Gastric Emptying In Diabetes Research Articles

Spontaneous or Deliberate: Effects of Acute Variations in Glycemia on Gastric Emptying in Type 1 Diabetes.

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). …

Diabetic Csf1op/op mice lacking macrophages are protected against the development of delayed gastric emptying.

Background & AimsDiabetic gastroparesis is associated with changes in interstitial cells of Cajal (ICC), neurons, and smooth muscle cells in both animal models and humans. Macrophages appear to be critical to the development of cellular damage that leads to delayed gastric emptying (GE), but the mechanisms involved are not well understood. Csf1op/op (Op/Op) mice lack biologically active Csf1 (macrophage colony stimulating factor), resulting in the absence of Csf1-dependent tissue macrophages. We used Csf1op/op mice to determine the role of macrophages in the development of delayed GE.MethodsAnimals were injected with streptozotocin to make them diabetic. GE was determined weekly. Immunohistochemistry was used to identify macrophages and ICC networks in the gastric muscular layers. Oxidative stress was measured by serum malondialdehyde (MDA) levels. Quantitative reverse-transcription polymerase chain reaction was used to measure levels of mRNA.ResultsCsf1op/op mice had normal ICC. With onset of diabetes both Csf1op/op and wild-type Csf1+/+ mice developed increased levels of oxidative stress (75.8 ± 9.1 and 41.2 ± 13.6 nmol/mL MDA, respectively). Wild-type Csf1+/+ mice developed delayed GE after the onset of diabetes (4 of 13) whereas no diabetic Csf1op/op mouse developed delayed GE (0 of 15, P = .035). The ICC were disrupted in diabetic wild-type Csf1+/+ mice with delayed GE but remained normal in diabetic Csf1op/op mice.ConclusionsCellular injury and development of delayed GE in diabetes requires the presence of muscle layer macrophages. Targeting macrophages may be an effective therapeutic option to prevent cellular damage and development of delayed GE in diabetes.

A 25-Year Longitudinal Evaluation of Gastric Emptying in Diabetes

OBJECTIVETo evaluate the natural history of gastric emptying in diabetes.RESEARCH DESIGN AND METHODSThirteen patients with diabetes (12, type 1; 1, type 2) had measurements of gastric emptying, blood glucose levels, glycated hemoglobin, upper gastrointestinal symptoms, and autonomic nerve function at baseline and after 24.7 ± 1.5 years.RESULTSThere was no change in gastric emptying of either solids (% retention at 100 min) (baseline 58.5 ± 5% vs. follow-up 51.9 ± 8%; P = 0.35) or liquids (50% emptying time) (baseline 29.8 ± 3 min vs. follow-up 34.3 ± 6 min; P = 0.37). Gastric emptying of solid at follow-up was related to emptying at baseline (r = 0.56, P < 0.05). At follow-up, blood glucose concentrations were lower (P = 0.006), autonomic function deteriorated (P = 0.03), and gastrointestinal symptoms remained unchanged (P = 0.17).CONCLUSIONSIn unselected patients with diabetes, gastric emptying appears remarkably stable over 25 years.

