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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, …

During the last 30 years, there has been a paradigm shift in knowledge relating to gastric emptying in diabetes, reflecting the application of novel investigative techniques. Scintigraphy, which utilizes radiolabeled solid and/or liquid meals and a γ-camera, remains the gold standard for quantifying gastric emptying (1,2). More recently, stable isotope breath tests, involving measurement of 13CO2 in breath samples after ingestion of a 13C-labeled meal, have been validated against scintigraphy with inherent advantages of simplicity, point-of-care sampling, and avoidance of radiation exposure (1). Key insights in diabetes include the recognition that solids and liquids empty from the stomach differentially and that interindividual variation—already substantial in health (1–4 kcal/min) (2)—is increased in diabetes because emptying is delayed in ∼30–40% of complicated, suboptimally controlled patients attending tertiary centers (2–4), while often modestly accelerated in well-controlled patients with type 1 or type 2 diabetes (2). Upper gastrointestinal symptoms, such as nausea and fullness, occur frequently and impact quality of life adversely, but their relationship to gastric emptying is weak (1–3). Rather than simply being a manifestation of autonomic neuropathy, the pathogenesis of gastroparesis is heterogeneous, involving loss of interstitial cells of Cajal (“pacemaker” cells), an immune infiltrate, and muscle atrophy in addition to changes in intrinsic and extrinsic (vagal) innervation (1). There is a relatively weak relationship between gastroparesis and autonomic dysfunction, as assessed by standardized cardiovascular reflexes (3). Finally, and perhaps most importantly, gastric emptying influences postprandial glycemic excursions, the dominant determinant of HbA1c when the latter is less than ∼64 mmol/mol (8.0%) (5), and emptying can be modulated by dietary or pharmacological approaches (e.g., short-acting glucagon-like peptide 1 receptor agonists or pramlintide) for therapeutic gain (2). Accordingly, gastric emptying is central to the pathogenesis and personalized management of diabetes (6). …

The authors wish to correct some minor errors in this article: 1. The fasting insulin secretion rate was correctly shown in Table 1 to be slightly increased after lixisenatide treatment, whereas the text of the Results and Conclusions sections incorrectly reported that it was decreased. 2. Change …

OBJECTIVE Cells releasing glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) are distributed predominately in the proximal and distal gut, respectively. Hence, the region of gut exposed to nutrients may influence GIP and GLP-1 secretion and impact on the incretin effect and gastrointestinal-mediated glucose disposal (GIGD). We evaluated glycemic and incretin responses to glucose administered into the proximal or distal small intestine and quantified the corresponding incretin effect and GIGD in health and type 2 diabetes mellitus (T2DM). RESEARCH DESIGN AND METHODS Ten healthy subjects and 10 patients with T2DM were each studied on four occasions. On two days, a transnasal catheter was positioned with infusion ports opening 13 cm and 190 cm beyond the pylorus, and 30 g glucose with 3 g 3-O-methylglucose (a marker of glucose absorption) was infused into either site and 0.9% saline into the alternate site over 60 min. Matching intravenous isoglycemic clamp studies were performed on the other two days. Blood glucose, serum 3-O-methylglucose, and plasma hormones were evaluated over 180 min. RESULTS In both groups, blood glucose and serum 3-O-methylglucose concentrations were higher after proximal than distal glucose infusion (all P < 0.001). Plasma GLP-1 increased minimally after proximal, but substantially after distal, glucose infusion, whereas GIP increased promptly after both infusions, with concentrations initially greater, but less sustained, with proximal versus distal infusion (all P < 0.001). Both the incretin effect and GIGD were less with proximal than distal glucose infusion (both P ≤ 0.009). CONCLUSIONS The distal, as opposed to proximal, small intestine is superior in modulating postprandial glucose metabolism in both health and T2DM.

If you haven’t measured something, you really don’t know much about it. —Karl Pearson (attributed) Gastrointestinal (GI) symptoms represent an important and often unappreciated cause of morbidity in diabetes, although the significance of this burden across the spectrum of patients and the underlying pathophysiology, including the relationship of symptoms with glycemic control, remain poorly defined. The relevance of GI symptoms and the necessity for their accurate assessment have increased with the greater focus on the gut as a therapeutic target for glucose lowering. This review addresses the prevalence, assessment, pathogenesis, and management of GI symptoms in diabetes, beginning with broad principles and then focusing on specific segments of the GI tract. We initially performed a literature search of PubMed by using synonyms and combinations of the following search terms: “gastrointestinal symptoms”, “diabetes”, “prevalence”, “pathogenesis”, “diagnosis”, and “management”. We restricted the search results to English only. Review papers and meta-analyses are presented as the highest level of evidence where possible followed by randomized controlled trials, uncontrolled trials, retrospective and observational data, and expert opinion.

