Inverse Relationship between Glucose Metabolism and Glucose-Induced Insulin Secretion in Rat Insulinoma Cells

AbstractA key event in the development of both major forms of diabetes is the loss of functional pancreatic islet β-cell mass. Strategies aimed at enhancing β-cell regeneration have long been pursued, but methods for reliably inducing human β-cell proliferation with full retention of key functions such as glucose-stimulated insulin secretion (GSIS) are still very limited. We have previously reported that overexpression of the homeobox transcription factor Nkx6.1 stimulates β-cell proliferation, while also enhancing GSIS and providing protection against β-cell cytotoxicity through induction of the VGF prohormone. We developed an Nkx6.1 pathway screen by stably transfecting 832/13 rat insulinoma cells with a VGF promoter-luciferase reporter construct, using the resultant cell line to screen a 630,000 compound chemical library. We isolated three compounds with consistent effects to stimulate human islet cell proliferation. Further studies of the most potent of these compounds, GNF-9228, revealed that it selectively activates human β-cell relative to α-cell proliferation and has no effect on δ-cell replication. In addition, pre-treatment, but not short term exposure of human islets to GNF-9228 enhances GSIS. GNF-9228 also protects 832/13 insulinoma cells against ER stress- and inflammatory cytokine-induced cytotoxicity. In contrast to recently emergent Dyrk1a inhibitors that stimulate human islet cell proliferation, GNF-9228 does not activate NFAT translocation. These studies have led to identification of a small molecule with pleiotropic positive effects on islet biology, including stimulation of human β-cell proliferation and insulin secretion, and protection against multiple agents of cytotoxic stress.

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Identification of a small molecule that stimulates human β-cell proliferation and insulin secretion, and protects against cytotoxic stress in rat insulinoma cells

PLoS ONE ◽

10.1371/journal.pone.0224344 ◽

2020 ◽

Vol 15 (3) ◽

pp. e0224344 ◽

Cited By ~ 4

Author(s):

Hans E. Hohmeier ◽

Lu Zhang ◽

Brandon Taylor ◽

Samuel Stephens ◽

Danhong Lu ◽

...

Keyword(s):

Cell Proliferation ◽

Insulin Secretion ◽

Small Molecule ◽

Β Cell ◽

Cytotoxic Stress ◽

Insulinoma Cells ◽

Rat Insulinoma

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Role of Extracellular Magnesium in Insulin Secretion from Rat Insulinoma Cells

Experimental Biology and Medicine ◽

10.3181/00379727-200-43459 ◽

1992 ◽

Vol 200 (4) ◽

pp. 490-494 ◽

Cited By ~ 10

Author(s):

M. Murakami ◽

J. Ishizuka ◽

S. Sumi ◽

G. A. Nickols ◽

C. W. Cooper ◽

...

Keyword(s):

Insulin Secretion ◽

Insulinoma Cells ◽

Rat Insulinoma

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A 70% Ethanol Extract of Mistletoe Rich in Betulin, Betulinic Acid, and Oleanolic Acid Potentiatedβ-Cell Function and Mass and Enhanced Hepatic Insulin Sensitivity

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2016/7836823 ◽

2016 ◽

Vol 2016 ◽

pp. 1-13 ◽

Cited By ~ 7

Author(s):

Byoung-Seob Ko ◽

Suna Kang ◽

Bo Reum Moon ◽

Jin Ah Ryuk ◽

Sunmin Park

Keyword(s):

Cell Proliferation ◽

Insulin Secretion ◽

Glucose Metabolism ◽

Oleanolic Acid ◽

Normal Control ◽

Insulin Signaling ◽

Betulinic Acid ◽

Diabetic Rats ◽

Glucose Output ◽

Insulinoma Cells

We investigated that the long-term consumption of the water (KME-W) and 70% ethanol (KME-E) mistletoe extracts had antidiabetic activities in partial pancreatectomized (Px) rats. Px rats were provided with a high-fat diet containing 0.6% KME-E, 0.6% KME-W, and 0.6% dextrin (control) for 8 weeks. As normal-control, Sham-operated rats were provided with 0.6% dextrin. In cell-based studies, the effects of its main terpenoids (betulin, betulinic acid, and oleanolic acid) on glucose metabolism were measured. Both KME-W and KME-E decreased epididymal fat mass by increasing fat oxidation in diabetic rats. KME-E but not KME-W exhibited greater potentiation of first-phase insulin secretion than the Px-control in a hyperglycemic clamp. KME-E also madeβ-cell mass greater than the control by increasingβ-cell proliferation and decreasing its apoptosis. In a euglycemic-hyperinsulinemic clamp, whole-body glucose infusion rate and hepatic glucose output increased with potentiating hepatic insulin signaling in the following order: Px-control, KME-W, KME-E, and normal-control. Betulin potentiated insulin-stimulated glucose uptake via increased PPAR-γactivity and insulin signaling in 3T3-L1 adipocytes, whereas oleanolic acid enhanced glucose-stimulated insulin secretion and cell proliferation in insulinoma cells. In conclusion, KME-E prevented the deterioration of glucose metabolism in diabetic rats more effectively than KME-W and KME-E can be a better therapeutic agent for type 2 diabetes than KME-W.

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