Meal Onset Research Articles

275-OR: Association between Treatment Adherence and CGM Outcomes in People with T1D Using Smart Insulin Pens in a Real-World Setting

Adherence to insulin therapy can be challenging for individuals with T1D. This analysis explored how adherence to basal and bolus insulin injections influences glycemic outcomes. Data were collected from adults (≥18 years) administering basal insulin (degludec) and bolus insulin (aspart or faster aspart) using smart insulin pens with CGM; data were aggregated in 14-day periods. Treatment adherence was defined as the number of missed basal insulin doses (>40 hrs between doses), flex basal insulin doses (dosing time deviated >±6 hrs from previous day) and missed bolus insulin doses (meals with no bolus dose within -15 to +60 mins from meal onset). Glycemic outcomes included time in range (TIR), time below range, glucose management index (GMI), and coefficient of variation. Multinational data from 403 adults who had 3588 14-day periods with ≥70% CGM coverage were analyzed. Individuals with one missed basal dose per 14-days had a lower TIR (-4.04% [95% CI: -6.83; -1.26]) and higher GMI (0.20% [95% CI: 0.02; 0.38]) than individuals without missed basal doses; flex basal doses were not associated with TIR changes. Missed bolus insulin doses were also associated with lower TIR (Table). These real-world data confirm associations between missed basal and bolus insulin doses and impaired TIR, highlighting a need for digital tools such as smart insulin pens to help individuals manage their diabetes. Disclosure T.Danne: Research Support; Abbott Diabetes, AstraZeneca, Bayer Inc., Boehringer-Ingelheim, Dexcom, Inc., Eli Lilly and Company, Novo Nordisk A/S, Sanofi, Medtronic, Stock/Shareholder; DreaMed Diabetes, Ltd. N.V.Hartvig: Employee; Novo Nordisk A/S, Stock/Shareholder; Novo Nordisk A/S. A.Kaas: Employee; Novo Nordisk A/S, Stock/Shareholder; Novo Nordisk A/S. N.N.Knudsen: Employee; Novo Nordisk. J.K.Mader: Advisory Panel; Novo Nordisk A/S, Abbott Diabetes, Roche Diabetes Care, Eli Lilly and Company, Sanofi, Medtronic, Becton, Dickinson and Company, Pharmasense, embecta, Research Support; A. Menarini Diagnostics, Abbott Diabetes, Roche Diabetes Care, Dexcom, Inc., Profusa, Inc., Speaker's Bureau; Novo Nordisk A/S, A. Menarini Diagnostics, Abbott Diabetes, Roche Diabetes Care, Eli Lilly and Company, Sanofi, Boehringer Ingelheim Inc., Becton, Dickinson and Company, Ypsomed AG, Viatris Inc., Servier Laboratories, Medtrust, Stock/Shareholder; Decide Clinical Software GmbH. Funding Novo Nordisk A/S

Increased Meal Size but Reduced Meal-Stimulated Plasma Cholecystokinin Concentrations in Women With Obesity.

To better understand the physiological basis of obesity in women, we investigated whether obesity or menstrual cycle phase affects laboratory test-meal size or meal-stimulated plasma cholecystokinin (CCK) concentration. Women with healthy weight (body mass index [BMI] of 18.5-24.9 kg/m2, N = 16) or obesity (BMI 30-39.9 kg/m2, N = 20) were tested once in the late-follicular or peri-ovulatory phase (LF/PO) and once in the mid-luteal phase (ML). Meals of ham sandwiches were offered and blood was sampled. Menstrual cycle phases were verified with participants' reports of menses and measurements of progesterone and luteinizing hormone (LH) concentrations. Women with obesity ate significantly larger meals than women with healthy weight, (mean, 711 [95% CI, 402-1013] kJ, P = 0.001, during the LF/PO and 426 [105-734] kJ, P = 0.027, larger during the ML). Women with healthy weight ate smaller meals during LF/PO than ML (decrease, 510 [192-821 kJ], P = 0.008), but women with obesity did not (decrease, 226 [-87-542] kJ, P = 0.15). CCK concentrations 18 to 30 minutes after meal onset were lower in women with obesity than in women with healthy weight during LF/PO (3.6 [3.1-4.1] vs 6.1 [4.5-7.7] pmol/L; P = 0.004), but not during ML, with a significant interaction effect (1.8 [1.2-2.4] pmol/L, P = 0.048). Women with obesity consumed larger meals than women with healthy weight but displayed reduced meal-stimulated plasma CCK concentrations. These data are consistent with the hypothesis that a defect in CCK secretion compromises satiation in obese women and contributes to the development or maintenance of obesity.

