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Context The relationships of gastric emptying (GE) with the glycemic response at 120 minutes, glucagon-like peptide-1 (GLP-1), and insulin secretion following a glucose load in type 2 diabetes (T2D) are uncertain. Objective We evaluated the relationship of plasma glucose, GLP-1, and insulin secretion with GE of a 75-g oral glucose load in T2D. Design Single-center, cross-sectional, post hoc analysis. Setting Institutional research center. Participants 43 individuals with T2D age 65.6 ± 1.1 years, hemoglobin A1c 7.2 ± 1.0%, median duration of diabetes 5 years managed by diet and/or metformin. Intervention Participants consumed the glucose drink radiolabeled with 99mTc-phytate colloid following an overnight fast. GE (scintigraphy), plasma glucose, GLP-1, insulin, and C-peptide were measured between 0 and 180 minutes. Main Outcome Measures The relationships of the plasma glucose at 120 minutes, plasma GLP-1, and insulin secretion (calculated by Δinsulin0-30/ Δglucose0-30 and ΔC-peptide0-30/Δglucose0-30) with the rate of GE (scintigraphy) were evaluated. Results There were positive relationships of plasma glucose at 30 minutes (r = 0.56, P Conclusion In T2D, while insulin secretion is the dominant determinant of the 120-minute plasma glucose, GE also correlates. Given the relevance to interpreting the results of an oral glucose tolerance test, this relationship should be evaluated further. There appears to be no direct effect of GE on either GLP-1 or insulin secretion.

We read with interest the study by Rosenstock et al. (1), which demonstrates that in patients with type 2 diabetes managed on a basal-bolus insulin regimen, switching three prandial insulin injections for a long-acting glucagon-like peptide 1 receptor agonist (GLP-1RA), albiglutide, while maintaining the basal insulin, represents an effective strategy for optimizing glycemic control with reduced risks of hypoglycemia and weight gain along with increased convenience. In the cohort studied, baseline glycated hemoglobin levels were 7.8 ± 0.6% (albiglutide group) and 7.7 ± 0.6% (placebo group), indicating that in many participants, postprandial glycemic excursions were the dominant contributor of hyperglycemia. Achieving good glycemic control in those patients would, …

Context Hypoglycemia is a major barrier to optimal glycemic control in insulin-treated diabetes. Recent guidelines from the American Diabetes Association have subcategorized “non-severe” hypoglycemia into level 1 ( Objective To determine the effects of 2 levels of hypoglycemia, 2.6 mmol/L (“marked”) and 3.6 mmol/L (“mild”), on gastric emptying in health. Design, Setting, and Subjects Fourteen healthy male participants (mean age: 32.9 ± 8.3 years; body mass index: 24.5 ± 3.4 kg/m2) from the general community underwent measurement of gastric emptying of a radiolabeled solid meal (100 g beef) by scintigraphy over 120 minutes on 3 separate occasions, while blood glucose was maintained at either ~2.6 mmol/L, ~3.6 mmol/L, or ~6 mmol/L in random order from 15 minutes before until 60 minutes after meal ingestion using glucose-insulin clamp. Blood glucose was then maintained at 6 mmol/L from 60 to 120 minutes on all days. Results Gastric emptying was accelerated during both mild (P = 0.011) and marked (P = 0.001) hypoglycemia when compared to euglycemia, and was more rapid during marked compared with mild hypoglycemia (P = 0.008). Hypoglycemia-induced gastric emptying acceleration during mild (r = 0.57, P = 0.030) and marked (r = 0.76, P = 0.0014) hypoglycemia was related to gastric emptying during euglycemia. Conclusion In health, acceleration of gastric emptying by insulin-induced hypoglycemia is dependent on the degree of hypoglycemia and baseline rate of emptying.

Aim: To evaluate the effects of the prandial glucagon-like peptide-1 receptor agonist lixisenatide on gastric emptying and blood pressure (BP) and superior mesenteric artery (SMA) blood flow, and the glycaemic responses to a 75-g oral glucose load in healthy people and those with type 2 diabetes (T2DM). Materials and methods: Fifteen healthy participants (nine men, six women; mean ± SEM age 67.2 ± 2.3 years) and 15 participants with T2DM (nine men, six women; mean ± SEM age 61.9 ± 2.3 years) underwent measurement of gastric emptying, BP, SMA flow and plasma glucose 180 minutes after a radiolabelled 75-g glucose drink on two separate days. All participants received lixisenatide (10 μg subcutaneously) or placebo in a randomized, double-blind, crossover fashion 30 minutes before the glucose drink. Results: Lixisenatide slowed gastric emptying (retention at 120 minutes, P < 0.01), attenuated the rise in SMA flow (P < 0.01) and markedly attenuated the decrease in systolic BP (area under the curve [AUC] 0-120 minutes, P < 0.001) compared to placebo in healthy participants and those with T2DM. Plasma glucose (incremental AUC 0-120 minutes) was greater in participants with T2DM (P < 0.005) than in healthy participants, and lower after lixisenatide in both groups (P < 0.001). Conclusions: In healthy participants and those with T2DM, the marked slowing of gastric emptying of glucose induced by lixisenatide was associated with attenuation of the increments in glycaemia and SMA flow and decrease in systolic BP. Accordingly, lixisenatide may be useful in the management of postprandial hypotension. usc Refereed/Peer-reviewed

