Macronutrient intake, appetite, food preferences and exocrine pancreas function after treatment with short- and long-acting glucagon-like peptide-1 receptor agonists in type 2 diabetes.

AIM: To clarify the distinct effects of a long-acting (liraglutide) and a short-acting (lixisenatide) glucagon-like peptide-1 receptor agonist (GLP-1 RA) on macronutrient intake, gastrointestinal side effects and pancreas function. MATERIALS AND METHODS: Fifty participants were randomized to either lixisenatide or liraglutide for a treatment period of 10 weeks. Appetite, satiety, macronutrient intake, gastrointestinal symptoms and variables related to pancreatic function and gastric emptying were assessed at baseline and after treatment. RESULTS: Both GLP-1 RAs reduced macronutrient intake similarly. Weight loss and appetite reduction were not related to the delay in gastric emptying or gastrointestinal side effects (P > .05). Lipase increased significantly with liraglutide treatment (by 18.3 ± 4.1 U/L; P = .0001), but not with lixisenatide (-1.8 ± 2.4 U/L; P = .46). Faecal elastase and serum ß-carotin levels (indicators for exocrine pancreas function) improved in both groups (P < .05). Changes in lipase activities did not correlate with gastrointestinal symptoms (P > .05 for each variable). CONCLUSIONS: Both GLP-1 RAs comparably affected body weight, energy and macronutrient intake. Both treatments were associated with indicators of improved exocrine pancreas function. Reductions in appetite and body weight as a result of treatment with short- or long-acting GLP-1 RAs are not driven by changes in gastric emptying or gastrointestinal side effects.

Effects of Lixisenatide Versus Liraglutide (Short- and Long-Acting GLP-1 Receptor Agonists) on Esophageal and Gastric Function in Patients With Type 2 Diabetes.

OBJECTIVE: Short-acting glucagon-like peptide 1 receptor agonists (GLP-1 RAs) decelerate gastric emptying more than long-acting GLP-1 RAs. Delayed gastric emptying is a risk factor for gastroesophageal reflux disease. We aimed to measure esophageal reflux and function as well as gastric emptying and acid secretion during treatment with short-acting (lixisenatide) and long-acting (liraglutide) GLP-1 RAs. RESEARCH DESIGN AND METHODS: A total of 57 subjects with type 2 diabetes were randomized to a 10-week treatment with lixisenatide or liraglutide. Changes from baseline in the number of reflux episodes during 24-h pH registration in the lower esophagus, lower esophagus sphincter pressure, gastric emptying (13C-sodium octanoate acid breath test), and gastric acid secretion (13C-calcium carbonate breath test) were analyzed. RESULTS: Gastric emptying half-time was delayed by 52 min (Δ 95% CI 16, 88) with lixisenatide (P = 0.0065) and by 25 min (3, 46) with liraglutide (P = 0.025). There was no difference in the number of reflux episodes (mean ± SEM 33.7 ± 4.1 vs. 40.1 ± 5.3 for lixisenatide and liraglutide, respectively, P = 0.17) or the extent of gastroesophageal reflux (DeMeester score) (35.1 ± 6.7 vs. 39.7 ± 7.5, P = 0.61), with similar results for the individual GLP-1 RAs. No significant changes from baseline in other parameters of esophageal motility and lower esophageal sphincter function were observed. Gastric acidity decreased significantly by -20.7% (-40.6, -0.8) (P = 0.042) with the GLP-1 RAs. CONCLUSIONS: Lixisenatide exerted a more pronounced influence on gastric emptying after breakfast than liraglutide. Neither lixisenatide nor liraglutide had significant effects on esophageal reflux or motility. Gastric acid secretion appears to be slightly reduced by GLP-1 RAs.

Effects of sequential treatment with lixisenatide, insulin glargine, or their combination on meal-related glycaemic excursions, insulin and glucagon secretion, and gastric emptying in patients with type 2 diabetes.

AIM: To examine the glucose-lowering mechanisms of the glucagon-like peptide-1 receptor agonist lixisenatide after two subsequent meals and in combination with basal insulin. MATERIALS AND METHODS: Twenty-eight metformin-treated patients with type 2 diabetes were randomly assigned to treatment sequences with either lixisenatide or insulin glargine alone for 4 weeks, and a combination of both treatments for 4 weeks. Metabolic examinations were performed before and after each treatment period following breakfast and a late lunch 8 hours later. RESULTS: Lixisenatide mainly reduced postprandial glycaemia, while insulin glargine mainly reduced fasting glucose after breakfast (P < 0.05). This was partially preserved after a late lunch (P < 0.05). After breakfast, lixisenatide reduced insulin secretion and glucagon levels significantly. These effects were lost after a late lunch. Insulin glargine did not significantly reduce glucagon or insulin secretion. Gastric emptying was slowed by lixisenatide, but not by insulin glargine after breakfast. After the late lunch, lixisenatide slightly accelerated gastric emptying. CONCLUSIONS: Lixisenatide decelerates gastric emptying after breakfast, thereby reducing glycaemic excursions, insulin secretion and glucagon levels. The glycaemic reduction persists until after a late lunch, despite accelerated gastric emptying. The combination with insulin glargine enhances the glucose-lowering effect because of complementary modes of action.

