Marlon E. Cerf
2013
Abstract
Beta cell dysfunction and insulin resistance are inherently complex with their interrelation for triggering the pathogenesis of diabetes also somewhat undefined. Both pathogenic states induce hyperglycemia and therefore increase insulin demand. Beta cell dysfunction results from inadequate glucose sensing to stimulate insulin secretion therefore elevated glucose concentrations prevail. Persistently elevated glucose concentrations above the physiological range result in the manifestation of hyperglycemia. With systemic insulin resistance, insulin signaling within glucose recipient tissues is defective therefore hyperglycemia perseveres. Beta cell dysfunction supersedes insulin resistance in inducing diabetes. Both pathological states influence each other and presumably synergistically exacerbate diabetes. Preserving beta cell function and insulin signaling in beta cells and insulin signaling in the glucose recipient tissues will maintain glucose homeostasis.
Introduction
Both beta cell dysfunction and insulin resistance lead to persistent hyperglycemia which characterizes type 2 diabetes. Many of the susceptibility genes associated with type 2 diabetes by genome-wide investigations (GWAS) were identified as regulators of cell turnover or regeneration (McCarthy and Hattersley, 2008). Most risk variants for type 2 diabetes in healthy populations act through impairing insulin secretion (resulting in beta cell dysfunction) rather than insulin action (resulting in insulin resistance) which establishes that inherited abnormalities of beta cell function or mass (or both) are critical precursors in type 2 diabetes (Florez, 2008; McCarthy, 2010; Voight et al., 2010; Petrie et al., 2011). Recent linkage studies and GWAS have identified >40 genes that increase the risk of type 2diabetes with the most important diabetes susceptibility gene identified as transcription factor 7-like 2 (tcf7l2), which increases diabetes risk 1.7-fold (Ashcroft and Rorsman, 2012). Potassium voltage-gated channel, KQT-like subfamily, member 1 (Kcnq1) is a type 2 diabetes susceptibility gene implicated in reduced beta cell function and decreased insulin secretion (Bonnefond et al., 2010). Common variants in several neonatal diabetes mellitus and maturity-onset diabetes of the young (MODY) [e.g., potassium inwardly rectifying channel, subfamily J, member 11 (kcnj11), glucokinase (gck), hepatocyte nuclear factor 4 alpha (hnf1α), and hnf1β] are recognized as type 2 diabetes susceptibility variants 6 and 43 (Bonnefond et al., 2010). Reduced expression of the transcription factor, prospero homeobox 1 (Prox1), by cis-regulatory variants altered beta cell insulin secretion which conferred susceptibility to type 2 diabetes (Lecompte et al., 2013).
Beta cell dysfunction is the critical determinant for type 2 diabetes (Ashcroft and Rorsman, 2012) which is compounded by insulin resistance. The interplay between beta cell dysfunction and insulin resistance remains highly complex. The onset of hyperglycemia can trigger both beta cell dysfunction and insulin resistance (Figure 1) Beta cell dysfunction is more severe than insulin resistance (Figure 1).
With beta cell dysfunction, insulin secretion is impaired whereas with insulin resistance, insulin may still be secreted but insulin insensitivity manifests in target tissues. As beta cell dysfunction and insulin resistance exacerbate, hyperglycemia amplifies leading to the progression to type 2 diabetes (Figure 1).This review focuses on beta cells: physiology and integrity, demise and dysfunction, compensation, and preservation.
Perspectives on Beta Cell Dysfunction and Insulin Resistance
Beta cell dysfunction signals an advanced state of diabetes as insufficient insulin is secreted to meet demand. Insulin resistance precedes the pathogenesis for several modern diseases (Samuel and Shulman, 2012). Thus understanding the pathogenesis of insulin resistance has become increasingly important to guide the development of future therapies and inform health and economic policy (Samuel and Shulman, 2012).
The relationship between insulin resistance and beta cell dysfunction is dynamic and largely dependent on the metabolic state that is primarily determined by glycemic status and consequently insulinemic status. Both a high fat diet and obesity trigger insulin resistance independently, with a high fat diet contributing to overweight and obesity (Figure 3).
In the etiology of beta cell dysfunction, firstly, beta cell physiology is maintained in healthy individuals (Figure 3). However, glucolipotoxicity and proinflammatory cytokines induce oxidative stress leading to beta cell demise, although other stressors exist (Figure 3). Beta cell compensation occurs when beta cell integrity is diminished. If beta cell compensation is successful, beta cell physiology is maintained (Figure 3). However if beta cell compensation is exhausted, beta cell dysfunction ensues (Figure 3). Insulin resistance impairs beta cell physiology and compensation thereby inducing beta cell demise and dysfunction. Beta cell replenishment and preservation, through novel agents, healthy lifestyles of balanced diets and regular exercise, maintains beta cell physiology, and compensation (when necessary) therefore protecting against beta cell demise and dysfunction (Figure 3).
The main intervention strategy is to maintain sufficient beta cell compensation to restore and maintain beta cell physiology to avoid beta cell dysfunction and the subsequent progression to diabetes. This is achieved by maintaining adequate beta cell preservation, i.e., by preserving beta cell structure and function, and replenishment by lifestyle and, if necessary, therapeutic interventions. Beta cell physiology should be preserved throughout life but is adversely impacted with aging and altered metabolic states such as obesity that requires a sustained increase in insulin. Insulin resistance promotes beta cell demise and inhibits beta cell compensation which thereby promotes beta cell dysfunction. Replenishing or preserving beta cells maintains beta cell physiology and allows for beta cell compensation which combats beta cell demise and beta cell dysfunction.The preservation of beta cells by replenishment to mitigate against insults and maintain beta cell physiology will improve the metabolic outcomes associated with diabetes.
