Regulation of islet hormone release and gastric emptying by endogenous glucagon-like peptide 1 after glucose ingestion

BACKGROUND: Exogenous administration of glucagon-like peptide (GLP)-1 improves glucose tolerance by stimulation of insulin secretion, inhibition of glucagon secretion, and delay of gastric emptying. It is not known which of these effects is involved in the action of endogenous GLP-1 to control blood glucose. To determine the role of endogenous GLP-1 on islet cell function and gastric emptying independent of variable glycemia, we clamped blood glucose before and during glucose ingestion with and without GLP-1 receptor blockade with exendin-[9-39] (Ex-9). METHODS: There were 10 healthy subjects that participated in two experiments each, one a control and one with infusion of 750 pm/kg . min Ex-9. Subjects consumed 75 g oral glucose solution mixed with d-xylose and (13)C-glucose while their blood glucose levels were held fixed at approximately 8.9 mmol/liter. RESULTS: Plasma insulin levels during hyperglycemia alone were similar in the two studies (control, 282.5 +/- 42 vs. Ex-9, 263.8 +/- 59 pmol/liter) but were reduced by approximately 30% by Ex-9 after glucose ingestion (control, 1154 +/- 203 vs. Ex-9, 835 +/- 120 pmol/liter; P < 0.05). Blocking the action of endogenous GLP-1 caused an approximate 80% increase in postprandial glucagon concentrations. The appearance of ingested d-xylose in the blood was not affected by Ex-9, suggesting that postprandial secretion of GLP-1 has only minimal effects on gastric emptying of oral glucose. CONCLUSIONS: These findings indicate that GLP-1 is an incretin in healthy humans at modestly supraphysiological blood glucose levels. The primary effect of GLP-1 to regulate oral glucose tolerance is mediated by effects on islet hormones and not on gastric emptying.     

Gender-related differences in gastric emptying rate of solid meals

Controversy exists about the occurrence of a gender-related difference in gastric emptying in humans. In this paper, a strictly standardized scintigraphic method, in which pancakes were labeled with technetium-99m-macroaggregated albumin, was used to follow gastric emptying in 16 male and 14 female healthy young subjects. The resulting mean gastric emptying curves described biphasic patterns. There was a similar lag period (30.6±4.2 vs 33.6±3.8 min; means±SEM) but a faster linear gastric emptying rate (32.9±1.4 vs 22.0±1.3%/hr), a shorter half-emptying time (111.2±8.6 vs 158.2±6.4 min) and lower residual radioactivity after 2 hr (43.0±3.5 vs 62.8±1.7%) in the male subgroup as compared with the female subgroup. The differences were highly statistically significant. As a result, separate reference values are recommended for young male and fertile female subjects.     

Addition of metformin to exogenous glucagon-like peptide-1 results in increased serum glucagon-like peptide-1 concentrations and greater glucose lowering in type 2 diabetes mellitus

Glucagon-like peptide-1 (GLP-1) is an incretin hormone that lowers blood glucose after meals in type 2 diabetes mellitus. The therapeutic potential of GLP-1 in diabetes is limited by rapid inactivation by the enzyme dipeptidylpeptidase-4 (DPP-4). Metformin has been reported to inhibit DPP-4. Here we investigated the acute effects of metformin and GLP-1 alone or in combination on plasma DPP-4 activity, active GLP-1 concentrations, and glucose lowering in type 2 diabetes mellitus. Ten subjects with type 2 diabetes mellitus (8 male and 2 female; age, 68.7 ± 2.6 years [mean ± SEM]; body mass index, 29.6 ± 1.7 kg/m²; hemoglobin A_1c, 7.0% ± 0.1%) received 1 of 3 combinations after an overnight fast in a randomized crossover design: metformin 1 g orally plus subcutaneous injection saline (Metformin), GLP-1 (1.5 nmol/kg body weight subcutaneously) plus placebo tablet (GLP-1), or metformin 1 g plus GLP-1(Metformin + GLP-1). At 15 minutes, glucose was raised to 15 mmol/L by rapid intravenous infusion of glucose; and responses were assessed over the next 3 hours. This stimulus does not activate the enteroinsular axis and secretion of endogenous GLP-1, enabling the effect of exogenously administered GLP-1 to be examined. Mean area under curve (AUC) _{0-180 minutes} plasma glucose responses were lowest after Metformin + GLP-1 (mean ± SEM, 1629 ± 90 mmol/[L min]) compared with GLP-1 (1885 ± 86 mmol/[L min], P < .002) and Metformin (2045 ± 115 mmol/[L min], P < .001). Mean AUC serum insulin responses were similar after either Metformin + GLP-1 (5426 ± 498 mU/[L min]) or GLP-1 (5655 ± 854 mU/[L min]) treatment, and both were higher than Metformin (3521 ± 410 mU/[L min]; P < .001 and P < .05, respectively). Mean AUC for plasma DPP-4 activity was lower after Metformin + GLP-1 (1505 ± 2 μmol/[mL min], P < .001) and Metformin (1508 ± 2 μmol/[mL min], P < .002) compared with GLP-1 (1587 ± 3 μmol/[mL min]). Mean AUC measures for plasma active GLP-1 concentrations were higher after Metformin + GLP-1 (820 × 10⁴ ± 51 × 10⁴ pmol/[L min]) compared with GLP-1 (484 × 10⁴ ± 31 × 10⁴ pmol/[L min], P < .001) and Metformin (419 × 10⁴ ± 34 × 10⁴ pmol/[L min], P < .001), respectively. In patients with type 2 diabetes mellitus, metformin inhibits DPP-4 activity and thus increases active GLP-1 concentrations after subcutaneous injection. In combination with GLP-1, metformin significantly lowers plasma glucose concentrations in type 2 diabetes mellitus subjects compared with GLP-1 alone, whereas insulin responses were similar. Metformin enhances serum concentrations of injected active GLP-1(7-36)amide, and the combination results in added glucose-lowering potency.     

