, necessitating blood glucose control by insulin. It has been indicated that the glucotoxicity and lipotoxicity of oral diabetes drugs cause malfunction of the pancreatic β cells, leading to a decrease in the pancreatic β cells by apoptosis. Oral diabetes drugs that can control blood glucose levels and protect the pancreatic β cells are under development. In this review, we will discuss the current developmental status of oral diabetes drugs and the possibility of treatments that can preserve the function of pancreatic β cells.

Key words

type 2 diabetes, incretins, GPR40, GPR119, glucokinase activators, 11β-hydroxysteroid dehydrogenase inhibitors

Introduction

According to an announcement by the International Diabetes Federation (IDF) in 2014, the number of people with diabetes is 387 million worldwide (prevalence, 8.3%) [1]. Diabetes is a chronic disease that significantly decreases the quality of life (QOL) in patients through complications such as retinopathy, neuropathy, nephropathy, and cardiovascular disorders. Not only the medical burden, but also the economic burden is huge. Patients with type 2 diabetes account for 90% of diabetes cases, and the incidence of type 2 diabetes is particularly increasing in people 40-59 years of age [1]. It is expected that appropriate blood glucose control be carried out from an early stage to prevent diabetic complications (especially cardiovascular events) that can lead to decreased QOL in patients [2]. However, the United Kingdom Prospective Diabetes Study (UKPDS) reported that, with increasing age, functional decline of the pancreatic β cells occurs; the pancreatic β cells are important for blood glucose control, and blood glucose control therefore becomes worse when their function declines [3]. In addition, a five-year follow-up survey conducted by the “A Diabetes Outcome Progression Trial” (ADOPT study) confirmed that blood glucose control by metformin or sulfourea (SUs) worsens with age, although blood glucose is well-controlled just after these drugs are first administered [4]. The age-related decrease in pancreatic β cell function is considered to be associated with lipotoxicity engendered by free fatty acids [5-7]. It is known that free fatty acids promote glucose-stimulated insulin secretion (GSIS) in pancreatic β cells via the pathway of G protein-coupled receptor 40 (GPR40) or the pathway of intracellular fatty acyl-coenzyme A (FA-CoA) [8,9] (Figure 1). However, the exposure of pancreatic β cells to highly concentrated free fatty acids over the long term increases the expression of carnitine palmitoyltransferase1 (CPT-1) and uncoupling protein-2 (UCP-2) and decreases FA-CoA levels, leading to a decrease in GSIS [5-7]. Moreover, it is considered that apoptosis of pancreatic β cells is easily induced by oxidative stress caused by glucotoxicity and oxidized low-density lipoprotein (LDL) [10,11]. It has been confirmed in diabetic patients and in a diabetic mouse model that pancreatic β cells decrease by apoptosis [12,13]. In addition, hypoglycemia is of concern because the promotion of insulin secretion by SUs does not depend on the concentration of glucose [14]. Although strict blood glucose control is important for the inhibition of cardiovascular events in diabetic patients [2], hypoglycemia increases the risk of cardiovascular events [15]. Therefore, medicines that promote GSIS or maintain pancreatic β cell function are needed.

Incretin-based drugs expected to protect pancreatic β cells

Incretins are gastrointestinal hormones secreted from the small intestine. The two main incretins are glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) (Figure 1). Approximately 10 years ago, the US Food and Drug Administration (FDA) approved exenatide, which is a GLP-1 analogue and one of several incretin-based drugs. The relationship between exenatide therapy and the risk of pancreatitis has been pointed out in case reports that were published after the clinical trial and release of the drug [16,17]. However, the increased risk for pancreatitis produced by incretin-based drugs was negated by the results of meta-analysis studies and cohort studies [18,19]. In addition to the promotion of GSIS, incretin-based drugs also protect pancreatic β cells through long-term administration [20-22].

