Publications
Results
- Showing results for:
- Reset all filters
Search results
-
Conference paperMarmugi AP, Carmichael L, Rutter GA, et al., 2015,
The calcium sensor sorcin lowers G6PC2 expression to protect against obesity-induced beta cell failure
, 51st Annual Meeting of the European-Association-for-the-Study-of-Diabetes (EASD), Publisher: SPRINGER, Pages: S88-S88, ISSN: 0012-186X -
Journal articleSolomou A, Meur G, Bellomo E, et al., 2015,
The Zinc Transporter Slc30a8/ZnT8 Is Required in a Subpopulation of Pancreatic α-Cells for Hypoglycemia-induced Glucagon Secretion.
, J Biol Chem, Vol: 290, Pages: 21432-21442SLC30A8 encodes a zinc transporter ZnT8 largely restricted to pancreatic islet β- and α-cells, and responsible for zinc accumulation into secretory granules. Although common SLC30A8 variants, believed to reduce ZnT8 activity, increase type 2 diabetes risk in humans, rare inactivating mutations are protective. To investigate the role of Slc30a8 in the control of glucagon secretion, Slc30a8 was inactivated selectively in α-cells by crossing mice with alleles floxed at exon 1 to animals expressing Cre recombinase under the pre-proglucagon promoter. Further crossing to Rosa26:tdRFP mice, and sorting of RFP(+): glucagon(+) cells from KO mice, revealed recombination in ∼ 30% of α-cells, of which ∼ 50% were ZnT8-negative (14 ± 1.8% of all α-cells). Although glucose and insulin tolerance were normal, female αZnT8KO mice required lower glucose infusion rates during hypoglycemic clamps and displayed enhanced glucagon release (p < 0.001) versus WT mice. Correspondingly, islets isolated from αZnT8KO mice secreted more glucagon at 1 mm glucose, but not 17 mm glucose, than WT controls (n = 5; p = 0.008). Although the expression of other ZnT family members was unchanged, cytoplasmic (n = 4 mice per genotype; p < 0.0001) and granular (n = 3, p < 0.01) free Zn(2+) levels were significantly lower in KO α-cells versus control cells. In response to low glucose, the amplitude and frequency of intracellular Ca(2+) increases were unchanged in α-cells of αZnT8KO KO mice. ZnT8 is thus important in a subset of α-cells for normal responses to hypoglycemia and acts via Ca(2+)-independent mechanisms.
-
Journal articleMarmugi A, Carmichael L, Rutter GA, et al., 2015,
Overexpression of the calcium sensor sorcin in the pancreatic beta cell improves glucose tolerance and protects against endoplasmic reticulum stress
, DIABETIC MEDICINE, Vol: 32, Pages: 34-34, ISSN: 0742-3071 -
Conference paperSayers S, Kantor C, Pullen TJ, et al., 2015,
Preserved insulin secretion despite impaired glucose signalling after pancreatic beta cell selective deletion of the tumour suppressor LKB1
, Publisher: WILEY-BLACKWELL, Pages: 13-13, ISSN: 0742-3071 -
Journal articleMitchell RK, Mondragon A, Chen L, et al., 2015,
Selective disruption of Tcf7l2 in the pancreatic beta cell impairs secretory function and lowers beta cell mass
, HUMAN MOLECULAR GENETICS, Vol: 24, Pages: 1390-1399, ISSN: 0964-6906- Author Web Link
- Open Access Link
- Cite
- Citations: 71
-
Journal articleSun G, Da Silva Xavier G, Gorman T, et al., 2015,
LKB1 and AMPKα1 are required in pancreatic alpha cells for the normal regulation of glucagon secretion and responses to hypoglycemia
, Molecular Metabolism, Vol: 4, Pages: 277-286, ISSN: 2212-8778Aims/Hypothesis: Glucagon release from pancreatic alpha cells is required for normal glucose homoeostasis and is dysregulated in both Type 1 and Type 2 diabetes. The tumour suppressor LKB1 (STK11) and the downstream kinase AMP-activated protein kinase (AMPK), modulate cellular metabolism and growth, and AMPK is an important target of the anti-hyperglycaemic agent metformin. While LKB1 and AMPK have emerged recently as regulators of beta cell mass and insulin secretion, the role of these enzymes in the control of glucagon production invivo is unclear. Methods: Here, we ablated LKB1 (αLKB1KO), or the catalytic alpha subunits of AMPK (αAMPKdKO, -α1KO, -α2KO), selectively in ~45% of alpha cells in mice by deleting the corresponding flox'd alleles with a preproglucagon promoter (. PPG) Cre. Results: Blood glucose levels in male αLKB1KO mice were lower during intraperitoneal glucose, aminoimidazole carboxamide ribonucleotide (AICAR) or arginine tolerance tests, and glucose infusion rates were increased in hypoglycemic clamps (p<0.01). αLKB1KO mice also displayed impaired hypoglycemia-induced glucagon release. Glucose infusion rates were also elevated (p<0.001) in αAMPKα1 null mice, and hypoglycemia-induced plasma glucagon increases tended to be lower (p=0.06). Glucagon secretion from isolated islets was sensitized to the inhibitory action of glucose in αLKB1KO, αAMPKdKO, and -α1KO, but not -α2KO islets. Conclusions/Interpretation: An LKB1-dependent signalling cassette, involving but not restricted to AMPKα1, is required in pancreatic alpha cells for the control of glucagon release by glucose.
-
Journal articleTomas A, Futter CE, 2015,
Stress reveals new destination for EGF receptor.
, Cell Cycle, Vol: 14, Pages: 3343-3344 -
Journal articlePiccand J, Strasser P, Hodson DJ, et al., 2014,
Rfx6 Maintains the Functional Identity of Adult Pancreatic β Cells
, Cell Reports, Vol: 9, Pages: 2219-2232, ISSN: 2211-1247Increasing evidence suggests that loss of β cell characteristics may cause insulin secretory deficiency indiabetes, but the underlying mechanisms remain unclear. Here, we show that Rfx6, whose mutation leads to neonatal diabetes in humans, is essential to maintain key features of functionally mature β cells in mice. Rfx6 loss in adult β cells leads to glucose intolerance, impaired β cell glucose sensing, and defective insulin secretion. This is associated with reduced expression of core components of the insulin secretion pathway, including glucokinase, the Abcc8/SUR1 subunit of KATP channels and voltage-gated Ca2+ channels, which are direct targets of Rfx6. Moreover, Rfx6 contributes to the silencing of the vast majority of "disallowed" genes, a group usually specifically repressed in adult β cells, and thus to the maintenance of β cell maturity. These findings raise the possibility that changes in Rfx6 expression or activity may contribute to β cell failure in humans.
This data is extracted from the Web of Science and reproduced under a licence from Thomson Reuters. You may not copy or re-distribute this data in whole or in part without the written consent of the Science business of Thomson Reuters.