13C-辛酸呼气试验评估糖尿病胃固体排空功能的研究

目的探讨老年2型糖尿病患者胃固体排空功能及其与心血管自主神经功能的关系。方法老年2型糖尿病组71例，正常对照组30例，应用^13C-辛酸呼气试验技术检测胃固体排空功能，并行心血管自主神经功能评估。结果（1）糖尿病患者胃半排空时间（GET1／2）、延迟相（Tlag）及120min胃残留率（Ret120min）明显高于正常对照组（P均〈0．01）；（2）糖尿病患者胃排空延迟患病率高于正常对照人群（P〈0．01）；（3）糖尿病合并胃排空延迟者心血管自主神经病变患病率明显高于胃排空正常糖尿病患者（P〈0．05）；（4）糖尿病组GET1/2与心血管自主神经功能积分呈显著正相关（r=0．353，P〈0．01）。结论（1）老年2型糖尿病患者胃动力明显下降，胃固体排空延迟常常与心血管自主神经病变合并存在。（2）^13C-辛酸呼气试验是检测胃排空的理想选择。     

Differing effects of liraglutide on gastric emptying in Japanese patients with type 2 diabetes

This study was performed to clarify the influence of liraglutide on gastric emptying in Japanese patients with type 2 diabetes. In 16 patients, the [¹³C]‐acetate breath test was performed to compare gastric emptying before and after liraglutide treatment. We found two patterns of response, with gastric emptying being delayed by liraglutide in seven patients (delayers) and not delayed in nine patients (non‐delayers). The mean increase of the maximum gastric emptying time was 31 ± 4 min (p < 0.01 vs. baseline) in the delayers, while it was only 2 ± 3 min (p = 0.60 vs. baseline) in the non‐delayers. The delayers showed a greater early decrease of AUC‐PG from 0 to 60 min, despite no increase of the plasma insulin level compared with non‐delayers. In conclusion, the effect of liraglutide treatment on gastric emptying shows heterogeneity, and patients can be classified as delayers or non‐delayers.     

Gastric emptying of solid and liquid meals in healthy controls compared with long-term type-1 diabetes mellitus under optimal glucose control.

BACKGROUND: Neuropathy of the enteric nervous system and hyperglycaemia are regarded as the main causes of diabetic gastroparesis. PATIENTS AND METHODS: In ten patients with Type-1 diabetes mellitus and sensomotoric neuropathy gastric emptying half times were compared with ten healthy controls by employing the 13C-octanoic acid and the 13C-sodiumacetate breath test, resp., following the intake of equally composed and isocaloric liquid and solid meals. Plasma glucose concentrations were controlled by permanent intravenous administration of insulin. RESULTS: In diabetes mellitus gastric emptying half times after the intake of the liquid meal (p < 0.05) but not after ingestion of the solid meal were slightly prolonged. Gastric emptying half times in patients and controls were not different when liquid and solid meals were compared. CONCLUSIONS: Acute hyperglycaemia appears to be more important than the neuropathy of the enteric nervous system in the pathophysiology of diabetic gastroparesis. The rate of gastric emptying is obviously not dependent on the phase of a meal, but rather on the composition and the caloric content.     

