Advertisement
Gastrointestinal motility and glycemic control in diabetes: the chicken and the egg revisited?
Christopher K. Rayner and Michael Horowitz
University of Adelaide Department of Medicine, Royal Adelaide Hospital, Adelaide, South Australia, Australia.
Address correspondence to: Chris Rayner, Department of Medicine, Royal Adelaide Hospital, North Terrace, Adelaide, South Australia 5000, Australia. Phone: 61-8-8222-2916; Fax: 61-8-8223-3870; E-mail: chris.rayner@adelaide.edu.au.
Find articles by Rayner, C. in: JCI | PubMed | Google Scholar
University of Adelaide Department of Medicine, Royal Adelaide Hospital, Adelaide, South Australia, Australia.
Address correspondence to: Chris Rayner, Department of Medicine, Royal Adelaide Hospital, North Terrace, Adelaide, South Australia 5000, Australia. Phone: 61-8-8222-2916; Fax: 61-8-8223-3870; E-mail: chris.rayner@adelaide.edu.au.
Find articles by Horowitz, M. in: JCI | PubMed | Google Scholar
Published February 1, 2006 - More info
J Clin Invest. 2006;116(2):299–302. https://doi.org/10.1172/JCI27758.
© 2006 The American Society for Clinical Investigation
It is now recognized that disordered gastrointestinal motor and sensory function occur frequently in diabetes mellitus and that this has substantial implications for the morbidity and effective management of patients with this condition. For example, gastric emptying is abnormally delayed in 30–50% of outpatients with long-standing type 1 or type 2 diabetes, with potential consequences of gastrointestinal symptoms, impaired nutrition, poor glycemic control, and delayed absorption of oral medications (1). However, the magnitude of the delay in gastric emptying is variable and in many cases modest (2). While diabetic gastroparesis is often associated with symptoms such as nausea, vomiting, postprandial fullness, and bloating, the relationship of symptoms to disordered emptying is relatively weak, and some patients are asymptomatic (2). Intestinal transit is also often disturbed in diabetes (rapid or slow) (3), and symptoms such as diarrhea and constipation occur more frequently than in the general population (4).
Disordered gastrointestinal motility in human diabetes has traditionally been attributed to irreversible autonomic neuropathy, but it is known that the association between delayed gastric emptying and the presence of cardiovascular autonomic neuropathy is relatively poor (2). While this may partly be attributable to a current lack of tests to evaluate gastrointestinal autonomic dysfunction directly, it has now been established that acute changes in blood glucose concentration — both hyper- and hypoglycemia — have a marked, reversible, effect on gut motility (1). For example, in type 1 diabetic patients, gastric emptying is slower when the blood glucose concentration is elevated to 16–20 mmol/l when compared with euglycemia (4–8 mmol/l) (5), while in type 2 diabetes patients, cross-sectional studies indicate that the rate of gastric emptying also varies inversely with increasing glycemia (6). Conversely, acute hypoglycemia (2.6 mmol/l) induced by insulin accelerates gastric emptying in type 1 diabetes patients, even when emptying is slower than normal during euglycemia (7). Changes in blood glucose level within the physiological postprandial range (4–8 mmol/l) also affect gastric emptying (8), suggesting that gastrointestinal motor function is highly sensitive to the glycemic state and varies over relatively brief intervals.
At the same time, the rate of gastric emptying (and probably also patterns of small intestinal flow) has a substantial impact on carbohydrate absorption and the release of gut peptides, such as the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), and is, accordingly, a major determinant of postprandial glycemic excursions — i.e., when gastric emptying is relatively slower, the initial glycemic and insulinemic responses to oral carbohydrate are less (1). This interrelationship of upper gut function with postprandial glycemia (the chicken and the egg) is a concept of profound relevance to management strategies for diabetes, given that postprandial glycemia is probably the major determinant of “average” glycemic control, as assessed by glycated hemoglobin, the traditional marker of the risk of diabetic complications (i.e., retinopathy, neuropathy, and nephropathy) (9). Interventions that slow gastric emptying are likely to benefit glycemic control in type 2 diabetes patients managed by diet or oral hypoglycemic drugs, who have impaired early, but intact late, postprandial insulin responses, while prokinetic drugs may allow more predictable entry of carbohydrate into the small intestine in type 1 diabetes patients and thereby optimize the coordination between glucose absorption and the action of exogenous insulin. Slowing of gastric emptying is likely to contribute to the efficacy of the GLP-1 agonist exenatide and the amylin analog pramlintide in reducing glycated hemoglobin in diabetes; both drugs have recently been approved for use in the United States.
