Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Gastric emptying and glycaemia in health and diabetes mellitus

Key Points

  • The rate of gastric emptying is a critical determinant of postprandial glycaemia

  • Disordered gastric emptying is common in patients with longstanding type 1 diabetes mellitus and type 2 diabetes mellitus; however, the prevalence and natural history of diabetic gastroparesis is poorly defined

  • A number of management strategies for patients with type 2 diabetes mellitus specifically target gastric emptying

  • A bidirectional relationship exists between the rate of gastric emptying and glycaemia, such that the rate of gastric emptying is partially modulated by acute changes in blood glucose concentrations

  • In patients with severe diabetic gastroparesis, histological abnormalities are heterogeneous; however, presence of an immune infiltrate and loss of interstitial cells of Cajal are evident in the majority of patients

  • Currently available management strategies for symptomatic diabetic gastroparesis have limited efficacy and further work in this area is required

Abstract

The rate of gastric emptying is a critical determinant of postprandial glycaemia and, accordingly, is fundamental to maintaining blood glucose homeostasis. Disordered gastric emptying occurs frequently in patients with longstanding type 1 diabetes mellitus and type 2 diabetes mellitus (T2DM). A complex bidirectional relationship exists between gastric emptying and glycaemia—gastric emptying accounts for 35% of the variance in peak postprandial blood glucose concentrations in healthy individuals and in patients with diabetes mellitus, and the rate of emptying is itself modulated by acute changes in glycaemia. Clinical implementation of incretin-based therapies for the management of T2DM, which diminish postprandial glycaemia, in part by slowing gastric emptying, is widespread. Other therapies for patients with T2DM, which specifically target gastric emptying include pramlintide and dietary-based treatment approaches. A weak association exists between upper gastrointestinal symptoms and the rate of gastric emptying. In patients with severe diabetic gastroparesis, pathological changes are highly variable and are characterized by loss of interstitial cells of Cajal and an immune infiltrate. Management options for patients with symptomatic gastroparesis remain limited in their efficacy, which probably reflects the heterogeneous nature of the underlying pathophysiology.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Bidirectional relationship between gastric emptying and glycaemia.
Figure 2: Pathophysiology of diabetic gastroparesis.

Similar content being viewed by others

References

  1. Baggio, L. L. & Drucker, D. J. Biology of incretins: GLP-1 and GIP. Gastroenterology 132, 2131–2157 (2007).

    CAS  PubMed  Google Scholar 

  2. Little, T. J. et al. The release of GLP-1 and ghrelin, but not GIP and CCK, by glucose is dependent upon the length of small intestine exposed. Am. J. Physiol. Endocrinol. Metab. 291, E647–E655 (2006).

    CAS  PubMed  Google Scholar 

  3. Trahair, L. G. et al. Comparative effects of variations in duodenal glucose load on glycemic, insulinemic, and incretin responses in healthy young and older subjects. J. Clin. Endocrinol. Metab. 97, 844–851 (2012).

    CAS  PubMed  Google Scholar 

  4. Marathe, C. S., Rayner, C. K., Jones, K. L. & Horowitz, M. Relationships between gastric emptying, postprandial glycemia, and incretin hormones. Diabetes Care 36, 1396–1405 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Chang, J., Rayner, C. K., Jones, K. L. & Horowitz, M. Diabetic gastroparesis and its impact on glycemia. Endocrinol. Metab. Clin. North Am. 39, 745–762 (2010).

    CAS  PubMed  Google Scholar 

  6. Stevens, J. E., Jones, K. L., Rayner, C. K. & Horowitz, M. Pathophysiology and pharmacotherapy of gastroparesis: current and future perspectives. Expert Opin. Pharmacother 14, 1171–1186 (2013).

    CAS  PubMed  Google Scholar 

  7. Horowitz, M. & Dent, J. Disordered gastric emptying: mechanical basis, assessment and treatment. Baillière's Clin. Gastroenterol. 5, 371–407 (1991).

    CAS  Google Scholar 

  8. Vittal, H., Farrugia, G., Gomez, G. & Pasricha, P. J. Mechanisms of disease: the pathological basis of gastroparesis—a review of experimental and clinical studies. Nat. Clin. Pract. Gastroenterol. Hepatol. 4, 336–346 (2007).

    CAS  PubMed  Google Scholar 

  9. Code, C. F. & Marlett, J. A. The interdigestive myo-electric complex of the stomach and small bowel of dogs. J. Physiol. 246, 289–309 (1975).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Vantrappen, G., Janssens, J., Hellemans, J. & Ghoos, Y. The interdigestive motor complex of normal subjects and patients with bacterial overgrowth of the small intestine. J. Clin. Invest. 59, 1158–1166 (1977).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Sarna, S. K. Cyclic motor activity; migrating motor complex: 1985. Gastroenterology 89, 894–913 (1985).

    CAS  PubMed  Google Scholar 

  12. Lin, Z. et al. Association of the status of interstitial cells of Cajal and electrogastrogram parameters, gastric emptying and symptoms in patients with gastroparesis. Neurogastroenterol. Motil. 22, 56–61, e10 (2010).

    CAS  PubMed  Google Scholar 

  13. Farrugia, G. Interstitial cells of Cajal in health and disease. Neurogastroenterol. Motil. 20 (Suppl, 1), 54–63 (2008).

    PubMed  Google Scholar 

  14. Ohno, T., Mochiki, E. & Kuwano, H. The roles of motilin and ghrelin in gastrointestinal motility. Int. J. Pept. 2010, 820794 (2010).

    PubMed  PubMed Central  Google Scholar 

  15. Ariga, H. et al. Endogenous acyl ghrelin is involved in mediating spontaneous phase III-like contractions of the rat stomach. Neurogastroenterol. Motil. 19, 675–680 (2007).

    CAS  PubMed  Google Scholar 

  16. Tack, J. et al. Influence of ghrelin on interdigestive gastrointestinal motility in humans. Gut 55, 327–333 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Gentilcore, D. et al. Effects of fat on gastric emptying of and the glycemic, insulin, and incretin responses to a carbohydrate meal in type 2 diabetes. J. Clin. Endocrinol. Metab. 91, 2062–2067 (2006).

    CAS  PubMed  Google Scholar 

  18. Wang, Y. R., Fisher, R. S. & Parkman, H. P. Gastroparesis-related hospitalizations in the United States: trends, characteristics, and outcomes, 1995–2004. Am. J. Gastroenterol. 103, 313–322 (2008).

