The Role of Preproglucagon Peptides in Regulating β-Cell Morphology and Responses to Streptozotocin-induced Diabetes

Authors

Deanna M. Arble, Marquette UniversityFollow
Chelsea R. Hutch, University of Michigan - Ann Arbor
Hannah Hafner, University of Michigan - Ann Arbor
Daria Stelmak, University of Michigan - Ann Arbor
Kyle Leix, University of Michigan - Ann Arbor
Joyce Sorrell, University of Cincinnati
Joshua W. Pressler, University of Cincinnati
Brigid Gregg, University of Michigan - Ann Arbor
Darleen A. Sandoval, University of Michigan - Ann Arbor

Document Type

Article

Publication Date

3-2023

Publisher

American Physiological Society

Source Publication

American Journal of Physiology: Endocrinology and Metabolism

Source ISSN

1522-1555

Original Item ID

DOI: 10.1152/ajpendo.00152.2022

Abstract

Insulin secretion from β-cells is tightly regulated by local signaling from preproglucagon (Gcg) products from neighboring α-cells. Physiological paracrine signaling within the microenvironment of the β-cell is altered after metabolic stress, such as high-fat diet or the β-cell toxin, streptozotocin (STZ). Here, we examined the role and source of Gcg peptides in β-cell function and in response to STZ-induced hyperglycemia. We used whole body Gcg null (Gcg^Null) mice and mice with Gcg expression either specifically within the pancreas (Gcg^ΔPanc) or the intestine (Gcg^ΔIntest). With lower doses of STZ exposure, insulin levels were greater and glucose levels were lower in Gcg^Null mice compared with wild-type mice. When Gcg was functional only in the intestine, plasma glucagon-like peptide-1 (GLP-1) levels were fully restored but these mice did not have any additional protection from STZ-induced diabetes. Pancreatic Gcg reactivation normalized the hyperglycemic response to STZ. In animals not treated with STZ, Gcg^Null mice had increased pancreas mass via both α- and β-cell hyperplasia and reactivation of Gcg in the intestine normalized β- but not α-cell mass, whereas pancreatic reactivation normalized both β- and α-cell mass. Gcg^Null and Gcg^ΔIntest mice maintained higher β-cell mass after treatment with STZ compared with control and Gcg^ΔPanc mice. Although in vivo insulin response to glucose was normal, global lack of Gcg impaired glucose-stimulated insulin secretion in isolated islets. Congenital replacement of Gcg either in the pancreas or intestine normalized glucose-stimulated insulin secretion. Interestingly, mice that had intestinal Gcg reactivated in adulthood had impaired insulin response to KCl. We surmise that the expansion of β-cell mass in the Gcg^Null mice compensated for decreased individual β-cell insulin secretion, which is sufficient to normalize glucose under physiological conditions and conferred some protection after STZ-induced diabetes.

NEW & NOTEWORTHY We examined the role of Gcg on β-cell function under normal and high glucose conditions. GcgNull mice had decreased glucose-stimulated insulin secretion, increased β-cell mass, and partial protection against STZ-induced hyperglycemia. Expression of Gcg within the pancreas normalized these endpoints. Intestinal expression of Gcg only normalized β-cell mass and glucose-stimulated insulin secretion. Increased β-cell mass in GcgNull mice likely compensated for decreased insulin secretion normalizing physiological glucose levels and conferring some protection after STZ-induced diabetes.

Comments

Accepted version. American Journal of Physiology: Endocrinology and Metabolism, Vol. 324, No. 3 (March 2023): E217-E225. DOI. © 2023 American Physiological Society. Used with permission.

Recommended Citation

Arble, Deanna M.; Hutch, Chelsea R.; Hafner, Hannah; Stelmak, Daria; Leix, Kyle; Sorrell, Joyce; Pressler, Joshua W.; Gregg, Brigid; and Sandoval, Darleen A., "The Role of Preproglucagon Peptides in Regulating β-Cell Morphology and Responses to Streptozotocin-induced Diabetes" (2023). Biological Sciences Faculty Research and Publications. 947.
https://epublications.marquette.edu/bio_fac/947