Elucidating the role of atypical Protein Kinase Czeta in free fatty-acid induced glucagon-like peptide-1 secretion in vivo
Zusammenfassung der Projektergebnisse
Appropriate food processing after a meal requires control of intestinal function by the nervous system as well as by body hormones. Additionally, some gut cells release hormones to adjust whole body metabolism to the specific nutrient constituents of the meal. More than 30 such hormones are synthesized in the intestine. In particular, the regulation of insulin secretion from the pancreatic β-cells is important for control of blood sugar levels to avoid tissue damage. Our previous publication has shown that specific intestinal cells, the ‘L’ cells, release the hormone glucagon-like peptide-1 (GLP-1) after ingestion of monounsaturated fat (e.g. olive oil), while saturated fat (e.g. coconut oil) does not affect GLP-1 secretion. GLP-1 then increases insulin secretion from the β-cells in glucose-dependent way, therefore safely reducing the blood sugar levels. Additionally, GLP-1 decreases hunger and, over the long-term, reduces body weight. Some publications also suggest that GLP-1 protects the β-cells against damage or death. Thus, GLP-1 is a natural anti-diabetic agent and has recently been approved in both the USA and Europe as a novel therapeutic agent to treat type 2 diabetes. In a recent publication we have shown that GLP-1 secretion induced by monounsaturated fat depends on the enzyme Protein Kinase Czeta (PKCzeta). However, the effects were shown only in isolated intestinal L cells in culture, and the role of this enzyme in GLP-1 secretion in living organisms remains unknown. We therefore synthesized a virus carrying a specific silencing gene (siRNA) which causes the downregulation of PKCzeta. This virus was injected directly into the lower intestine by a rectal enema, causing a decrease in the intestinal PKCzeta levels. We have verified the feasibility of this method by an enema containing barium, showing the distribution of solution in complete large intestine and parts of small intestine, as shown by X-Ray; these are the primary intestinal tissues in which the L cell is found. Additionally, we have shown that the administration of fat directly into the large intestine can directly stimulate GLP-1 secretion. Therefore, by injecting the virus to downregulate PKCzeta, and subsequently infusing the fat, we determined the relationship between monounsaturated fats, PKCzeta and GLP-1 secretion in rats. To verify the effects of downregulation of PKCzeta we measured the content of GLP-1 in blood, as well as protein expression levels of PKCzeta. A better understanding of GLP-1 secretion is necessary for the development of novel therapeutic approaches for diabetes therapy. Although GLP-1-related drugs have already been approved in the USA and Europe for type 2 diabetes treatment, direct stimulation of the L cells to increase GLP-1 secretion could increase the available therapeutic options. Such drugs based on this principle will likely have a high safety profile, as the L cells can be stimulated in the gut without drug uptake into the blood system.
Projektbezogene Publikationen (Auswahl)
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GPR119: "double-dipping" for better glycemic control. Endocrinology. 2008 May;149(5):2035-7
Lauffer L, Iakoubov R, Brubaker PL
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Carcinogenic effects of exogenous and endogenous glucagon-like peptide-2 in azoxymethane-treated mice. Endocrinology. 2009 Sep;150(9):4033-43
Iakoubov R, Lauffer LM, Trivedi S, Kim YI, Brubaker PL
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GPR119 is essential for oleoylethanolamide-induced glucagon-like peptide-1 secretion from the intestinal enteroendocrine L-cell. Diabetes. 2009 May;58(5):1058-66
Lauffer LM, Iakoubov R, Brubaker PL
