Proteasome inhibitors, including curcumin, improve pancreatic β-cell function and insulin sensitivity in diabetic mice.
BACKGROUND
Type 2 diabetes stems from obesity-associated insulin resistance, and in the genetically susceptible, concomitant pancreatic β-cell failure can occur, which further exacerbates hyperglycemia. Recent work by our group and others has shown that the natural polyphenol curcumin attenuates the development of insulin resistance and hyperglycemia in mouse models of hyperinsulinemic or compensated type 2 diabetes. Although several potential downstream molecular targets of curcumin exist, it is now recognized to be a direct inhibitor of proteasome activity. We now show that curcumin also prevents β-cell failure in a mouse model of uncompensated obesity-related insulin resistance (Lepr(db/db) on the Kaliss background).


RESULTS
In this instance, dietary supplementation with curcumin prevented hyperglycemia, increased insulin production and lean body mass, and prolonged lifespan. In addition, we show that short-term in vivo treatment with low dosages of two molecularly distinct proteasome inhibitors celastrol and epoxomicin reverse hyperglycemia in mice with β-cell failure by increasing insulin production and insulin sensitivity.


CONCLUSIONS
These studies suggest that proteasome inhibitors may prove useful for patients with diabetes by improving both β-cell function and relieving insulin resistance.
Naomi Berrie Diabetes Center, Columbia University, New York, NY, USA.
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S
Weisberg
Naomi Berrie Diabetes Center, Columbia University, New York, NY, USA.
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R
Leibel
Naomi Berrie Diabetes Center, Columbia University, New York, NY, USA.|Sher Institute for Reproductive Medicine, New York, NY, USA.
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Tortoriello
D041721:3T3-L1 Cells; D000818:Animals; D001823:Body Composition; D002470:Cell Survival / Q000187:drug effects; D003474:Curcumin / Q000494:pharmacology*; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy*; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy; D019587:Dietary Supplements; D006442:Glycated Hemoglobin / Q000378:metabolism; D006706:Homeostasis; D006943:Hyperglycemia / Q000517:prevention & control; D007328:Insulin / Q000097:blood / Q000378:metabolism; D007333:Insulin Resistance; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000097:blood / Q000188:drug therapy; D009842:Oligopeptides / Q000494:pharmacology; D053978:Pentacyclic Triterpenes; D059808:Polyphenols / Q000494:pharmacology; D061988:Proteasome Inhibitors / Q000494:pharmacology*; D054411:Receptors, Leptin / Q000235:genetics / Q000378:metabolism; D014315:Triterpenes / Q000494:pharmacology
D003474:Curcumin; D006442:Glycated Hemoglobin; D007328:Insulin; D009842:Oligopeptides; D053978:Pentacyclic Triterpenes; D059808:Polyphenols; D061988:Proteasome Inhibitors; D054411:Receptors, Leptin; D014315:Triterpenes; C050414:celastrol; C078846:epoxomicin