151-LB: Postprandial Glucose Metabolism Differs between Early Adolescents and Adults with Type 1 Diabetes

Postprandial glucose turnover in adolescents with type 1 diabetes (T1D) has not been investigated. To do so, we studied adolescents (n=15, age 11.5±0.5 yrs, BMI 19±2.3 kg/m2, HbA1c 7.5±1%, diabetes duration 4.6±3 yrs) and adults (n=15, age 36.3±9.4 yrs, BMI 27.1±2.1 kg/m2, HbA1c 6.9±1.1%, diabetes duration 18.1±9.6 yrs) with T1D after a mixed meal. Healthy adults (n=14, age 26.9 ± 7 yrs, BMI 24.9±2.5 kg/m2, HbA1c 5.0±0.3%) served as controls. T1D subjects administered their customary insulin bolus dose at meal onset. Rates of endogenous glucose production (EGP) , meal glucose appearance (MRa) and glucose disappearance (Rd) were calculated by the triple tracer method with stable isotopes ([1-13C] glucose, [2-13C] glucose and [6, 6-2H2] glucose) . Integrated glucose excursions did not differ between adolescents and adults with T1D during early (0-120 min) and total (0-300 min) postprandial periods. While basal EGP at start of the meal was higher (p<0.01) , integrated rates of EGP, MRa, Rd and glucose clearance were all lower (p<0.03) in adolescents than in adults with T1D during the early postprandial period and were numerically lower (p=0.08) during the total postprandial period (Figure1) . Taken together, the data demonstrates significant differences in postprandial glucose metabolism between adolescents and adults with T1D. Additional studies are ongoing to determine the causes of these differences. Disclosure F. Ruchi: None. D. Romeres: None. S. Gururaj: None. M. D. Deboer: Research Support; Dexcom, Inc., Tandem Diabetes Care, Inc. R. Basu: Consultant; Sparrow Pharmaceuticals Inc, Research Support; Abbott Diabetes, AstraZeneca. A. Basu: Speaker's Bureau; Zealand Pharma A/S. Funding DK 124886, DK 085516, DK 029953

1377-P: Pramlintide Lowers Postprandial Glucagon Concentrations by Inhibiting Glucagon Secretion without Altering Clearance in Type 1 Diabetes: A [13C15N]-Glucagon Study

To determine the underlying mechanism of pramlintide effects on postprandial (PP) glucagon concentrations, we studied thirteen C-peptide negative T1D subjects (Age 35±yrs, BMI 27.6±2.2 kg/m2, fasting plasma glucose 9.4±4 mM, HbA1c 7.1±1%) on two occasions in random order, with and without 30 μg of sc pramlintide at the onset of a mixed meal (75 gm carb, 15% fat and 35% protein; 8 kcal/kg) . Subjects administered insulin bolus at meal onset. 13C15N glucagon tracer was infused intravenously to estimate PP glucagon turnover. Arterialized venous samples were drawn periodically for measurements of glucose (YSI) , 13C15N-glucagon (LC-MS/MS) and glucagon (Mercodia) concentrations. Systemic glucagon turnover was calculated using non-steady state Steele's equation after determining glucagon volume of distribution. Integrated PP glucagon concentrations were lower (p<0.01) in pramlintide (Pram) than without pramlintide (No Pram) . Integrated rates of glucagon appearance and glucagon disappearance were lower (p<0.01) in Pram vs. No Pram. When adjusted for plasma glucagon concentrations, glucagon clearance was not different (p=0.7) between Pram vs. No Pram. These data demonstrate that pramlintide lowers postprandial glucagon concentrations by lowering glucagon secretion without altering clearance in subjects with T1D. Disclosure F.Ruchi: None. D.Romeres: None. M.Schiavon: None. S.Renuse: None. A.Pandey: None. C.Dalla man: Research Support; Becton, Dickinson and Company, Sanofi-Aventis Deutschland GmbH. C.Cobelli: None. R.Basu: Consultant; Sparrow Pharmaceuticals Inc, Research Support; Abbott Diabetes, AstraZeneca. A.Basu: Speaker's Bureau; Zealand Pharma A/S. Funding National Institute of Health (DK 085516, DK 029953)