We read with interest the recent papers relating to the onset 1 and onset 2 trials (1,2), which compared the clinical efficacy and safety profiles of fast-acting insulin aspart (faster aspart) with insulin aspart (IAsp) in patients with type 1 and type 2 diabetes who concurrently received basal insulin. The authors recognize the importance of lowering postprandial glycemia to achieve HbA1c goals, particularly when fasting glucose is adequately controlled or only modestly elevated. The central hypothesis underlying the trials is that mealtime insulin with a faster action will provide better control of postprandial glycemia and, potentially, HbA1c when used with basal insulin. However, postprandial blood glucose concentrations are determined by glucose disposal and both exogenous and endogenous glucose production, i.e., interrelated …

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

OBJECTIVE To evaluate effects of vildagliptin and metformin on blood pressure (BP) and heart rate (HR) responses to intraduodenal (ID) glucose in diet-controlled type 2 diabetes. RESEARCH DESIGN AND METHODS Study A compared vildagliptin (50 mg) and placebo, given 60 min before a 120-min ID glucose infusion at 2 or 4 kcal/min (ID2 or ID4) in 16 patients. Study B compared metformin (850 mg) and placebo, given 30 min before ID2 over 120 min in 9 patients. RESULTS Systolic (P = 0.002) and diastolic (P < 0.001) BP were lower and HR greater (P = 0.005) after vildagliptin compared with placebo, without interaction between vildagliptin and the glucose infusion rate. In contrast, HR was greater after metformin than placebo (P < 0.001), without any difference in systolic or diastolic BP. CONCLUSIONS Vildagliptin reduces BP and increases HR, whereas metformin increases HR without affecting BP during ID glucose infusion in type 2 diabetes. These distinct cardiovascular profiles during enteral nutrient exposure may have implications for postprandial hypotension.

OBJECTIVE Acute hyperglycemia markedly slows gastric emptying. Exogenous GLP-1 also slows gastric emptying, leading to diminished glycemic excursions. The primary objective was to determine whether hyperglycemia potentiates the slowing of gastric emptying induced by GLP-1 administration. RESEARCH DESIGN AND METHODS Ten healthy participants were studied on 4 separate days. Blood glucose was clamped at hyperglycemia using an intravenous infusion of 25% dextrose (∼12 mmol/L; hyper) on 2 days, or maintained at euglycemia (∼6 mmol/L; eu) on 2 days, between t = −15 and 240 min. During hyperglycemic and euglycemic days, participants received intravenous GLP-1 (1.2 pmol/kg/min) and placebo in a randomized double-blind fashion. At t = 0 min, subjects ingested 100 g beef mince labeled with 20 MBq technetium-99m–sulfur colloid and 3 g 3-O-methyl-glucose (3-OMG), a marker of glucose absorption. Gastric emptying was measured scintigraphically from t = 0 to 240 min and serum 3-OMG taken at regular intervals from t = 15 to 240 min. The areas under the curve for gastric emptying and 3-OMG were analyzed using one-way repeated-measures ANOVA with Bonferroni-Holm adjusted post hoc tests. RESULTS Hyperglycemia slowed gastric emptying (eu/placebo vs. hyper/placebo; P < 0.001) as did GLP-1 (eu/placebo vs. eu/GLP-1; P < 0.001). There was an additive effect of GLP-1 and hyperglycemia, such that gastric emptying was markedly slower compared with GLP-1 administration during euglycemia (eu/GLP-1 vs. hyper/GLP-1; P < 0.01). CONCLUSIONS Acute administration of exogenous GLP-1 profoundly slows gastric emptying during hyperglycemia in excess of the slowing induced by GLP-1 during euglycemia. Studies are required to determine the effects of hyperglycemia on gastric emptying with the subcutaneously administered commercially available GLP-1 agonists in patients with type 2 diabetes.

