Beta cells of the pancreas, which make and secrete insulin, do not respond like those of non-diabetic subjects when type 2 diabetes is present. Specifically, subjects suffering from type 2 diabetes have a blunted or even absolute loss of first phase and a severely blunted second phase insulin release in response to glucose. In conjunction with this, and despite all treatments currently available to treat diabetes, beta cell function continues to deteriorate over time. With the data now available from the United Kingdom Prospective Diabetes Study (Sept. 1998) this point was brought home even more forcefully. Despite continual monitoring of patients enrolled in the study, euglycemia could not be maintained even with intensive therapy, because of declining beta cell function. We have been working for some time with GLP-1, a naturally occurring incretin peptide produced and released from the gut in response to food. The amount released depends on the amount of glucose and fat that has been ingested. After its plasma levels increase, GLP-1 binds to the GLP-1 receptor (GLP-1R) on beta cells, and increases PKA activity because of adenylyl cyclase (AC) activation and cAMP generation. Downstream of the increased PKA activity, glucose-induced insulin secretion is enhanced. The end result is a restoration of plasma glucose back to baseline. Consequently, GLP-1 analogs and GLP-1R agonists are under intense study as treatments for type 2 diabetes. A naturally occurring GLP-1R agonist, exendin-4, is now available for treatment. However, there are cellular and hormonal mechanisms within islets that negatively impact beta-cell secretion and proliferation, which cannot be fully overcome with incretin receptor agonists. Another incretin, GIP, also enhances glucose-induced insulin secretion, however, unlike GLP-1, when it is given in pharmacological concentrations to patients with type 2 diabetes it actually worsens post-prandial glucose because in also increases glucagon secretion. As regards inhibitors of insulin secretion, somatostatin production from delta cells in islets, for example, could serve to inhibit insulin secretion, though there is no evidence for its over-activity in type 2 diabetes and there are very few delta cells in adult islets to begin with ( about 100:1, beta to delta cells, respectively). We looked for other potential adenylyl cyclase inhibitors that may be produced within islets and found that endogenous cannabinoids are produced exclusively in beta cells. When cannabinoid 1 receptors (CB1R) are inhibited or genetically removed in adult rodents, insulin secretion and beta-cell function is enhanced because a brake on AC activity is lifted. Additionally we have determined that hepatocytes and beta cells express a particular isoform of the CB1R, not present in the brain. It may be possible to target the particular isoform by pharmaceutics or oligonucleotides to inhibit its function in those cell types.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIAAG000905-22
Application #
9770173
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
22
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Aging
Department
Type
DUNS #
City
State
Country
Zip Code
González-Mariscal, Isabel; Montoro, Rodrigo A; Doyle, Máire E et al. (2018) Absence of cannabinoid 1 receptor in beta cells protects against high-fat/high-sugar diet-induced beta cell dysfunction and inflammation in murine islets. Diabetologia 61:1470-1483
Shin, Hanho; Han, Ji Hye; Yoon, Juhwan et al. (2018) Blockade of cannabinoid 1 receptor improves glucose responsiveness in pancreatic beta cells. J Cell Mol Med 22:2337-2345
González-Mariscal, Isabel; Egan, Josephine M (2018) Endocannabinoids in the Islets of Langerhans: the ugly, the bad, and the good facts. Am J Physiol Endocrinol Metab 315:E174-E179
Chia, Chee W; Carlson, Olga D; Liu, David D et al. (2017) Incretin Secretion in Humans is under the Influence of Cannabinoid Receptors. Am J Physiol Endocrinol Metab :ajpendo.00080.2017
Kim, Jihye; Lee, Kyung Jin; Kim, Jung Seok et al. (2016) Cannabinoids Regulate Bcl-2 and Cyclin D2 Expression in Pancreatic ? Cells. PLoS One 11:e0150981
Elahi, Dariush; Ruff, Dennis A; Carlson, Olga D et al. (2016) Does GLP-1 suppress its own basal secretion? Endocr Res 41:16-20
González-Mariscal, Isabel; Krzysik-Walker, Susan M; Doyle, Máire E et al. (2016) Human CB1 Receptor Isoforms, present in Hepatocytes and ?-cells, are Involved in Regulating Metabolism. Sci Rep 6:33302
Kim, Wook; Fiori, Jennifer L; Shin, Yu-Kyong et al. (2014) Pancreatic polypeptide inhibits somatostatin secretion. FEBS Lett 588:3233-9
Milaneschi, Yuri; Sutin, Angelina R; Terracciano, Antonio et al. (2014) The association between leptin and depressive symptoms is modulated by abdominal adiposity. Psychoneuroendocrinology 42:1-10
Chia, Chee W; Odetunde, Juliana O; Kim, Wook et al. (2014) GIP contributes to islet trihormonal abnormalities in type 2 diabetes. J Clin Endocrinol Metab 99:2477-85

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