Meal detection and carbohydrate estimation based on a feedback scheme with application to the artificial pancreas

Current glucose control systems automatically regulate basal insulin infusion, but users still need to manually announce meals (major disturbances) to dose prandial insulin boluses. This issue needs to be solved to reach a fully automated artificial pancreas. Automatic meal detection and carbohydrate amount estimation from readings of blood glucose (BG) and insulin infusion can improve the artificial pancreas control system from two possible paths: (i) the off-line reconstruction of the carbohydrate intake signal which allows a reliable identification of a control-relevant model, and (ii) the on-line prediction of meal onset and amount of carbohydrates ingested, which allows safety supervision of manually entered meal announcements. The aim of this work is the item (i), for which an automatic algorithm is developed to detect the consumption of a meal and estimate its carbohydrate amount in people with type 1 diabetes. The unknown input estimation is based on a feedback scheme where the measured BG is compared with a BG prediction. Glycemic behavior is predicted using a personalized model by means of the patient's functional insulin therapy parameters defined by the treating physician. The proposed algorithm is evaluated with data extracted from the 30-patient cohort of the UVA/Padova simulator approved by the FDA and with retrospective data from 11 real patients of a diabetes center. Diabetes care data from free-living adult patients were collected during regular screening and the meals were identified by experts. For the in silico dataset, the detection accuracy is near 100%, the absolute error of the estimation of ingested carbohydrates is 10% on average, and the average bias of meal onset estimation is 5 min. For the clinical dataset, the meal detection performance is 98% and the estimation accuracy measures are 13% and 2 min, respectively. In this work, the impact of reconstructing the carbohydrate intake signal on the identification proved to be beneficial. In addition, the feedback scheme and the easily personalized prediction model make the strategy efficient.

Hypoglycemia attenuates acute amylin-induced reduction of food intake in male rats

The ability of amylin to inhibit gastric emptying and glucagon secretion in rats is reduced under hypoglycemic conditions. These effects are considered part of a fail-safe mechanism that prevents amylin from further decreasing nutrient supply when blood glucose levels are low. Because these actions and amylin-induced satiation are mediated by the area postrema (AP), it is plausible that these phenomena are based on the co-sensitivity of AP neurons to amylin and glucose. Using hyperinsulinemic glucose clamps in unrestrained and freely-feeding rats, we investigated whether amylin's ability to inhibit food intake is also reduced by hypoglycemia (HYPO). Following an 18 h fast, rats were infused with insulin and glucose for 45 min to clamp blood glucose at baseline levels (between 90 and 100 mg/dL). HYPO (approximately 55 mg/dL) was induced between 45 and 60 min and then maintained for the remainder of the clamp. Rats were injected with amylin (20 µg/kg) or saline and offered normal chow at 85 min. Food intake was measured at 30 and 60 min after amylin. Control hyperinsulinemic/euglycemic (EU) rats were maintained at approximately 150 mg/dL (which is a physiological periprandial glucose level) before and after amylin injection. Terminal experiments tested the effect of amylin to induce the phosphorylation of ERK, a marker of amylin action in the AP, in EU and HYPO conditions. Amylin significantly reduced 30- and 60-min food intake in EU rats, but the effect at 60-min was attenuated in HYPO rats. Interestingly, glucose infusion rate had to be dramatically reduced at meal onset in saline-treated, but not in amylin-treated, EU or HYPO rats; this suggests that meal-related glucose appearance in the blood was inhibited by amylin under both EU and HYPO. Finally, amylin induced a similar pERK response in the AP in EU and HYPO rats. We conclude that amylin's action to decrease eating is blunted in hypoglycemia, and this effect seems to be downstream from amylin-induced pERK in AP neurons. These data allow us to extend the idea of a hypoglycemic brake on amylin's actions to its food intake-reducing effect, but also demonstrate that amylin can buffer meal-induced glucose appearance at EU and HYPO levels.

When do children learn how to select a portion size?

