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OBJECTIVE Tachyphylaxis for slowing of gastric emptying is seen with continuous exposure to glucagon-like peptide 1 (GLP-1). We therefore aimed to establish whether prolonged use of a “short-acting” GLP-1 receptor agonist, lixisenatide, achieves sustained slowing of gastric emptying and reduction in postprandial glycemia. RESEARCH DESIGN AND METHODS A total of 30 patients with metformin-treated type 2 diabetes underwent assessment of gastric emptying (scintigraphy) and glucose metabolism (dual tracer technique) after a 75-g glucose drink, before and after 8 weeks’ treatment with lixisenatide (20 μg subcutaneously daily) or placebo, in a double-blind randomized parallel design. RESULTS Gastric retention of the glucose drink was markedly increased after lixisenatide versus placebo (ratio of adjusted geometric means for area under the curve [AUC] over 240 min of 2.19 [95% CI 1.82, 2.64], P < 0.001), associated with substantial reductions in the rate of systemic appearance of oral glucose (P < 0.001) and incremental AUC for blood glucose (P < 0.001). Lixisenatide suppressed both glucagon (P = 0.003) and insulin (P = 0.032), but not endogenous glucose production, over 120 min after oral glucose intake. Postprandial glucose lowering over 240 min was strongly related to the magnitude of slowing of gastric emptying by lixisenatide (r = −0.74, P = 0.002) and to the baseline rate of emptying (r = 0.52, P = 0.048) but unrelated to β-cell function (assessed by β-cell glucose sensitivity). CONCLUSIONS Eight weeks’ treatment with lixisenatide is associated with sustained slowing of gastric emptying and marked reductions in postprandial glycemia and appearance of ingested glucose. Short-acting GLP-1 receptor agonists therefore potentially represent an effective long-term therapy for specifically targeting postprandial glucose excursions.

The short-acting glucagon-like peptide 1 receptor agonist exenatide reduces postprandial glycemia, partly by slowing gastric emptying, although its impact on small intestinal function is unknown. In this study, 10 healthy subjects and 10 patients with type 2 diabetes received intravenous exenatide (7.5 μg) or saline (230 to 240 min) in a double-blind randomized crossover design. Glucose (45 g), together with 5 g 3-O-methylglucose (3-OMG) and 20 MBq 99mTc-sulfur colloid (total volume 200 mL), was given intraduodenally (t = 0-60 min; 3 kcal/min). Duodenal motility and flow were measured using a combined manometry-impedance catheter and small intestinal transit using scintigraphy. In both groups, duodenal pressure waves and antegrade flow events were fewer, and transit was slower with exenatide, as were the areas under the curves for serum 3-OMG and blood glucose concentrations. Insulin concentrations were initially lower with exenatide than with saline and subsequently higher. Nausea was greater in both groups with exenatide, but suppression of small intestinal motility and flow was observed even in subjects with little or no nausea. The inhibition of small intestinal motor function represents a novel mechanism by which exenatide can attenuate postprandial glycemia usc Refereed/Peer-reviewed

The impact of variations in gastric emptying, which influence the magnitude of glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) secretion, on glucose lowering by dipeptidyl peptidase-4 (DPP-4) inhibitors is unclear. We evaluated responses to intraduodenal glucose infusion (60 g over 120 min [i.e., 2 kcal/min], a rate that predominantly stimulates GIP but not GLP-1) after sitagliptin versus control in 12 healthy lean, 12 obese, and 12 type 2 diabetic subjects taking metformin 850 mg b.i.d. versus placebo. As expected, sitagliptin augmented plasma-intact GIP substantially and intact GLP-1 modestly. Sitagliptin attenuated glyce-mic excursions in healthy lean and obese but not type 2 diabetic subjects, without affecting glucagon or energy intake. In contrast, metformin reduced fasting and glucose-stimulated glycemia, suppressed energy intake, and augmented total and intact GLP-1, total GIP, and glucagon in type 2 diabetic subjects, with no additional glucose lowering when combined with sitagliptin. These observations indicate that in type 2 diabetes, 1) the capacity of endogenous GIP to lower blood glucose is impaired; 2) the effect of DPP-4 inhibition on glycemia is likely to depend on adequate endogenous GLP-1 release, requiring gastric emptying >2 kcal/min; and 3) the action of metformin to lower blood glucose is not predominantly by way of the incretin axis. Refereed/Peer-reviewed

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: 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 …

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 …