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Optimizing intestinal glucotonic effect via atypical protein kinase C

ABSTRACT: Intestinal glucotonic transformation, defined as increased intestinal serum glucose uptake and secretion into the lumen, influences bariatric surgery-associated glycermic control. This study aims to identify downstream molecules that mediate the function of the identified target as an effective intestinjal glucotonic activator. Altered transcriptomes were evaluated in variable intestinal glucotonic models and big data-based drug discovery systems. Protein kinase C (PKC) activation mimicked transcriptome alterations observed during intestinal glucotonic transformation. Among the PKC subfamilies, atypical PKC (aPKC) promoted glucose transporter 1 (GLUT1)-mediated intestinal glucotonic transformation without inducing oncogenic proliferation. Intestinal aPKC activation via a transposon expression vector induced serum glucose uptake into intestinal tissues and excretion into the lumen. Prostratin, a non-tumorigenic phorbol ester, activated aPKC and induced a similar glucotonic effect. Collectively, we identified the prostratin and aPKC/GLUT1 signaling pathways as effective targets for treating diabetes, providing insights into the future development of antidiabetic and weight loss drugs.

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE312264 | GEO | 2026/01/13

REPOSITORIES: GEO

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Project description:The intestinal manifestations of Cystic Fibrosis (CF) continue to be a source of morbidity despite major advances in CF therapies over the past several years. CF intestinal disease may include obstruction at birth or throughout the lifespan, dysmotility, constipation, small intestinal bacterial overgrowth, and abdominal pain and discomfort. People with CF also have a five to ten-fold increased risk of developing gastrointestinal cancers earlier in life, the reason for which remains largely unknown. The mechanisms underlying the intestinal manifestations of CF are not fully understood. Impaired chloride and bicarbonate ion transport due to absent or dysfunctional CFTR results in dehydrated, viscous mucus that coats the intestinal lumen and altered pH. These changes are thought to create an environment that hinders digestive enzymatic and immune function to promote dysbiosis, dysmotility, and obstruction. The other major organs of digestion, including the pancreas and hepatobiliary system, are also affected in CF, which can result in a variety of symptoms mainly related to fat malabsorption, in addition to various hepatic and biliary pathologies. Most of what is known about the CF intestines has been garnered from studies on the luminal function pertaining to digestion, absorption, mucus accumulation, and bacterial dysbiosis, but little has been described regarding the serosal side. In the process of evaluating systemic carbohydrate utilization in CF mice, we identified the intestine as a key site of increased glucose uptake from circulation in CF. Consequently, we employed a series of complementary in vivo and ex vivo, transcriptional and functional approaches to characterize intestinal glucose demand and metabolism in a mouse model of CF to gain new insights into mechanisms of intestinal disease. We show elevated GLUT1 (Slc2a1) expression in both CF intestinal tissue and isolated crypts, suggesting GLUT1 is responsible for the increased intestinal glucose uptake from the circulation in CF mice. We also identified concomitant increases in glycolysis, in addition to evidence of a proliferative adaptive response in the CF intestine. Taken together, these results are indicative of an increased intestinal glucose demand in CF to maintain intestinal homeostasis and offer a novel approach to understanding CF intestinal disease that may result in new markers of disease status and potentially new critical insight into cancer risk in people with CF. Our findings emphasize a continued need to investigate how the interplay of numerous digestive and absorptive defects in CF contribute to disease pathogenesis to develop more effective therapies for the gastrointestinal manifestations of CF.

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Optimizing intestinal glucotonic effect via atypical protein kinase C

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