Glucoregulatory Relevance of Small Intestinal Nutrient Sensing in Physiology, Bariatric Surgery, and Pharmacology

Duca, Frank A.; Bauer, Paige V.; Hamr, Sophie C.; Lam, Tony K.T.

doi:10.1016/j.cmet.2015.07.003

Cited by 53 publications

(39 citation statements)

References 193 publications

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“…While in the preabsorptive state, nutrients activate various signaling events and trigger the release of gut-derived peptides such as CCK and GLP-1 to activate negative feedback, whole-body metabolic pathways that regulate food intake and glucose homeostasis (107,108). In fact, direct inhibition of small intestinal CCK receptor (92) or knockdown of GLP-1 receptors in the vagal afferent nerves (93) disrupt glucose homeostasis in rodents, indicating that a gut/brain axis mediates the ability of nutrient-dependent CCK and GLP-1 action to regulate glucose homeostasis.…”

Section: Figure 2 An Integrative and Neuronal-dependent Intestinal Imentioning

confidence: 99%

“…These studies collectively highlight the potential converging role of intestinal SCFA sensing in the regulation of immunity and whole-body glucose homeostasis (Figure 2). Changes in gut microbiota are not only associated with obesity and diabetes but also with changes of intestinal immunity, as well as metformin and bariatric surgical therapies (107). The potential mechanistic links between metformin and bariatric surgery as well as small intestinal nutrient-sensing mechanisms in lowering plasma glucose have been reviewed elsewhere (107).…”

Section: Figure 2 An Integrative and Neuronal-dependent Intestinal Imentioning

confidence: 99%

“…Changes in gut microbiota are not only associated with obesity and diabetes but also with changes of intestinal immunity, as well as metformin and bariatric surgical therapies (107). The potential mechanistic links between metformin and bariatric surgery as well as small intestinal nutrient-sensing mechanisms in lowering plasma glucose have been reviewed elsewhere (107). It should be noted that although metformin action in the gut can recapitulate the systemic effect of metformin in lowering plasma glucose levels in rodents (113) and people with type 2 diabetes (114), the underlying intestinal molecular events remain unclear.…”

Section: Figure 2 An Integrative and Neuronal-dependent Intestinal Imentioning

confidence: 99%

See 2 more Smart Citations

Immunologic impact of the intestine in metabolic disease

Winer¹,

Winer²,

Dranse³

et al. 2017

Journal of Clinical Investigation

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Section: Figure 2 An Integrative and Neuronal-dependent Intestinal Imentioning

confidence: 99%

Section: Figure 2 An Integrative and Neuronal-dependent Intestinal Imentioning

confidence: 99%

Section: Figure 2 An Integrative and Neuronal-dependent Intestinal Imentioning

confidence: 99%

See 1 more Smart Citation

Immunologic impact of the intestine in metabolic disease

Winer¹,

Winer²,

Dranse³

et al. 2017

Journal of Clinical Investigation

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“…Although the medical and technological knowledge of these disorders has improved tremendously, the pathogenesis of diabetes remains poorly understood, and efficient therapeutic tools are still lacking. In this respect, the success of gastric bypass surgery and new promising gut-derived pharmacological treatments, such as the use of glucagon-like peptide-1 (GLP-1) analogs, highlights the importance of the gastrointestinal tract in regulating glucose homeostasis (23). Moreover, the socalled "gut-brain axis" is currently an intriguing topic in the search for new antidiabetic tools (23).…”

mentioning

confidence: 99%

“…In this respect, the success of gastric bypass surgery and new promising gut-derived pharmacological treatments, such as the use of glucagon-like peptide-1 (GLP-1) analogs, highlights the importance of the gastrointestinal tract in regulating glucose homeostasis (23). Moreover, the socalled "gut-brain axis" is currently an intriguing topic in the search for new antidiabetic tools (23). Thus, a better understanding of the pathways involved in glucosensing inside and outside the gastrointestinal tract will likely contribute to the identification of future therapeutic targets for the treatment of diabetes.…”

