Cephalic Phase Insulin Release Research Articles

Mice Condition Cephalic-Phase Insulin Release to Flavors Associated with Postoral Actions of Concentrated Glucose.

Rats can condition cephalic-phase insulin responses (CPIRs) to specific sounds or times of the day that predict food availability. The present study asked whether mice can condition a CPIR to the flavor of sapid solutions that produce postoral glucose stimulation. To this end, we subjected C57BL/6 mice to one of six experimental protocols. We varied both the duration of the five training sessions (i.e., 23 h or 1 h) and the nature of the training solution. In Experiment 1, consumption of a 0.61% saccharin solution was paired with IG co-infusion of a 16% glucose solution. In Experiments 2-6, the mice consumed a training solution containing a mixture of 0.61% saccharin + 16% glucose, 32% sucrose, 32% maltodextrin, flavored 32% maltodextrin, or 16% maltodextrin. We subsequently asked whether consumption of any of these fluids conditioned a CPIR to a test solution that produced a similar flavor, but which did not elicit a CPIR in naïve mice. The mice did condition a CPIR, but only to the solutions containing 32% maltodextrin. We attribute this conditioning to postoral actions of the concentrated maltodextrin solutions.

Sucralose Mouth Rinse Enhances Cephalic Phase Insulin Release

Objective: To assess the combined and independent effects of energy content and sweetness on cephalic phase insulin release (CPIR) and compare responses in adults with normal weight (NW) and obese (OB) body mass indexes (BMI). Methods: In this randomized, double-blind crossover study, 39 adults (NW: n=21; OB: n=18), aged 18-45y (24±5y), rinsed with mouth rinses containing either sucrose, sucralose, maltodextrin, or water for 2min before expectorating the solution. Blood sampling occurred at -5, 1, 3, 5, 7, 10, and 15min following each mouth rinse to assess changes in glucose and CPIR. Results: All rinses elicited increases in insulin (d = -0.5) and glucose (d = -1.1) (p<0.05). There was enhanced CPIR in response to sucralose vs. sucrose (d = 0.4, p=0.004), driven by OB (d = 0.3, p=0.001) vs. NW (p=0.99). For glucose, there was a greater increase following maltodextrin vs. water (d = 0.3, p=0.01), driven by OB (d = 0.2, p=0.02) vs. NW (p=0.99).Conclusion: Sucralose and maltodextrin elicited more robust CPIR and enhanced glucose release, with differences occurring only amongst OB. As postprandial hyperglycemia is a hallmark of obesity, sucralose and maltodextrin rinsing may be important for improving post-meal responses in adults with obesity.

Oral glucose sensing in cephalic phase insulin release

Oral stimulation with foods or food components elicits cephalic phase insulin release (CPIR), which limits postprandial hyperglycemia. Despite its physiological importance, the specific gustatory mechanisms that elicit CPIR have not been clearly defined. While most studies point to glucose and glucose-containing saccharides (e.g., sucrose, maltodextrins) as being the most consistent elicitors, it is not apparent whether this is due to the detection of glucose per se, or to the perceived taste cues associated with these stimuli (e.g., sweetness, starchiness). This study investigated potential sensory mechanisms involved with eliciting CPIR in humans, focusing on the role of oral glucose detection and associated taste. Four stimulus conditions possessing different carbohydrate and taste profiles were designed: 1) glucose alone; 2) glucose mixed with lactisole, a sweet taste inhibitor; 3) maltodextrin, which is digested to starchy- and sweet-tasting products during oral processing; and 4) maltodextrin mixed with lactisole and acarbose, an oral digestion inhibitor. Healthy adults (N = 22) attended four sessions where blood samples were drawn before and after oral stimulation with one of the target stimuli. Plasma c-peptide, insulin, and glucose concentrations were then analyzed. Whereas glucose alone elicited CPIR (one-sample t-test, p < 0.05), it did not stimulate the response in the presence of lactisole. Likewise, maltodextrin alone stimulated CPIR (p < 0.05), but maltodextrin with lactisole and acarbose did not. Together, these findings indicate that glucose is an effective CPIR stimulus, but that an associated taste sensation also serves as an important cue for triggering this response in humans.

