Review
Natural history of β-cell adaptation and failure in type 2 diabetes

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Abstract

Type 2 diabetes mellitus (T2D) is a complex disease characterized by β-cell failure in the setting of insulin resistance. The current evidence suggests that genetic predisposition, and environmental factors can impair the capacity of the β-cells to respond to insulin resistance and ultimately lead to their failure. However, genetic studies have demonstrated that known variants account for less than 10% of the overall estimated T2D risk, suggesting that additional unidentified factors contribute to susceptibility of this disease. In this review, we will discuss the different stages that contribute to the development of β-cell failure in T2D. We divide the natural history of this process in three major stages: susceptibility, β-cell adaptation and β-cell failure, and provide an overview of the molecular mechanisms involved. Further research into mechanisms will reveal key modulators of β-cell failure and thus identify possible novel therapeutic targets and potential interventions to protect against β-cell failure.

Introduction

Type 2 diabetes (T2D) is characterized by relative insulin deficiency in response to increase in insulin demand induced by insulin resistance. Experiments in rodent models and human specimens suggest that the failure of β-cells to increase mass and function is a central event in the development of this disease. Multiple factors play a role in the adaption of β-cells during the natural history of T2D. Based on our current understanding of the disease, we would like to divide the adaptation of β-cells during the natural history of T2D in three phases: susceptibility, adaptation, and failure (Fig. 1). The susceptibility of individuals to develop diabetes is determined by genetic components, the fetal environment, and the nutrient environment during the first few years of life (Fig. 1). It is currently believed that these factors are crucial to control the functional β-cell mass before adulthood. Most individuals will not develop T2D unless they are exposed to conditions of increased insulin demand such as obesity-induced insulin resistance. In fact, the majority of the obese population develops insulin resistance and β-cells compensate in response to increased insulin demand by expansion and increase in insulin secretion. Glucose homeostasis in these individuals is conserved at the expense of elevated insulin levels by enhancing insulin secretion and β-cell mass (adaptation phase, Fig. 1). However, in a fraction of obese individuals β-cells fail to properly compensate and hyperglycemia occurs. Human epidemiologic studies using self-reported survey-based data place estimates that only a fraction adult males and females BMI>30 develop T2D (Mokdad et al, 2001, Must et al, 1999, Narayan et al, 2007). The chronic exposure of β-cells to hyperglycemia and other metabolic abnormalities triggered by obesity induces detrimental effects on β-cells manifested with progressive loss of β-cells, deterioration of function and possibly dedifferentiation (β-cell failure, Fig. 1). In the current review, we provide an overview of some of the major established factors that regulate each of the different stages of β-cells during the pathogenesis of T2D.

Section snippets

Susceptibility: Factors regulating the accrual of β-cell mass

The β-cell mass in adult humans and rodents is achieved during the first two decades or four weeks of postnatal life respectively (Finegood et al, 1995, Meier et al, 2008, Perl et al, 2010). Theoretically while there is no data to support this concept, it is plausible to believe that the β-cell mass at the end of these early stages can provide some measure of protection from or risk for T2D. Therefore, an understanding of what establishes β-cell mass at birth and early postnatal stages have

Rodents

Most of our understanding about pancreas development comes from rodent experiments (extensively reviewed here (Oliver-Krasinski, Stoffers, 2008, Wilson et al, 2003)). The earliest stage of pancreas development begins in the mouse on embryonic day (E)8.5. Under the influence of a number of secreted factors from the adjacent primitive gut and vascularization, the presumptive pancreas is progressively defined within early endoderm. A dorsal anlage (quickly followed by a ventral one) expressing

Humans

Human epidemiologic studies established a link between gestational or early life nutrient stressors and a risk for metabolic disease in adulthood, and this concept was termed developmental programming, Infants born to mothers exposed to famine during mid or late pregnancy were found to have a higher glucose response to oral glucose challenge when compared to controls (Ravelli et al., 1998). Moreover, other studies showed that low birth weight was associated with abnormal glucose homeostasis and

Rodents

Another important influence on pancreatic β-cell mass is the expansion that occurs postnatally. At this point the animal is adapting to the postnatal nutrient environment and continuing to undergo significant pancreatic development. In rodents there is a high level of β-cell proliferation that has been reported to reach rates of 4% on day 2 of life (Miller et al, 2009, Scaglia et al, 1997). The proliferation rate continues to be elevated throughout the lactation period, when compared to adult

Rodents

Animal models have also demonstrated an influence of nutritional interventions limited to the postnatal period on adult β-cell mass. High-fat diet exposure during lactation only led to an increase in body fat and glucose intolerance, but no change in β-cell mass (Vogt et al., 2014). Low-protein diet administered only during lactation resulted in a decrease in β-cell mass at postnatal day 21 (Rodriguez-Trejo et al., 2012). Thus, the lactation period is also a critical period of β-cell