Effect of Glucose Control on Delayed Gastric Emptying in Diabetic Patients

TO THE EDITOR: I read the report entitled Do HbA1C levels correlate with delayed gastric emptying in diabetic patients? by Reddy et al1 with great interest. The authors investigated the relationship between serum HbA1C and gastric emptying (GE), assessed by gastric emptying scintigraphy, in diabetics. Based on the data, the authors suggest that HbA1C is not as important as daily glycemic control in terms of GE in diabetics.1 I believe that the diabetic subjects in your study might have had symptoms of gastroparesis because they underwent gastric emptying scintigraphy. Diabetic patients in whom gastroparesis develops have often had diabetes for at least 10 years and typically have retinopathy, neuropathy and nephropathy.2 Additionally, the contribution of postprandial, as opposed to fasting, glycemia to overall glycemic control (indicated by HbA1C) is reportedly more closely associated with diabetic retinopathy and neuropathy than is either fasting blood glucose or HbA1C.3-5 Although your study had several limitations due to the fact that it was a retrospective study, information about postprandial glucose levels over the previous few months, such as that given by HbA1C, might be available.1 Thus, I am curious about the relationship between postprandial glucose and GE. Diabetic gastroparesis is usually chronic and, indeed, has been arbitrarily defined as persisting for more than 3 months. Therefore, investigation of the relationship between postprandial glucose levels over the previous 3 months and GE might be valuable. Although postprandial glycemia was reported to be more closely associated with diabetic neuropathy related to diabetic gastroparesis, overall glycemic control might also have importance in diabetic gastroparesis. Thus, despite negative results with respect to the relationship between HbA1C and GE in your study, I wonder whether categorical analysis of patients with abnormal HbA1C levels and GE times was performed according to variable criteria such as GE times of 90, 120 and 180 minutes (what is the normal criteria for T1/2 in your institution? The abstract states 120 minutes, whereas the main body of the paper states 90 minutes) or HbA1C levels of 7%, 8% and 9%. I am also curious about the relationship between HbA1C tendency and GE. That is, was the serum HbA1C level within the previous 3 months increased or decreased compared with the previous HbA1C? Despite several limitations of the present study, it provides interesting data about the relationship between HbA1C and GE in diabetics. Further studies with prospective settings are needed to reinforce the findings in this study.

Diabetic gastroparesis—Backwards and forwards

Diabetic gastroparesis was once thought to be rare, associated with a poor prognosis, and to affect only patients with type 1 diabetes and irreversible autonomic neuropathy. A landmark study conducted by Horowitz et al. and published in JGH in 1986 paved the way for further studies to examine the pathophysiology, natural history and prognosis of diabetic gastroparesis, as well as its optimal management. This review summarizes the developments in knowledge gained over the last ∼25 years that have led to understanding about normal and disordered gastric emptying in diabetes, with a particular emphasis on the inter-relationship between the rate of gastric emptying and the regulation of blood glucose.

S2057 Diabetes-Induced Changes in the Expression of Proteins Involved in the Regulation of Sustained Mlc 20 Phosphorylation and cGMP Levels in Gastrointestinal Smooth Muscle

The gastrointestinal complications of diabetes mellitus include nausea, vomiting, increase in intragastric pressure and delay in gastric emptying. Several studies showed that the changes in gastric emptying in diabetes are associated with the loss of enteric neurons and interstitial cells of Cajal, and dysfunction of neuronal nitric oxide synthase activity. We have previously shown that in gastrointestinal smooth muscle sustained MLC20 phosphorylation and contraction are dependent on inhibition of MLC phosphatase, which is mediated by RhoA-dependent pathway involving phosphorylation of MYPT1 (at Thr696) by Rho kinase and CPI-17 (at Thr38) by PKC. Smooth muscle relaxation is dependent on stimulation of cAMP and cGMP levels and activation of cAMPand cGMP-dependent protein kinases. The levels of cAMP and cGMP are regulated mainly by phosphodiesterase (PDE) 4D5 and PDE5, respectively. We hypothesized that diabetes induces changes in the expression of proteins involved in the maintenance of smooth muscle tone and regulation of cGMP levels. Aim. To determine the expression of PDE5, CPI-17 and Rho kinase as well as agonist-induced Rho kinase activity in gastric smooth muscle from control and diabetic animal models.Methods. Gastric smooth muscle was isolated from spontaneously type II diabetic ob/ob mice and type I diabetic rats. Type I diabetes was induced in rats by intravenous injection of streptozotocin. The rats were kept for 9 weeks and induction of diabetes was ascertained by the determination of blood glucose concentrations. Expression of CPI-17, Rho kinase and PDE5 was measured by immunoblot analysis and acetylcholine-induced Rho kinase activity was measured by immunokinase assay. Results. Expression of CPI-17, Rho kinase and PDE5 are significantly higher in gastric smooth muscle from both models of diabetic animals than from control animals. Consistent with the increased expression of Rho kinase, acetylcholine-induced Rho kinase activity was also significantly higher in smooth muscle from both models of diabetic animals than from control animals. Conclusion. This study identified mechanisms for increased smooth muscle tone and decreased smooth muscle relaxation in diabetes that are directly attributable to changes in smooth muscle physiology. The mechanisms involved increased expression of proteins involved in the regulation of sustained MLC20 phosphorylation (CPI-17 and Rho kinase) and cGMP levels (PDE5). Upregulation CPI-17 and Rho kinase could contribute to increased intragastric pressure, whereas upregulation of PDE5 could contribute to rapid hydrolysis of cGMP and decreased relaxation leading to delay in gastric emptying.