    PubMed  Google Scholar 

  19. Bharucha, A. E., Camilleri, M., Forstrom, L. A. & Zinsmeister, A. R. Relationship between clinical features and gastric emptying disturbances in diabetes mellitus. Clin. Endocrinol. (Oxf.) 70, 415–420 (2009).

    Google Scholar 

  20. Horowitz, M. et al. Relationships between oesophageal transit and solid and liquid gastric emptying in diabetes mellitus. Eur. J. Nucl. Med. 18, 229–234 (1991).

    CAS  PubMed  Google Scholar 

  21. Jones, K. L. et al. Relationships between gastric emptying, intragastric meal distribution and blood glucose concentrations in diabetes mellitus. J. Nucl. Med. 36, 2220–2228 (1995).

    CAS  PubMed  Google Scholar 

  22. Jones, K. L. et al. Predictors of delayed gastric emptying in diabetes. Diabetes Care 24, 1264–1269 (2001).

    CAS  PubMed  Google Scholar 

  23. Jung, H. K. et al. The incidence, prevalence, and outcomes of patients with gastroparesis in Olmsted County, Minnesota, from 1996 to 2006. Gastroenterology 136, 1225–1233 (2009).

    PubMed  Google Scholar 

  24. [No authors listed] The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. The Diabetes Control and Complications Trial Research Group. N. Engl. J. Med. 329, 977–986 (1993).

  25. [No authors listed] Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group. Lancet 352, 837–853 (1998).

  26. Rayner, C. K., Samsom, M., Jones, K. L. & Horowitz, M. Relationships of upper gastrointestinal motor and sensory function with glycemic control. Diabetes Care 24, 371–381 (2001).

    CAS  PubMed  Google Scholar 

  27. Samsom, M. et al. Prevalence of delayed gastric emptying in diabetic patients and relationship to dyspeptic symptoms: a prospective study in unselected diabetic patients. Diabetes Care 26, 3116–3122 (2003).

    CAS  PubMed  Google Scholar 

  28. Ariga, H. et al. Does ghrelin explain accelerated gastric emptying in the early stages of diabetes mellitus? Am. J. Physiol. Regul. Integr. Comp. Physiol. 294, R1807–R1812 (2008).

    CAS  PubMed  Google Scholar 

  29. Schwartz, J. G., Green, G. M., Guan, D., McMahan, C. A. & Phillips, W. T. Rapid gastric emptying of a solid pancake meal in type II diabetic patients. Diabetes Care 19, 468–471 (1996).

    CAS  PubMed  Google Scholar 

  30. Choung, R. S. et al. Risk of gastroparesis in subjects with type 1 and 2 diabetes in the general population. Am. J. Gastroenterol. 107, 82–88 (2012).

    PubMed  Google Scholar 

  31. Friedenberg, F. K., Kowalczyk, M. & Parkman, H. P. The influence of race on symptom severity and quality of life in gastroparesis. J. Clin. Gastroenterol. 47, 757–761 (2013).

    PubMed  Google Scholar 

  32. Rayner, C. K. & Horowitz, M. New management approaches for gastroparesis. Nat. Clin. Pract. Gastroenterol. Hepatol. 2, 454–462 (2005).

    PubMed  Google Scholar 

  33. O'Grady, G. et al. Abnormal initiation and conduction of slow-wave activity in gastroparesis, defined by high-resolution electrical mapping. Gastroenterology 143, 589–598 e1–e3 (2012).

    PubMed  Google Scholar 

  34. Vinik, A. I., Maser, R. E., Mitchell, B. D. & Freeman, R. Diabetic autonomic neuropathy. Diabetes Care 26, 1553–1579 (2003).

    PubMed  Google Scholar 

  35. Chang, J. et al. A 25-year longitudinal evaluation of gastric emptying in diabetes. Diabetes Care 35, 2594–2596 (2012).

    PubMed  PubMed Central  Google Scholar 

  36. Chang, J., Rayner, C. K., Jones, K. L. & Horowitz, M. Prognosis of diabetic gastroparesis—a 25-year evaluation. Diabet. Med. 30, e185–e188 (2013).

    CAS  PubMed  Google Scholar 

  37. Kong, M. F., Horowitz, M., Jones, K. L., Wishart, J. M. & Harding, P. E. Natural history of diabetic gastroparesis. Diabetes Care 22, 503–507 (1999).

    CAS  PubMed  Google Scholar 

  38. Hyett, B. et al. Delayed radionucleotide gastric emptying studies predict morbidity in diabetics with symptoms of gastroparesis. Gastroenterology 137, 445–452 (2009).

    PubMed  Google Scholar 

  39. Woerle, H. J. et al. Importance of changes in gastric emptying for postprandial plasma glucose fluxes in healthy humans. Am. J. Physiol. Endocrinol. Metab. 294, E103–E109 (2008).

    CAS  PubMed  Google Scholar 

  40. Woerle, H. J. et al. Pathways for glucose disposal after meal ingestion in humans. Am. J. Physiol. Endocrinol. Metab. 284, E716–E725 (2003).

    CAS  PubMed  Google Scholar 

  41. Horowitz, M., Edelbroek, M. A., Wishart, J. M. & Straathof, J. W. Relationship between oral glucose tolerance and gastric emptying in normal healthy subjects. Diabetologia 36, 857–862 (1993).

    CAS  PubMed  Google Scholar 

  42. Jones, K. L. et al. Gastric emptying in early noninsulin-dependent diabetes mellitus. J. Nucl. Med. 37, 1643–1648 (1996).

    CAS  PubMed  Google Scholar 

  43. McIntyre, N., Holdsworth, C. D. & Turner, D. S. New interpretation of oral glucose tolerance. Lancet 2, 20–21 (1964).

    CAS  PubMed  Google Scholar 

  44. Elrick, H., Stimmler, L., Hlad, C. J., Jr & Arai, Y. Plasma insulin response to oral and intravenous glucose administration. J. Clin. Endocrinol. Metab. 24, 1076–1082 (1964).

    CAS  PubMed  Google Scholar 

  45. Kjems, L. L., Holst, J. J., Volund, A. & Madsbad, S. The influence of GLP-1 on glucose-stimulated insulin secretion: effects on β-cell sensitivity in type 2 and nondiabetic subjects. Diabetes 52, 380–386 (2003).