The reduction of portion sizes supports weight-loss. This study looks at whether children have a conceptual understanding of portion size, by studying their ability to manually serve a portion size that corresponds to what they eat. In a clinical setting, discussion around portion size is subjective thus a computerised portion size tool is also trialled, with the portion sizes chosen on the screen being compared to amounts served manually. Children (n = 76) age 5–6, 7–8 and 10–11 were asked to rate their hunger (VAS scale), liking (VAS scale) and ‘ideal portion size for lunch’ of eight interactive meal images using a computerised portion size tool. Children then manually self-served and consumed a portion of pasta. Plates were weighed to allow for the calculation of calories served and eaten. A positive correlation was found between manually served food portions and the amount eaten (r = 0.53, 95%CI [0.34, 0.82, P < .001), indicating that many children were able to anticipate their likely food intake prior to meal onset. A regression model demonstrates that age contributes to 9.4% of the variance in portion size accuracy (t(68) = −2.3, p = .02). There was no relationship between portion size and either hunger or liking. The portion sizes chosen on the computer at lunchtime correlated to the amount manually served overall (r = .34, 95%CI [0.07, 0.55], p < .01), but not in 5-6-year-old children. Manual portion-size selection can be observed in five-year olds and from age seven, children's ‘virtual’ responses correlate with their manual portion selections. The application of the computerised portion-size tool requires further development but offers considerable potential.

How oro-sensory exposure and eating rate affect satiation and associated endocrine responses—a randomized trial

BackgroundLonger oral processing decreases food intake. This can be attributed to greater oro-sensory exposure (OSE) and a lower eating rate (ER). How these factors contribute to food intake, and the underlying physiological mechanisms, remain unclear.ObjectivesWe aimed to determine the independent and simultaneous effects of OSE and ER on satiation and associated endocrine responses.MethodsForty participants in study 1 [mean ± SD age: 24 ± 4 y; BMI (in kg/m2): 22 ± 2] and 20 in study 2 (mean ± SD age: 23 ± 3 y; BMI: 23 ± 2) participated in a 2 × 2 randomized trial. In both studies, participants ate chocolate custard with added caramel sauce (low OSE) or caramel fudge (high OSE) and with short (fast ER) or long breaks (slow ER) in between bites, until fullness. In study 2, endocrine responses were measured during the meal.ResultsIn study 1, participants ate (mean ± SEM) 42 ± 15 g less in the slow- than in the fast-ER condition, only within the high-OSE condition (P = 0.04). In study 2, participants ate 66 ± 21 g less in the high- than in the low-OSE condition and there were no intake differences between slow and fast ER (P = 0.35). Eight minutes after starting to eat, insulin concentrations increased by 42%–65% in all treatments compared with the control. At the end of the meal, insulin concentrations were 81% higher in the high-OSE, slow-ER than in the low-OSE, fast-ER condition (P = 0.049). Pancreatic polypeptide (PP) increased by 62%, 5 min after meal onset in the low-OSE, fast-ER condition (P = 0.005). Ghrelin concentrations did not change.ConclusionsGreater OSE increases insulin responsiveness. In contrast, PP responses are stronger when OSE is reduced and ER is fast. Insulin and PP responses may mediate the independent effects of OSE and ER on food intake. These may be beneficial eating strategies, particularly for type 2 diabetic patients, to control food intake and maintain glucose homeostasis.This trial was registered at trialregister.nl as NL6544.

Pattern Recognition Reveals Characteristic Postprandial Glucose Changes: Non-Individualized Meal Detection in Diabetes Mellitus Type 1.

Accurate continuous glucose monitoring (CGM) is essential for fully automated glucose control in diabetes mellitus type 1. State-of-the-art glucose control systems automatically regulate the basal insulin infusion. Users still need to manually announce meals to dose the prandial insulin boluses. An automated meal detection could release the user and improve the glucose regulation. In this study, patterns in the postprandial CGM data are exploited for meal detection. Binary classifiers are trained to recognize the postprandial pattern in horizons of the estimated glucose rate of appearance and in CGM data. The appearance rate is determined by moving horizon estimation based on a simple model. Linear discriminant analysis (LDA) is used for classification. The proposed method is compared to methods that detect meals when thresholds are violated. Diabetes care data from 12 free-living pediatric patients was downloaded during regular screening. Experts identified meals and their start by retrospective evaluation. The classification was tested by cross-validation. Compared to the threshold-based methods, LDA showed higher sensitivity to meals with a low rate of false alarms. Classifying horizons outperformed the other methods also with respect to time of detection. The onset of meals can be detected by pattern recognition based on estimated model states and consecutive CGM measurements. No individual tuning is necessary. This makes the method easily adopted in the clinical practice.

Efficacy Comparison of Preprandial and Postprandial Prandilin 25 Administration in Patients with Newly Diagnosed Type 2 Diabetes Using a Continuous Glucose Monitoring System.