Does ghrelin explain accelerated gastric emptying in the early stages of diabetes mellitus?

During the early stages of diabetes, gastric emptying is often accelerated, rather than delayed. The mechanism of accelerated gastric emptying in diabetes has not been fully studied. A recent study showed that plasma ghrelin levels were elevated in diabetes. As postprandial antropyloric coordination plays an important role in mediating solid gastric emptying, we hypothesize that the elevated plasma ghrelin levels increase postprandial antropyloric coordination to accelerate emptying in the early stages of diabetes. To test this hypothesis, rats were made diabetic by streptozotocin (STZ; 50 mg/kg) injection, and, 2 wk later, pre- and postprandial plasma ghrelin levels, antropyloric coordination, and solid gastric emptying were determined. In control rats, plasma ghrelin levels were immediately reduced after feeding. In contrast, plasma ghrelin levels remained within the fasted levels in STZ rats after feeding. In STZ rats, gastric emptying was significantly accelerated (77.4 +/- 3.2%, n = 6), compared with that of control rats (58.8 +/- 2.5%, n = 6, P < 0.05). Treatments with anti-ghrelin antibodies attenuated accelerated gastric emptying in STZ rats (50.1 +/- 3.5%, n = 6, P < 0.05), while having little effect in vehicle control rats. The incidence of postprandial antropyloric coordination was significantly increased in STZ rats, compared with that of control rats (P < 0.05). Treatments with anti-ghrelin antibodies suppressed this enhanced antropyloric coordination in STZ rats. Our study suggests that elevated endogenous ghrelin enhances antropyloric coordination, which accelerates gastric emptying in the early stages of diabetes.

Effect of Itopride Hydrochloride on Gastric Emptying in Longstanding Diabetes Mellitus

Purpose: Delayed gastric emptying (GE) occurs in 30–50% of patients with longstanding type 1 or type 2 diabetes mellitus and may be associated with upper gastrointestinal (GI) symptoms and poor glycemic control. Current therapeutic options are limited. Itopride has been tested in functional dyspepsia (NEJM 2006; 23; 354: 832). The aim of this study was to evaluate the effect of itopride on GE in diabetes. Methods: Twenty five patients (20 type 1, 5 type 2; 10M, 15 F; mean age 45.2 ± 2.7 yr; BMI 27.5 ± 0.9 kg/m2; duration 20.2 ± 2.4 yr) were enrolled in a double-blind, placebo-controlled, randomized, crossover trial; 15 had autonomic neuropathy (3.0 ± 0.2). Patients received both itopride (200 mg tid) and placebo for 7 days, separated by 7–14 days. GE was assessed by scintigraphy immediately following each treatment period. Autonomic nerve function (cardiovascular reflex tests) was assessed at enrolment. The test meal comprised 100g ground beef labeled with 20MBq 99mTc-sulfur colloid and 150 ml 10% dextrose labeled with 7MBq 67Ga-EDTA. Results: There was a trend for itopride to accelerate both solid (p= 0.09) and liquid (p= 0.09) GE. Of the 25 patients, 12 (48%) had gastroparesis (ie delayed solid and/or liquid GE) on placebo and in this group, itopride accelerated liquid (p < 0.05) but not solid (p= 0.39) GE. The magnitude of improvement in GE of liquids (r = 0.44; p < 0.03) and solids (r = 0.39; p= 0.057) was related to GE on placebo (Figure).Figure 1Conclusions: Itopride accelerates GE of liquids, and possibly solids, in diabetic gastroparesis, however, the magnitude of this effect appears to be relatively modest and dependent on the basal rate of GE. [Figure 1]

Gastric emptying in diabetes: clinical significance and treatment.