    CAS  PubMed  Google Scholar 

  46. Meier, J. J. GLP-1 receptor agonists for individualized treatment of type 2 diabetes mellitus. Nat. Rev. Endocrinol. 8, 728–742 (2012).

    CAS  PubMed  Google Scholar 

  47. Ma, J. et al. Effects of variations in duodenal glucose load on glycaemic, insulin, and incretin responses in type 2 diabetes. Diabet. Med. 29, 604–608 (2012).

    CAS  PubMed  Google Scholar 

  48. Pilichiewicz, A. N. et al. Load-dependent effects of duodenal glucose on glycemia, gastrointestinal hormones, antropyloroduodenal motility, and energy intake in healthy men. Am. J. Physiol. Endocrinol. Metab. 293, E743–E753 (2007).

    CAS  PubMed  Google Scholar 

  49. O'Donovan, D. G. et al. Effect of variations in small intestinal glucose delivery on plasma glucose, insulin, and incretin hormones in healthy subjects and type 2 diabetes. J. Clin. Endocrinol. Metab. 89, 3431–3435 (2004).

    CAS  PubMed  Google Scholar 

  50. Trahair, L. G. et al. Effects of variations in duodenal glucose load on blood pressure, heart rate, superior mesenteric artery blood flow and plasma noradrenaline in healthy young and older subjects. Clin. Sci. (Lond.) 122, 271–279 (2012).

    CAS  Google Scholar 

  51. Marathe, C. S. et al. Small intestinal glucose exposure determines the magnitude of the incretin effect in health and type 2 diabetes. Diabetes 63, 2668–2675 (2014).

    CAS  PubMed  Google Scholar 

  52. Thazhath, S. S., Wu, T., Young, R. L., Horowitz, M. & Rayner, C. K. Glucose absorption in small intestinal diseases. Expert Rev. Gastroenterol. Hepatol. 8, 301–312 (2014).

    CAS  PubMed  Google Scholar 

  53. Corvilain, B. et al. Effect of short-term starvation on gastric emptying in humans: relationship to oral glucose tolerance. Am. J. Physiol. 269, G512–G517 (1995).

    CAS  PubMed  Google Scholar 

  54. Horowitz, M., Cunningham, K. M., Wishart, J. M., Jones, K. L. & Read, N. W. The effect of short-term dietary supplementation with glucose on gastric emptying of glucose and fructose and oral glucose tolerance in normal subjects. Diabetologia 39, 481–486 (1996).

    CAS  PubMed  Google Scholar 

  55. O'Donovan, D. et al. Effect of aging on transpyloric flow, gastric emptying, and intragastric distribution in healthy humans—impact on glycemia. Dig. Dis. Sci. 50, 671–676 (2005).

    PubMed  Google Scholar 

  56. Schwartz, J. G., McMahan, C. A., Green, G. M. & Phillips, W. T. Gastric emptying in Mexican Americans compared to non-Hispanic whites. Dig. Dis. Sci. 40, 624–630 (1995).

    CAS  PubMed  Google Scholar 

  57. Stevens, J. E. et al. Measurement of gastric emptying of a high-nutrient liquid by 3D ultrasonography in diabetic gastroparesis. Neurogastroenterol. Motil. 23, 220–e114 (2011).

    CAS  PubMed  Google Scholar 

  58. Mourot, J. et al. Relationship between the rate of gastric emptying and glucose and insulin responses to starchy foods in young healthy adults. Am. J. Clin. Nutr. 48, 1035–1040 (1988).

    CAS  PubMed  Google Scholar 

  59. Benini, L. et al. Gastric emptying of a solid meal is accelerated by the removal of dietary fibre naturally present in food. Gut 36, 825–830 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Brener, W., Hendrix, T. R. & McHugh, P. R. Regulation of the gastric emptying of glucose. Gastroenterology 85, 76–82 (1983).

    CAS  PubMed  Google Scholar 

  61. Collins, P. J., Horowitz, M., Cook, D. J., Harding, P. E. & Shearman, D. J. Gastric emptying in normal subjects—a reproducible technique using a single scintillation camera and computer system. Gut 24, 1117–1125 (1983).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Ishii, M. et al. Altered postprandial insulin requirement in IDDM patients with gastroparesis. Diabetes Care 17, 901–903 (1994).

    CAS  PubMed  Google Scholar 

  63. Gonlachanvit, S. et al. Effect of altering gastric emptying on postprandial plasma glucose concentrations following a physiologic meal in type-II diabetic patients. Dig. Dis. Sci. 48, 488–497 (2003).

    CAS  PubMed  Google Scholar 

  64. Vanis, L. et al. Effects of variations in intragastric volume on blood pressure and splanchnic blood flow during intraduodenal glucose infusion in healthy older subjects. Am. J. Physiol. Regul. Integr. Comp. Physiol. 302, R391–R399 (2012).

    CAS  PubMed  Google Scholar 

  65. Chaikomin, R. et al. Initially more rapid small intestinal glucose delivery increases plasma insulin, GIP, and GLP-1 but does not improve overall glycemia in healthy subjects. Am. J. Physiol. Endocrinol. Metab. 289, E504–E507 (2005).

    CAS  PubMed  Google Scholar 

  66. Unwin, N., Shaw, J., Zimmet, P. & Alberti, K. G. Impaired glucose tolerance and impaired fasting glycaemia: the current status on definition and intervention. Diabet. Med. 19, 708–723 (2002).

    CAS  PubMed  Google Scholar 

  67. Abdul-Ghani, M. A., Williams, K., DeFronzo, R. A. & Stern, M. What is the best predictor of future type 2 diabetes? Diabetes Care 30, 1544–1548 (2007).

    PubMed  Google Scholar 

  68. Phillips, W. T. Gastric emptying in ethnic populations: possible relationship to development of diabetes and metabolic syndrome. Ethn. Dis. 16, 682–692 (2006).

    PubMed  Google Scholar 

  69. Duchman, S. M. et al. Upper limit for intestinal absorption of a dilute glucose solution in men at rest. Med. Sci. Sports Exerc. 29, 482–488 (1997).

    CAS  PubMed  Google Scholar 

  70. Schirra, J. et al. Gastric emptying and release of incretin hormones after glucose ingestion in humans. J. Clin. Invest. 97, 92–103 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Stevens, J. E. et al. Acute effects of C-peptide on gastric emptying in longstanding type 1 diabetes. Clin. Auton. Res. 16, 55–57 (2006).