Sugar signals from oral glucose transporters elicit cephalic-phase insulin release in mice

Cephalic-phase insulin release (CPIR) occurs before blood glucose increases after a meal. Although glucose is the most plausible cue to induce CPIR, peripheral sensory systems involved are not fully elucidated. We therefore examined roles of sweet sensing by a T1R3-dependent taste receptor and sugar sensing by oral glucose transporters in the oropharyngeal region in inducing CPIR. Spontaneous oral ingestion of glucose significantly increased plasma insulin 5 min later in wild-type (C57BL/6) and T1R3-knockout mice, but intragastric infusion did not. Oral treatment of glucose transporter inhibitors phlorizin and phloretin significantly reduced CPIR after spontaneous oral ingestion. In addition, a rapid increase in plasma insulin was significantly smaller in WT mice with spontaneous oral ingestion of nonmetabolizable glucose analog than in WT mice with spontaneous oral ingestion of glucose. Taken together, the T1R3-dependent receptor is not required for CPIR, but oral glucose transporters greatly contribute to induction of CPIR by sugars.

Adrenomedullin Enhances Mouse Gustatory Nerve Responses to Sugars via T1R-Independent Sweet Taste Pathway.

On the tongue, the T1R-independent pathway (comprising glucose transporters, including sodium-glucose cotransporter (SGLT1) and the KATP channel) detects only sugars, whereas the T1R-dependent (T1R2/T1R3) pathway can broadly sense various sweeteners. Cephalic-phase insulin release, a rapid release of insulin induced by sensory signals in the head after food-related stimuli, reportedly depends on the T1R-independent pathway, and the competitive sweet taste modulators leptin and endocannabinoids may function on these two different sweet taste pathways independently, suggesting independent roles of two oral sugar-detecting pathways in food intake. Here, we examined the effect of adrenomedullin (ADM), a multifunctional regulatory peptide, on sugar sensing in mice since it affects the expression of SGLT1 in rat enterocytes. We found that ADM receptor components were expressed in T1R3-positive taste cells. Analyses of chorda tympani (CT) nerve responses revealed that ADM enhanced responses to sugars but not to artificial sweeteners and other tastants. Moreover, ADM increased the apical uptake of a fluorescent D-glucose derivative into taste cells and SGLT1 mRNA expression in taste buds. These results suggest that the T1R-independent sweet taste pathway in mouse taste cells is a peripheral target of ADM, and the specific enhancement of gustatory nerve responses to sugars by ADM may contribute to caloric sensing and food intake.

The local GLP-1 system in the olfactory bulb is required for odor-evoked cephalic phase of insulin release in mice

ObjectiveThe olfactory bulb (OB) codes for sensory information and contributes to the control of energy metabolism by regulating foraging and cephalic phase responses. Mitral cells are the main output neurons of the OB. The glucagon-like peptide-1 (GLP-1)/GLP-1 receptor (GLP-1R) system in the OB (GLP-1OB) has been shown to be a major regulator of mitral cell activity but its function in vivo is unclear. Therefore, we investigated the role of GLP-1OB in foraging behavior and odor-evoked Cephalic Phase Insulin Release (CPIR). Methods and resultsBy fluorescent labeling, we confirmed the presence of GLP-1 producing neurons and the expression of GLP-1R in the mouse OB. In response to food odor presentation, we collected blood, quantified plasma insulin by ELISA and showed the existence of an odor-evoked CPIR in lean mice but its absence in obese animals. Expression of shRNA against preproglucagon mRNA in the OB resulted in blunted CPIR in lean mice. Injecting Exendin (9-39), a GLP-1R antagonist, into the OB of lean mice also resulted in decreased CPIR. Since parasympathetic cholinergic input to the pancreas is known to be partly responsible for CPIR, we systemically administered the muscarinic M3 receptor antagonist 4-DAMP which resulted in a reduced odor-evoked CPIR. Finally, local injection of Exendin (9-39) in the OB extinguished olfactory foraging in lean mice whereas the injection of the GLP-1R agonist Exendin-4 rescued the loss of foraging behavior in obese mice. ConclusionsOur results demonstrate that GLP-1OB controls olfactory foraging and is required for odor-evoked CPIR. We describe a new crucial brain function for GLP-1 and GLP-1R expressed within the brain.

