Expansion of β-cell mass in response to pregnancy

doi:10.1016/j.tem.2009.11.001

Trends in Endocrinology & Metabolism

Volume 21, Issue 3, March 2010, Pages 151-158

https://doi.org/10.1016/j.tem.2009.11.001 Get rights and content

Inadequate β-cell mass can lead to insulin insufficiency and diabetes. During times of prolonged metabolic demand for insulin, the endocrine pancreas can respond by increasing β-cell mass, both by increasing cell size and by changing the balance between β-cell proliferation and apoptosis. In this paper, we review recent advances in our understanding of the mechanisms that control the adaptive expansion of β-cell mass, focusing on the islet's response to pregnancy, a physiological state of insulin resistance. Functional characterization of factors controlling both β-cell proliferation and survival might not only lead to the development of successful therapeutic strategies to enhance the response of the β-cell to increased metabolic loads, but also improve islet transplantation regimens.

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.

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Trends in Endocrinology & Metabolism

ReviewExpansion of β-cell mass in response to pregnancy

Section snippets

β-cell mass and diabetes mellitus

Homeostatic control of β-cell mass

Postnatal β-cell mass is regulated by proliferation and apoptosis

Reversible β-cell mass expansion during pregnancy

Both proliferative and survival signals are required for β-cell expansion

Potential factors regulating β-cell proliferation, survival and function during pregnancy

Conclusions

Acknowledgements

Cell

Cell

Am J. Obstet. Gynecol.

J. Biol. Chem.

Diabetes Res. Clin. Pract.

Diabetes Res. Clin. Pract.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

Cell

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

Review
Expansion of β-cell mass in response to pregnancy