Dietary Selenium Deficiency Partially RescuesType 2 Diabetes–Like Phenotypes of Glutathione

Peroxidase-1 Overexpressing Male Mice

Xi Yan, Matthew P. Pepper, Marko Z. Vatamaniuk, Carol A. Roneker, Li Li, and Xin Gen Lei

Department of Animal Science, Cornell University, Ithaca, NY; and Robert W. Holley Center for Agriculture and Health, Agricultural

Research Service, U.S. Department of Agriculture, Ithaca, NY

Funding source: NIH DK53018

What Is This Study about?

1. To determine if prolonged dietary Se depletion in GPX1 overexpressing (OE) mice rescued their type 2 diabetes–like phenotypes

Scopes

Metabolic disorders of over-producing a selenoenzyme

Se regulation of insulin physiology

Novel roles of Se in energy metabolism

Objectives

2. To explore if the presumed rescue was mediated by modulating expression and function of key factors related to insulin synthesis, secretion, and function in islets and lipogenesis, glycolysis, and gluconeogenesis in liver and muscle

High Se status with adverse blood glucose

and lipid profiles

High Se on diabetes and insulin resistance

in rats and pigs

Pro-diabetic

Why Is This Study Important?

Insulin-mimeticDiabetic association with Se deficiency

Anti-diabetic Diabetogenic

Dietary Se

Mechanism for the multiphased impacts of Se on diabetes?

• Study 1: Diet restriction (Wang et al., 2008)

– Primary phenotype: hyperinsulinemia and elevated insulin secretion

• Study 2: Diet restriction and Se deficiency (Pepper et al., 2011)

– Diet restriction was too drastic to show effect of Se

• Study 3: Se deficiency on full-fed mice – The present research

Proc Natl Acad Sci U S A. 2004 Jun 15;101(24):8852-7. Epub 2004 Jun 7.

Experimental Protocol

♂

Weanling mice(1 month old)

4 groups (n = 5), Se-def. Torula yeast-sucrose

basal diet

4 months

Groups WT- WT+ OE- OE+

Se, mg/kg (Na2SeO3)

0 0.3 0 0.3

Initial:Body weightITT, GTT, GSISBlood analysis

MonthlyAll tests as at initial

Final (Month 4):All tests as at initialTissue collection

Laboratory Analysis

Biochemical (n=5)• Plasma insulin (GSIS)• Blood glucose (ITT, GTT)• Liver Gpx and lipids

Gene regulation (Q-PCR) (n=5)• 21 genes in islets• 10 genes in liver• Controls: β-actin

and Gapdh

Protein functions (n = 5)

• Liver/muscle GK & PEPCK• Liver p53 protein

Data analysis• 2 x 2 factorial• 6 figures (3 OSM)

Dietary Se Deficiency on Phenotype I (Fig. 1)

Highlight 1:

Se deficiency• Liver GPX activity• Blood glucose• Plasma insulin

Genotype differences

Dietary Se Deficiency on Phenotype II (Fig. 2)

Highlight 2:

Se deficiency• GTT in OE• ITT in OE > WT• GSIS in OE

Genotype differences

Dietary Se Deficiency on Phenotype III (Fig. 3)

Highlight 3

Se deficiency• Liver TG• Liver TC• Liver NEFA

or removed genotype differences

OE > WT

WT:• Cat, Cfos, Foxo1, Gk1 Hnf4a, Ins1, and p53

OE:• Beta2, Foxa2, Cfos,

and Pregluc• Cat, Hnf1a, Hnf4a, and Kir6.2

Dietary Se Deficiency on Islet Gene Expression (Fig. 4)

Overall:• Affected 16 genes • Removed OE/WT

differences in Beta2, Cfos, Foxa2, Ins1, Pregluc, p53, and Sur1

WT:• Gk1 Cyp7a1, Srebp1a, and Srebp2

OE: Pparγ Acc1 & Gk1

Dietary Se Deficiency on Liver Gene Expression (Fig. 5)

OE vs WT:• 53-fold Gk1• Higher: Acc1, Cyp7a1,

Fasn, Mccc1, and Pparγ • Lower: F1,6bp & Hmgcs2

WT:• Liver p53 Liver GK & PEPCK

Genotype differences decreased by Se deficiency

OE:• Liver GK Muscle PEPCK•

Dietary Se Deficiency on Tissue Enzymes and p53 (Fig. 6)

OE vs WT:• 3.5-fold liver GK• 7-fold muscle PEPCK• Lower liver p53 protein

Main Findings and Implications

Dietary Se deficiency disallowed the GPX1 overproduction in the full-fed OE mice and partially rescued their type 2 diabetes–like phenotypes

The rescue was associated with down-regulationof pro-insulin genes in islets, lipogenesis rate-limiting enzyme genes in liver, and key glycolysis and gluconeogenesis enzymes in liver and/or muscle.

We have revealed a strong regulation of hepatic GK mRNA and activity by GPX1 overproduction and dietary Se deficiency, and a novel link of Se/GPX1 to p53 on body energy metabolism.

Scheme of Potential Regulatory Pathways

Thank you for watching!

For additional questions or comments, please contact:

Professor X. G. Lei, Ph.D.Cornell University

email: xl20@cornell.edu phone: (607) 254-4703