OBJECTIVE: The major aim of this study was to evaluate the prognosis of diabetic gastroparesis. RESEARCH DESIGN AND METHODS: Between 1984 and 1989, 86 outpatients with diabetes (66 type 1, 20 type 2; 40 male, 46 female) underwent assessment of solid and liquid gastric emptying and esophageal transit (by scintigraphy), gastrointestinal symptoms (by questionnaire), autonomic nerve function (by cardiovascular reflex tests), and glycemic control (by HbAlc and blood glucose concentrations during gastric emptying measurement). These patients were followed up in 1998. RESULTS: Of the 86 patients, solid gastric emptying (percentage of retention at 100 min) was delayed in 48 (56%) patients and liquid emptying (50% emptying time) was delayed in 24 (28%) patients. At follow-up in 1998, 62 patients were known to be alive, 21 had died, and 3 were lost to follow-up. In the group who had died, duration of diabetes (P = 0.048), score for autonomic neuropathy (P = 0.046), and esophageal transit (P = 0.032) were greater than in those patients who were alive, but there were no differences in gastric emptying between the two groups. Of the 83 patients who could be followed up, 32 of the 45 patients (71%) with delayed solid emptying and 18 of the 24 patients (75%) with delay in liquid emptying were alive. After adjustment for the effects of other factors that showed a relationship with the risk of dying, there was no significant relationship between either gastric emptying or esophageal transit and death. CONCLUSIONS: In this relatively large cohort of outpatients with diabetes, there was no evidence that gastroparesis was associated with a poor prognosis.

Type 2 diabetes is four- to sixfold more common in the South Asian population of the U.K. than in the indigenous white Caucasian population. A subset of all patients initially diagnosed with type 2 diabetes shows evidence of slowly evolving islet autoimmunity, termed latent autoimmune diabetes in adults (LADA). LADA is characterized by the presence of circulating autoantibodies specific for islet proteins and by insulin independence for at least 6 months postdiagnosis (1). A recent pilot study in Birmingham, U.K., suggested that 27% of South Asians initially presenting with type 2 diabetes were positive for autoantibodies to GAD65 and/or insulinoma-associated protein (IA)-2 (2). This is significantly higher than the islet autoimmunity frequency of 10% observed in white Caucasians diagnosed with type 2 diabetes (3,4). The study in South Asians was carried out in a very small cohort, however, and the findings require confirmation in a much larger study group. The aim of this study was to determine the prevalence of LADA in a larger U.K.-resident South Asian population and to characterize the phenotypic features and genetic basis of the disease in this ethnic group. A total of 500 South Asian subjects with type 2 diabetes (mean [range] age 55 years [31-89] and disease duration 7 years [0-29]) (Table 1) were consecutively recruited in Birmingham, U.K., and Coventry, U.K., as part of the U.K. Asian Diabetes Study. A total of 206 normoglycemic …

OBJECTIVE—To define the predictors of the rate of gastric emptying in patients with diabetes. RESEARCH DESIGN AND METHODS—A total of 101 outpatients with diabetes (79 type 1 and 22 type 2) underwent measurements of gastric emptying of a solid/liquid meal (scintigraphy), upper gastrointestinal symptoms (questionnaire), glycemic control (blood glucose concentrations during gastric emptying measurement), and autonomic nerve function (cardiovascular reflexes). RESULTS—The gastric emptying of solid and/or liquid was delayed in 66 (65%) patients. Solid (retention at 100 min 64 ± 3.2 vs. 50.2 ± 3.6%, P < 0.005) and liquid (retention at 100 min 22.7 ± 1.7 vs. 16.0 ± 1.8%, P < 0.001) gastric emptying was slower in women than in men. Of all upper gastrointestinal symptoms (including nausea and vomiting), only abdominal bloating/fullness was associated with slower gastric emptying (P < 0.005). A multiple regression analysis demonstrated that both abdominal bloating/fullness and female sex were predictors of slower gastric emptying of both solids and liquids. CONCLUSIONS—We conclude that the presence of abdominal bloating/fullness but not any other upper gastrointestinal symptom is associated with diabetic gastroparesis and that gastric emptying is slower in diabetic women than in diabetic men.