IntroductionThe aim of this study was to determine the clinical efficacy of preprandial and postprandial Prandilin 25 (premixed insulin lispro 25) administration in patients with newly diagnosed type 2 diabetes mellitus (T2DM) using a continuous glucose monitoring (CGM) system.MethodsThis was a single-center, self-controlled comparative clinical trial. Newly diagnosed T2DM patients with hemoglobin A1c > 8.0% were hospitalized and received Prandilin 25 plus metformin treatment. Glycemic control was reached after a 7-to-8-day run-in period. Patients underwent 2 days of treatment consisting of preprandial Prandilin 25 on day 1 and postprandial Prandilin 25 on day 2 at the same dosage. The primary outcome was the 24-h mean amplitude of glycemic excursion (24 hMAGE); secondary outcomes were other daily glycemic variability parameters, including 24-h mean blood glucose (24hMBG), 24-h standard deviation of blood glucose (24hSDBG), large amplitude of glycemic excursion (LAGE), incremental area under the curve (AUC) values for different glucose levels, postprandial glucose excursion, and incidence of hypoglycemia, which were assessed using a CGM system.ResultsEighty-five patients completed this study. There was no statistically significant difference in 24hMAGE, 24hMBG, 24hSDBG, or LAGE between the preprandial injection group and the postprandial injection group. Similarly, there was no between-treatment difference in the AUC for a blood glucose level below 3.9 mmol/L, in the AUC for a blood glucose level above 10.0 mmol/L, or in the percentages of time that the blood glucose level was below 3.9 mmol/L or above 10.0 mmol/L. Further analysis showed that the pre-meal glucose, peak height, and time to peak after each meal, the relative areas under the CGM curve at 1–4 h after each meal, as well as the incidence of hypoglycemia, were similar for the preprandial and postprandial Prandilin 25 groups.ConclusionIn patients with T2DM managed with premixed insulin lispro 25, postprandial injection (within 30 min of meal onset) may be an acceptable alternative to preprandial injection when the regular preprandial insulin dose is omitted.Trial RegistrationChinese Clinical Trial Register identifier: ChiCTR1800015828.

Feasibility of Early Meal Detection Based on Abdominal Sound.

In classical approaches for an artificial pancreas, continuous glucose monitoring (CGM) is the only measured variable used for insulin dosing and additional control functions. The CGM values are subject to time delays and slow dynamics between blood and the sensing location. These time lags compromise the controller’s performance in maintaining (near to) normal glucose levels. Meal information could enhance the control outcome. However, meal announcement by the user is not reliable, and it takes 30 min to 40 min from meal onset until a meal is detected by methods based on CGM. In this pilot study, the use of bowel sounds for meal detection was investigated. In particular, we focused on whether bowel sounds change qualitatively during or shortly after meal ingestion. After fasting for at least 4 h, 11 healthy volunteers ingested a lunch meal at their usual time. Abdominal sound was recorded by a condenser microphone that was attached to the right upper quadrant of the abdomen by medical tape. Features that describe the power distribution over the frequency spectrum were extracted and used for classification by support vector machines. These classifiers were trained in a leave-one-out cross-validation scheme. Meals could be detected on average 10 min (std: 4.4 min) after they had started. Half of these were detected without false alarms. This shows that abdominal sound monitoring could provide an early meal detection. Further studies should investigate this possibility on a larger population in more general settings.

Postmeal Optogenetic Inhibition of Dorsal or Ventral Hippocampal Pyramidal Neurons Increases Future Intake.

Memory of a recently eaten meal can serve as a powerful mechanism for controlling future eating behavior because it provides a record of intake that likely outlasts most physiological signals generated by the meal. In support, impairing the encoding of a meal in humans increases the amount ingested at the next eating episode. However, the brain regions that mediate the inhibitory effects of memory on future intake are unknown. In the present study, we tested the hypothesis that dorsal hippocampal (dHC) and ventral hippocampal (vHC) glutamatergic pyramidal neurons play a critical role in the inhibition of energy intake during the postprandial period by optogenetically inhibiting these neurons at specific times relative to a meal. Male Sprague Dawley rats were given viral vectors containing CaMKIIα-eArchT3.0-eYFP or CaMKIIα-GFP and fiber optic probes into dHC of one hemisphere and vHC of the other. Compared to intake on a day in which illumination was not given, inhibition of dHC or vHC glutamatergic neurons after the end of a chow, sucrose, or saccharin meal accelerated the onset of the next meal and increased the amount consumed during that next meal when the neurons were no longer inhibited. Inhibition given during a meal did not affect the amount consumed during that meal or the next one but did hasten meal initiation. These data show that dHC and vHC glutamatergic neuronal activity during the postprandial period is critical for limiting subsequent ingestion and suggest that these neurons inhibit future intake by consolidating the memory of the preceding meal.

