Obesity is associated with an increased risk of developing insulin resistance and type 2 diabetes In obese individuals, adipose tissue releases increased amounts of non-esterified fatty acids, glycerol, hormones, pro-inflammatory cytokines and other factors that are involved in the development of insulin resistance When insulin resistance is accompanied by dysfunction of pancreatic islet beta-cells - the cells that release insulin - failure to control blood glucose levels results Abnormalities in beta-cell function are therefore critical in defining the risk and development of type 2 diabetes This knowledge is fostering exploration of the molecular and genetic basis of the disease and new approaches to its treatment and prevention

Mechanisms linking obesity to insulin resistance and type 2 diabetes

Biology of Incretins: GLP-1 and GIP

Glucagon-like peptide 1 (GLP-1) is a 30-amino acid peptide hormone produced in the intestinal epithelial endocrine L-cells by differential processing of proglucagon, the gene which is expressed in ...

The Physiology of Glucagon-like Peptide 1

The biology of incretin hormones.

Maintenance of normal blood glucose levels depends on a complex interplay between the insulin responsiveness of skeletal muscle and liver and glucose-stimulated insulin secretion by pancreatic β cells. Defects in the former are responsible for insulin resistance, and defects in the latter are responsible for progression to hyperglycemia. Emerging evidence supports the potentially unifying hypothesis that both of these prominent features of type 2 diabetes are caused by mitochondrial dysfunction.

https://science.sciencemag.org/content/sci/307/5708/384.full.pdf

Mitochondrial dysfunction and type 2 diabetes.

We have proposed the “glucolipotoxicity” hypothesis in which elevated free fatty acids (FFAs) together with hyperglycemia are synergistic in causing islet β-cell damage because high glucose inhibits fat oxidation and consequently lipid detoxification. The effects of 1–2 d culture of both rat INS 832/13 cells and human islet β-cells were investigated in medium containing glucose (5, 11, 20 mm) in the presence or absence of various FFAs. A marked synergistic effect of elevated concentrations of glucose and saturated FFA (palmitate and stearate) on inducing β-cell death by apoptosis was found in both INS 832/13 and human islet β-cells. In comparison, linoleate (polyunsaturated) synergized only modestly with high glucose, whereas oleate (monounsaturated) was not toxic. Treating cells with the acyl-coenzyme A synthase inhibitor triacsin C, or the AMP kinase activators metformin and 5-aminoimidazole-4-carboxamide-1-β-d-ribofuranoside that redirect lipid partitioning to oxidation, curtailed glucolipotoxicity. In...

Saturated Fatty Acids Synergize with Elevated Glucose to Cause Pancreatic β-Cell Death

β-Cells possess inherent mechanisms to adapt to overnutrition and the prevailing concentrations of glucose, fatty acids, and other fuels to maintain glucose homeostasis. However, this is balanced by potentially harmful actions of the same nutrients. Both glucose and fatty acids may cause good/adaptive or evil/toxic actions on the β-cell, depending on their concentrations and the time during which they are elevated. Chronic high glucose dramatically influences β-cell lipid metabolism via substrate availability, changes in the activity and expression of enzymes of glucose and lipid metabolism, and modifications in the expression level of key transcription factors. We discuss here the emerging view that β-cell “glucotoxicity” is in part indirectly caused by “lipotoxicity,” and that β-cell abnormalities will become particularly apparent when both glucose and circulating fatty acids are high. We support the concept that elevated glucose and fatty acids synergize in causing toxicity in islets and other organs, a process that may be instrumental in the pleiotropic defects associated with the metabolic syndrome and type 1 and type 2 diabetes. The mechanisms by which hyperglycemia and hyperlipidemia alter insulin secretion are discussed and a model of β-cell “glucolipotoxicity” that implicates alterations in β-cell malonyl-CoA concentrations; peroxisome proliferator-activated receptor-α and -γ and sterol regulatory element binding protein-1c expression; and lipid partitioning is proposed.

