Oxidative Stress of Pancreas Putative Cause of Diabetes Mellitus?

Here is evidence that alpha cells increase and beta cells decrease their output under oxidative stress.

This parallels the FAR farsenoid x receptor vs PPAR alpha which signals the Fed or fasting state acutely and chronically.

Here hyperglycemia produces oxidative stress that inhibits the fasting state tone for beta cells but enhances the fasting state of alpha cells.  It is analogous to a stuck accelerator in which glucagon, gluconeogenesis and inadequate insulin sensitivity produce a positive feedback loop.

Restoring reduced or normal oxidative flux would  release the beta cell to make and release required insulin, and restoring normal alpha cell function in the "fasting" state.

How?

Sulforaphane activates PPAR alpha and turns on the antioxidant response element which reduces oxidative stress.

Hydrogen rich water absorbed by the portal vein would supply high concentrations of antioxidant hydrogen to both pancreas and liver thereby reducing oxidative stress!

Both should function to restore normal oxidative flux and normal command and control of glucose control via insulin glucagon signaling.

http://www.sciencedirect.com/science/article/pii/S0168822717302073

Comparison of pancreatic beta cells and alpha cells under hyperglycemia: Inverse coupling in pAkt-FoxO1

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  Hyperglycemia increased alpha cell proliferation and glucagon contents.
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  Hyperglycemia decreased beta cell proliferation and insulin contents.
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  Beta cells activated FoxO1 factors and antioxidant enzymes under hyperglycemia.
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  Alpha cells increased the PI3K/pAkt signaling under hyperglycemia.

Type 2 diabetes manifests beta cell deficiencies and alpha cell expansion which is consistent with relative insulin deficiency and glucagon oversecretion. The effects of hyperglycemia on alpha cells are not as understood in comparison to beta cells. Hyperglycemia increases oxidative stress, which induces Akt activation or FoxO activation, depending on cell type. Several studies independently reported that FoxO1 translocations in alpha cells and beta cells were opposite. We compared the responses of pancreatic alpha cells and beta cells against hyperglycemia.

Alpha TC-1 cells and Beta TC-6 cells were incubated with control (5mM Glucose) or high glucose (33mM Glucose) with or without PI3K inhibitor or FoxO1 inhibitor. We assessed PI3K, pAkt and phosphorylated FoxO1 (pFoxO1) in both cell lines. Immunostaining of BrdU and FoxO1 was detected by green fluorescence microscopy and confocal microscopy.

Hyperglycemia and H₂O₂ decreased PI3K and pAKT in beta cells, but increased them in alpha cells. FoxO1 localizations and pFoxO1 expressions between alpha cells and beta cells were opposite. Proliferation of beta cells was decreased, but alpha cell proliferation was increased under hyperglycemia. Antioxidant enzymes including superoxide dismutase (SOD) and catalase were increased in beta cells and they were reversed with FoxO1 inhibitor treatment. Increased proliferation in alpha cells under hyperglycemia was attenuated with PI3K inhibitor.

In conclusion, hyperglycemia increased alpha cell proliferation and glucagon contents which are opposite to beta cells. These differences may be related to contrasting PI3K/pAkt changes in both cells and subsequent FoxO1 modulation.

Energy Balance Acutely Hormonal, Chronically Pathway Activation

The "nuclear receptors farnesoid X receptor (FXR) and peroxisome proliferator activated receptor α (PPARα) provide an intriguing, coordinated response to maintain energy balance in the liver" the metabolic control center.

They respectfully signal the fed and fasting state and every state in between like mixing cold and hot water.  The average temperature can be shifted by the activity of "hot or cold" agonist.

Ursolic acid and sulforaphane are PPAR alpha agonist.  They increase fatty acid oxidation and produces beta hydroxybutyrate.

The article highlights the acute hormone effects of insulin and glucagon and the chronic effects of FXR  and PPAR alpha pathways  in the fed and fasting state.

I believe these are analog and not digital states that degrade with oxidative stress just as oxidative stress is associated with insulin resistance syndrome.  If true, then promoting  autophagy and proteostasis maintains insulin sensitivity and robust energy AND repair required for cell quality control. Improved cell quality control is anti-aging and anti inflamaging!

http://www.karger.com/Article/Abstract/450912

Regulation of Liver Energy Balance by the Nuclear Receptors Farnesoid X Receptor and Peroxisome Proliferator Activated Receptor α