Sensor-based detection and estimation of meal carbohydrates for people with diabetes

Abstract People with type 1 diabetes (T1D) must estimate the carbohydrate (CHO) content in meals to compute the bolus insulin correctly. To release T1D patients from the cumbersome task of counting CHO, we develop a method for detecting meals that can be used in blood glucose (BG) control. The algorithm detects a meal and estimates the meal onset and the amount of CHO. The inputs of the meal detector are the continuous glucose monitoring (CGM) data and the insulin infusion rate. We use second-order linear input-output models for insulin to subcutaneous glucose dynamics and for CHO to subcutaneous glucose dynamics. The models are converted to a linear discrete-time state-space model. A white noise double integrator models the unknown meal disturbances. The state-space model is augmented with the unknown meal disturbance (CHO ingestion rate) and a Kalman filter (KF) estimates the CHO rate (g/min). The algorithm uses two tests to announce a meal. The first test is a cumulative sum algorithm that detects changes in the KF innovation and estimates the onset of change. The second test is comparison of the estimated CHO rate with a threshold to detect a change in the rate. If both tests simultaneously detect a change, an optimal smoother estimates the meal-size. If the estimated meal-size reaches a certain amount, the algorithm announces a meal. Furthermore, we integrate a bolus calculator (BC) with the meal detector. We test the algorithm for nine virtual T1D patients. In total, the patients eat 45 meals in 13.5 days. The detection sensitivity is 93% and the detection delay has a median of 40 min. The median of the meal onset estimation bias is 5 min. Out of 42 detected meals, the algorithm underestimates 26 meals with a median bias of −19 g, and it overestimates 16 meals with a median bias of 21 g. The meal detector with the BC reduces the BG postprandial peak from 274 mg/dL (unbolused meals) to 207 mg/dL, and it increases the mean time in euglycemia from 50% to 79%. The meal detector combined with the BC improves glycemia for the virtual patients in this study.

Oleoylethanolamide-induced anorexia in rats is associated with locomotor impairment.

The endogenous peroxisome proliferator‐activated receptor alpha (PPAR‐α) agonist Oleoylethanolamide (OEA) inhibits eating in rodents, mainly by delaying the onset of meals. The underlying mechanisms of OEA‐induced anorexia, however, remain unclear. Animals treated with high OEA doses were shown to display signs of discomfort and impaired locomotion. Therefore, we first examined whether the impaired locomotion may contribute to OEA's anorectic effect. Second, it is controversial whether abdominal vagal afferents are necessary for OEA's anorectic effect. Thus, we explored alternative peripheral neural pathways mediating IP OEA's anorectic effect by performing a celiac‐superior mesenteric ganglionectomy (CGX) or a subdiaphragmatic vagal deafferentation (SDA) alone or in combination. Exogenously administered OEA at a commonly used dose (10 mg/kg BW, IP) concurrently reduced food intake and compromised locomotor activity. Attempts to dissociate both phenomena using the dopamine D2/D3 receptor agonist Quinpirole (1 mg/kg BW, SC) failed because Quinpirole antagonized both, OEA‐induced locomotor impairment and delay in eating onset. CGX attenuated the prolongation of the latency to eat by IP OEA, but neither SDA nor CGX prevented IP OEA‐induced locomotor impairment. Our results indicate that IP OEA's anorectic effect may be secondary to impaired locomotion rather than due to physiological satiety. They further confirm that vagal afferents do not mediate exogenous OEA's anorectic effects, but suggest a role for spinal afferents in addition to an alternative, nonneuronal signaling route.

An automated meal detector and bolus calculator in combination with closed-loop blood glucose control

Abstract The aim of this study is to develop an algorithm for detection of unannounced meals and an insulin bolus calculator (BC) to work in combination with the meal detector. The input of the meal detector are the continuous glucose monitoring (CGM) data and the insulin infusion rate. During daytime, the automated meal detector and the BC control the blood glucose concentration. During nighttime, a model predictive control (MPC) algorithm regulates the basal insulin rate. The meal detector detects the occurrence of a meal, estimates the amount of carbohydrate (CHO) in the meal, and estimates the meal onset time. The BC computes a bolus dose to cover the detected meal. We test the meal detector and the BC on nine virtual type 1 diabetes (T1D) patients. The meal detection algorithm, applied on the virtual patients, has a median detection delay of 40 min, detection sensitivity of 80% and a median meal onset estimation bias of 15 min. The algorithm does not have false positive.