    PubMed  Google Scholar 

  72. Fraser, R. J. et al. Hyperglycaemia slows gastric emptying in type 1 (insulin-dependent) diabetes mellitus. Diabetologia 33, 675–680 (1990).

    CAS  PubMed  Google Scholar 

  73. Russo, A. et al. Insulin-induced hypoglycemia accelerates gastric emptying of solids and liquids in long-standing type 1 diabetes. J. Clin. Endocrinol. Metab. 90, 4489–4495 (2005).

    CAS  PubMed  Google Scholar 

  74. Schvarcz, E. et al. Physiological hyperglycemia slows gastric emptying in normal subjects and patients with insulin-dependent diabetes mellitus. Gastroenterology 113, 60–66 (1997).

    CAS  PubMed  Google Scholar 

  75. Kumar, A., Attaluri, A., Hashmi, S., Schulze, K. S. & Rao, S. S. Visceral hypersensitivity and impaired accommodation in refractory diabetic gastroparesis. Neurogastroenterol. Motil. 20, 635–642 (2008).

    CAS  PubMed  Google Scholar 

  76. Karamanolis, G., Caenepeel, P., Arts, J. & Tack, J. Determinants of symptom pattern in idiopathic severely delayed gastric emptying: gastric emptying rate or proximal stomach dysfunction? Gut 56, 29–36 (2007).

    CAS  PubMed  Google Scholar 

  77. Sharma, D., Morrison, G., Joseph, F., Purewal, T. S. & Weston, P. J. The role of continuous subcutaneous insulin infusion therapy in patients with diabetic gastroparesis. Diabetologia 54, 2768–2770 (2011).

    CAS  PubMed  Google Scholar 

  78. Kuo, P. et al. The nitric oxide synthase inhibitor, Ng-nitro-L-arginine-methyl-ester, attenuates the delay in gastric emptying induced by hyperglycaemia in healthy humans. Neurogastroenterol. Motil. 21, 1175-e103 (2009).

    PubMed  Google Scholar 

  79. Vinik, A., Nakave, A. & Chuecos Mdel, P. A break in the brake mechanism in diabetes: a cause of postprandial hyperglycemia. Diabetes Care 31, 2410–2413 (2008).

    PubMed  PubMed Central  Google Scholar 

  80. Nathan, D. M. et al. Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes. N. Engl. J. Med. 353, 2643–2653 (2005).

    PubMed  Google Scholar 

  81. Gaber, A. O. et al. Changes in gastric emptying in recipients of successful combined pancreas-kidney transplants. Dig. Dis. 9, 437–443 (1991).

    CAS  PubMed  Google Scholar 

  82. Laway, B. A., Malik, T. S., Khan, S. H. & Rather, T. A. Prevalence of abnormal gastric emptying in asymptomatic women with newly detected diabetes and its reversibility after glycemic control-a prospective case control study. J. Diabetes Complications 27, 78–81 (2013).

    PubMed  Google Scholar 

  83. Parkman, H. P. et al. Gastroparesis and functional dyspepsia: excerpts from the AGA/ANMS meeting. Neurogastroenterol. Motil. 22, 113–133 (2010).

    CAS  PubMed  Google Scholar 

  84. Parkman, H. P. et al. Clinical features of idiopathic gastroparesis vary with sex, body mass, symptom onset, delay in gastric emptying, and gastroparesis severity. Gastroenterology 140, 101–115 (2011).

    PubMed  Google Scholar 

  85. Mashimo, H., Kjellin, A. & Goyal, R. K. Gastric stasis in neuronal nitric oxide synthase-deficient knockout mice. Gastroenterology 119, 766–773 (2000).

    CAS  PubMed  Google Scholar 

  86. Watkins, C. C. et al. Insulin restores neuronal nitric oxide synthase expression and function that is lost in diabetic gastropathy. J. Clin. Invest. 106, 373–384 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Takahashi, T., Nakamura, K., Itoh, H., Sima, A. A. & Owyang, C. Impaired expression of nitric oxide synthase in the gastric myenteric plexus of spontaneously diabetic rats. Gastroenterology 113, 1535–1544 (1997).

    CAS  PubMed  Google Scholar 

  88. Cellek, S., Foxwell, N. A. & Moncada, S. Two phases of nitrergic neuropathy in streptozotocin-induced diabetic rats. Diabetes 52, 2353–2362 (2003).

    CAS  PubMed  Google Scholar 

  89. Ordog, T., Takayama, I., Cheung, W. K., Ward, S. M. & Sanders, K. M. Remodeling of networks of interstitial cells of Cajal in a murine model of diabetic gastroparesis. Diabetes 49, 1731–1739 (2000).

    CAS  PubMed  Google Scholar 

  90. Tashima, K., Nishijima, M., Fujita, A., Kubomi, M. & Takeuchi, K. Acid secretory changes in streptozotocin-diabetic rats: different responses to various secretagogues. Dig. Dis. Sci. 45, 1352–1358 (2000).

    CAS  PubMed  Google Scholar 

  91. Li, S. & Chen, J. D. Decreased L-type calcium current in antral smooth muscle cells of STZ-induced diabetic rats. Neurogastroenterol. Motil. 26, 971–979 (2014).

    CAS  PubMed  Google Scholar 

  92. Choi, K. M. et al. CD206-positive M2 macrophages that express heme oxygenase-1 protect against diabetic gastroparesis in mice. Gastroenterology 138, 2399–2409.e1 (2010).

    CAS  PubMed  Google Scholar 

  93. Kashyap, P. C. et al. Carbon monoxide reverses diabetic gastroparesis in NOD mice. Am. J. Physiol. Gastrointest. Liver Physiol. 298, G1013–G1019 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  94. Grover, M. et al. Cellular changes in diabetic and idiopathic gastroparesis. Gastroenterology 140, 1575–1585.e8 (2011).

    CAS  PubMed  Google Scholar 

  95. Forster, J. et al. Absence of the interstitial cells of Cajal in patients with gastroparesis and correlation with clinical findings. J. Gastrointest. Surg. 9, 102–108 (2005).

    PubMed  Google Scholar 

  96. He, C. L. et al. Loss of interstitial cells of cajal and inhibitory innervation in insulin-dependent diabetes. Gastroenterology 121, 427–434 (2001).

    CAS  PubMed  Google Scholar 

  97. Iwasaki, H. et al. A deficiency of gastric interstitial cells of Cajal accompanied by decreased expression of neuronal nitric oxide synthase and substance P in patients with type 2 diabetes mellitus. J. Gastroenterol. 41, 1076–1087 (2006).