Oral stimulation with maltodextrin: Effect on cephalic phase insulin release

Cephalic phase insulin release (CPIR) occurs following sensory stimulation with food-related stimuli, and has been shown to limit postabsorptive hyperglycemia. While the specific stimuli that elicit CPIR in humans have not been clearly defined, previous research points to sugars as having potential importance. Maltodextrins are a starch-derived food ingredient commonly found in a variety of processed food products. When consumed, salivary α-amylase rapidly cleaves its component saccharides into smaller units, leading to the production of sugars in the mouth. Here, we investigated whether humans elicit CPIR after tasting but not swallowing maltodextrin, and whether the degree of CPIR exhibited is affected by individuals’ salivary α-amylase activity. We found that a gelatin-based stimulus containing 22% w/v maltodextrin elicited CPIR in healthy individuals (N = 22) following a modified sham-feeding protocol using both insulin and c-peptide as indices of the response. However, the degree of CPIR measured did not differ across three groupings (low, medium, or high) of effective α-amylase activity by either index. In a follow-up experiment, a subset of participants (N = 14) underwent the same protocol using a gelatin stimulus without maltodextrin, and no observable CPIR ensued. These findings suggest that oral stimulation with maltodextrin elicits CPIR in humans, but that individual differences in effective salivary α-amylase activity may not necessarily be predictive of the degree of CPIR.

Consumption of glucose syrup enhances glucose tolerance in mice

There is debate about the metabolic impact of sugar-sweetened beverages. Here, we tested the hypothesis that ad lib consumption of glucose (Gluc) or high-fructose (HiFruc) syrups improves glucose tolerance in mice. We provided C57BL/6 mice with a control (chow and water) or experimental (chow, water and sugar solution) diet across two consecutive 28-day exposure periods, and monitored changes in body composition, glucose tolerance, cephalic-phase insulin release (CPIR) and insulin sensitivity. The sugar solutions contained 11% concentrations of Gluc or HiFruc syrup; these syrups were derived from either corn starch or cellulose. In Experiment 1, consumption of the Gluc diets reliably enhanced glucose tolerance, while consumption of the HiFruc diets did not. Mice on the Gluc diets exhibited higher CPIR (relative to baseline) by the end of exposure period 1, whereas mice on the control and HiFruc diets did not do so until the end of exposure period 2. Mice on the Gluc diets also exhibited higher insulin sensitivity than control mice at the end of exposure period 2, while mice on the HiFruc diets did not. In Experiment 2, we repeated the previous experiment, but limited testing to the corn-based Gluc and HiFruc syrups. We found, once again, that consumption of the Gluc (but not the HiFruc) diet enhanced glucose tolerance, in part by increasing CPIR and insulin sensitivity. These results show that mice can adapt metabolically to high glucose diets, and that this adaptation process involves upregulating at least two components of the insulin response system.