-
Clues to the pathogenesis of disordered motility in animal models of diabetes
To explain the disturbed gastrointestinal motility associated with diabetes, investigators have turned to animal models, primarily in search of evidence for gastrointestinal autonomic neuropathy. Diabetic rodents exhibit morphological changes involving axons and dendrites in the extrinsic autonomic nerves supplying the gut, particularly the distal segments of axons and nerve terminals, without much neuronal loss (10). Impaired retrograde transport of neurotrophic factors has been observed in the vagus nerve of streptozotocin-induced (STZ-induced) diabetic rats and may account for abnormalities of axonal growth and differentiation; recently, decreased activity of the PI3K pathway was implicated in the pathogenesis of impaired transport (11). Importantly, the axonopathy observed in the autonomic nerves of diabetic rodents is reversible with improved glycemic control, induced by exogenous insulin or pancreatic islet transplantation (12).
While the extrinsic autonomic nerves allow for central modulation of gut function, it is the enteric nervous system, incorporating the submucus and myenteric plexuses, that coordinates gastrointestinal motility more directly. In STZ-induced diabetic rats, there is a reduction in the number of myenteric neurons in both the stomach (13) and the colon (14); the latter is evident within 7 days of the onset of diabetes. The interstitial cells of Cajal (ICCs) play a central role in coordinating gut motility, generating an electrical slow wave that determines the rhythmicity of smooth muscle contraction. In the NOD mouse, in which gastric emptying is delayed, the number of gastric ICCs is markedly diminished (15). In rodent models of diabetes, neurotransmission is also impaired, with apparently selective loss of neuronal NOS expression in the gastric myenteric plexus (16), associated with delayed gastric emptying that is reversed by both the phosphodiesterase inhibitor sildenafil and insulin (16). Dysfunction of the autonomic/enteric nervous system in diabetes and impairment of the PI3K pathway in particular could potentially result from hyperglycemia (with its attendant oxidative stress), insulin deficiency (insulin activates PI3K and is antiapoptotic), and/or accumulation of advanced glycation end products (11). Horvath et al. recently reported that deficiency of insulin and IGF-1, as opposed to hyperglycemia per se, accounts for the depletion of gastric ICCs in the NOD mouse (17).
In this issue of the JCI, Anitha et al. report that hyperglycemia induces apoptosis of rodent enteric neurons in culture in association with impaired activity of the PI3K pathway (18) (Figure 1). Apoptosis was prevented by glial cell line–derived neurotrophic factor (GDNF). STZ-induced diabetic mice also displayed apoptosis in the myenteric plexus, which specifically involved nitrergic (inhibitory) neurons, and had delayed gastric emptying and more rapid intestinal transit than controls. Again, the PI3K pathway was implicated, and the changes were prevented in transgenic mice that overexpressed GDNF. These observations imply that hyperglycemia is responsible for apoptosis, but only allow speculation as to the mechanisms by which high glucose concentrations suppress PI3K activity. Furthermore, the potential contribution of insulin deficiency to the loss of enteric neurons was not examined, and while a means of preventing neuronal loss was demonstrated, the reversibility of this loss was not.
Figure 1The pathogenesis of gastrointestinal dysfunction in a diabetic mouse model, as proposed by Anitha et al. (18). Mice that are hyperglycemic as a result of STZ-induced diabetes have apoptosis of enteric neurons in the myenteric plexus, associated with delayed gastric emptying and rapid intestinal transit when compared with control mice. Activity of the PI3K/Akt pathway is decreased in the diabetic mice, which implies an impairment of retrograde axonal transport of neurotropic factors. Both neuronal apoptosis and disordered gastrointestinal motility are prevented in mice that overexpress GDNF.
Copyright © 2024 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)