    CAS  PubMed  Google Scholar 

  98. Miller, S. M. et al. Distribution of interstitial cells of Cajal and nitrergic neurons in normal and diabetic human appendix. Neurogastroenterol. Motil. 20, 349–357 (2008).

    CAS  PubMed  Google Scholar 

  99. Pasricha, P. J. et al. Changes in the gastric enteric nervous system and muscle: a case report on two patients with diabetic gastroparesis. BMC Gastroenterol. 8, 21 (2008).

    PubMed  PubMed Central  Google Scholar 

  100. Sokol, H., Lavergne-Slove, A., Mikol, J., Sabate, J. M. & Coffin, B. Severe isolated myopathic gastroparesis: a case report with pathological findings. Gut 55, 1662 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  101. Grover, M. et al. Clinical-histological associations in gastroparesis: results from the Gastroparesis Clinical Research Consortium. Neurogastroenterol. Motil. 24, 531–539 (2012).

    CAS  PubMed  Google Scholar 

  102. Faussone-Pellegrini, M. S. et al. Ultrastructural differences between diabetic and idiopathic gastroparesis. J. Cell. Mol. Med. 16, 1573–1581 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  103. Emdin, M. et al. Hyperinsulinemia and autonomic nervous system dysfunction in obesity: effects of weight loss. Circulation 103, 513–519 (2001).

    CAS  PubMed  Google Scholar 

  104. Guy, R. J. et al. Diabetic gastroparesis from autonomic neuropathy: surgical considerations and changes in vagus nerve morphology. J. Neurol. Neurosurg. Psychiatry 47, 686–691 (1984).

    CAS  PubMed  PubMed Central  Google Scholar 

  105. Feldman, M., Corbett, D. B., Ramsey, E. J., Walsh, J. H. & Richardson, C. T. Abnormal gastric function in longstanding, insulin-dependent diabetic patients. Gastroenterology 77, 12–17 (1979).

    CAS  PubMed  Google Scholar 

  106. Kristensson, K., Nordborg, C., Olsson, Y. & Sourander, P. Changes in the vagus nerve in diabetes mellitus. Acta Pathol. Microbiol. Scand. A 79, 684–685 (1971).

    CAS  PubMed  Google Scholar 

  107. Merio, R. et al. Slow gastric emptying in type I diabetes: relation to autonomic and peripheral neuropathy, blood glucose, and glycemic control. Diabetes Care 20, 419–423 (1997).

    CAS  PubMed  Google Scholar 

  108. Hasler, W. L. Gastroparesis: pathogenesis, diagnosis and management. Nat. Rev. Gastroenterol. Hepatol. 8, 438–453 (2011).

    CAS  PubMed  Google Scholar 

  109. Owyang, C. Phenotypic switching in diabetic gastroparesis: mechanism directs therapy. Gastroenterology 141, 1134–1137 (2011).

    PubMed  Google Scholar 

  110. Revicki, D. A. et al. Development and validation of a patient-assessed gastroparesis symptom severity measure: the Gastroparesis Cardinal Symptom Index. Aliment. Pharmacol. Ther. 18, 141–150 (2003).

    CAS  PubMed  Google Scholar 

  111. Revicki, D. A. et al. Development and content validity of a gastroparesis cardinal symptom index daily diary. Aliment. Pharmacol. Ther. 30, 670–680 (2009).

    CAS  PubMed  Google Scholar 

  112. Reddymasu, S. C. & McCallum, R. W. Small intestinal bacterial overgrowth in gastroparesis: are there any predictors? J. Clin. Gastroenterol. 44, e8–e13 (2010).

    PubMed  Google Scholar 

  113. George, N. S., Sankineni, A. & Parkman, H. P. Small intestinal bacterial overgrowth in gastroparesis. Dig. Dis. Sci. 59, 645–652 (2014).

    PubMed  Google Scholar 

  114. Lysy, J., Israeli, E., Strauss-Liviatan, N. & Goldin, E. Relationships between hypoglycaemia and gastric emptying abnormalities in insulin-treated diabetic patients. Neurogastroenterol. Motil. 18, 433–440 (2006).

    CAS  PubMed  Google Scholar 

  115. Horowitz, M., Jones, K. L., Rayner, C. K. & Read, N. W. 'Gastric' hypoglycaemia—an important concept in diabetes management. Neurogastroenterol. Motil. 18, 405–407 (2006).

    CAS  PubMed  Google Scholar 

  116. Hasler, W. L. Dumping Syndrome. Curr. Treat. Options Gastroenterol. 5, 139–145 (2002).

    PubMed  Google Scholar 

  117. Shin, A. S. & Camilleri, M. Diagnostic assessment of diabetic gastroparesis. Diabetes 62, 2667–2673 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  118. Bursztein-De Myttenaere, S. et al. Gastric emptying in humans: influence of different regimens of parenteral nutrition. Am. J. Clin. Nutr. 60, 244–248 (1994).

    CAS  PubMed  Google Scholar 

  119. Abell, T. L. et al. Consensus recommendations for gastric emptying scintigraphy: a joint report of the American Neurogastroenterology and Motility Society and the Society of Nuclear Medicine. J. Nucl. Med. Technol. 36, 44–54 (2008).

    PubMed  Google Scholar 

  120. Sachdeva, P. et al. Gastric emptying of solids and liquids for evaluation for gastroparesis. Dig. Dis. Sci. 56, 1138–1146 (2011).

    PubMed  Google Scholar 

  121. Ziegler, D. et al. 13C octanoic acid breath test for non-invasive assessment of gastric emptying in diabetic patients: validation and relationship to gastric symptoms and cardiovascular autonomic function. Diabetologia 39, 823–830 (1996).

    CAS  PubMed  Google Scholar 

  122. Viramontes, B. E. et al. Validation of a stable isotope gastric emptying test for normal, accelerated or delayed gastric emptying. Neurogastroenterol. Motil. 13, 567–574 (2001).

    CAS  PubMed  Google Scholar 

  123. Rao, S. S. et al. Evaluation of gastrointestinal transit in clinical practice: position paper of the American and European Neurogastroenterology and Motility Societies. Neurogastroenterol. Motil. 23, 8–23 (2011).

    CAS  PubMed  Google Scholar 

  124. Stein, E. et al. Wireless motility capsule versus other diagnostic technologies for evaluating gastroparesis and constipation: a comparative effectiveness review. Agency for Healthcare Research and Quality[online] (2013).

