Kinetics of Blood Glucose in Mice Carrying Hemizygous Pax6

Nitta, Yumiko; Shigeyoshi, Yasufumi; Nakagata, Naomi; Kaneko, Takehito; Nitta, Katsumi; Harada, Taishi; Ishizaki, Fumiko; Townsend, Jana

doi:10.1538/expanim.58.105

Cited by 4 publications

(4 citation statements)

References 32 publications

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“…Thus, low expression level of Pdx1 and Pax6 upon Gpr142-KD can explain, at least in part, the reduced β-cell viability and dysfunctionality. These findings are thus in good agreement with previous reports showing that the heterozygous Pax6 mutations are associated with glucose intolerant and susceptibility to diabetes in both human and rodents [23]. …”

Section: Discussionsupporting

confidence: 93%

The functional impact of G protein-coupled receptor 142 (Gpr142) on pancreatic β-cell in rodent

Al-Amily

Dunér

Groop

et al. 2019

Pflugers Arch - Eur J Physiol

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We have recently shown that the G protein-coupled receptor 142 (GPR142) is expressed in both rodent and human pancreatic β-cells. Herein, we investigated the cellular distribution of GPR142 within islets and the effects of selective agonists of GPR142 on glucose-stimulated insulin secretion (GSIS) in the mouse islets and INS-1832/13 cells. Double-immunostaining revealed that GPR142 immunoreactivity in islets mainly occurs in insulin-positive cells. Potentiation of GSIS by GPR142 activation was accompanied by increased cAMP content in INS-1832/13 cells. PKA/Epac inhibition markedly suppressed the effect of GPR142 activation on insulin release. Gpr142 knockdown (Gpr142-KD) in islets was accompanied by elevated release of MCP-1, IFNγ, and TNFα during culture period and abolished the modulatory effect of GPR142 activation on the GSIS. Gpr142-KD had no effect on Ffar1, Ffar2, or Ffar3 mRNA while reducing Gpr56 and increasing Tlr5 and Tlr7 mRNA expression. Gpr142-KD was associated with an increased expression of Chrebp, Txnip, RhoA, and mitochondrial Vdac1 concomitant with a reduced Pdx1, Pax6, and mitochondrial Vdac2 mRNA levels. Long-term exposure of INS-1832/13 cells to hyperglycemia reduced Gpr142 and Vdac2 while increased Chrebp, Txnip, and Vdac1 mRNA expression. GPR142 agonists or Bt2-cAMP counteracted this effect. Glucotoxicity-induced decrease of cell viability in Gpr142-KD INS-1 cells was not affected by GPR142-agonists while Bt2-cAMP prevented it. The results show the importance of Gpr142 in the maintenance of pancreatic β-cell function in rodents and that GPR142 agonists potentiate GSIS by an action, which most likely is due to increased cellular generation of second messenger molecule cAMP.Electronic supplementary materialThe online version of this article (10.1007/s00424-019-02262-7) contains supplementary material, which is available to authorized users.

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Section: Discussionsupporting

confidence: 93%

The functional impact of G protein-coupled receptor 142 (Gpr142) on pancreatic β-cell in rodent

Al-Amily

Dunér

Groop

et al. 2019

Pflugers Arch - Eur J Physiol

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“…Pax6 expression in adult islets of Langerhans has also been documented [19], [21], and is confirmed by our data, which demonstrates that the continued presence of Pax6 is essential for endocrine hormone production. There is increasingly convincing evidence that glucose handling and insulin production are also disturbed in adult rodents and humans who carry heterozygous PAX6 mutations [19], [20], [21], [28]. This suggests that not only is PAX6 essential for pancreatic endocrine maintenance, but that correct dosage of the protein is required for this role, as it is for some other transcription factors associated with diabetes, such as HNF1A and HNF4A, in which heterozygous mutations have been found in a significant portion of MODY cases [35].…”

Section: Discussionmentioning

confidence: 99%

“…Functional deficits in PAX6-expressing tissues have been observed in patients with PAX6 haploinsufficiency, most notably associated with the developmental eye anomaly aniridia (absence of the iris), where corneal limbal stem cell defects [25] and deficits of olfactory function and neurological organisation [26] have been reported [22]. There have also been reports of glucose intolerance and predisposition to diabetes in some individuals, and in some rodent models, with heterozygous PAX6 mutations [19], [20], [21], [27], [28]. Because of the multiple essential functions fulfilled by Pax6 during development, it is difficult to dissect its role in adult tissues where Pax6 expression is maintained.…”