Defects in α-Cell Function in Patients With Diabetes Due to Chronic Pancreatitis Compared With Patients With Type 2 Diabetes and Healthy Individuals.

OBJECTIVE: Diabetes frequently develops in patients with chronic pancreatitis. We examined the alterations in the glucagon response to hypoglycemia and to oral glucose administration in patients with diabetes due to chronic pancreatitis. RESEARCH DESIGN AND METHODS: Ten patients with diabetes secondary to chronic pancreatitis were compared with 13 patients with type 2 diabetes and 10 healthy control subjects. A stepwise hypoglycemic clamp and an oral glucose tolerance test (OGTT) were performed. RESULTS: Glucose levels during the OGTT were higher in patients with diabetes and chronic pancreatitis and lower in control subjects (P < 0.0001). Insulin and C-peptide levels were reduced, and the glucose-induced suppression of glucagon was impaired in both groups with diabetes (all P < 0.0001 vs. control subjects). During hypoglycemia, glucagon concentrations were reduced in patients with chronic pancreatitis and with type 2 diabetes (P < 0.05). The increase in glucagon during the clamp was inversely related to the glucose-induced glucagon suppression and positively related to ß-cell function. Growth hormone responses to hypoglycemia were lower in patients with type 2 diabetes (P = 0.0002) but not in patients with chronic pancreatitis. CONCLUSIONS: α-Cell responses to oral glucose ingestion and to hypoglycemia are disturbed in patients with diabetes and chronic pancreatitis and in patients with type 2 diabetes. The similarities between these defects suggest a common etiology.

Impact of insulin glargine and lixisenatide on ß-cell function in patients with type 2 diabetes mellitus: A randomized open-label study.

It is known that ß-cell function can be enhanced by direct stimulation of insulin secretion or by induction of ß-cell rest, but whether both strategies can complement each other has not yet been examined. A total of 28 people with type 2 diabetes (glycated haemoglobin 7.8% ± 0.5%) were treated with either lixisenatide or titrated insulin glargine, followed by their combined administration, each over 4 weeks. First- and second-phase insulin secretion during an intravenous glucose challenge were calculated. First- and second-phase insulin secretion were not increased with glargine alone, but increased after addition of lixisenatide ( P < .001). Lixisenatide alone increased first- and second-phase insulin secretion ( P < .01). Addition of insulin glargine tended to further increase first-phase insulin secretion (P = .054), as well as insulin and C-peptide concentrations ( P < .05). Second-phase insulin secretion was not affected by the addition of glargine. The sequence of initiating lixisenatide or glargine had no effect on the final measures of glycaemia or insulin secretion. Thus, lixisenatide and, to a lesser extent, insulin glargine, increase glucose-stimulated insulin secretion in an additive manner.

Upper gastrointestinal motility and symptoms in individuals with diabetes, prediabetes and normal glucose tolerance.

AIMS/HYPOTHESIS: Type 2 diabetes has been associated with upper gastrointestinal motility dysfunction, but the relationship with diabetes duration and glucose control is less well understood. Gastric emptying, oesophageal motility and gastrointestinal symptoms were examined in volunteers with diabetes, prediabetes (impaired fasting glucose [IFG] or impaired glucose tolerance [IGT]) and normal glucose tolerance (NGT). METHODS: The study included 41 patients with type 2 diabetes, 17 individuals with IFG/IGT and 31 individuals with NGT. A gastric emptying breath test and high-resolution oesophageal manometry were performed. Gastrointestinal symptoms were assessed using questionnaires. RESULTS: Gastric emptying was delayed in individuals with IFG/IGT (p < 0.05) but was normal in the diabetic group. Amongst the diabetic patients, gastric emptying rate was fastest in those with longer diabetes duration and the highest HbA1c levels (p < 0.001). Oesophageal motility variables were similar between the groups. However, the lower oesophagus resting pressure was reduced in patients with longer diabetes duration (p = 0.01). Abdominal pain/discomfort was more frequent amongst patients with diabetes (p = 0.04) but was unrelated to gastric emptying. Significant associations between various oesophageal motility variables and gastrointestinal symptoms were observed. CONCLUSIONS/INTERPRETATION: Gastric emptying and oesophageal motility are not generally altered in patients with type 2 diabetes. In more advanced disease stages, however, gastric emptying and oesophageal motility may be disturbed, probably as a consequence of autonomic neuropathy. Delayed gastric emptying in IFG/IGT individuals might be secondary to acute hyperglycaemia. Determination of gastric emptying and oesophageal manometry should be considered for the diagnostic workup of patients with diabetes and gastrointestinal symptoms.