Use of c-peptide as a measure of cephalic phase insulin release in humans

Cephalic phase insulin release (CPIR) is a rapid pulse of insulin secreted within minutes of food-related sensory stimulation. Understanding the mechanisms underlying CPIR in humans has been hindered by its small observed effect size and high variability within and between studies. One contributing factor to these limitations may be the use of peripherally measured insulin as an indicator of secreted insulin, since a substantial portion of insulin is metabolized by the liver before delivery to peripheral circulation. Here, we investigated the use of c-peptide, which is co-secreted in equimolar amounts to insulin from pancreatic beta cells, as a proxy for insulin secretion during the cephalic phase period. Changes in insulin and c-peptide were monitored in 18 adults over two repeated sessions following oral stimulation with a sucrose-containing gelatin stimulus. We found that, on average, insulin and c-peptide release followed a similar time course over the cephalic phase period, but that c-peptide showed a greater effect size. Importantly, when insulin and c-peptide concentrations were compared across sessions, we found that changes in c-peptide were significantly correlated at the 2 min (r = 0.50, p = 0.03) and 4 min (r = 0.65, p = 0.003) time points, as well as when participants’ highest c-peptide concentrations were considered (r = 0.64, p = 0.004). In contrast, no significant correlations were observed for changes in insulin measured from the sessions (r = -0.06–0.35, p > 0.05). Herein, we detail the individual variability of insulin and c-peptide concentrations measured during the cephalic phase period, and identify c-peptide as a valuable metric for insulin secretion alongside insulin concentrations when investigating CPIR.

The cephalic phase of insulin release is modulated by IL-1β

The initial cephalic phase of insulin secretion is mediated through the vagus nerve and is not due to glycemic stimulation of pancreatic β cells. Recently, IL-1β was shown to stimulate postprandial insulin secretion. Here, we describe that this incretin-like effect of IL-1β involves neuronal transmission. Furthermore, we found that cephalic phase insulin release was mediated by IL-1β originating from microglia. Moreover, IL-1β activated the vagus nerve to induce insulin secretion and regulated the activity of the hypothalamus in response to cephalic stimulation. Notably, cephalic phase insulin release was impaired in obesity, in both mice and humans, and in mice, this was due to dysregulated IL-1β signaling. Our findings attribute a regulatory role to IL-1β in the integration of nutrient-derived sensory information, subsequent neuronally mediated insulin secretion, and the dysregulation of autonomic cephalic phase responses in obesity.

The Cephalic Phase of Insulin Release is Modulated by Il-1β

The initial cephalic phase of insulin secretion is mediated through the vagus nerve and is not due to glycemic stimulation of pancreatic β-cells. Recently, IL-1β was shown to stimulate postprandial insulin secretion. Here, we describe that this incretin-like effect of IL-1β involves neuronal transmission. Further we found that cephalic phase insulin release was mediated by IL-1β originating from long-lived CX3CR1+ myeloid cells. Moreover, IL-1β activated the vagus nerve to induce insulin secretion and regulated the activity of neurons of the paraventricular nucleus of the hypothalamus in response to cephalic stimulation. Notably, cephalic phase insulin release was impaired in obesity, in both mice and humans, and in mice this was due to dysregulated IL-1β signaling. Our findings attribute a regulatory role to IL-1β in the integration of nutrient-derived sensory information, subsequent neuronally-mediated insulin secretion and the dysregulation of autonomic cephalic phase responses in obesity.

Satiety, Taste and the Cephalic Phase: A Crossover Designed Pilot Study into Taste and Glucose Response.

The glycemic response produced by a food depends on both the glycemic index of the food itself, and on how the body reacts to the food as it is consumed and digested, in turn dependent on sensory cues. Research suggests that taste stimulation can induce the cephalic phase insulin response before food has reached the digestion, priming the body for an incoming glucose load. This glycemic response can consequently affect the amount of food consumed in a subsequent meal. The aim of this study was to investigate the effects on satiety of four preloads that differed in caloric content and sensory properties, in a small group of female and male participants (n = 10). Water, sucrose, sucralose, and maltodextrin were used to represent 4 different conditions of the preload, with or without energy, and with or without sweet taste. Individual plasma glucose concentrations were sampled at baseline, 45 min after consuming the preload, and after consuming an ad-libitum test meal. Hunger, fullness, desire to eat, and thoughts of food feeling were assessed every 15 min using visual analog scales. Results in male participants when comparing two solutions of equal caloric content, maltodextrin and sucrose, showed that plasma glucose concentration spiked in the absence of taste input (p = 0.011). Maltodextrin, while providing calories does not have the sweet taste that can serve to trigger cephalic phase insulin release to attenuate an incoming glucose load, and was accompanied by significantly greater change in feelings of satiety than with the other preloads. Despite the difference in postprandial blood glucose, the energy consumed in the test meal across the treatments was not significantly different in either males or females. Results highlight the importance of taste in stimulating the body for the efficient and effective glucose homeostasis.