Sex-dependent effects of early life inflammatory pain on sucrose intake and sucrose-associated hippocampal Arc expression in adult rats

We hypothesize that dorsal hippocampal (dHC) neurons, which are critical for episodic memory, form a memory of a meal and inhibit the initiation of the next meal and the amount ingested during that meal. In support, we showed previously that (1) consuming a sucrose meal induces expression of the synaptic plasticity marker activity-regulated cytoskeleton-associated protein (Arc) in dHC neurons and (2) reversible inactivation of these neurons immediately following a sucrose meal accelerates the onset of the next meal and increases the size of that meal. These data suggest that hippocampal-dependent memory inhibits intake; therefore, the following experiments were conducted to determine whether hippocampal-dependent memory impairments are associated with increased intake. We reported recently that one episode of early life inflammatory pain impairs dHC-dependent memory in adult rats. The present study determined whether neonatal inflammatory pain also increases sucrose intake and attenuates sucrose-associated Arc expression. Male and female Sprague-Dawley rats were given an intraplantar injection of the inflammatory agent carrageenan (1%) on the day of birth and sucrose intake and sucrose-associated dHC Arc expression were measured in adulthood. Neonatal inflammatory pain increased sucrose intake in adult female and male rats, decreased sucrose-associated dHC Arc expression in female rats, and tended to have a similar effect on Arc expression in male rats. Neonatal inflammatory pain significantly decreased the interval between two sucrose meals in female but not in male rats. Morphine administration at the time of insult attenuated the effects of injury on sucrose intake. Collectively, these findings indicate that one brief episode of inflammatory pain on the day of birth has a long long-lasting, sex-dependent impact on intake of a palatable food in adulthood.

Calcium-Dependent Eukaryotic Initiation Factor 2α Phosphatase Restores Control to Anterior Piriform Cortex Neural Circuitry after Activation by Essential Amino Acid Deficiency

Essential (dietary-indispensable) amino acids (IAA)s are vital precursors for protein synthesis; they cannot be synthesized in metazoans but must be obtained from food to survive. In sensing a reduction of an IAA, the mammalian anterior piriform cortex (APC)Ɨ is rapidly activated. The initial behavioral response is an abrupt end to an IAA deficient meal about 20 min after meal onset. IAA depletion in the APC activates the conserved eukaryotic initiation factor 2α (eIF2α) kinase, GCN2, via uncharged tRNA. GCN2 kinase activity increases levels of phosphorylated eIF2α (P-eIF2α), which blocks global protein synthesis such that APC inhibitory elements with short half-lives cannot be replaced. This results in disinhibition of this highly sensitive brain area. Following APC activation, a reduction in P-eIF2α releases the blockade on protein synthesis to allow recovery of inhibition in the circuit and complete the homeostatic response, restoring control in the APC. A role for calcium (Ca2+) in regulating P-eIF2α was explored here using Ca2+ blockers with immunohistochemistry and electrophysiology in APC brain slices. The responses to IAA depletion in the APC were Ca2+ dependent, showing a role for Ca2+ in the system. Yet, the kinase activity of GCN2 was unaffected by intracellular Ca2+ chelation. Thus, control must be accomplished by phosphatase activity. We suggest that regulation of P-eIF2α, and neuronal stability in the APC, require the activity of a Ca2+-dependent subunit, protein phosphatase1, of the phosphatase acting on P-eIF2α. This would implicate the Ca2+/calmodlin dependent calcineurin, and the constitutive repressor of eIF2 phosphorylation (PPP1R15B/CReP) after GCN2 activation in the brain.

Sweet orosensation induces Arc expression in dorsal hippocampal CA1 neurons in an experience-dependent manner.