Hypoglycaemia is arguably the most important complication of insulin therapy in type 1 and type 2 diabetes. Counter-regulation of hypoglycaemia is dependent on autonomic function and frequent hypoglycaemia may lead to reductions in both autonomic warning signals and the catecholamine response, the so-called “impaired awareness of hypoglycaemia”. It is now appreciated that gastric emptying is a major determinant of the glycaemic response to carbohydrate-containing meals in both health and diabetes, that disordered (especially delayed) gastric emptying occurs frequently in diabetes, and that acute hypoglycaemia accelerates gastric emptying substantially. However, the potential relevance of gastric emptying to the predisposition to, and counter-regulation of, hypoglycaemia has received little attention. In insulin-treated patients, the rate of gastric emptying influences the timing of the postprandial insulin requirement, and gastroparesis is likely to predispose to postprandial hypoglycaemia. Conversely, the marked acceleration of gastric emptying induced by hypoglycaemia probably represents an important counter-regulatory response to increase the rate of carbohydrate absorption. This review summarizes the current knowledge of the inter-relationships between hypoglycaemia and gastric emptying, with a focus on clinical implications usc Refereed/Peer-reviewed

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Context: The early glycemic response during a 75-g oral glucose tolerance test (OGTT) is directly related to the rate of gastric emptying (GE). There is little information about the effect of GE on the blood glucose at either 60 min (a predictor of diabetes) or 120 min (used diagnostically). Objective: This study aimed to evaluate the relationships between glycemic responses at 30, 60, and 120 min and GE following a 75-g OGTT in subjects with normal glucose tolerance (NGT), impaired glucose tolerance (IGT), and type 2 diabetes (T2D). Design, Setting, and Subjects: Eighty-two subjects in the general community without diabetes (57 NGT, 25 IGT) and 16 with T2D consumed a 75-g glucose drink labeled with 99mTc-sulfur colloid. GE (by scintigraphy) and glycemia were measured from t = 0-120 min and relationships between blood glucose (absolute, change from baseline, and area under the curve) and GE at 30, 60, and 120 min determined. Results: There were no differences in GE. There were relationships between the blood glucose at 30 min and GE (NGT: r = 0.40; P < .01; IGT: r = 0.49; P = .02; T2D: r = 0.62; P = .01). There was also a relationship between the blood glucose at 60 min and GE in IGT (r = 0.52; P = .02) and T2D (r = 0.77; P < .01), but not NGT (r = 0.16; P = .24). In NGT, there was an inverse relationship between blood glucose at 120 min and GE (r=-0.30; P = .02), but not in IGT (r = 0.05; P = .82) or T2D (r = 0.37; P = .16). Conclusions: GE is a determinant of the glycemic response to an OGTT in NGT, IGT, and T2D but these relationships differ and are time dependent. Refereed/Peer-reviewed

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It is increasingly advocated that management of type 1 and type 2 diabetes be “personalized” (i.e., targeted to the characteristics of the individual patient). This approach has major implications for health care costs, has proven successful in monogenic diabetes (2), and is practiced widely in other areas of medicine, such as oncology. Management strategies for type 1 diabetes currently focus on the achievement of targeted glycemic control, as assessed by a glycated hemoglobin (HbA1c) value

The importance of achieving tight glycemic control, usually assessed by glycated hemoglobin (HbA1c), for both the prevention and delay in the progression of diabetes-related microvascular complications, is established, and the American Diabetes Association/European Association for the Study of Diabetes joint committee has recommended an HbA1c