An alternative pathway for sweet sensation: possible mechanisms and physiological relevance.

Sweet substances are detected by taste-bud cells upon binding to the sweet-taste receptor, a T1R2/T1R3 heterodimeric G protein-coupled receptor. In addition, experiments with mouse models lacking the sweet-taste receptor or its downstream signaling components led to the proposal of a parallel "alternative pathway" that may serve as metabolic sensor and energy regulator. Indeed, these mice showed residual nerve responses and behavioral attraction to sugars and oligosaccharides but not to artificial sweeteners. In analogy to pancreatic β cells, such alternative mechanism, to sense glucose in sweet-sensitive taste cells, might involve glucose transporters and KATP channels. Their activation may induce depolarization-dependent Ca2+ signals and release of GLP-1, which binds to its receptors on intragemmal nerve fibers. Via unknown neuronal and/or endocrine mechanisms, this pathway may contribute to both, behavioral attraction and/or induction of cephalic-phase insulin release upon oral sweet stimulation. Here, we critically review the evidence for a parallel sweet-sensitive pathway, involved signaling mechanisms, neural processing, interactions with endocrine hormonal mechanisms, and its sensitivity to different stimuli. Finally, we propose its physiological role in detecting the energy content of food and preparing for digestion.

1955-P: Interleukin-1ß Orchestrates Non–Glucose Dependent Cephalic Phase Insulin Release in Health and Obesity

The non-glucose dependent spike in insulin levels immediately following the beginning of a meal is called the cephalic or pre-absorptive phase of insulin secretion. Even though this early insulin response is of marked consequence for overall postprandial insulin release, its basic mechanisms remain largely unexplored. Here, we show that both genetic and pharmacologic blockade of interleukin-1β (IL-1β) leads to a pronounced reduction in cephalic phase insulin secretion (-0.65 [95%CI= -1.137 to -0.172]). Assessing mice fed a high-fat diet, we found that the cephalic phase insulin response was abolished in obesity. In a systematic review and meta-analysis of trials studying cephalic phase insulin release in healthy human volunteers, we found that this was equally the case in humans. In contrast, high-fat diet-fed mice pre-treated with a specific anti-IL-1β antibody once a week developed no such impairment. We therefore conclude, that dysregulation of physiologic IL-1β signaling, specifically during cephalic phase, may contribute to the overall pathology of metabolic disease. Thus, we identify cephalic phase inflammatory signaling as a novel and potentially modifiable target in the regulation of glucose metabolism. Disclosure S.J. Wiedemann: None. E. Dror: None. D.T. Meier: None. K. Trimigliozzi: None. J. Molina-Tijeras: None. F. Schulze: None. L. Rachid: None. S.P. Häuselmann: None. T.V. Rohm: None. H. Mereau: None. C. Magnan: None. M. Boeni-Schnetzler: None. M.Y. Donath: Advisory Panel; Self; AstraZeneca, Bayer Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Lilly Diabetes, Merck Sharp &amp; Dohme Corp., Novo Nordisk Inc., Roche Pharma, Sanofi-Aventis.