Impact of postprandial and fasting glucose concentrations on HbA1c in patients with type 2 diabetes

AimThis study aimed to assess the relative contributions of postprandial and fasting glucose concentrations to overall hyperglycaemia.MethodsPatients with type 2 diabetes (n = 973) carried out self-monitored blood glucose (SMBG) profiles on entry into the European Exenatide (EUREXA) trial. Glucose area under the curve was calculated for postprandial excursions (AUC_ppg) and total daytime concentrations > 6.1 mmol/L (AUC_total), as well as for the percentage of glycaemia due to postprandial excursions (%_ppg). In addition, OGTT scores were assessed for each patient. Results were evaluated according to defined HbA_1c categories.ResultsThere was a significant linear relationship between HbA_1c and the derived variables of AUC_ppg, AUC_total and %_ppg (P < 0.001 for each), with explained variance greatest for AUC_total (r² = 37.4%). AUC_ppg increased only slightly up to an HbA_1c of 7.0%, but showed a steeper increase in higher HbA_1c categories. Also, the increase in AUC_total with increasing HbA_1c was much more pronounced. As a result, the postprandial glucose excursion as a proportion of total glucose (%_ppg) decreased across HbA_1c categories from 61.0% at HbA_1c < 6.5% to 22.0% at HbA_1c ≥ 9.0%. HOMA-IR remained virtually unchanged through all HbA_1c categories, while HOMA-B showed no large changes up to HbA_1c 7.0%, but then decreased at higher HbA_1c values. The ΔI30/ΔG30 ratio decreased in the HbA_1c 7.0–7.9% category, but did not change greatly at higher HbA_1c categories.ConclusionWith increasing HbA_1c, there was a decrease in the contribution of postprandial hyperglycaemia to total glycaemia, and fasting hyperglycaemia became more important. This is consistent with impaired insulin release, particularly first-phase release, at higher HbA_1c levels.     

Elevated plasma levels of glucagon-like peptide-1 after oral glucose ingestion in patients with pancreatic diabetes

OBJECTIVE: The purpose of the present study was to evaluate plasma glucagon-like peptide-1 (GLP-1) responses after oral glucose ingestion in patients with chronic pancreatitis and to clarify how GLP-1 secretion relates to pancreatic diabetes. METHODS: An oral glucose tolerance test (OGTT) was performed in 17 patients with chronic pancreatitis. Plasma glucose, immunoreactive insulin (IRI), C-peptide, glucagon, and GLP-1 levels at each time point during OGTT were measured. The diagnosis of chronic pancreatitis was made by the findings of endoscopic retrograde pancreatography (ERP): evident dilation of the main pancreatic duct with or without pancreatolithiasis. RESULTS: The patients were divided into three groups according to the World Health Organization classification of diabetes based on plasma glucose levels after OGTT. The groups were: normal (three patients), impaired glucose tolerant (IGT) (six patients), and diabetic (DM) (eight patients). In the DM group, IRI and C-peptide response levels after oral glucose ingestion were significantly reduced as compared with those of the normal and IGT groups. No significant glucagon responses to oral glucose ingestion were found in the three groups. In contrast, plasma GLP-1 levels were significantly elevated after oral glucose ingestion in the DM groups as compared with normal and IGT groups. CONCLUSIONS: The present study affords evidence that plasma GLP-1 levels become elevated with development of pancreatic diabetes, although the precise mechanism of this elevation remains undetermined.     

2型糖尿病胃转流术后胰高血糖素样肽-1的变化及其意义

目的 探讨2型糖尿病患者行胃转流术后血清胰高血糖素样肽-1 （GLP-1）的变化及意义.方法 对37例2型糖尿病患者行胃转流术,手术前后检测空腹血糖（FPG）、餐后2h血糖（2 h PG）、糖化血红蛋白（HbA1c）、空腹胰高血糖素样肽-1（FGLP-1）、餐后2h胰高血糖素样肽-1（2 h GLP-1）,并计算胰岛素敏感指数（（ISI）=1/FPG×FIns.结果 37例患者均获随访1年以上,29例达到完全缓解,5例部分缓解,3例无效,总有效率为91.9％.与术前比较,术后FPG、2 h PG、及HbA1c呈显著下降,FGLP-1、2 h GLP-1及ISI则较术前明显升高（P均＜0.05）;FGLP-1、2 h GLP-1与ISI呈正相关（r分别为0.64、0.58,P＜0.01或＜0.05）.结论 胃转流术治疗2型糖尿病有明显效果,其作用机制之一是术后患者肠源性GLP-1的分泌增加进而改善胰岛素敏感性.     