β-cell adaptation to insulin resistance states

β-cell mass exhibits a slow turnover after the remodeling phase observed during the first four weeks (rodents) and five years (humans) of life. However, β-cells can expand during conditions of insulin resistance (pregnancy (Sorenson and Brelje, 1997), obesity (Kloppel et al., 1985) and genetic models of insulin resistance (Bruning et al, 1997, Hull et al, 2005, Parsons et al, 1992), and these responses determine the susceptibility to T2D. Proliferation of β-cells has been proposed as a major

β-cell mass in response to pregnancy

During times of prolonged metabolic demand for insulin, including pregnancy, the endocrine pancreas can respond via maternal β-cell hyperplasia and increased insulin secretion to maintain normal blood glucose. Several experimental models in rodents have shown that when β-cell expansion fails to compensate during pregnancy, diabetes occurs, suggesting that defective maternal β-cell adaptation can lead to gestational diabetes mellitus (Karnik et al, 2007, Rieck, Kaestner, 2010, Van Assche et al,

β-cell mass in response to obesity

Obesity is a persistent state of hyperinsulinemia and is a known risk factor for T2D. However, most obese individuals do not develop T2D because β-cells adapt to insulin resistance by increasing β-cell mass and insulin secretion (Prentki and Nolan, 2006). The current view is consistent with the concept that genetic and environmental factors contribute to one's susceptibility to T2D. In rodents, β-cell mass increases throughout the post-weaning lifespan, closely matching the increment in body

β-cell failure

The failure of β-cells to adapt to insulin resistance is necessary for the development of T2D. Therefore, the molecular mechanisms responsible for β-cell failure (loss of both function and mass) have been the focus of study for multiple laboratories around the world in an attempt to prevent or slow the progression of this disease. In addition to all the components mentioned in previous sections, it is well accepted that multiple pathways acting synergistically ultimately result in β-cell

ER stress

The ER is responsible for the biosynthesis and folding of newly synthesized insulin destined for secretion in response to high metabolic demand (reviewed in Back and Kaufman, 2012). A functional ER requires several factors such as adequate levels of ATP and Ca,2+ as well as an optimal oxidizing environment to allow for disulfide-bond formation and proper protein folding (Gaut and Hendershot, 1993). Because of this specialized environment, the ER is highly sensitive to stresses that perturb ATP

Oxidative stress

Chronic hyperglycemia causes increased glucose metabolism through oxidative phosphorylation. This induces mitochondrial dysfunction and the production of reactive oxygen species (ROS) (Tanaka et al., 1999). β-cells are highly susceptible to oxidative stress due to the overabundance of ROS in the islet microenvironment in response to high concentrations of glucose and intrinsically low expression of anti-oxidant enzyme defense mechanisms. For example, the principal antioxidant enzymes superoxide

Islet inflammation

Obesity and T2D are associated with chronic inflammation characterized by the presence of cytokines and immune cell infiltration in tissues involved in energy homeostasis, including fat, liver, muscle, and islets. Although inflammation can be triggered by metabolic signals, how over-nutrition and obesity (high concentration of glucose, lipids, and BCAA) initiate and sustain inflammation in metabolically active tissues including the β-cells is not fully characterized. In response to a

Hexosamine biosynthetic pathway and O-GlcNAcylation

Among the different mechanisms involved in the deleterious effects of glucose, less attention has been given to the hexosamine biosynthetic pathway (HBP) and O-GlcNac Glycosylation (O-GlcNAcylation). O-GlcNAcylation, a reversible post-translational protein modification, consists of the attachment of N-acetylglucosamine (GlcNAc) N-acetylglucosamine (GlcNAc) to the serine or threonine residues of cytosolic or nuclear proteins. This process is controlled by two enzymes; O-GlcNAc transferase (OGT)

β-cell dedifferentiation

β-cell dedifferentiation is an emerging concept that has been the focus of a number of recent studies. In the past few years, new evidence accumulated to illustrate that the pancreas was more “plastic” than we originally thought and that dedifferentiation and transdifferentiation were taking place with increased physiological demand, or inflammation (reviewed in Weir et al, 2013, Ziv et al, 2013). The process and its implications were described in more details in different models of

Summary: Crosstalk among ER and oxidative stress, islet inflammation, and the hexosamine pathway leads to β-cell exhaustion

β-cell failure is driven by β-cell “hyper-stimulation” and subsequent “exhaustion” in the presence of insulin resistance, glucolipotoxic and aminoacidotoxic conditions, and insufficient functional β-cell mass. Crosstalk among different signaling systems and cellular responses such as ER and oxidative stress and pathways activating pro-inflammatory cascades sets a vicious feed-forward cycle that worsens β-cell dysfunction and possibly promotes dedifferentiation. The complexity of the natural

Acknowledgments

The authors apologize to the many authors whose important publications were not cited because of lack of space. The authors wish to acknowledge funding resources for this essential contribution to this work. E.B-M. is supported by the National Institutes of Health (NIH) Grant RO1-DK073716, DK084236, and MERIT award IBX002728A and Juvenile Diabetes Research Foundation (JDRF) grant 17-2013-416. E.U.A was supported by an NIH training grant (2T32DK071212-06), Post-Doctoral Fellowship from the

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