  125. Kuo, B. et al. Comparison of gastric emptying of a nondigestible capsule to a radio-labelled meal in healthy and gastroparetic subjects. Aliment. Pharmacol. Ther. 27, 186–196 (2008).

    CAS  PubMed  Google Scholar 

  126. Kunz, P. et al. Gastric emptying and motility: assessment with MR imaging—preliminary observations. Radiology 207, 33–40 (1998).

    CAS  PubMed  Google Scholar 

  127. de Zwart, I. M. & de Roos, A. MRI for the evaluation of gastric physiology. Eur. Radiol. 20, 2609–2616 (2010).

    PubMed  PubMed Central  Google Scholar 

  128. Clements, J. A., Heading, R. C., Nimmo, W. S. & Prescott, L. F. Kinetics of acetaminophen absorption and gastric emptying in man. Clin. Pharmacol. Ther. 24, 420–431 (1978).

    CAS  PubMed  Google Scholar 

  129. McCallum, R. W. et al. A multicenter placebo-controlled clinical trial of oral metoclopramide in diabetic gastroparesis. Diabetes Care 6, 463–467 (1983).

    CAS  PubMed  Google Scholar 

  130. Ricci, D. A., Saltzman, M. B., Meyer, C., Callachan, C. & McCallum, R. W. Effect of metoclopramide in diabetic gastroparesis. J. Clin. Gastroenterol. 7, 25–32 (1985).

    CAS  PubMed  Google Scholar 

  131. Wu, T. et al. Effects of different sweet preloads on incretin hormone secretion, gastric emptying, and postprandial glycemia in healthy humans. Am. J. Clin. Nutr. 95, 78–83 (2012).

    CAS  PubMed  Google Scholar 

  132. Ma, J. et al. Effects of a protein preload on gastric emptying, glycemia, and gut hormones after a carbohydrate meal in diet-controlled type 2 diabetes. Diabetes Care 32, 1600–1602 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  133. Ma, J. et al. Effect of the artificial sweetener, sucralose, on small intestinal glucose absorption in healthy human subjects. Br. J. Nutr. 104, 803–806 (2010).

    CAS  PubMed  Google Scholar 

  134. Ma, J. et al. Effect of the artificial sweetener, sucralose, on gastric emptying and incretin hormone release in healthy subjects. Am. J. Physiol. Gastrointest. Liver Physiol. 296, G735–G739 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  135. Meier, J. J., Kemmeries, G., Holst, J. J. & Nauck, M. A. Erythromycin antagonizes the deceleration of gastric emptying by glucagon-like peptide 1 and unmasks its insulinotropic effect in healthy subjects. Diabetes 54, 2212–2218 (2005).

    CAS  PubMed  Google Scholar 

  136. Kolterman, O. G. et al. Synthetic exendin-4 (exenatide) significantly reduces postprandial and fasting plasma glucose in subjects with type 2 diabetes. J. Clin. Endocrinol. Metab. 88, 3082–3089 (2003).

    CAS  PubMed  Google Scholar 

  137. Horowitz, M., Rayner, C. K. & Jones, K. L. Mechanisms and clinical efficacy of lixisenatide for the management of type 2 diabetes. Adv. Ther. 30, 81–101 (2013).

    CAS  PubMed  Google Scholar 

  138. Linnebjerg, H. et al. Effect of exenatide on gastric emptying and relationship to postprandial glycemia in type 2 diabetes. Regul. Pept. 151, 123–129 (2008).

    CAS  PubMed  Google Scholar 

  139. Deane, A. M. et al. Effects of exogenous glucagon-like peptide-1 on gastric emptying and glucose absorption in the critically ill: relationship to glycemia. Crit. Care Med. 38, 1261–1269 (2010).

    CAS  PubMed  Google Scholar 

  140. van Can., J. et al. Effects of the once-daily GLP-1 analog liraglutide on gastric emptying, glycemic parameters, appetite and energy metabolism in obese, non-diabetic adults. Int. J. Obes. (Lond.) 38, 784–793 (2014).

    CAS  Google Scholar 

  141. Nauck, M. A., Kemmeries, G., Holst, J. J. & Meier, J. J. Rapid tachyphylaxis of the glucagon-like peptide 1-induced deceleration of gastric emptying in humans. Diabetes 60, 1561–1565 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  142. Umapathysivam, M. M. et al. Comparative effects of prolonged and intermittent stimulation of the glucagon-like Peptide 1 receptor on gastric emptying and glycemia. Diabetes 63, 785–790 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  143. Plummer, M. P. et al. Glucagon-like Peptide 1 attenuates the acceleration of gastric emptying induced by hypoglycemia in healthy subjects. Diabetes Care 37, 1509–1515 (2014).

    CAS  PubMed  Google Scholar 

  144. Nonaka, T. et al. Early effect of single-dose sitagliptin administration on gastric emptying: crossover study using the 13C breath test. J. Neurogastroenterol. Motil. 19, 227–232 (2013).

    PubMed  PubMed Central  Google Scholar 

  145. Stevens, J. E. et al. The effects of sitagliptin on gastric emptying in healthy humans—a randomised, controlled study. Aliment. Pharmacol. Ther. 36, 379–390 (2012).

    CAS  PubMed  Google Scholar 

  146. Vella, A. et al. Effects of dipeptidyl peptidase-4 inhibition on gastrointestinal function, meal appearance, and glucose metabolism in type 2 diabetes. Diabetes 56, 1475–1480 (2007).

    CAS  PubMed  Google Scholar 

  147. Aulinger, B. A. et al. Defining the role of GLP-1 in the enteroinsulinar axis in type 2 diabetes using DPP-4 inhibition and GLP-1 receptor blockade. Diabetes 63, 1079–1092 (2014).

    CAS  PubMed  Google Scholar 

  148. Wu, T. et al. Effects of sitagliptin on glycemia, incretin hormones, and antropyloroduodenal motility in response to intraduodenal glucose infusion in healthy lean and obese humans, and patients with type 2 diabetes treated with or without metformin. Diabetes 63, 2776–2787 (2014).

    CAS  PubMed  Google Scholar 

  149. Samsom, M. et al. Pramlintide, an amylin analog, selectively delays gastric emptying: potential role of vagal inhibition. Am. J. Physiol. Gastrointest. Liver Physiol. 278, G946–G951 (2000).