The outcome of recent studies has led to redefinition of concepts relating to the prevalence, pathogenesis and clinical significance of disordered gastric emptying in patients with diabetes mellitus. The use of scintigraphic techniques has established that gastric emptying is abnormally slow in approx. 30-50% of outpatients with long-standing Type 1 or Type 2 diabetes, although the magnitude of this delay is modest in many cases. Upper gastrointestinal symptoms occur frequently and affect quality of life adversely in patients with diabetes, although the relationship between symptoms and the rate of gastric emptying is weak. Acute changes in blood glucose concentration affect both gastric motor function and upper gastrointestinal symptoms. Gastric emptying is slower during hyperglycaemia when compared with euglycaemia and accelerated during hypoglycaemia. The blood glucose concentration may influence the response to prokinetic drugs. Conversely, the rate of gastric emptying is a major determinant of post-prandial glycaemic excursions in healthy subjects, as well as in Type 1 and Type 2 patients. A number of therapies currently in development are designed to improve post-prandial glycaemic control by modulating the rate of delivery of nutrients to the small intestine.

Predictors of delayed gastric emptying in diabetes.

To define the predictors of the rate of gastric emptying in patients with diabetes. 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). 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. 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.

Gastric emptying of different stages in diabetes mellitus

Patients with diabetic mellitus (DM) may not present symptoms with dyspepsia. Our DM animal study showed that there were accelerated gastric emptying at early stage. Aims of this study were to investigate that gastric motility in different stages of DM, and role of hyperglycemia on gastric emptying in diabetes. Subjects and Methods: 27 cases of NIDDM (M:F= 11:16, Mean age:56)participated the study. Among them, 18 with diabetic dyspepsia, and other complication (DD), 9 without diabetic dyspepsia and other complication (NDD). 20 healthy subjects (HS, M:F=8: 12, mean age:4l) as control. After a test meal (490kcal, 99mTc-SC 300/Lci labled), gastric emptying was investigated by means of SPECT for 120min. Preand postprandial blood glucose levels at 120 min were also measured. Results: (I)Tl/2 of total and proximal stomach were 55.7±3.68min, 50.29±3.5Imin in HS, 86.19±7.30min (Vs HS, p<0.05), 67.48±6.60min (NS) in NDD, 91.46±9.28min and 81.87±8.24min(Vs HS, P<0.005, P<O.OI) in DD, respectively. (2)Retention rate of proximal stomach at end of 120min were 23.16%±2.02% in HS, 17.54±3.08% in NDD(Vs HS, P=0.06) and 33.72± 3.68% in DD (Vs HS, P=0.08,Vs NDD, P<0.005). (3)Velocity of proximal stomach in NDD was 1.l0±0.12% Imin, which was significantly increased when compared with HS (0.82±0.04%/min, P<0.05). (4)fasting and postprandual blood glucose were 8.38±0.56 and 12.75±.0.9ImmollL, no correlation between blood glucose level and parameters of gastric emptying in DD. While there were negative corrlations between blood glucose (fasting or postprandual) and retention rate of total (r-0.60, P<0.05), proximal (r=-0.62, P<0.025) and distal(r=-0.65, P<0.025) stomach at end of 120min in NDD. Conclusion: There were different patterns of gastric emptying in different stages of diabetes. Abnormal gastric emptying in DM may develop from the proximal stomach, impaired relaxation function of proximal stomach in early stage might be its mechanism. Hyperglycemia could accelerate proximal gastric emptying in NDD, but in DD, indicating that neuropathy instead of hyperglycemia may play an important role in later stage of diabetes.