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Leprdb Mouse Model of Type 2 Diabetes: Pancreatic Islet Isolation and Live-cell 2-Photon Imaging Of Intact Islets
Published on: May 11, 2015
Mice deficient in GEM GTPase show abnormal glucose homeostasis due to defects in beta-cell calcium handling
Jenny E Gunton1, Mary Sisavanh, Rebecca A Stokes
1Diabetes and Transcription Factors Group, Garvan Institute of Medical Research, Sydney, Australia. j.gunton@garvan.org.au
Aims And Hypothesis:
Glucose-stimulated insulin secretion from beta-cells is a tightly regulated process that requires calcium flux to trigger exocytosis of insulin-containing vesicles. Regulation of calcium handling in beta-cells remains incompletely understood. Gem, a member of the RGK (Rad/Gem/Kir) family regulates calcium channel handling in other cell types, and Gem over-expression inhibits insulin release in insulin-secreting Min6 cells. The aim of this study was to explore the role of Gem in insulin secretion. We hypothesised that Gem may regulate insulin secretion and thus affect glucose tolerance in vivo.
Methods:
Gem-deficient mice were generated and their metabolic phenotype characterised by in vivo testing of glucose tolerance, insulin tolerance and insulin secretion. Calcium flux was measured in isolated islets.
Results:
Gem-deficient mice were glucose intolerant and had impaired glucose stimulated insulin secretion. Furthermore, the islets of Gem-deficient mice exhibited decreased free calcium responses to glucose and the calcium oscillations seen upon glucose stimulation were smaller in amplitude and had a reduced frequency.
Conclusions:
These results suggest that Gem plays an important role in normal beta-cell function by regulation of calcium signalling.
Insights
Gem deficiency impairs glucose tolerance and insulin secretion by disrupting beta-cell calcium signaling. This study reveals Gem
Area of Science:
- Endocrinology and Metabolism
- Cell Biology
- Molecular Physiology
Background:
- Glucose-stimulated insulin secretion (GSIS) is crucial for glucose homeostasis.
- Calcium (Ca2+) flux is essential for insulin vesicle exocytosis.
- The role of Gem, an RGK family member, in beta-cell function is largely unknown.
Purpose of the Study:
- To investigate the role of Gem in regulating insulin secretion.
- To determine if Gem influences glucose tolerance in vivo.
Main Methods:
- Generation and metabolic phenotyping of Gem-deficient mice.
- In vivo assessment of glucose tolerance, insulin tolerance, and insulin secretion.
- Measurement of calcium flux in isolated pancreatic islets.
Main Results:
- Gem-deficient mice exhibited glucose intolerance and impaired GSIS.
- Islets from Gem-deficient mice showed reduced glucose-induced calcium responses.
- Calcium oscillations in response to glucose were diminished in amplitude and frequency in Gem-deficient islets.
Conclusions:
- Gem plays a significant role in normal beta-cell function.
- Gem regulates calcium signaling pathways critical for insulin secretion.
- Gem deficiency negatively impacts glucose metabolism via disrupted beta-cell calcium handling.