East Asians appear to secrete less insulin than Caucasians following oral glucose suggesting that impaired insulin secretion is fundamental to the pathogenesis of type 2 diabetes [1]. Information about the secretion of the incretin hormones, GIP and GLP-1, dependent on duodenal glucose load [2], in East Asians is limited [3]. We have evaluated glycemic, insulinemic and incretin hormone responses to intraduodenal glucose in healthy Han Chinese. We studied eleven Han Chinese (HC) and eight Caucasian (C) healthy men; the latter included in a previous study [2]. Each subject attended following an overnight fast. A catheter, incorporating an infusion channel opening 12 cm beyond the pylorus, was inserted intranasally [2]. An IV cannula was placed in an antecubital vein. Intraduodenal (ID) glucose (25 g/100 mL) was infused at 4 kcal/min from t = 0 to 120 min. Blood was collected at t = 0, 15, 30, 45, 60, 90, 105 and 120 min for measurements of blood glucose, plasma insulin, GIP and GLP-1. Insulin secretion was estimated as the change in insulin divided by the change in glucose at 30 min (∆I0–30/∆G0–30). Insulin sensitivity was estimated as 1/fasting insulin. The disposition index (DIO) was calculated as ∆I0–30/∆G0–30X 1/fasting insulin. Unpaired Student’s t test was used in analysis. Han Chinese younger than Caucasians (24.8 ± 1.3 HC vs. 45.3 ± 3.8 C years, P

Meal consumption leads to an increase in sympathetic output to compensate for hemodynamic changes and maintain blood pressure (BP). Obesity is associated with a blunting of the sympathetic response to meal ingestion, but interpretation of studies investigating these responses is compromised by their failure to account for the rate of gastric emptying, which is an important determinant of postprandial cardiovascular and sympathetic responses and, in both health and obesity, exhibits a wide interindividual variation. We sought to determine the effects of intraduodenal glucose infusion, bypassing gastric emptying, on BP, heart rate (HR), and noradrenaline responses in obese and healthy control subjects. 12 obese subjects (age 36.6 ± 3.9 years, body mass index (BMI) 36.1 ± 1.3 kg/m2) and 23 controls (age 27.8 ± 2.4 years, BMI 22.4 ± 0.5 kg/m2) received intraduodenal infusions of glucose at 1 or 3 kcal/min, or saline, for 60 min (t = 0–60 min), followed by intraduodenal saline (t = 60–120 min). BP and HR were measured with an automatic cuff, and blood samples collected for measurement of plasma noradrenaline. Intraduodenal glucose at 1 kcal/min was associated with a fall in diastolic BP in the control subjects only (P < 0.01), with no change in systolic BP, HR or noradrenaline in either group. In both groups, intraduodenal glucose at 3 kcal/min was associated with a fall in diastolic (P < 0.01), but not systolic, BP, and rises in HR (P < 0.001) and plasma noradrenaline (P < 0.01), with no difference in responses between the groups. We conclude that cardiovascular and sympathetic responses to intraduodenal glucose infusion are comparable between obese and control subjects, and dependent on the rate of glucose delivery. usc Refereed/Peer-reviewed

The potential influence of gastric emptying on the "incretin effect," mediated by glucose-dependent insu-linotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), is unknown. The objectives of this study were to determine the effects of intraduodenal (ID) glucose infusions at 2 (ID2) and 4 (ID4) kcal/min (equating to two rates of gastric emptying within the physiological range) on the size of the incretin effect, gastrointestinal glucose disposal (GIGD), plasma GIP, GLP-1, and gluca-gon secretion in health and type 2 diabetes. We studied 10 male BMI-matched controls and 11 male type 2 patients managed by diet or metformin only. In both groups, GIP, GLP-1, and the magnitude of incretin effect were greater with ID4 than ID2, as was GIGD; plasma glucagon was suppressed by ID2, but not ID4. There was no difference in the incretin effect between the two groups. Based on these data, we conclude that the rate of small intestinal glucose exposure (i.e., glucose load) is a major determinant of the comparative secretion of GIP and GLP-1, as well as the magnitude of the incretin effect and GIGD in health and type 2 diabetes. Refereed/Peer-reviewed

The oral disposition index, the product of the early insulin secretory response during an oral glucose tolerance test and insulin sensitivity, is used widely for both the prediction of, and evaluation of the response to interventions, in type 2 diabetes. Gastric emptying, which determines small intestinal exposure of nutrients, modulates postprandial glycemia. The aim of this study was to determine whether the insulin secretory response and the disposition index (DI) related to gastric emptying in subjects with normal glucose tolerance. Thirty‐nine subjects consumed a 350 mL drink containing 75 g glucose labeled with 99m Tc‐sulfur colloid. Gastric emptying (by scintigraphy), blood glucose (G) and plasma insulin (I) were measured between t = 0–120 min. The rate of gastric emptying was derived from the time taken for 50% emptying ( T 50 ) and expressed as kcal/min. The early insulin secretory response was estimated by the ratio of the change in insulin (∆I 0–30 ) to that of glucose at 30 min (∆G 0–30 ) represented as ∆I 0–30 /∆G 0–30 . Insulin sensitivity was estimated as 1/fasting insulin and the DI was then calculated as ∆I 0–30 /∆G 0–30 × 1/fasting insulin. There was a direct relationship between ∆G 0–30 and gastric emptying ( r = 0.47, P = 0.003). While there was no association of either ∆I 0–30 ( r = −0.16, P = 0.34) or fasting insulin ( r = 0.21, P = 0.20), there were inverse relationships between the early insulin secretory response ( r = −0.45, P = 0.004) and the DI ( r = −0.33, P = 0.041), with gastric emptying. We conclude that gastric emptying is associated with both insulin secretion and the disposition index in subjects with normal glucose tolerance, such that when gastric emptying is relatively more rapid, both the early insulin secretory response and the disposition index are less. These findings should be interpreted as “hypothesis generating” and provide the rationale for longitudinal studies to examine the impact of baseline rate of gastric emptying on the prospective risk of type 2 diabetes.