    CAS  PubMed  Google Scholar 

  150. US Department of Health and Human Services US Food and Drug Administration [online] (2005).

  151. Ryan, G. J., Jobe, L. J. & Martin, R. Pramlintide in the treatment of type 1 and type 2 diabetes mellitus. Clin. Ther. 27, 1500–1512 (2005).

    CAS  PubMed  Google Scholar 

  152. Wu, T. et al. Effects of a D-xylose preload with or without sitagliptin on gastric emptying, glucagon-like peptide-1, and postprandial glycemia in type 2 diabetes. Diabetes Care 36, 1913–1918 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  153. Nair, N. S. et al. Reproducibility of energy intake, gastric emptying, blood glucose, plasma insulin and cholecystokinin responses in healthy young males. Br. J. Nutr. 101, 1094–1102 (2009).

    CAS  PubMed  Google Scholar 

  154. Hanefeld, M. Cardiovascular benefits and safety profile of acarbose therapy in prediabetes and established type 2 diabetes. Cardiovasc. Diabetol. 6, 20 (2007).

    PubMed  PubMed Central  Google Scholar 

  155. Cukier, K. et al. Effect of small intestinal glucose load on plasma ghrelin in healthy men. Am. J. Physiol. Regul. Integr. Comp. Physiol. 295, R459–R462 (2008).

    CAS  PubMed  Google Scholar 

  156. Parkman, H. P. et al. Dietary intake and nutritional deficiencies in patients with diabetic or idiopathic gastroparesis. Gastroenterology 141, 486–498 (2011).

    CAS  PubMed  Google Scholar 

  157. Patrick, A. & Epstein, O. Review article: gastroparesis. Aliment. Pharmacol. Ther. 27, 724–740 (2008).

    CAS  PubMed  Google Scholar 

  158. Dishy, V. et al. The effect of sildenafil on gastric emptying in patients with end-stage renal failure and symptoms of gastroparesis. Clin. Pharmacol. Ther. 76, 281–286 (2004).

    CAS  PubMed  Google Scholar 

  159. Abell, T. L. et al. Treatment of gastroparesis: a multidisciplinary clinical review. Neurogastroenterol. Motil. 18, 263–283 (2006).

    CAS  PubMed  Google Scholar 

  160. Camilleri, M. Clinical practice. Diabetic gastroparesis. N. Engl. J. Med. 356, 820–829 (2007).

    CAS  PubMed  Google Scholar 

  161. Institute of Medicine. Dietary reference intakes: energy, carbohydrate, fiber, fat, fatty acids, cholesterol, protein, and amino acids (National Academy Press, 2002).

  162. Olausson, E. A. et al. A small particle size diet reduces upper gastrointestinal symptoms in patients with diabetic gastroparesis: a randomized controlled trial. Am. J. Gastroenterol. 109, 375–385 (2014).

    CAS  PubMed  Google Scholar 

  163. Perkel, M. S., Moore, C., Hersh, T. & Davidson, E. D. Metoclopramide therapy in patients with delayed gastric emptying: a randomized, double-blind study. Dig. Dis. Sci. 24, 662–666 (1979).

    CAS  PubMed  Google Scholar 

  164. Snape, W. J., Jr. et al. Metoclopramide to treat gastroparesis due to diabetes mellitus: a double-blind, controlled trial. Ann. Intern. Med. 96, 444–446 (1982).

    PubMed  Google Scholar 

  165. Sugumar, A., Singh, A. & Pasricha, P. J. A systematic review of the efficacy of domperidone for the treatment of diabetic gastroparesis. Clin. Gastroenterol. Hepatol. 6, 726–733 (2008).

    PubMed  Google Scholar 

  166. Sturm, A., Holtmann, G., Goebell, H. & Gerken, G. Prokinetics in patients with gastroparesis: a systematic analysis. Digestion 60, 422–427 (1999).

    CAS  PubMed  Google Scholar 

  167. Lartigue, S. et al. Inter- and intrasubject variability of solid and liquid gastric emptying parameters. A scintigraphic study in healthy subjects and diabetic patients. Dig. Dis. Sci. 39, 109–115 (1994).

    CAS  PubMed  Google Scholar 

  168. Janssen, P. et al. The relation between symptom improvement and gastric emptying in the treatment of diabetic and idiopathic gastroparesis. Am. J. Gastroenterol. 108, 1382–1391 (2013).

    CAS  PubMed  Google Scholar 

  169. Parkman, H. P., Carlson, M. R. & Gonyer, D. Metoclopramide nasal spray is effective in symptoms of gastroparesis in diabetics compared to conventional oral tablet. Neurogastroenterol. Motil. 26, 521–528 (2014).

    CAS  PubMed  Google Scholar 

  170. Simmons, K. & Parkman, H. P. Granisetron transdermal system improves refractory nausea and vomiting in gastroparesis. Dig. Dis. Sci. 59, 1231–1234 (2014).

    PubMed  Google Scholar 

  171. Sawhney, M. S., Prakash, C., Lustman, P. J. & Clouse, R. E. Tricyclic antidepressants for chronic vomiting in diabetic patients. Dig. Dis. Sci. 52, 418–424 (2007).

    CAS  PubMed  Google Scholar 

  172. Parkman, H. P. et al. Effect of nortriptyline on symptoms of idiopathic gastroparesis: the NORIG randomized clinical trial. JAMA 310, 2640–2649 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  173. Jones, K. L. et al. Hyperglycemia attenuates the gastrokinetic effect of erythromycin and affects the perception of postprandial hunger in normal subjects. Diabetes Care 22, 339–344 (1999).

    CAS  PubMed  Google Scholar 

  174. Horowitz, M., Jones, K. L., Harding, P. E. & Wishart, J. M. Relationship between the effects of cisapride on gastric emptying and plasma glucose concentrations in diabetic gastroparesis. Digestion 65, 41–46 (2002).

    CAS  PubMed  Google Scholar 

  175. Pasricha, P. J., Pehlivanov, N., Sugumar, A. & Jankovic, J. Drug Insight: from disturbed motility to disordered movement--a review of the clinical benefits and medicolegal risks of metoclopramide. Nat. Clin. Pract. Gastroenterol. Hepatol. 3, 138–148 (2006).