Acute changes in the blood glucose concentration have a major reversible effect on esophageal, gastric, intestinal, gallbladder, and anorectal motility in both healthy subjects and diabetic patients. For example, gastric emptying is slower during hyperglycemia than euglycemia and accelerated during hypoglycemia. Acute hyperglycemia also affects perceptions arising from the gastrointestinal tract and may, accordingly, be important in the etiology of gastrointestinal symptoms in diabetes. Elevations in blood glucose that are within the normal postprandial range also affect gastrointestinal motor and sensory function. Upper gastrointestinal motor function is a critical determinant of postprandial blood glucose concentrations by influencing the absorption of ingested nutrients. Interventions that reduce postprandial hyperglycemia, by modulating the rate of gastric emptying, have the potential to become mainstream therapies in the treatment of diabetes.

OBJECTIVE Upper gastrointestinal (GI) symptoms and delayed gastric emptying both occur frequently in patients with long-standing IDDM, but the relationship between them is relatively weak. Recent studies in normal subjects have indicated that blood glucose concentration may increase the perception of sensations arising from the upper GI tract. The purpose of this study was to examine the relationships among postprandial fullness, the rate of gastric emptying, and blood glucose concentration in IDDM patients. RESEARCH DESIGN AND METHODS We studied measurements of gastric emptying, blood glucose concentrations, cardiovascular autonomic nerve function, upper GI symptoms, and postprandial hunger and fullness in 40 IDDM patients (16 men, 24 women). ages 19–63 years. Gastric emptying of solids and liquids was measured scintigraphically, upper GI symptoms were measured by questionnaire immediately before ingestion of the test meal, and fullness and hunger were measured by visual analog scales every 15 min. Blood glucose concentrations were measured at −5, 30, 60, 90, and 120 min. RESULTS Solid gastric emptying was delayed in 58% of the patients, and both solid and liquid gastric emptying were slower (P < 0.05) in women than in men. The score for upper GI symptoms was not significantly related to gastric emptying. In contrast, postprandial fullness, but not hunger, was related to the amount of solid (r = 0.36, P < 0.05) but not liquid in the stomach. Both before (r = 0.39, P < 0.05) and after (r = 0.47, P < 0.01) the meal, fullness was related to blood glucose concentration. Postprandial fullness was also related to autonomic nerve dysfunction (r = 0.39, P < 0.05). Multiple regression analysis confirmed that blood glucose concentration, the rate of solid gastric emptying, and autonomic nerve dysfunction were independent determinants of postprandial fullness, together accounting for 47% of the variance. CONCLUSIONS These observations demonstrated that, in IDDM, postprandial fullness is influenced by blood glucose concentration, the rate of solid gastric emptying, and autonomic nerve function.

We thank Dr. Dhatariya (1) for his interest in our recent article (2) and are pleased to have the opportunity to clarify the issues raised. Our primary aim was to evaluate the stability of gastric emptying over time in individuals with diabetes, and we found a remarkably strong relationship between the measurements of solid emptying obtained at baseline and some 25 years later. In other words, in contrast to the substantial interindividual variation in the rate of emptying, there was minimal …

To evaluate the effect of a prebreakfast high-protein snack upon postbreakfast hyperglycemia.We studied 10 men and women with diet- and/or metformin-controlled type 2 diabetes. Metabolic changes after breakfast were compared between 2 days: breakfast taken only and soya-yogurt snack taken prior to breakfast.There was a significant lower rise in plasma glucose on the snack day. The incremental area under the glucose curve was 450 ± 55 mmol · min/l on the snack day compared with 699 ± 99 mmol · min/l on the control day (P = 0.013). The concentration of plasma free fatty acids immediately before breakfast correlated with the increment in plasma glucose (r = 0.50, P = 0.013).Consuming a high-protein prebreakfast snack results in almost 40% reduction of postprandial glucose increment. The second-meal effect can be applied simply and practically to improve postbreakfast hyperglycemia in people with type 2 diabetes.

Damci et al. (1) suggest that the lipase inhibitor, orlistat, stimulates the postprandial secretion of glucagon-like peptide-1 (GLP-1) after meals containing fat and speculate that this may lead to reductions in both postprandial glycemia and energy intake. The authors observed (in a cohort of 29 type 2 diabetic patients) that after ingestion of a 600 kcal breakfast (comprising 38% fat, 50% carbohydrate, and 12% protein), the increases from baseline in plasma GLP-1 and serum C-peptide were slightly greater and that of serum glucose slightly less, as measured in a single blood sample taken 60 min after commencement of the …