Taste of glucose elicits cephalic-phase insulin release in mice

We reported previously that when C57BL/6 (B6) mice ingest glucose, plasma insulin levels rise above baseline before blood glucose levels do so. This observation led us to speculate that the taste of glucose elicits cephalic-phase insulin release (CPIR) in mice. Here, we examined the specific contributions of taste and glucose to CPIR. In Experiment 1, we bypassed the mouth and delivered glucose directly to the stomach. We found that plasma insulin levels did not rise above baseline until after blood glucose levels did so. This revealed that taste stimulation is necessary for rapid insulin release (i.e., CPIR) in mice. In Experiment 2, we examined the observation that sucrose, maltose and Polycose (a maltodextrin) all elicit CPIR. We proposed in a prior study that these carbohydrates did not directly elicit CPIR; instead, they were digested by oral amylases and alpha-glucosidases, and that it was the enzymatically liberated glucose that elicited CPIR. In support of this possibility, we reported that acarbose (an alpha-glucosidase inhibitor) prevented sucrose, maltose and Polycose from eliciting CPIR. Here, we sought to confirm that glucose alone could elicit CPIR in the presence of acarbose. Indeed, we found that glucose alone and glucose+acarbose each elicited equally robust CPIR. Taken together, these results provide further support for the hypothesis that mice possess a glucose-specific taste transduction pathway that triggers rapid insulin release.

Glucose elicits cephalic-phase insulin release in mice by activating KATP channels in taste cells.

The taste of sugar elicits cephalic-phase insulin release (CPIR), which limits the rise in blood glucose associated with meals. Little is known, however, about the gustatory mechanisms that trigger CPIR. We asked whether oral stimulation with any of the following taste stimuli elicited CPIR in mice: glucose, sucrose, maltose, fructose, Polycose, saccharin, sucralose, AceK, SC45647, or a nonmetabolizable sugar analog. The only taste stimuli that elicited CPIR were glucose and the glucose-containing saccharides (sucrose, maltose, Polycose). When we mixed an α-glucosidase inhibitor (acarbose) with the latter three saccharides, the mice no longer exhibited CPIR. This revealed that the carbohydrates were hydrolyzed in the mouth, and that the liberated glucose triggered CPIR. We also found that increasing the intensity or duration of oral glucose stimulation caused a corresponding increase in CPIR magnitude. To identify the components of the glucose-specific taste-signaling pathway, we examined the necessity of Calhm1, P2X2+P2X3, SGLT1, and Sur1. Among these proteins, only Sur1 was necessary for CPIR. Sur1 was not necessary, however, for taste-mediated attraction to sugars. Given that Sur1 is a subunit of the ATP-sensitive K+ channel (KATP) channel and that this channel functions as a part of a glucose-sensing pathway in pancreatic β-cells, we asked whether the KATP channel serves an analogous role in taste cells. We discovered that oral stimulation with drugs known to increase (glyburide) or decrease (diazoxide) KATP signaling produced corresponding changes in glucose-stimulated CPIR. We propose that the KATP channel is part of a novel signaling pathway in taste cells that mediates glucose-induced CPIR.

A single night of partial sleep loss impairs fasting insulin sensitivity but does not affect cephalic phase insulin release in young men.

The present study sought to investigate whether a single night of partial sleep deprivation (PSD) would alter fasting insulin sensitivity and cephalic phase insulin release (CPIR) in humans. A rise in circulating insulin in response to food-related sensory stimulation may prepare tissues to break down ingested glucose, e.g. by stimulating rate-limiting glycolytic enzymes. In addition, given insulin's anorexigenic properties once it reaches the brain, the CPIR may serve as an early peripheral satiety signal. Against this background, in the present study 16 men participated in two separate sessions: one night of PSD (4.25 h sleep) versus one night of full sleep (8.5 h sleep). In the morning following each sleep condition, subjects' oral cavities were rinsed with a 1-molar sucrose solution for 45 s, preceded and followed by blood sampling for repeated determination of plasma glucose and serum insulin concentrations (-3, +3, +5, +7, +10 and +20 min). Our main result was that PSD, compared with full sleep, was associated with significantly higher peripheral insulin resistance, as indicated by a higher fasting homeostasis model assessment of insulin resistance index (+16%, P = 0.025). In contrast, no CPIR was observed in any of the two sleep conditions. Our findings indicate that a single night of PSD is already sufficient to impair fasting insulin sensitivity in healthy men. In contrast, brief oral cavity rinsing with sucrose solution did not change serum insulin concentrations, suggesting that a blunted CPIR is an unlikely mechanism through which acute sleep loss causes metabolic perturbations during morning hours in humans.