The gut derived peptides, glucagon-like peptides 1 and 2 (GLP-1 and GLP-2), are secreted following nutrient ingestion. GLP-1 and another gut peptide, glucose-dependent insulinotropic polypeptide (GIP) are collectively referred to as 'incretin' hormones, and play an important role in glucose homeostasis. Incretin secretion shares a complex interdependent relationship with both postprandial glycemia and the rate of gastric emptying. GLP-1 based therapies are now well established in the management of type 2 diabetes, while recent literature has suggested potential applications to treat obesity and protect against cardiovascular and neurological disease. The mechanism of action of GLP-2 is not well understood, but it shows promise as an intestinotropic agent. Refereed/Peer-reviewed

Glucagon-like peptide 1 (GLP-1) is a hormone secreted predominantly by the distal small intestine and colon and released in response to enteral nutrient exposure. GLP-1-based therapies are now used widely in the management of type 2 diabetes and have the potential to be effective antiobesity agents. Although widely known as an incretin hormone, there is a growing body of evidence that GLP-1 also acts as an enterogastrone, with profound effects on the gastrointestinal motor system. Moreover, the effects of GLP-1 on gastrointestinal motility appear to be pivotal to its effect of reducing postprandial glycaemic excursions and may, potentially, represent the dominant mechanism. This review summarizes current knowledge of the enterogastrone properties of GLP-1, focusing on its effects on gut motility at physiological and pharmacological concentrations, and the motor actions of incretin-based therapies. While of potential importance, the inhibitory action of GLP-1 on gastric acid secretion is beyond the scope of this paper. Refereed/Peer-reviewed

The majority of studies relating to the oral glucose tolerance test (OGTT) have not taken gastric emptying (GE), which exhibits a substantial inter‐individual variation, into account. We sought to evaluate the impact of GE, on the glycemic and insulinemic responses to a 75‐g oral glucose load in older subjects with normal and impaired glucose tolerance. Eighty‐seven healthy ‘older’ subjects (47F, 40M; age 71.0 ± 0.5 year) were given a drink comprising of 75‐g glucose and 150 mg C13‐acetate made up to 300 mL with water on a single occasion. Exhaled breath was obtained for analysis of 13CO2 and calculation of the 50% GE time (T50). Blood glucose, serum insulin and plasma glucagon‐like peptide‐1 (GLP‐1) and glucose‐dependent insulinotropic peptide (GIP) were measured, and the insulin sensitivity index (ISI), and the disposition index (DI), were calculated. Thirty‐one subjects had normal glucose tolerance (NGT) and 46 had impaired glucose tolerance (IGT). Blood glucose at t = 60 min and t = 120 min were related inversely to ISI (P < 0.001) and DI P < 0.001). The rise in blood glucose at t = 60 min was related inversely to the T50 in all subjects (P < 0.01), and those with IGT (P < 0.001), but not NGT. There were no significant relationships between the blood glucose at t = 120 min with the T50, but in both groups the change in blood glucose from baseline at t = 180 min was related (NGT: P < 0.001; IGT: P < 0.001) to the T50. We conclude that in NGT and IGT, the effect of GE on both the ‘early’ and ‘late’ glycemic responses to a 75‐g oral glucose load is complementary to that of insulin sensitivity., The 75‐g oral glucose tolerance test is regarded as the ‘gold standard’ for the diagnosis of impaired glucose tolerance and diabetes, however, it is subject to substantial variability. This is likely to be accounted for not only by differences in insulin resistance and beta cell function but also by gastric emptying, which exhibits a wide inter‐individual variation. Our study characterized the impact of gastric emptying on glycemic, insulinemic, and incretin responses to a 75‐g oral glucose load in subjects with normal glucose tolerance and impaired glucose tolerance. We demonstrated that both the rate of gastric emptying and insulin sensitivity are independent, and complementary, determinants of both the ‘early’ and ‘late’ responses to an oral glucose tolerance test in healthy older subjects.