The simple sight and smell of a meal prior to consumption triggers insulin release

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The simple sight and smell of a meal prior to consumption triggers insulin release. This insulin release depends on a short-term inflammatory response. In those who are overweight, this inflammatory response is so excessive it can impair insulin secretion.

Even before carbohydrates reach the bloodstream, the very sight and smell of a meal trigger the release of insulin.

For the first time, researchers from the University of Basel and University Hospital Basel have shown that this insulin release depends on a short-term inflammatory response that takes place in these circumstances.

In overweight individuals, however, this inflammatory response is so excessive that it can impair insulin secretion.

Even the anticipation of a forthcoming meal triggers a series of responses in the body, perhaps the most familiar of which is the watering of the mouth. But the hormone insulin, which regulates blood sugar, also arrives on the scene even before we tuck into the first mouthful of food. Experts refer to this as the neurally mediated (or cephalic) phase of insulin secretion.

Meal stimulates immune defense

In the past, however, it was unclear how the sensory perception of a meal generated a signal to the pancreas to ramp up insulin production.

Now, researchers from the University of Basel and University Hospital Basel have identified an important piece of the puzzle: an inflammatory factor known as interleukin 1 beta (IL1B), which is also involved in the immune response to pathogens or in tissue damage.

The team have reported their findings in the journal Cell Metabolism.

“The fact that this inflammatory factor is responsible for a considerable proportion of normal insulin secretion in healthy individuals is surprising, because it’s also involved in the development of type 2 diabetes,” explains study leader Professor Marc Donath from the Department of Biomedicine and the Clinic of Endocrinology.

Also known as “adult-onset diabetes,” this form of diabetes is caused by chronic inflammation that damages the insulin-producing cells of the pancreas, among other things. This is another situation in which IL1B plays a key role – in this case, it is produced and secreted in excessively large quantities.

With this in mind, clinical studies are now examining whether inhibitors against this inflammatory factor are suitable for use as therapeutic agents for diabetes.

Short-lived inflammatory response

Circumstances are different when it comes to neurally mediated insulin secretion: “The smell and sight of a meal stimulate specific immune cells in the brain known as the microglia,” says study author Dr. Sophia Wiedemann, resident physician for internal medicine.

“These cells briefly secrete IL1B, which in turn affects the autonomic nervous system via the vagus nerve.” This system then relays the signal to the site of insulin secretion – that is, the pancreas.

In the case of morbid obesity, however, this neurally mediated phase of insulin secretion is disrupted. Specifically, by the initial excessive inflammatory response, as explained by doctoral candidate Kelly Trimigliozzi, who carried out the main part of the study in collaboration with Wiedemann.

“Our results indicate that IL1B plays an important role in linking up sensory information such as the sight and smell of a meal with subsequent neurally mediated insulin secretion – and in regulating this connection,” summarizes Marc Donath.


Proinflammatory cytokines impact islet β-cell mass and function by altering the transcriptional activity within pancreatic β-cells, producing increases in intracellular nitric oxide abundance and the synthesis and secretion of immunomodulatory proteins such as chemokines.

Herein, we report that IL-1β, a major mediator of inflammatory responses associated with diabetes development, coordinately and reciprocally regulates chemokine and insulin secretion. We discovered that NF-κB controls the increase in chemokine transcription and secretion as well as the decrease in both insulin secretion and proliferation in response to IL-1β.

Nitric oxide production, which is markedly elevated in pancreatic β-cells exposed to IL-1β, is a negative regulator of both glucose-stimulated insulin secretion and glucose-induced increases in intracellular calcium levels. By contrast, the IL-1β-mediated production of the chemokines CCL2 and CCL20 was not influenced by either nitric oxide levels or glucose concentration.