Outcome after gastrectomy in gastric cancer patients with type 2 diabetes

AIM: To evaluate the prognosis of type II diabetes mellitus (T2DM) after gastrectomy and related factors in gastric cancer patients.METHODS: 403 gastric cancer patients with T2DM were studied, who underwent gastrectomy between May 2003 and September 2009. A review of medical records and telephone interviews was performed in this cross-sectional study. The factors included in the statistical analysis were as follows: gender, age, type of surgery, preoperative body mass index (BMI), current BMI, BMI reduction ratio, preoperative insulin or oral diabetic medicine requirement, follow-up duration, and current state of diabetes. Assessment of diabetes status after surgery was classified into four categories according to the change in hypoglycemic agents after surgery and present status of T2DM: resolution, improvement, same, and worse.RESULTS: The mean follow-up duration was 33.7 mo (± 20.6 mo), preoperative BMI was 24.7 kg/m² (± 3.0 kg/m²), and BMI reduction ratio was 9.8% (± 8.6%). After surgery, T2DM was cured in 58 patients (15.1%) and was improved in 117 patients (30.4%). According to the type of surgery, the BMI reduction ratio was significantly higher in the total gastrectomy and Roux-en-Y reconstruction group [14.2% ± 9.2% vs 9.2% ± 7.7% (Billroth II group), P < 0.001] and significantly lower in the subtotal gastrectomy and Billroth I reconstruction group [7.6% ± 8.0%, 9.2% ± 7.7% (Billroth II group), P < 0.001]. The BMI reduction ratio, follow-up duration after surgery, type of surgery, extent of gastrectomy, and performance of duodenal bypass were significantly correlated to the course of T2DM (P < 0.05). The BMI reduction ratio was the most influential factor on T2DM status. In a subgroup analysis of patients with a BMI reduction ratio of 10% or less (n = 206), T2DM was cured in 15 (7.6%) patients and was improved in 57 (28.8%) patients after surgery, and only the duration of surgery was significantly correlated to T2DM status (P = 0.022).CONCLUSION: The course of T2DM was significantly correlated to the BMI reduction ratio but not to the type of surgery without a significant change in BMI.     

Prevalence and predictors of delayed gastric emptying among Indian patients with long-standing type 2 diabetes mellitus

Background and Aims

Upper gastrointestinal symptoms are more prevalent among type 2 diabetes mellitus (T2DM) patients. The prevalence of delayed gastric emptying (GE) and factors predictive of it have not been studied in Indian T2DM patients and the present study aimed to study the same.

Methods

This hospital-based cross-sectional study involved adult (age between 18 and 65 years) outpatients with T2DM of ≥5-year duration. Measurements of GE of a labelled standardized solid rice idli meal by gastric emptying scintigraphy (GES), symptoms of delayed GE (by standardized questionnaire) and autonomic function by cardiovascular autonomic function tests (AFTs) were carried out. Thirty healthy subjects served as controls for GES and AFTs.

Results

One hundred and forty T2DM patients (age range: 32–65 years) were studied. Delayed GE was documented in ≈29 % (40/140) and rapid GE in 2 % (3/140) of T2DM patients. Univariate analysis showed significant positive association between delayed GE and duration of DM, body mass index (BMI), HbA1c, retinopathy, peripheral neuropathy, autonomic dysfunction and coronary artery disease (p < 0.05 for all). However, there was no significant correlation of age, sex, symptoms suggestive of gastroparesis and nephropathy with delayed GE. Hypoglycemic episodes were significantly more frequent in those with delayed GE (p < 0.05). Multiple logistic regression analysis revealed only BMI and HbA1c to be significant independent predictors of delayed GE.

Conclusion

Presence and severity of symptoms of gastroparesis did not predict delayed GE. Delayed GE, irrespective of symptoms, was associated with microvascular and macrovascular diabetic complications and increased risk of hypoglycemic episodes. HbA_1c and BMI were independent predictors of delayed GE.