There is limited knowledge regarding how the brain controls the timing of meals. Similarly, there is a large gap in our understanding of how top-down cognitive processes, such as memory influence energy intake. We hypothesize that dorsal hippocampal (dHC) neurons, which are critical for episodic memory, form a memory of a meal and inhibit meal onset during the postprandial period. In support, we showed previously that reversible inactivation of these neurons during the period following a sucrose meal accelerates the onset of the next meal. If dHC neurons form a memory of a meal, then consumption should induce synaptic plasticity in dHC neurons. To test this, we determined (1) whether a sucrose meal increases the expression of the synaptic plasticity marker activity-regulated cytoskeleton-associated protein (Arc) in dHC CA1 neurons, (2) whether previous experience with sucrose influences sucrose-induced Arc expression, and (3) whether the orosensory stimulation produced by the noncaloric sweetener saccharin is sufficient to induce Arc expression. Male Sprague-Dawley rats were trained to consume a sweetened solution at a scheduled time daily. On the experimental day, they were given a solution for 7 min, euthanized, and then fluorescence in situ hybridization procedures were used to measure meal-induced Arc mRNA. Compared to caged control rats, Arc expression was significantly higher in rats that consumed sucrose or saccharin. Interestingly, rats given additional experience with sucrose had less Arc expression than rats with less sucrose experience, even though both groups consumed similar amounts on the experimental day. Thus, this study is the first to suggest that orosensory stimulation produced by consuming a sweetened solution and possibly the hedonic value of that sweet stimulation induces synaptic plasticity in dHC CA1 neurons in an experience-dependent manner. Collectively, these findings are consistent with our hypothesis that dHC neurons form a memory of a meal.

Arcuate hypothalamic AgRP and putative POMC neurons show opposite changes in spiking across multiple timescales.

Agouti-related-peptide (AgRP) neurons—interoceptive neurons in the arcuate nucleus of the hypothalamus (ARC)—are both necessary and sufficient for driving feeding behavior. To better understand the functional roles of AgRP neurons, we performed optetrode electrophysiological recordings from AgRP neurons in awake, behaving AgRP-IRES-Cre mice. In free-feeding mice, we observed a fivefold increase in AgRP neuron firing with mounting caloric deficit in afternoon vs morning recordings. In food-restricted mice, as food became available, AgRP neuron firing dropped, yet remained elevated as compared to firing in sated mice. The rapid drop in spiking activity of AgRP neurons at meal onset may reflect a termination of the drive to find food, while residual, persistent spiking may reflect a sustained drive to consume food. Moreover, nearby neurons inhibited by AgRP neuron photostimulation, likely including satiety-promoting pro-opiomelanocortin (POMC) neurons, demonstrated opposite changes in spiking. Finally, firing of ARC neurons was also rapidly modulated within seconds of individual licks for liquid food. These findings suggest novel roles for antagonistic AgRP and POMC neurons in the regulation of feeding behaviors across multiple timescales.DOI: http://dx.doi.org/10.7554/eLife.07122.001

Conditioned Intake and Fattening/Diabetes

Background: Obesity, diabetes, asthma, autism, birth defects, dyslexia, attention deficit-hyperactivity disorder, and schizophrenia have increased in children in the last half century. The will (decision) to eat develops often when previous energy intake has been incompletely exhausted. Objective: The will to eat develops after stimuli (often external) that do not correlate with energy availability in blood. Training a relation between hunger sensations (Initial Hunger, IH) and Blood Glucose (BG) as an index of energy availability allows an IH Meal Pattern that is associated with low mean BG and insulin sensitivity. Lack of any relation between the will to eat and the energy availability is a widespread error that may be responsible of health deterioration in children as well as in adults. Methods: After meal suspension and with synchronous blood glucose (BG) measurements, we taught patients to distinguish hunger sensations that are conditioned from those that arise after meal suspension (Initial Hunger, IH). This hunger (after meal suspension) signals a complete exhaustion of previous intake and is appropriate for meal onset to obtain meal-by-meal fasting nutrient levels and low BG prior to the next meal and establish an even balance. This pattern has been termed the Initial Hunger Meal Pattern (IHMP). Results: In contrast with untrained control subjects, trained subjects accurately recognized IH by synchronous BG measurements. We report here the identification of Initial Hunger (the subjective limit), the daily adjustments to three arousals for weeks and months, the diffusion of the error in untrained child and adult population, the validations of the IH and BG assessments and the improvements of 18 parameters by IHMP. Conclusion: The will to eat develops as a conditioned event and this conditioned will causes positive energy imbalance and insulin resistance/fattening. The imbalancing will to eat may be corrected by becoming aware of differences between the conditioned sensations of hunger and the sensations that develop after meal suspension.