Review
Special issue: Pharmacology in The Netherlands
Preservation of β-cell function by targeting β-cell mass

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Type 2 diabetes is characterized by progressive β-cell dysfunction and a reduction in β-cell mass. Pancreatic islets are a target for adverse effectors such as high concentrations of glucose, pro-inflammatory cytokines and increased free fatty acid concentrations – which are associated with adiposity, insulin resistance and the induction of β-cell apoptosis. If the β-cell mass is already below the threshold for maintaining normoglycemia, the expansion of β-cell mass is the only option for achieving normoglycemia without the use of additional glucose-lowering agents. Therapies based on glucagon-like peptide-1 and combinations of growth factors such as epidermal growth factor and gastrin are promising new strategies for β-cell preservation. In this review, we address the mechanisms involved in β-cell dysfunction and β-cell loss, and provide a rationale for pharmacological intervention for the preservation and/or expansion of β-cell mass in type 2 diabetes.

Introduction

Although there are several subtypes of diabetes mellitus, each with a different pathogenesis, it is now recognized that a defect in insulin secretion caused by a deficit and/or functional impairment in insulin-producing β cells in the pancreatic islets of Langerhans has a key role in the development of hyperglycemia (Figure 1, Figure 2). The time of onset, the speed of progression and the nature of precipitating external and genetic factors that cause the defect in insulin secretion vary in the different subtypes.

Type 2 diabetes is by far the most common subtype, and its occurrence is increasing rapidly because of an imbalance between food intake and energy expenditure, which leads to obesity and insulin resistance [1]. A combination of genetic factors and the adverse metabolic milieu causes a gradual deterioration in β-cell function until hyperglycemia develops in susceptible individuals: for instance, those with abdominal obesity or a history of gestational diabetes mellitus [2]. Once hyperglycemia has developed, oral anti-hyperglycemic drugs are prescribed to improve glycemic control. But this strategy clearly fails to halt the progressive insulin secretion defect in type 2 diabetes, as reflected by the eventual need for additional oral anti-hyperglycemic medication and conversion to insulin treatment in a large number of patients.

In this article, we address the mechanisms involved in β-cell dysfunction and β-cell loss to provide a rationale for why preservation and/or expansion of a functional β-cell mass is a logical approach for pharmacological intervention in type 2 diabetes.

Section snippets

β-Cell mass in normal physiology and in type 2 diabetes

β-Cell mass is determined and maintained by the balance of islet neogenesis (formation of islets from islet precursor cells), hyperplasia (replication of pre-existing β cells), hypertrophy (increase in size of individual β cells) and apoptosis (programmed cell death) [3]. During growth and development, islet neogenesis and β-cell replication are key mechanisms in β-cell mass expansion.

Changes in insulin sensitivity induce changes in insulin secretion to keep glucose concentrations within a

Mechanisms of β-cell dysfunction that can be targeted by pharmacological intervention

The concept that pancreatic islets are a target for adverse effectors associated with adiposity and insulin resistance, which result in islet (target organ) damage, indicates that pharmacological intervention strategies could be aimed at counteracting these factors or protecting the target β cells (Figure 3). Monitoring such a strategy is not easy because β-cell mass cannot be visualized and there are no circulating biomarkers for it. In clinical practice, a crude proxy for preservation of

Anti-hyperglycemic agents

Many observations indicate a detrimental effect (via several biochemical pathways) of high concentrations of glucose on glucose sensing, insulin gene expression, insulin secretion and β-cell survival once overt diabetes has developed (reviewed in Refs 20, 21) (Figure 3, Figure 4). This adverse effect, termed glucotoxicity, has relevant therapeutic consequences, implying that every glucose-lowering strategy aimed at achieving normoglycemia would improve β-cell function and glucose homeostasis.

GLP-1 and GLP-1 receptor agonists

It has long been recognized that there is greater insulin secretion in response to an oral glucose load than to an intravenous glucose load, even when the glucose concentrations after both challenges are similar. This observation has been termed the ’incretin’ effect and is due to the release of incretin hormones from gastrointestinal neuroendocrine cells. The two main incretin hormones are glucagon-like peptide (GLP)-1 and glucose-dependent insulinotropic polypeptide (GIP) (reviewed in Refs 52

Future pharmacological targets: expansion of β-cell mass

The in vivo expansion of β-cell mass is an attractive new area of pharmacological intervention [99]. Identifying and understanding the mechanisms of effectors that are crucial in islet neogenesis and β-cell proliferation, not only during growth and development but also during adaptation of the β-cell mass in a changing metabolic environment in adulthood, are essential. Several factors that stimulate β-cell growth in rodents have been identified and could offer a similar expansion in humans.

One

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