Impaired crosstalk between pulsatile insulin and glucagon secretion in prediabetic individuals.

INTRODUCTION: Postprandial hyperglucagonemia is frequently found in patients with diabetes. Recently, a loss of the inverse relationship between pulsatile insulin and glucagon secretion has been reported in patients with type 2 diabetes. The crosstalk between pulsatile islet hormone secretion in prediabetic individuals has not yet been examined. PATIENTS AND METHODS: Eleven individuals with impaired glucose tolerance and/or impaired fasting glucose and 13 nondiabetic controls were examined after mixed meal ingestion. Glucose, insulin, and glucagon levels were determined frequently and analyzed by deconvolution and cross-correlation methods. RESULTS: Postprandial glucose levels were higher in prediabetic individuals (P = 0.017). Insulin concentrations were not different between the groups (P = 0.29). Postprandial glucagon levels were higher in the impaired glucose tolerance/impaired fasting glucose individuals (P = 0.039). Pulsatile insulin and glucagon secretion was apparent in both groups, but there were no differences in the frequency or mass of insulin and glucagon pulses between the groups. An inverse relationship between the insulin and glucagon concentration time curves was found in the control subjects (P < 0.05). This association was not detectable in the prediabetic individuals. CONCLUSIONS: Increased postprandial glucagon concentrations in prediabetic individuals are accompanied by a loss of the pulsatile insulin-glucagon crosstalk. This suggests that disturbances in islet hormone pulsatility precede the actual manifestation of hyperglycemia.

Chronic reduction of fasting glycemia with insulin glargine improves first- and second-phase insulin secretion in patients with type 2 diabetes.

OBJECTIVE: Insulin secretion is often diminished in hyperglycemic patients with type 2 diabetes. We examined whether chronic basal insulin treatment with insulin glargine improves glucose-induced insulin secretion. RESEARCH DESIGN AND METHODS: Fourteen patients with type 2 diabetes on metformin monotherapy received an add-on therapy with insulin glargine over 8 weeks. Intravenous glucose tolerance tests (IVGTTs) were performed before and after the intervention, with and without previous adjustment of fasting glucose levels using a 3-h intravenous insulin infusion. RESULTS: Fasting glycemia was lowered from 179.6 ± 7.5 to 117.6 ± 6.5 mg/dL (P < 0.001), and HbA(1c) levels declined from 8.4 ± 0.5 to 7.1 ± 0.2% (P = 0.0046). The final insulin dose was 59.3 ± 10.2 IU. Acute normalization of fasting glycemia by intravenous insulin reduced C-peptide levels during the IVGTT (P < 0.0001). In contrast, insulin and C-peptide responses to intravenous glucose administration were significantly greater after the glargine treatment period (P < 0.0001, respectively). Both first- and second-phase insulin secretion increased significantly after the glargine treatment period (P < 0.05, respectively). These improvements in insulin secretion were observed during both the experiments with and without acute adjustment of fasting glycemia. CONCLUSIONS: Chronic supplementation of long-acting basal insulin improves glucose-induced insulin secretion in hyperglycemic patients with type 2 diabetes, whereas acute exogenous insulin administration reduces the ß-cell response to glucose administration. These data provide a rationale for basal insulin treatment regiments to improve postprandial endogenous insulin secretion in hyperglycemic patients with type 2 diabetes.

Loss of inverse relationship between pulsatile insulin and glucagon secretion in patients with type 2 diabetes.

OBJECTIVE: In patients with type 2 diabetes, glucagon levels are often increased. Furthermore, pulsatile secretion of insulin is disturbed in such patients. Whether pulsatile glucagon secretion is altered in type 2 diabetes is not known. RESEARCH DESIGN AND METHODS: Twelve patients with type 2 diabetes and 13 nondiabetic individuals were examined in the fasting state and after mixed meal ingestion. Deconvolution analyses were performed on insulin and glucagon concentration time series sampled at 1-min intervals. RESULTS: Both insulin and glucagon were secreted in distinct pulses, occurring at ∼5-min intervals. In patients with diabetes, postprandial insulin pulse mass was reduced by 74% (P < 0.001). Glucagon concentrations were increased in the patients during fasting and after meal ingestion (P < 0.05), specifically through an increased glucagon pulse mass (P < 0.01). In healthy subjects, the increase in postprandial insulin levels was inversely related to respective glucagon levels (P < 0.05). This relationship was absent in the fasting state and in patients with diabetes. CONCLUSIONS: Glucagon and insulin are secreted in a coordinated, pulsatile manner. A plausible model is that the postprandial increase in insulin burst mass represses the corresponding glucagon pulses. Disruption of the insulin-glucagon interaction in patients with type 2 diabetes could potentially contribute to hyperglucagonemia.