Sugar-induced cephalic-phase insulin release is mediated by a T1r2+T1r3-independent taste transduction pathway in mice.

Sensory stimulation from foods elicits cephalic phase responses, which facilitate digestion and nutrient assimilation. One such response, cephalic-phase insulin release (CPIR), enhances glucose tolerance. Little is known about the chemosensory mechanisms that activate CPIR. We studied the contribution of the sweet taste receptor (T1r2+T1r3) to sugar-induced CPIR in C57BL/6 (B6) and T1r3 knockout (KO) mice. First, we measured insulin release and glucose tolerance following oral (i.e., normal ingestion) or intragastric (IG) administration of 2.8 M glucose. Both groups of mice exhibited a CPIR following oral but not IG administration, and this CPIR improved glucose tolerance. Second, we examined the specificity of CPIR. Both mouse groups exhibited a CPIR following oral administration of 1 M glucose and 1 M sucrose but not 1 M fructose or water alone. Third, we studied behavioral attraction to the same three sugar solutions in short-term acceptability tests. B6 mice licked more avidly for the sugar solutions than for water, whereas T1r3 KO mice licked no more for the sugar solutions than for water. Finally, we examined chorda tympani (CT) nerve responses to each of the sugars. Both mouse groups exhibited CT nerve responses to the sugars, although those of B6 mice were stronger. We propose that mice possess two taste transduction pathways for sugars. One mediates behavioral attraction to sugars and requires an intact T1r2+T1r3. The other mediates CPIR but does not require an intact T1r2+T1r3. If the latter taste transduction pathway exists in humans, it should provide opportunities for the development of new treatments for controlling blood sugar.

The Artificial Pancreas: Is it Important to Understand How the β Cell Controls Blood Glucose?

It has been more than 7 years since the first fully automated closed-loop insulin delivery system that linked subcutaneous insulin delivery and glucose sensing was published. Since the initial report, the physiologic insulin delivery (PID) algorithm used to emulate the β cell has been modified from the original proportional-integral-derivative terms needed to fit the β cell's biphasic response to a hyperglycemic clamp to include terms emulating cephalic phase insulin release and the effect of insulin per se to inhibit insulin secretion. In this article, we compare the closed-loop glucose profiles obtained as each new term has been added, reassess the ability of the revised PID model to describe the β cells' insulin response to a hyperglycemic clamp, and look for the first time at its ability to describe the response to a hypoglycemic clamp. We also consider changes that might be added to the model based on perfused pancreas data. We conclude that the changes introduced in the PID model have systematically improved the closed-loop meal response. We note that the changes made do not adversely affect the ability of the model to fit hyperglycemic clamp data but are necessary to fit the response to a hypoglycemic clamp. Finally, we note a number of β cell characteristics observed in the perfused pancreas have not been included in the model. We suggest that continuing the effort to understand and incorporate aspects of how the β cell achieves glucose control can provide valuable insights into how improvements in future artificial pancreas algorithms might be achieved.

How neural mediation of anticipatory and compensatory insulin release helps us tolerate food.

Learned anticipatory and compensatory responses allow the animal and human to maintain metabolic homeostasis during periods of nutritional challenges, either acutely within each meal or chronically during periods of overnutrition. This paper discusses the role of neurally-mediated anticipatory responses in humans and their role in glucoregulation, focusing on cephalic phase insulin and pancreatic polypeptide release as well as compensatory insulin release during the etiology of insulin resistance. The necessary stimuli required to elicit CPIR and vagal activation are discussed and the role of CPIR and vagal efferent activation in intra-meal metabolic homeostasis and during chronic nutritional challenges are reviewed.