Neuro-endocrine basis for altered plasma glucose homeostasis in the Fragile X mouse.
BACKGROUND
The fragile X mouse model shows an increase in seizure susceptibility, indicating an involvement of the GABAergic system via an alteration in cellular excitability. In the brain, we have previously described a reduction in GABAA receptor expression as a likely basis for this susceptibility. In the brains of fragile X mice, this reduction in receptor expression culminates with a concomitant increase in the expression of glutamic acid decarboxylase (GAD), the enzyme responsible for GABA synthesis. Further, voltage-sensitive calcium channel expression is reduced in the pancreas of the fragile X mouse. Since there are considerable similarities in the GABAergic system in the brain and pancreas, we evaluated the protective role of taurine in pancreatic islet development in both wild type (WT) and fragile X mice (KO).


METHODS
One-month-old FVB/NJ males or age-matched fmr1-knockout (KO) mice were supplemented with taurine in drinking water (0.05% w/v) for four weeks. Age-matched controls were fed water only for the same duration. At four weeks, mice were sacrificed and pancreases processed for histology and immunohistochemical studies on changes of insulin, glucagon and somatostatin expression. Additional mice were subjected to a glucose tolerance test.


RESULTS
Taurine treatment resulted in a significant increase in the number and size of islets. WT taurine-fed mice, slightly hypoglycemic prior to glucose injection, showed significantly reduced plasma glucose at 30 min post-injection when compared to control mice. KO mice had normal baseline plasma glucose concentration; however, following glucose injection they had higher plasma glucose levels at 30 min when compared to controls. Supplementation of taurine to KO mice resulted in reduced baseline levels of plasma glucose. After glucose injection, the taurine-fed KO mice had reduced plasma glucose at 30 min compared to KO. Concomitant with the increased islets size and glucose tolerance observed in taurine-fed mice there was an increase in insulin, glucagon and somatostatin immunoreactivity in the islets of WT mice. In the KO mice however, insulin levels were not affected whereas glucagon and somatostatin levels were reduced. Exocytosis of these hormones is calcium-dependent, therefore any exacerbation of calcium homeostasis could affect hormone release. We found the expression of the voltage sensitive calcium channels (VSCC) is drastically reduced in the pancreas of fragile X mice.


CONCLUSIONS
During early development, the VSCC play an important role in calcium-dependent gene expression. Since these channels are also involved in depolarization and calcium-mediated vesicular release of neurotransmitters and pancreatic hormones, alterations in the expression of VSCC not only will affect calcium-mediated gene expression but also hormonal and neurotransmitter release creating therefore a neuroendocrine perturbation in the fragile X that may potentially affect other organ systems. We find that in the fragile X mouse, taurine treatment may partially restore functionality of the neuro-endocrine pancreas.
El Idrissi
Abdeslem
A
Department of Biology, College of Staten Island, The City University of New York, 2800 Victory Boulevard, Staten Island, NY 10314, USA. Abdeslem.Elidrissi@csi.cuny.edu
Yan
Xin
X
Sidime
Francoise
F
L'Amoreaux
William
W
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism*; D015220:Calcium Channels / Q000235:genetics / Q000378:metabolism; D019587:Dietary Supplements; D004195:Disease Models, Animal; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics; D005600:Fragile X Syndrome / Q000097:blood / Q000378:metabolism*; D005934:Glucagon / Q000378:metabolism; D006706:Homeostasis; D006801:Humans; D006946:Hyperinsulinism; D007328:Insulin / Q000378:metabolism; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D013004:Somatostatin / Q000378:metabolism; D013654:Taurine / Q000008:administration & dosage* / Q000494:pharmacology
D001786:Blood Glucose; D015220:Calcium Channels; D051860:Fragile X Messenger Ribonucleoprotein 1; D005934:Glucagon; D007328:Insulin; D013004:Somatostatin; D013654:Taurine; C497684:Fmr1 protein, mouse
Curr Opin Clin Nutr Metab Care. 2006 Jan;9(1):32-6
16444816
J Neurosci. 1999 Nov 1;19(21):9459-68
10531449
Diabetes Metab Res Rev. 2001 Sep-Oct;17(5):330-46
11747139
Am J Med Genet. 1991 Feb-Mar;38(2-3):476-80
2018089
Amino Acids. 2002;22(1):27-38
12025872
J Endocrinol. 2001 Nov;171(2):299-308
11691650
Amino Acids. 2008 Feb;34(2):321-8
16955229
J Nutr. 2003 Sep;133(9):2820-5
12949371
Amino Acids. 2000;19(3-4):509-26
11140356
Adv Exp Med Biol. 2000;483:57-69
11787642
J Endocrinol. 1998 Nov;159(2):341-8
9795376
Neurosci Lett. 2005 Apr 4;377(3):141-6
15755515
Adv Exp Med Biol. 2006;583:315-22
17153616
Epilepsia. 2000 Jan;41(1):19-23
10643918
Amino Acids. 1998;15(1-2):99-108
9871490
Endocrinology. 1997 Apr;138(4):1736-41
9075738
Diabetes. 1991 Dec;40 Suppl 2:115-20
1748239
Genes Brain Behav. 2004 Dec;3(6):337-59
15544577
Neurochem Res. 2002 Feb;27(1-2):21-6
11926272
Epilepsy Res. 1993 Feb;14(2):105-13
8453948
Physiol Rev. 1992 Jan;72(1):101-63
1731369
J Neurochem. 1985 Jul;45(1):268-75
2987414
Brain Res Mol Brain Res. 1998 Aug 31;59(2):189-95
9729377
Cell. 1994 Jul 15;78(1):23-33
8033209
Nutr Hosp. 2002 Nov-Dec;17(6):262-70
12514918
Am J Med Genet. 1996 Aug 9;64(2):241-5
8844056
Diabetologia. 2004 Oct;47(10):1831-7
15502919
Neuroscience. 2001;103(4):1043-50
11301211
Endocrinology. 1998 Jun;139(6):2994-3004
9607811
Neurochem Res. 2004 Jan;29(1):189-97
14992278
Neurosci Lett. 1988 Aug 15;91(1):53-8
3173785
Adv Exp Med Biol. 2003;526:515-25
12908638
Curr Opin Genet Dev. 2002 Jun;12(3):278-83
12076670
Neurosci Lett. 2008 May 2;436(1):19-22
18375059