Lipotoxicity, which causes malfunction of pancreatic β cells, can be reduced by the ATP-binding cassette, subfamily A member 1 (ABCA1) transporter, which promotes cholesterol efflux from cells. Loss of function of ABCA1 in pancreatic β cells results in the accumulation of cholesterol and a reduction in insulin secretion [23,24]. In contrast, increased expression of ABCA1 leads to improved insulin secretion and protection of pancreatic β cells from lipotoxicity [25]. Li et al. reported that exendin-4, a GLP-1 agonist, induced the expression of ABCA1 in pancreatic β cells via the CaMKK/CaMKIV signaling pathway [26]. Therefore, the induction of ABCA1 by GLP-1 is likely to protect pancreatic β cells from lipotoxicity. In addition, GLP-1 agonists induce the expression of B-cell lymphoma 2 (BCL2), an anti-apoptotic protein, and reduce the expression of caspase-3, a protein with a central role in the execution phase of apoptosis. GLP-1 agonists also inhibit apoptosis induced by glucose or fats [27,28]. Thus, it is considered that GLP-1 agonists function to protect pancreatic β cells as well as improve their insulin secretion.

Development of oral diabetes drugs

Incretin-based drugs offer superior GSIS promotion and protect pancreatic β cells, and have extensively changed the treatment of type 2 diabetes. Incretin-based drugs must be administered by injection because incretin-based drugs are GLP-1 analogues. Thus, incretin-based drugs have the disadvantage that they cannot be administered to all patients, necessitating the development of new oral diabetes drugs. Candidates for new oral diabetes drugs are G protein-coupled receptor (GPR) 40 agonists, GRP119 agonists, glucokinase activators, and 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) inhibitors [29-37] (Tables 1 and 2).

Table 1. The different types of oral diabetes drugs under development

Target

Compound

Company

Status

Ref.

GPR40 agonist

 

 

 

GPR119 agonist

 

 

 

 

glucokinase activator

 

 

 

 

 

11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) inhibitor

 

Other

Fasiglifam (TAK-875)

JTT-851

LY2881835

 

PSN821

MBX-2982

GSK1292263

DS-8500a

 

TAK-329

PF-04937319

AZD6370

AZD1656

Piragliatin

 

PF-00915275

INCB-13739


Colestilan

Takeda

Japan Tobacco

Eli Lilly

 

Prosidion

CymaBay Therapeutics

GlaxoSmithKline

Daiichi-Sankyo

 

Takeda

Pfizer

AstraZeneca

AstraZeneca

Roche

 

Pfizer

Incyte

 

Mitsubishi Tanabe

Phase3  discontinued

Phase2

Phase1

 

Phase2  inetrruption

Phase2

Phase2  discontinued

Phase2

 

Phase1  discontinued

Phase2

Phase1  discontinued

Phase1  discontinued

Phase2

 

Phase1

Phase2

Phase2  additional indication

46

29

29

 

30

30

30

31

 

33

32

56

57

52

 

34

64

 

68

Table 2. Structures of diabetes drugs under development

compound

Ref.

Fasiglifam

(TAK-875)

29

LY2881835

29

MBX-2982

30

GSK1292263

30

PF-04937319

34

AZD1656

PubChem16039797

Piragliatin

34

PF-00915275

36,37

Agonists for GPR40 and GPR119

GRP40 is expressed in pancreatic β cells and the intestinal tract [9,38]. GSIS is enhanced by an inositol-3-phosphate-mediated increase in the intracellular calcium concentration via GRP40 in pancreatic β cells (Figure 1) [9,39,40]. The tissue distribution of GPR40 overlaps with GPR119, a Gs-coupled receptor [41,42]. GSIS in pancreatic β cells is also enhanced by a cyclic AMP (cAMP)-mediated increase in the intracellular calcium concentration via GRP119 [42]. Moreover, both GPR40 and GPR119 are expressed in K and L cells in the small intestine, and lipids induce GLP-1 and GIP via GPR40 or GPR119 [9,29,43]. Thus, it may be possible for agonists for GPR40 and GPR119 to enhance GSIS by the direct stimulation of pancreatic β cells and induction of incretins. Moreover, since it is possible to administer agonists for GPR40 and GPR119 orally (Table 1), they are expected to be developed as alternative drugs for GLP-1 analogues that are administered by injection only. At least GPR40 agonists do not cause lipotoxicity [44,45].

