Trends in Endocrinology & Metabolism
ReviewExpansion of β-cell mass in response to pregnancy
Section snippets
β-cell mass and diabetes mellitus
The endocrine pancreas is a microorgan that is essential for glucose homeostasis. Of the five endocrine cell types in the pancreas, the β-cell is arguably the most important, as it produces and secretes the amount of insulin necessary for optimal control of glucose homeostasis. β-cell mass is determined by the product of the number and size of pancreatic β-cells. Once thought to be static and slow in turnover, it is now known that adult β-cells can dynamically respond to systemic increases in
Homeostatic control of β-cell mass
In adult mammals, β-cell mass is maintained by the balance between cell renewal and growth (cell replication, hypertrophy, neogenesis) and cell loss (cell death, atrophy, autophagy) (Figure 1a). There is now growing evidence suggesting that β-cell replication and hypertrophy, in both young mice and humans, occurs during periods of intense metabolic demand 6, 9, 10, 11, e.g. in hyperglycemia after β-cell ablation 12, 13 and in the neonatal period 14, 15, 16, 17, 18 (Figure 1b). Evidence for
Postnatal β-cell mass is regulated by proliferation and apoptosis
Genetic lineage tracing studies performed in the young adult mouse indicate that the great majority of new β-cells are derived through replication of pre-existing β-cells and few, if any, newly formed β-cells stem from progenitor populations under normal circumstances, at least in rodents [23]. Additional genetic experiments in mice support this conclusion. For instance, when cell cycle arrest is induced specifically in β-cells by overexpression of p27 [24] or by deletion of Cdk4 postnatally,
Reversible β-cell mass expansion during pregnancy
It has been recognized for decades that increased β-cell mass is an adaptation to the progressive insulin resistance that develops during pregnancy in women. Placental lactogen and growth hormone increase hepatic gluconeogenesis and lipolysis, and maternal IGF-1 levels increase in response to increased growth hormone levels 2, 39. The precise mechanism of β-cell mass expansion, i.e. proliferation, neogenesis or increase in size, has been elucidated only in part 2, 40, 41 (Figure 2a). However,
Both proliferative and survival signals are required for β-cell expansion
The onset of type 2 diabetes in both humans and rodents is accompanied by a progressive decrease in β-cell mass resulting from an increase in β-cell apoptosis. In this context, it is interesting that during the peak of β-cell proliferation in pregnancy, the antiapoptotic gene Birc5 was upregulated [10]. In pancreatic tissue sections from type 2 diabetics, apoptotic β-cells are often organized in pairs, a finding that has been interpreted as β-cell apoptosis following mitosis as a mechanism of
Potential factors regulating β-cell proliferation, survival and function during pregnancy
Identifying the mediators affecting both β-cell proliferation and survival is a prerequisite for novel treatment options for diabetes. The current view of the major players in the pro-proliferative response of the β-cell to pregnancy is summarized schematically in Figure 3. Of the transcriptional mediators, Foxm1 has been shown to directly activate the transcription of Birc5, the antiapoptotic gene induced during pregnancy discussed previously in this review [63]. Indeed, Foxm1 is required for
Conclusions
Comparison of several paradigms of β-cell expansion suggests that diverse mechanisms can be used by the islet to expand its mass depending on the metabolic setting [10]. This points to the potential development of several therapies to enhance β-mass expansion in patients with diabetes. However, many advances must be made to fully appreciate all the mechanisms available to enhance β-cell proliferation and/or hypertrophy, not only within the β-cell itself, but also encompassing signals
Acknowledgements
We regret the omission of important contributions that we could not discuss because of space constraints. We thank Dr Jake Kushner, Dr John Le Lay and three anonymous reviewers for valuable suggestions on the manuscript. Work on the topic in the Kaestner lab is supported by the JDRF, NIDDK grant R01-DK055243 and the Beta Cell Biology Consortium.
References (84)
Development of a novel polygenic model of NIDDM in mice heterozygous for IR and IRS-1 null alleles
Cell
(1997)Beta cells can be generated from endogenous progenitors in injured adult mouse pancreas
Cell
(2008)Human placental growth hormone
Am J. Obstet. Gynecol.
(1997)Targeted expression of placental lactogen in the beta cells of transgenic mice results in beta cell proliferation, islet mass augmentation, and hypoglycemia
J. Biol. Chem.
(2000)The endocrine pancreas in virgin and pregnant offspring of diabetic pregnant rats
Diabetes Res. Clin. Pract.
(1997)- et al.
Ultrastructural evaluation of B–cell recruitment in virgin and pregnant offspring of diabetic mothers
Diabetes Res. Clin. Pract.