Instead, the synthesis and secretion of CCL2 and CCL20 in response to IL-1β were dependent on NF-κB transcriptional activity. We conclude that IL-1β-induced transcriptional reprogramming via NF-κB reciprocally regulates chemokine and insulin secretion while also negatively regulating β-cell proliferation. These findings are consistent with NF-κB as a major regulatory node controlling inflammation-associated alterations in islet β-cell function and mass.

the progression to both type 1 (T1DM) and type 2 diabetes mellitus (T2DM) proceeds via immune cell-associated alterations in islet β-cell mass and function. Alterations in islet β-cell mass and function are two major determinants controlling the total amount of insulin produced and secreted in response to physiological stimuli (e.g., glucose).

Proinflammatory cytokines such as IL-1β and IFNγ contribute significantly to losses in islet β-cell viability and insulin secretion. Islet β-cells exposed to IL-1β and IFNγ undergo extensive genetic reprogramming, which includes transcriptional increases in the inducible nitric oxide synthase (iNOS) gene (13, 26) and various genes encoding chemokines (8–10, 12, 44).

IL-1β induces the expression of the iNOS gene, promoting marked accumulation of iNOS protein, a phenotype potentiated by the addition of IFNγ (13, 16, 17, 26). The active iNOS enzyme produces nitric oxide, a free radical signaling molecule that impacts numerous cellular functions (5, 28, 46). In pancreatic β-cells, nitric oxide influences insulin secretion, DNA damage and repair, and overall cellular viability. In addition to controlling the abundance of iNOS, IL-1β also promotes increased production of a variety of chemokines (8, 44), which are soluble secreted factors that regulate immune cell recruitment and activation (25).

For example, CCL2 (a.k.a. MCP-1) is elevated in islets isolated from diabetic mice (8) and from human islets exposed to cytokines (21, 44). Transgenic mice with CCL2 production driven within pancreatic β-cells display enhanced recruitment of immune cells into the pancreatic islets, although disease outcome differs depending on genetic background (35, 36). The chemokine CCL20 (a.k.a. LARC/MIP-3α) is also elevated within islets from mouse, rat, and humans during inflammation (11, 14, 44). CCL20 and CCL2 recruit distinct populations of leukocytes via the use of specific receptors. CCL2 signals through CCR2 (present on monocytes and macrophages), whereas CCL20 is a ligand for the CCR6 receptor (42).

Interestingly, CCL2, CCL20, and iNOS are all bona fide target genes controlled by the NF-κB family of transcription factors (8, 11, 13). NF-κB subunits include p65 (RelA), RelB, c-Rel, p50 (NF-κB1), and p52 (NF-κB2). The NF-κB pathway is one of the major intracellular systems regulating inflammatory responses (2).

Therefore, understanding the mechanisms underlying the IL-1β-mediated, NF-κB-regulated production of chemokines and other signaling molecules, such as nitric oxide, within pancreatic β-cells is essential for developing novel therapeutic strategies to prevent or reverse β-cell death and dysfunction. However, the precise mechanisms underlying the phenotypic changes in pancreatic β-cells in response to IL-1β and nitric oxide are not completely understood.

Toward this end, we have undertaken a systematic analysis of the timing of insulin secretion, nitric oxide accumulation, and chemokine production and release from pancreatic β-cells. We report herein that chemokine secretion increases, whereas insulin secretion decreases, in response to IL-1β. The NF-κB pathway is the central mediator of these outcomes.

We further found that elevations in nitric oxide negatively regulate insulin secretion but have no effect on chemokine release. Moreover, the secretion of chemokines is not influenced by changes in glucose concentration but rather is controlled directly by NF-κB activity. We conclude that NF-κB is the central regulator of the reciprocal and coordinated changes in insulin and chemokine secretion in pancreatic β-cells during receipt of proinflammatory signals.

reference link :https://journals.physiology.org/doi/full/10.1152/ajpendo.00153.2015


Original Research: Open access.
The cephalic phase of insulin release is modulated by IL-1b” by Marc Donath et al. Cell Metabolism

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