https://diabetes.diabetesjournals.org/content/diabetes/51/suppl_3/S405.full.pdf

Malonyl-CoA Signaling, Lipid Partitioning, and Glucolipotoxicity: Role in β-Cell Adaptation and Failure in the Etiology of Diabetes

We previously provided evidence that glucagon-like peptide 1 (GLP-1) induces pancreatic beta-cell growth nonadditively with glucose in a phosphatidylinositol (PI) 3-kinase- and protein kinase C zeta-dependent manner. However, the exact mechanism by which the GLP-1 receptor (GLP-1R), a member of the G protein-coupled receptor (GPCR) superfamily, activates the PI 3-kinase signaling pathway to promote beta-cell growth remains unknown. We hypothesized that the GLP-1R could activate PI 3-kinase and promote beta-cell proliferation through transactivation of the epidermal growth factor (EGF) receptor (EGFR), an event possibly linked to GPCRs via activation of c-Src and the production of putative endogenous EGF-like ligands. Both the c-Src inhibitor PP1 and the EGFR-specific inhibitor AG1478 blocked GLP-1-induced [(3)H]thymidine incorporation in INS(832/13) cells as well as in isolated rat islets, while only AG1478 inhibited the proliferative action of betacellulin (BTC), an EGFR agonist. Both compounds also suppressed GLP-1-induced PI 3-kinase activation. A time-dependent increase in tyrosine phosphorylation of the EGFR in response to GLP-1 was observed in INS(832/13) cells. This transactivation of the EGFR was sensitive to both the pharmacological agents PP1 and AG1478. The action of GLP-1 and BTC on INS cell proliferation was found to be not additive. Overexpression of a dominant-negative EGFR in INS cells with a retroviral expression vector curtailed GLP-1-induced beta-cell proliferation. GLP-1 treatment of INS cells caused a decrease in cell surface-associated BTC, as shown by FACS analysis. Also, the metalloproteinase inhibitor GM6001 and an anti-BTC neutralizing antibody suppressed the GLP-1 proliferative effect. Finally, coculturing the prostatic cancer cell line LNCaP that lacks GLP-1 responsiveness with INS cells increased LNCaP cell proliferation in the presence of GLP-1, thus revealing that INS cells secrete a growth factor in response to GLP-1. GM6001 and an anti-BTC neutralizing antibody suppressed increased LNCaP cell proliferation in the presence of GLP-1 in the coculture experiments. The results are consistent with a model in which GLP-1 increases PI 3-kinase activity and enhances beta-cell proliferation via transactivation of the EGFR that would require the proteolytic processing of membrane-anchored BTC or other EGF-like ligands.

https://diabetes.diabetesjournals.org/content/diabetes/52/1/124.full.pdf

Glucagon-Like Peptide 1 Induces Pancreatic β-Cell Proliferation Via Transactivation of the Epidermal Growth Factor Receptor

Aims/hypothesis
We have provided evidence that glucagon-like peptide-1, a potential therapeutic agent in the treatment of diabetes, activates phosphatidylinositol-3 kinase/protein kinase B signalling in the pancreatic beta cell. Since this pathway promotes cell survival in a variety of systems, we tested whether glucagon-like peptide-1 protects beta cells against cell death induced by elevated glucose and/or non-esterified fatty acids.

/pdf/glucagon-like-peptide-1-prevents-beta-cell-glucolipotoxicity-5fo598t3xl.pdf

Erik Joly

Papers

Saturated Fatty Acids Synergize with Elevated Glucose to Cause Pancreatic β-Cell Death

Malonyl-CoA Signaling, Lipid Partitioning, and Glucolipotoxicity: Role in β-Cell Adaptation and Failure in the Etiology of Diabetes

Glucagon-Like Peptide 1 Induces Pancreatic β-Cell Proliferation Via Transactivation of the Epidermal Growth Factor Receptor

Glucagon-like peptide-1 prevents beta cell glucolipotoxicity.

Saturated Fatty Acid-induced Apoptosis in MDA-MB-231 Breast Cancer Cells: A ROLE FOR CARDIOLIPIN *