Decreasing Cx36 Gap Junction Coupling Compensates for Overactive KATP Channels to Restore Insulin Secretion and Prevent Hyperglycemia in a Mouse Model of Neonatal Diabetes
Open accessAbstract
Mutations to the ATP-sensitive K+ channel (KATP channel) that reduce the sensitivity of ATP inhibition cause neonatal diabetes mellitus via suppression of β-cell glucose-stimulated free calcium activity ([Ca2+]i) and insulin secretion. Connexin-36 (Cx36) gap junctions also regulate islet electrical activity; upon knockout of Cx36, β-cells show [Ca2+]i elevations at basal glucose. We hypothesized that in the presence of overactive ATP-insensitive KATP channels, a reduction in Cx36 would allow elevations in glucose-stimulated [Ca2+]i and insulin secretion to improve glucose homeostasis. To test this, we introduced a genetic knockout of Cx36 into mice that express ATP-insensitive KATP channels and measured glucose homeostasis and islet metabolic, electrical, and insulin secretion responses. In the normal presence of Cx36, after expression of ATP-insensitive KATP channels, blood glucose levels rapidly rose to >500 mg/dL. Islets from these mice showed reduced glucose-stimulated [Ca2+]i and no insulin secretion. In mice lacking Cx36 after expression of ATP-insensitive KATP channels, normal glucose levels were maintained. Islets from these mice had near-normal glucose-stimulated [Ca2+]i and insulin secretion. We therefore demonstrate a novel mechanism by which islet function can be recovered in a monogenic model of diabetes. A reduction of gap junction coupling allows sufficient glucose-stimulated [Ca2+]i and insulin secretion to prevent the emergence of diabetes.
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- Authors
- Nguyen, L. M., Pozzoli, M., Hraha, T. H., & Benninger, R. K. P.
- Affiliations
- University of Colorado Anschutz (US)
- Corresponding author
- Benninger, Richard K.P.
- Venue
- Diabetes
- Publisher
- American Diabetes Association
- Published
- 2014-04-12
- Volume
- 63
- Issue
- 5
- Pages
- 1685-1697
- ISSN
- 0012-1797 (ISSN-L)
- 1939-327X
- PMC
- PMC3994954
- OpenAlex
- W2140435648
- Cited by
- 23
- References
- 40
- Citations by year
- 2025: 1 · 2024: 2 · 2023: 1 · 2022: 1 · 2021: 2 · 2020: 1 · 2017: 3 · 2016: 4 · 2015: 4 · 2014: 4
- FWCI
- 4.95
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Diabetes (publishedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (UL1TR001082)
- National Institute of Diabetes and Digestive and Kidney Diseases (R00DK085145)
- National Institute of Neurological Disorders and Stroke (P30NS048154)
- National Center for Research Resources (UL1RR025780)
- National Center for Advancing Translational Sciences
- Topics
- Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Connexins and lens biology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Diabetes and associated disorders
- Keywords
- connexin 36, electrical coupling, ATP-sensitive potassium channels, neonatal diabetes, insulin secretion, pancreatic beta cells, hyperglycemia, glucose homeostasis, monogenic diabetes
- MeSH terms
- Insulin Secretion, Gap Junction delta-2 Protein, Animals, Animals, Newborn, Blood Glucose, Calcium, Diabetes Mellitus, Homeostasis, Hyperglycemia, Insulin, Islets of Langerhans, Mice, Transgenic, Connexins, Mice, Knockout, Mice, KATP Channels
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