ReviewNatural history of β-cell adaptation and failure in type 2 diabetes
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
References (281)
- et al.
Type 2 diabetes mellitus after gestational diabetes: a systematic review and meta-analysis
Lancet
(2009) - et al.
Development of a novel polygenic model of NIDDM in mice heterozygous for IR and IRS-1 null alleles
Cell
(1997) - et al.
Gestational high-fat programming impairs insulin release and reduces Pdx-1 and glucokinase immunoreactivity in neonatal Wistar rats
Metabolism
(2009) - et al.
TNF-alpha and IFN-gamma potentiate the deleterious effects of IL-1 beta on mouse pancreatic islets mainly via generation of nitric oxide
Cytokine
(1994) - et al.
Inflammation in obesity and diabetes: islet dysfunction and therapeutic opportunity
Cell Metab
(2013) - et al.
Interleukin-1 beta induces the expression of an isoform of nitric oxide synthase in insulin-producing cells, which is similar to that observed in activated macrophages
FEBS Lett
(1992) - et al.
Obesity and hyperinsulinemia in a family with pancreatic agenesis and MODY caused by the IPF1 mutation Pro63fsX60
Transl. Res
(2010) - et al.
Lactogens promote beta cell survival through JAK2/STAT5 activation and Bcl-XL upregulation
J. Biol. Chem
(2007) - et al.
Pdx1 maintains beta cell identity and function by repressing an alpha cell program
Cell Metab
(2014) - et al.
The modification and assembly of proteins in the endoplasmic reticulum
Curr. Opin. Cell Biol
(1993)
Non-beta-cell progenitors of beta-cells in pregnant mice
Organogenesis
Thyroid hormone promotes postnatal rat pancreatic beta-cell development and glucose-responsive insulin secretion through MAFA
Diabetes
Increased O-GlcNAc transferase in pancreas of rats with streptozotocin-induced diabetes
Diabetologia
Elevation of the post-translational modification of proteins by O-linked N-acetylglucosamine leads to deterioration of the glucose-stimulated insulin secretion in the pancreas of diabetic Goto-Kakizaki rats
Glycobiology
Maternal diet-induced microRNAs and mTOR underlie beta cell dysfunction in offspring
J. Clin. Invest
Glucose infusion in mice: a new model to induce beta-cell replication
Diabetes
Prolactin-signal transduction in neonatal rat pancreatic islets and interaction with the insulin-signaling pathway
Horm. Metab. Res
Participation of prolactin receptors and phosphatidylinositol 3-kinase and MAP kinase pathways in the increase in pancreatic islet mass and sensitivity to glucose during pregnancy
J. Endocrinol
Notch signalling controls pancreatic cell differentiation
Nature
Control of beta-cell differentiation by the pancreatic mesenchyme
Diabetes
Defective prolactin signaling impairs pancreatic beta-cell development during the perinatal period
Am. J. Physiol. Endocrinol. Metab
Glucose amplifies fatty acid-induced endoplasmic reticulum stress in pancreatic beta-cells via activation of mTORC1
PLoS ONE
Stimulation of autophagy improves endoplasmic reticulum stress-induced diabetes
Diabetes
Endoplasmic reticulum stress and type 2 diabetes
Annu. Rev. Biochem
Type 2 (non-insulin-dependent) diabetes mellitus, hypertension and hyperlipidaemia (syndrome X): relation to reduced fetal growth
Diabetologia
Insulin stimulates primary beta-cell proliferation via Raf-1 kinase
Endocrinology
Endocrine pancreas development in growth-retarded human fetuses
Diabetes
Islet beta cell expression of constitutively active Akt1/PKB alpha induces striking hypertrophy, hyperplasia, and hyperinsulinemia
J. Clin. Invest
Human beta-cell proliferation and intracellular signaling part 2: still driving in the dark without a road map
Diabetes
Dynamic interaction of BiP and ER stress transducers in the unfolded-protein response
Nat. Cell Biol
Fgf10 is essential for maintaining the proliferative capacity of epithelial progenitor cells during early pancreatic organogenesis
Development
Free fatty acids induce a proinflammatory response in islets via the abundantly expressed interleukin-1 receptor I
Endocrinology
Compensatory growth of pancreatic beta-cells in adult rats after short-term glucose infusion
Diabetes
Distinctive roles for prolactin and growth hormone in the activation of signal transducer and activator of transcription 5 in pancreatic islets of langerhans
Endocrinology
Obese children with low birth weight demonstrate impaired beta-cell function during oral glucose tolerance test
J. Clin. Endocrinol. Metab
Beta-cell deficit and increased beta-cell apoptosis in humans with type 2 diabetes
Diabetes
Adaptive changes in pancreatic beta cell fractional area and beta cell turnover in human pregnancy
Diabetologia
Transcriptional control of mammalian pancreas organogenesis
Cell. Mol. Life Sci
Cytokines downregulate the sarcoendoplasmic reticulum pump Ca2+ ATPase 2b and deplete endoplasmic reticulum Ca2+, leading to induction of endoplasmic reticulum stress in pancreatic beta-cells
Diabetes
GATA4 and GATA6 control mouse pancreas organogenesis
J. Clin. Invest
Impairment of the ubiquitin-proteasome pathway is a downstream endoplasmic reticulum stress response induced by extracellular human islet amyloid polypeptide and contributes to pancreatic beta-cell apoptosis
Diabetes
Islet cell response in the neonatal rat after exposure to a high-fat diet during pregnancy
Am. J. Physiol. Regul. Integr. Comp. Physiol
Compromised beta-cell development and beta-cell dysfunction in weanling offspring from dams maintained on a high-fat diet during gestation
Pancreas
Differential regulation of adaptive and apoptotic unfolded protein response signalling by cytokine-induced nitric oxide production in mouse pancreatic beta cells
Diabetologia
Causes and cures for endoplasmic reticulum stress in lipotoxic beta-cell dysfunction
Diabetes Obes. Metab
Restoring Insulin Secretion (RISE): design of studies of beta-cell preservation in prediabetes and early type 2 diabetes across the life span
Diabetes Care
Hexosamines regulate sensitivity of glucose-stimulated insulin secretion in beta-cells
Am. J. Physiol. Endocrinol. Metab
O-GlcNAcomics – revealing roles of O-GlcNAcylation in disease mechanisms and development of potential diagnostics
Proteomics Clin. Appl
Induction of beta-cell proliferation and retinoblastoma protein phosphorylation in rat and human islets using adenovirus-mediated transfer of cyclin-dependent kinase-4 and cyclin D1
Diabetes
Molecular control of cell cycle progression in the pancreatic beta-cell
Endocr. Rev
Cited by (178)
Naringenin protects pancreatic β cells in diabetic rat through activation of estrogen receptor β
2023, European Journal of PharmacologyStearoyl-CoA desaturase 1 deficiency exacerbates palmitate-induced lipotoxicity by the formation of small lipid droplets in pancreatic β-cells
2023, Biochimica et Biophysica Acta - Molecular Basis of DiseaseAssociation of triglyceride–glucose index and its 6-year change with risk of hypertension: A prospective cohort study
2023, Nutrition, Metabolism and Cardiovascular Diseasesβ-cell neogenesis: A rising star to rescue diabetes mellitus
2023, Journal of Advanced ResearchCombined therapy of GABA and sitagliptin prevents high-fat diet impairment of beta-cell function
2023, Molecular and Cellular EndocrinologyAssociation between protein undernutrition and diabetes: Molecular implications in the reduction of insulin secretion
2024, Reviews in Endocrine and Metabolic Disorders