Section: Introductionmentioning

confidence: 99%

The Developmental Regulator Pax6 Is Essential for Maintenance of Islet Cell Function in the Adult Mouse Pancreas

et al. 2013

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The transcription factor Pax6 is a developmental regulator with a crucial role in development of the eye, brain, and olfactory system. Pax6 is also required for correct development of the endocrine pancreas and specification of hormone producing endocrine cell types. Glucagon-producing cells are almost completely lost in Pax6-null embryos, and insulin-expressing beta and somatostatin-expressing delta cells are reduced. While the developmental role of Pax6 is well-established, investigation of a further role for Pax6 in the maintenance of adult pancreatic function is normally precluded due to neonatal lethality of Pax6-null mice. Here a tamoxifen-inducible ubiquitous Cre transgene was used to inactivate Pax6 at 6 months of age in a conditional mouse model to assess the effect of losing Pax6 function in adulthood. The effect on glucose homeostasis and the expression of key islet cell markers was measured. Homozygous Pax6 deletion mice, but not controls, presented with all the symptoms of classical diabetes leading to severe weight loss requiring termination of the experiment five weeks after first tamoxifen administration. Immunohistochemical analysis of the pancreata revealed almost complete loss of Pax6 and much reduced expression of insulin, glucagon, and somatostatin. Several other markers of islet cell function were also affected. Notably, strong upregulation in the number of ghrelin-expressing endocrine cells was observed. These findings demonstrate that Pax6 is essential for adult maintenance of glucose homeostasis and function of the endocrine pancreas.

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“…To start the glucose level measurements, the animals were anesthetized intraperitoneally with a dose of 40 mg/kg of sodium pentobarbital (Anestesal) after which there was a 15-minute stabilization period. A blood sample was then drawn from the tip of the tail to quantify the blood glucose level in a control condition; a dose of 2 g/kg of glucose (Pisa) was administered intraperitoneally from a 40% solution [ 24 , 32 ]. The glycemia levels were determined at 30 minutes, 60 minutes, and 120 minutes after the administration of the glucose solution.…”

Section: Methodsmentioning

confidence: 99%

Effect of an avocado oil-enhanced diet ( Persea americana ) on sucrose-induced insulin resistance in Wistar rats

Toro-Equihua

Velasco-Rodríguez

López-Ascencio

et al. 2016

Journal of Food and Drug Analysis

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A number of studies have been conducted to evaluate the effects of vegetable oils with varying percentages of monounsaturated and polyunsaturated fatty acids on insulin resistance. However, there is no report on the effect of avocado oil on this pathologic condition. The aim of this work was to evaluate the effect of avocado oil on sucrose-induced insulin resistance in Wistar rats. An experimental study was carried out on Wistar rats that were randomly assigned into six groups. Each group received a different diet over an 8-week period (n = 11 in each group): the control group was given a standard diet, and the other five groups were given the standard feed plus sucrose with the addition of avocado oil at 0%, 5%, 10%, 20%, and 30%, respectively. Variables were compared using Student t test and analysis of variance. Statistically significant difference was considered when p < 0.05. Rats that were given diets with 10% and 20% avocado oil showed lower insulin resistance (p = 0.022 and p = 0.024, respectively). Similar insulin resistance responses were observed in the control and 30% avocado oil addition groups (p = 0.85). Addition of 5-30% avocado oil lowered high sucrose diet-induced body weight gain in Wistar rats. It was thus concluded that glucose tolerance and insulin resistance induced by high sucrose diet in Wistar rats can be reduced by the dietary addition of 5-20% avocado oil.

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Kinetics of Blood Glucose in Mice Carrying Hemizygous Pax6

Cited by 4 publications

References 32 publications

The functional impact of G protein-coupled receptor 142 (Gpr142) on pancreatic β-cell in rodent

The functional impact of G protein-coupled receptor 142 (Gpr142) on pancreatic β-cell in rodent

The Developmental Regulator Pax6 Is Essential for Maintenance of Islet Cell Function in the Adult Mouse Pancreas

Effect of an avocado oil-enhanced diet ( Persea americana ) on sucrose-induced insulin resistance in Wistar rats

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