Figure 1. The mechanisms of major diabetes drugs

Fasiglifam (TAK-875) (Tables 1 and 2), the most-developed GPR40 agonist, effectively reduces blood glucose. However, the development of fasiglifam was stopped due to its hepatotoxicity [46]. There are dozens of candidate agonists for GPR40 and GPR119. JTT-851, MBX-2982, and DS-8500a (Table 2) are in phase II trials, and are expected to become new oral diabetes drugs [29-31].

Glucokinase activators

Pancreatic β cells function as glucose sensors and control GSIS. Insulin from pancreatic β cells inhibits gluconeogenesis and induces glycogen synthesis in the liver, which is the important organ in controlling blood glucose. Glucokinase is the rate-limiting enzyme that converts glucose to glucose-6-phosphate during glycolysis. The activity of glucokinase is reduced in the livers of diabetic patients [47]. Glucokinase activators, which activate glucokinase by binding to the allosteric site, are expected to promote glycometabolism in the liver and promote increased control of blood glucose [48]. In addition, it is considered that glucokinase activators contribute to the promotion of insulin secretion in pancreatic β cells via the ATP-dependent potassium channel that is opened by the glucose-dependent increase of ATP (Figure 1) [49]. Moreover, glucokinase activators stimulate the growth of pancreatic β cells and inhibit apoptosis caused by oxidative stress and glucotoxicity [50,51]. In a mouse model of diabetes, glucokinase activators have been shown to effectively reduce blood glucose and increase pancreatic β cells [49,52]. PF-04937319 and piragliatin (Tables 1 and 2) have been shown to effectively control blood glucose in clinical trials [53,54]. Although AZD1656 and AZD6370 can also effectively control blood glucose just after administration [55,56], their effectiveness in controlling blood glucose was found to decrease with long-term administration [57,58]. More clinical trials of glucokinase activators are necessary.

11 β-HSD1 inhibitors

11β-HSD1 is expressed in hepatocytes and adipocytes and converts cortisone to cortisol (Figure 1). The expression level of 11β-HSD1 is up-regulated in the adipose tissue of patients with acquired obesity. Cortisol induces insulin resistance and the secretion of inflammatory cytokines, such as tumor necrosis factor-α, interleukin (IL)-1, and IL-6, by activating the glucocorticoid receptor in adipocytes (Figure 1) [59,60]. Since a high-fat diet did not induce diabetes and dyslipidemia in 11β-HSD1–knockout mice, it is suggested that 11β-HSD1 is associated with the progression from obesity to insulin resistance and diabetes [61,62]. Metformin, a first-line drug for diabetes, together with INCB-13739 (Table 1), an 11β-HSD1 inhibitor, resulted in a 24% reduction in homeostasis model assessment-insulin resistance (HOMA-IR, the index of insulin resistance) and a 0.6% reduction in glycated hemoglobin (HbA1c) compared to metformin only [63,64]. Thus, 11β-HSD1 inhibitors can be candidate drugs for diabetes with obesity.