     

Effect of mosapride on glycemic control and gastric emptying in type 2 diabetes mellitus patients with gastropathy

Delay of gastric emptying is one of the factors responsible for unfavorable glycemic control. We investigated the possible effects of mosapride, a digestive tract prokinetic agent, on glycemic control in diabetic patients complicated with gastropathy. Enrolled were 36 type II diabetic patients presenting with mild digestive tract symptoms. They were given mosapride 15 mg per day for 6 months. Seventeen cases were subjected to gastric emptying test according to marker method (administration of a capsule containing 20 pieces of radiopaque marker during breakfast, followed by abdominal X-ray imaging 3 and 5 h later). In 18 cases, HbA(1C) was improved by more than 0.3% for 6 months, whereby these 18 cases were defined as the improvement group. The remaining 18 cases were defined as the non-improvement group. In the gastric emptying study, basal number of the residual markers before administration of mosapride was determined 3 and 5 h later to show 18.3+/-1.8 and 7.6+/-5.1, respectively, in the improvement group while after administration, they were reduced down to 11.2+/-5.1 and 1.4+/-2.5, respectively. In sharp contrast, the basal counterparts in the non-improvement group were 19.1+/-1.5, and 16.4+/-3.4, respectively, whereas administration failed to reduce the number of the residual markers and they remained to be as high as 19.0+/-1.4 and 11.1+/-6.4, respectively. Gastric motility in the improvement group was much more improved by mosapride administration relative to those in the non-improvement group. Mosapride might elicit improvement in the glycemic control in the patients with diabetic gastropathy.     

康复运动与老年2型糖尿病胃排空关系

目的观察康复运动对老年2型糖尿病胃排空的影响。方法将华东医院80例老年糖尿病患者随机分成4组,（康复运动＋口服促动力药组;康复运动组;口服促动力药组及对照组。在人选时及完成2年随访后均给予^99mITc标记的试餐,各测定一次固相胃排空时间。每6个月对患者空腹及餐后血糖进行一次评价。结果（1）第1、2、3组经随访两年后固相GET1／2胃排空时间与随访前相比降低,差异有统计学意义（P〈0．05）。第4组经随访两年后固相GET1／2胃排空时间与试验前相比,差异无统计学意义（P〉0．05）。（2）各组患者空腹血糖均比治疗前有下降,第2组治疗2年时空腹血糖值较治疗前差异有统计学意义（P〈0．05）。第1组经治疗18个月及2年时空腹血糖值较治疗前差异有统计学意义（P〈0．05）。（3）各组患者餐后2h血糖均比治疗前有下降,第2、3组治疗2年后餐后2h血糖值较治疗前差异有统计学意义（P〈0．05）。第1组治疗18个月及2年时餐后2h血糖值较治疗前差异有统计学意义（P〈0．05）。对照前治疗前后差异无统计学意义。结论胃排空与血糖控制互相影响,初步明确合适的康复运动联合促动力药能改善部分老年糖尿病患者胃排空,有利于血糖控制,减少并发症的发生。     

Effects of co-ingesting glucose and whey protein on blood glucose,plasma insulin and glucagon concentrations,and gastric emptying,in older men with and without type 2 diabetes

Aim

To investigate whether co-ingestion of dietary protein with, or before, carbohydrate may be a useful strategy to reduce postprandial hyperglycaemia in older men with type 2 diabetes (T2D).

Materials and Methods

Blood glucose, plasma insulin and glucagon concentrations were measured for 180 minutes following ingestion of a drink containing 30 g of glucose (G; 120 kcal), 30 g of whey protein (120 kcal), 30 g of glucose plus 30 g of whey protein (GP; 240 kcal), or control (~2 kcal) in older men with T2D (n = 10, 77 ± 1 years; 31 ± 1.7 kg/m²) and without T2D (n = 10, 78 ± 2 years; 27 ± 1.4 kg/m²). Mixed model analysis was used.

Results

GP versus G markedly reduced the increase in blood glucose concentrations (P < .001) and had a synergistic effect on the increase in insulin concentrations (P < .001), in men both with and without T2D. Glucose concentrations were higher in men with T2D compared with those without T2D, whereas insulin and glucagon concentrations were largely unaffected by the presence of T2D. Gastric emptying was faster in men with T2D than in those without T2D.

Conclusions

The ability of whey protein to reduce carbohydrate-induced, postprandial hyperglycaemia is retained in older men with T2D compared with those without T2D, and whey protein supplementation may be a useful strategy in the prevention and management of T2D in older people.