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J Clin Endocrinol Metab. 2014 Mar;99(3):748-56. doi: 10.1210/jc.2013-2952. Epub 2013 Nov 27.

Pancreatic α-cell hyperplasia: facts and myths.

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1
Division of Endocrinology and Carcinoid and Neuroendocrine Tumor Center, Cedars-Sinai Medical Center, Los Angeles, California 90048.

Abstract

CONTEXT:

Pancreatic α-cell hyperplasia (ACH) was once an esoteric pathological entity, but it has become an important differential diagnosis of hyperglucagonemia after inactivating glucagon receptor (GCGR) genomic mutations were found in patients with ACH. Recently, the controversy over the pancreatic effects of incretins has stimulated much discussion of ACH that often includes inaccurate statements not supported by the literature.

DATA ACQUISITION:

Literature related to ACH was reviewed.

EVIDENCE SYNTHESIS:

ACH is defined as a diffuse and specific increase in the number of α-cells. A dozen cases have been reported and fall into three clinical types: reactive, functional, and nonfunctional. Characterized by remarkable hyperglucagonemia without glucagonoma syndrome, reactive ACH is caused by inactivating GCGR mutations, and its main clinical significance is pancreatic neuroendocrine tumors diagnosed at middle age. The Gcgr(-/-) mice, a model of reactive ACH, exhibit a multistage tumorigenesis in their pancreata. Pharmacological agents that inhibit glucagon signaling also cause reactive ACH in animals and possibly in humans as well. The pancreata of incretin-treated humans and those of reactive ACH murine models share similarities. Functional ACH features hyperglucagonemia with glucagonoma syndrome. Nonfunctional ACH is associated with normal glucagon levels. The causes of functional and nonfunctional ACH are unknown as yet.

CONCLUSIONS:

ACH is a histological diagnosis and clinically heterogeneous. Caused by GCGR mutations, reactive ACH is a preneoplastic lesion giving rise to slow-developing pancreatic neuroendocrine tumors. The effects of treatments targeting glucagon signaling in this regard remain controversial. The strong negative feedback control of glucagon signaling conserved in all mammals studied, including humans, makes long-term pancreatic tumor surveillance advisable for the glucagon signaling-targeting therapies.

PMID:
24285676
DOI:
10.1210/jc.2013-2952
[Indexed for MEDLINE]
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