Re: Adult Pancreas Generates Multipotent Stem Cells and Pancreatic and Nonpancreatic Progeny

Hi Nico:

(snipped)
Basically, we already knew from that work that adult stem cells can and will produce insulin producing cells as needed, *if you control the problem that destroys beta cells*. Also, it won't provide a cure for Type 2 unless you get the factors that cause insulin resistance under control. There are plenty of diaetics who have a full complement of insulin producing cells but still have Type 2 because of the insulin resistance, so it's hardly a panacea for Type 2.

There are type 2s that have significantly reduced their insulin resistance. Other t2s might be more motivated to take the action if they could see some light at the end of the tunnel.

It's interesting work: the mechanisms by which adult stem cells differentiate into useful cells need to be understood, but it's not that big a development for diabetes as we might wish. They're focusing on the generation of new cells, which is a classic mistake: the ability of the mis-aimed immune system to destroy new insulin producing cells is surely larger than the available reservoir in the diabetic, or even of any reasonable source of transplantable stem cells. Focus on the immune problem first, and Faustman's work shows that you don't need to worry about the source of beta cells, they'll happen naturally, at least in lab animals.

In some of his earlier interviews, Dr. Vinik mentioned that the immune problem could be overcome by repetitive treatment with INGAP. Also some people with type 1 may no longer have the autoimmune problem after a number of years.

The following is still using animal models:
Adult Pancreas Generates Multipotent Stem Cells and Pancreatic and Nonpancreatic Progeny -
http://stemcells.alphamedpress.org/cgi/content/full/22/6/1070

The problem for type 2s maybe islet amyloid polypeptide and amyloid plaque formation.

Aberrant Processing of Human Proislet Amyloid Polypeptide Results in Increased Amyloid Formation -
http://diabetes.diabetesjournals.org/cgi/content/full/54/7/2117

"Human islet amyloid observed postmortem is almost exclusively extracellular. Early amyloidogenesis has thus been thought to occur outside the ß-cells (24). ... In humans, intracellular amyloid has also been observed in insulinomas (26). These findings may indicate that the first aggregation of IAPP into fibrils occurs intracellularly. The human proinsulin molecule is preferentially processed at the B-chain/C-peptide junction by PC1/3 and subsequently processed at the C-peptide/A-chain junction by PC2 (27). An increased ratio of secreted proinsulin and proinsulin intermediates versus insulin is found during the early stages of type 2 diabetes. This enhanced ratio could depend on changes in expression or activity of the prohormone convertases (28). ... Because proIAPP and proinsulin are processed by the same enzymes at the same location, it is likely that factors promoting aberrant proinsulin processing would also affect proIAPP processing. It is known that synthetic proIAPP can aggregate and form amyloid-like fibrils (30). Therefore, increased concentrations of proIAPP or IAPP intermediates could theoretically predispose to intracellular amyloid formation and thus represent the initial site for amyloid deposition. ... In vitro, h(human)-IAPP 1–37 has an intrinsic capacity to assemble into amyloid-like fibrils, and h-IAPP has been said to be one of the most amyloidogenic peptides known. ... Therefore, it is remarkable that h-IAPP does not form amyloid in normal human islets. This has led to the suggestion that there are natural inhibitors present in ß-cells. In vitro studies on IAPP 1–37 fibrillogenesis have shown that insulin is a potent inhibitor for amyloid-like fibril formation (40–43). This inhibitory effect is concentration dependent and independent of IAPP concentrations. IAPP has binding sites for insulin (43), and the lack of fibril formation could depend on the occurrence of complexes between IAPP and insulin. ... In conclusion, our study indicates that insufficient processing of proIAPP to mature IAPP may be important in initial islet amyloid formation. It must be noted, however, that other factors influence that event because alterations in PC2 and/or PC1/3 by themselves did not produce amyloid in a large percentage of cells transfected with h-proIAPP. One such factor is oxidative stress, which is a product of chronically elevated glucose (49). Islets of type 2 diabetic individuals do, in fact, display increased levels of protein markers for oxidative damage to DNA and phospholipids, as well as decreased levels of the antioxidant enzyme Cu, Zn-superoxide dismutase (50). Increased oxidation of membrane lipids increases their negative charge density (51), which greatly accelerates islet amyloid fiber formation (i.e., fibrillogenesis) in vitro by enhancing the binding of h-IAPP to lipid membranes (52)."

Frank
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