mentioning

confidence: 99%

Glucosensing in the gastrointestinal tract: Impact on glucose metabolism

Fournel

Marlin

Abot

et al. 2016

American Journal of Physiology-Gastrointestinal and Liver Physi

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The gastrointestinal tract is an important interface of exchange between ingested food and the body. Glucose is one of the major dietary sources of energy. All along the gastrointestinal tube, e.g., the oral cavity, small intestine, pancreas, and portal vein, specialized cells referred to as glucosensors detect variations in glucose levels. In response to this glucose detection, these cells send hormonal and neuronal messages to tissues involved in glucose metabolism to regulate glycemia. The gastrointestinal tract continuously communicates with the brain, especially with the hypothalamus, via the gut-brain axis. It is now well established that the cross talk between the gut and the brain is of crucial importance in the control of glucose homeostasis. In addition to receiving glucosensing information from the gut, the hypothalamus may also directly sense glucose. Indeed, the hypothalamus contains glucose-sensitive cells that regulate glucose homeostasis by sending signals to peripheral tissues via the autonomous nervous system. This review summarizes the mechanisms by which glucosensors along the gastrointestinal tract detect glucose, as well as the results of such detection in the whole body, including the hypothalamus. We also highlight how disturbances in the glucosensing process may lead to metabolic disorders such as type 2 diabetes. A better understanding of the pathways regulating glucose homeostasis will further facilitate the development of novel therapeutic strategies for the treatment of metabolic diseases.glucosensing; glucose homeostasis; diabetes GLUCOSE REPRESENTS ONE of the major sources of energy circulating throughout the body. The tight and continuous control of glycemia in the face of fluctuations in glucose absorption, storage, and production is crucial for all living organisms. Not surprisingly, the gastrointestinal tract constitutes the first anatomic site for the detection of nutrients, including glucose. Glucose detection involves specialized cells referred to as glucosensors (21,44,64). These cells, which are present in the oral cavity as well as the small intestine, pancreas, and portal vein, express various glucose transporters and G proteincoupled receptors (GPCRs) implicated in the physiological response to glucosensing (21,44,64). Glucosensing by these cells evokes complex neural and endocrine responses that control glucose metabolism. Moreover, glucose detection in the gastrointestinal tract also transmits afferent nervous impulses to the brain, which, in turn, controls peripheral glucose utilization. Indeed, the brain, specifically the hypothalamus, is a key player in the regulation of glucosensing mechanisms. In addition to receiving information via the gut-brain axis, the hypothalamus also contains glucosensitive cells able to detect glucose (91). Upon the integration of these messages, the hypothalamus sends specific signals to the tissues involved in glucose metabolism via the autonomous nervous system (ANS).Metabolic disorders such as type 2 diabetes (T2D) are considered as ...

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mTOR Signaling in X/A‐Like Cells Contributes to Lipid Homeostasis in Mice

Yin

et al. 2018

Hepatology

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Gastric mechanistic target of rapamycin (mTOR) signaling is inversely associated with the expression and secretion of ghrelin, a 28-aa peptide hormone produced by gastric X/A-like cells. Ghrelin contributes to obesity and hepatic steatosis. We sought to control global lipid metabolism through manipulating gastric mTOR signaling in X/A-like cells METHODS: We established a ghrl-cre transgene in which the cre enzyme is expressed in X/A-like cells under the control of the ghrelin-promoter. mTOR and TSC1 mice were separately bred with ghrl-cre mice to generate mTOR-ghrl-cre (mG) or TSC1-ghrl-cre (TG) mice, within which mTOR signaling was suppressed or activated respectively. Lipid metabolism in liver and adipose depots was analyzed RESULTS: Under the control of the ghrelin-promoter, cre enzyme is exclusively expressed in stomach X/A-like cells in adult animals. Knockout of mTOR in X/A-like cells increased circulating acyl-ghrelin and promoted hepatic lipogenesis with effects on adipose depots. Activation of mTOR signaling by deletion of its upstream inhibitor, tuberous sclerosis 1 (TSC1), decreased ghrelin expression and secretion, altering lipid metabolism as evidenced by resistance to high fat diet-induced obesity and hepatic steatosis. Both ghrelin administration and rapamycin, an inhibitor of mTOR, altered the phenotypes of TG mice CONCLUSION: Gastric mTOR signaling in X/A-like cells contributes to organism lipid homeostasis by regulating hepatic and adipose lipid metabolism. Gastric mTOR signaling may provide an alternative strategy for intervention in lipid disorders. This article is protected by copyright. All rights reserved.

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Glucoregulatory Relevance of Small Intestinal Nutrient Sensing in Physiology, Bariatric Surgery, and Pharmacology

Cited by 53 publications

References 193 publications

Immunologic impact of the intestine in metabolic disease

Immunologic impact of the intestine in metabolic disease

Glucosensing in the gastrointestinal tract: Impact on glucose metabolism

mTOR Signaling in X/A‐Like Cells Contributes to Lipid Homeostasis in Mice

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