(1998) Absence of caspase-3 protects pancreatic {beta}-cells from c-Myc-induced apoptosis without leading to tumor formation
J. Biol. Chem.
(2009)Lactogens promote beta cell survival through JAK2/STAT5 activation and Bcl-XL upregulation
J. Biol. Chem.
(2007)Hepatocyte growth factor overexpression in the islet of transgenic mice increases beta cell proliferation, enhances islet mass, and induces mild hypoglycemia
J. Biol. Chem.
(2000)Endocrine regulation of energy metabolism by the skeleton
Cell
(2007)
Adaptations in pulsatile insulin secretion, hepatic insulin clearance, and beta-cell mass to age-related insulin resistance in rats
Am. J. Physiol. Endocrinol. Metab.
Adaptation of islets of Langerhans to pregnancy: beta-cell growth, enhanced insulin secretion and the role of lactogenic hormones
Horm. Metab. Res.
Islet pathology and the pathogenesis of type 1 and type 2 diabetes mellitus revisited
Surv. Synth. Pathol. Res.
Global and societal implications of the diabetes epidemic
Nature
Beta-cell deficit and increased beta-cell apoptosis in humans with type 2 diabetes
Diabetes
Sustained beta cell apoptosis in patients with long-standing type 1 diabetes: indirect evidence for islet regeneration?
Diabetologia
Relationship between beta-cell mass and fasting blood glucose concentration in humans
Diabetes Care
Adaptation of islets of Langerhans to pregnancy: increased islet cell proliferation and insulin secretion correlates with the onset of placental lactogen secretion
Endocrinology
The transcriptional response of the islet to pregnancy in mice
Mol. Endocrinol.
Role of apoptosis in failure of beta-cell mass compensation for insulin resistance and beta-cell defects in the male Zucker diabetic fatty rat
Diabetes
Recovery from diabetes in mice by beta cell regeneration
J. Clin. Invest.
Regulated beta-cell regeneration in the adult mouse pancreas
Diabetes
Perspective: Postnatal pancreatic beta cell growth
Endocrinology
Growth dynamics of pancreatic islet cell populations during fetal and neonatal development of the rat
Dev. Dyn.
Beta-cell replication is the primary mechanism subserving the postnatal expansion of beta-cell mass in humans
Diabetes
Apoptosis participates in the remodeling of the endocrine pancreas in the neonatal rat
Endocrinology
Beta cell replication is the primary mechanism for maintaining postnatal beta cell mass
J. Clin. Invest.
PANIC-ATTAC: a mouse model for inducible and reversible beta-cell ablation
Diabetes
Carbonic anhydrase II-positive pancreatic cells are progenitors for both endocrine and exocrine pancreas after birth
Proc. Natl. Acad. Sci. U. S. A.
Pancreatic and duodenal homeobox gene 1 induces expression of insulin genes in liver and ameliorates streptozotocin-induced hyperglycemia
Nat. Med.
Adult pancreatic beta-cells are formed by self-duplication rather than stem-cell differentiation
Nature
Deletion of Cdkn1b ameliorates hyperglycemia by maintaining compensatory hyperinsulinemia in diabetic mice
Nat. Med.
Loss of Cdk4 expression causes insulin-deficient diabetes and Cdk4 activation results in beta-islet cell hyperplasia
Nat. Genet.
Genetic rescue of Cdk4 null mice restores pancreatic beta-cell proliferation but not homeostatic cell number
Oncogene
Survey of the human pancreatic beta-cell G1/S proteome reveals a potential therapeutic role for cdk-6 and cyclin D1 in enhancing human beta-cell replication and function in vivo
Diabetes
Age-dependent decline in beta-cell proliferation restricts the capacity of beta-cell regeneration in mice
Diabetes
Adaptive beta-cell proliferation is severely restricted with advanced age
Diabetes
Bmi-1 regulates the Ink4a/Arf locus to control pancreatic beta-cell proliferation
Genes Dev.
Polycomb protein Ezh2 regulates pancreatic beta-cell Ink4a/Arf expression and regeneration in diabetes mellitus
Genes Dev.
p16INK4a induces an age-dependent decline in islet regenerative potential
Nature
A gene expression network model of type 2 diabetes links cell cycle regulation in islets with diabetes susceptibility
Genome Res.
Replication of genome-wide association signals in UK samples reveals risk loci for type 2 diabetes
Science
Cited by (284)
Pancreatic beta cell regenerative potential of Zanthoxylum chalybeum Engl. Aqueous stem bark extract
2024, Journal of EthnopharmacologyIslet architecture in adult mice is actively maintained by Robo2 expression in β cells
2024, Developmental BiologyBeta-cell compensation and gestational diabetes
2023, Journal of Biological ChemistryAn update on pancreatic regeneration mechanisms: Searching for paths to a cure for type 2 diabetes
2023, Molecular Metabolism