Other diabetes drugs under clinical trials

Many patients with type 2 diabetes also have dyslipidemia, which leads to insulin resistance and lipotoxicity in pancreatic β cells. Therefore, treatment of dyslipidemia in addition to diabetes can improve blood glucose levels. Colestilan (Table 1) is one dyslipidemia drugs that improves hypercholesterolemia and promotes the metabolism of cholesterol to bile acid through facilitating bile acid secretion. It has been known that colestilan reduces blood glucose in diabetic patients [65]. Moreover, colestilan has been observed to increase GLP-1 levels as well as reduce cholesterol levels in a mouse model of diabetes [66,67]. In a 12-week clinical trial conducted by Kondo et al., patients with type 2 diabetes received colestilan, which reduced not only LDL cholesterol levels, but also HbA1c, compared with patients with type 2 diabetes who received placebo therapy [68]. Administration of colesevelam, a dyslipidemia drug, also reduced LDL and HbA1c in patients with type 2 diabetes [69]. Colestilan is expected to become the diabetes drug of choice for treating patients with diabetes having high LDL cholesterol.

Oral diabetes drugs expected to protect pancreatic β cells

Diabetes treatment in the past has focused on the glucotoxicity created by high blood glucose levels. An important focus for diabetes treatment has been the development of drugs to control blood glucose levels by promoting insulin secretion. However, the importance of protecting pancreatic β cells and not causing hypoglycemia has been recognized.

Currently, dipeptidyl peptidase-4 (DPP-4) inhibitors, incretin-based drugs, and GLP-1 analogues are already on the market; these drugs are the most useful because they protect pancreatic β cells as well as control blood glucose. In addition, although the present GLP-1 analogues must be administered once daily, a new GLP-1 analogue has been developed for administration once weekly [70].

In this review, we described oral diabetes drugs under development that aim to protect pancreatic β cells and decrease insulin resistance. New oral diabetes drugs are expected to provide different types of treatment that can be adapted for the particular conditions of individual diabetic patients.

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Editorial Information

Editor-in-Chief

Masayoshi Yamaguchi
Emory University School of Medicine

Article Type

Review Article

Publication history

Received date: November 28, 2015
Accepted date: December 09, 2015
Published date: December 12, 2015

Copyright

©2016 Nakatsuma A. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Citation

Nakatsuma A, Kiriyama Y, Kino K, Ninomiya M (2016) Diabetes drugs that protect pancreatic β cells. Integr Mol Med 3: DOI: 10.15761/IMM.1000189.

Corresponding author

Masaki Ninomiya

Tokushima Bunri University, Kagawa School of Pharmaceutical Sciences, Shido 1314-1, Sanuki, Kagawa 769-2193, Japan, Tel: +81-87-899-7100; Fax: +81-87-894-0181

E-mail : m-nino@kph.bunri-u.ac.jp

Table 1. The different types of oral diabetes drugs under development

Target

Compound

Company

Status

Ref.

GPR40 agonist

 

 

 

GPR119 agonist

 

 

 

 

glucokinase activator

 

 

 

 

 

11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) inhibitor

 

Other

Fasiglifam (TAK-875)

JTT-851

LY2881835

 

PSN821

MBX-2982

GSK1292263

DS-8500a

 

TAK-329

PF-04937319

AZD6370

AZD1656

Piragliatin

 

PF-00915275

INCB-13739


Colestilan

Takeda

Japan Tobacco

Eli Lilly

 

Prosidion

CymaBay Therapeutics

GlaxoSmithKline

Daiichi-Sankyo

 

Takeda

Pfizer

AstraZeneca

AstraZeneca

Roche

 

Pfizer

Incyte

 

Mitsubishi Tanabe

Phase3  discontinued

Phase2

Phase1

 

Phase2  inetrruption

Phase2

Phase2  discontinued

Phase2

 

Phase1  discontinued

Phase2

Phase1  discontinued

Phase1  discontinued

Phase2

 

Phase1

Phase2

Phase2  additional indication

46

29

29

 

30

30

30

31

 

33

32

56

57

52

 

34

64

 

68

Table 2. Structures of diabetes drugs under development

compound

Ref.

Fasiglifam

(TAK-875)

29

LY2881835

29

MBX-2982

30

GSK1292263

30

PF-04937319

34

AZD1656

PubChem16039797

Piragliatin

34

PF-00915275

36,37

Figure 1. The mechanisms of major diabetes drugs