    CAS  PubMed  Google Scholar 

  176. Hasler, W. L. Emerging drugs for the treatment of gastroparesis. Expert Opin. Emerg. Drugs 19, 261–279 (2014).

    CAS  PubMed  Google Scholar 

  177. Heddle, R., Fone, D., Dent, J. & Horowitz, M. Stimulation of pyloric motility by intraduodenal dextrose in normal subjects. Gut 29, 1349–1357 (1988).

    CAS  PubMed  PubMed Central  Google Scholar 

  178. Ezzeddine, D., Jit, R., Katz, N., Gopalswamy, N. & Bhutani, M. S. Pyloric injection of botulinum toxin for treatment of diabetic gastroparesis. Gastrointest. Endosc. 55, 920–923 (2002).

    PubMed  Google Scholar 

  179. Lacy, B. E., Crowell, M. D., Schettler-Duncan, A., Mathis, C. & Pasricha, P. J. The treatment of diabetic gastroparesis with botulinum toxin injection of the pylorus. Diabetes Care 27, 2341–2347 (2004).

    CAS  PubMed  Google Scholar 

  180. Lacy, B. E., Zayat, E. N., Crowell, M. D. & Schuster, M. M. Botulinum toxin for the treatment of gastroparesis: a preliminary report. Am. J. Gastroenterol. 97, 1548–1552 (2002).

    CAS  PubMed  Google Scholar 

  181. Arts, J. et al. Influence of intrapyloric botulinum toxin injection on gastric emptying and meal-related symptoms in gastroparesis patients. Aliment. Pharmacol. Ther. 24, 661–667 (2006).

    CAS  PubMed  Google Scholar 

  182. Miller, L. S. et al. Treatment of idiopathic gastroparesis with injection of botulinum toxin into the pyloric sphincter muscle. Am. J. Gastroenterol. 97, 1653–1660 (2002).

    CAS  PubMed  Google Scholar 

  183. Ben-Youssef, R. et al. Intrapyloric injection of botulinum toxin a for the treatment of persistent gastroparesis following successful pancreas transplantation. Am. J. Transplant. 6, 214–218 (2006).

    CAS  PubMed  Google Scholar 

  184. Bromer, M. Q. et al. Endoscopic pyloric injection of botulinum toxin A for the treatment of refractory gastroparesis. Gastrointest. Endosc. 61, 833–839 (2005).

    PubMed  Google Scholar 

  185. Kent, M. S. et al. A pilot study of botulinum toxin injection for the treatment of delayed gastric emptying following esophagectomy. Surg. Endosc. 21, 754–757 (2007).

    CAS  PubMed  Google Scholar 

  186. Wiesel, P. H. et al. Botulinum toxin for refractory postoperative pyloric spasm. Endoscopy 29, 132 (1997).

    CAS  PubMed  Google Scholar 

  187. Arts, J. et al. Clinical trial: a randomized-controlled crossover study of intrapyloric injection of botulinum toxin in gastroparesis. Aliment. Pharmacol. Ther. 26, 1251–1258 (2007).

    CAS  PubMed  Google Scholar 

  188. Friedenberg, F. K., Palit, A., Parkman, H. P., Hanlon, A. & Nelson, D. B. Botulinum toxin A for the treatment of delayed gastric emptying. Am. J. Gastroenterol. 103, 416–423 (2008).

    CAS  PubMed  Google Scholar 

  189. McCallum, R. W. et al. Gastric electrical stimulation improves outcomes of patients with gastroparesis for up to 10 years. Clin. Gastroenterol. Hepatol. 9, 314–319 (2011).

    PubMed  Google Scholar 

  190. Lin, Z., Sarosiek, I., Forster, J. & McCallum, R. W. Symptom responses, long-term outcomes and adverse events beyond 3 years of high-frequency gastric electrical stimulation for gastroparesis. Neurogastroenterol. Motil. 18, 18–27 (2006).

    CAS  PubMed  Google Scholar 

  191. Anand, C. et al. Gastric electrical stimulation is safe and effective: a long-term study in patients with drug-refractory gastroparesis in three regional centers. Digestion 75, 83–89 (2007).

    PubMed  Google Scholar 

  192. Abell, T. et al. Gastric electrical stimulation for medically refractory gastroparesis. Gastroenterology 125, 421–428 (2003).

    PubMed  Google Scholar 

  193. Jones, M. P. Gastric electrical stimulation for refractory gastroparesis. Gastroenterology 126, 629–630 (2004).

    PubMed  Google Scholar 

  194. Ayinala, S. et al. Temporary gastric electrical stimulation with orally or PEG-placed electrodes in patients with drug refractory gastroparesis. Gastrointest. Endosc. 61, 455–461 (2005).

    PubMed  Google Scholar 

  195. Toro, J. P. et al. Efficacy of laparoscopic pyloroplasty for the treatment of gastroparesis. J. Am. Coll. Surg. 218, 652–660 (2014).

    PubMed  Google Scholar 

  196. Kashyap, P. & Farrugia, G. Diabetic gastroparesis: what we have learned and had to unlearn in the past 5 years. Gut 59, 1716–1726 (2010).

    CAS  PubMed  Google Scholar 

  197. Ray, W. A. et al. Oral erythromycin and the risk of sudden death from cardiac causes. N. Engl. J. Med. 351, 1089–1096 (2004).

    CAS  PubMed  Google Scholar 

  198. Javid, F. A. et al. Anti-emetic and emetic effects of erythromycin in Suncus murinus: role of vagal nerve activation, gastric motility stimulation and motilin receptors. Eur. J. Pharmacol. 699, 48–54 (2013).

    CAS  PubMed  Google Scholar 

  199. Straus, S. M. et al. Non-cardiac QTc-prolonging drugs and the risk of sudden cardiac death. Eur. Heart J. 26, 2007–2012 (2005).

    PubMed  Google Scholar 

  200. Larson, J. M., Tavakkoli, A., Drane, W. E., Toskes, P. P. & Moshiree, B. Advantages of azithromycin over erythromycin in improving the gastric emptying half-time in adult patients with gastroparesis. J. Neurogastroenterol. Motil. 16, 407–413 (2010).

    PubMed  PubMed Central  Google Scholar 

  201. McCallum, R. W., Cynshi, O. & Investigative Team. Clinical trial: effect of mitemcinal (a motilin agonist) on gastric emptying in patients with gastroparesis - a randomized, multicentre, placebo-controlled study. Aliment. Pharmacol. Ther. 26, 1121–1130 (2007).

    CAS  PubMed  Google Scholar 

  202. Camilleri, M. Pharmacological agents currently in clinical trials for disorders in neurogastroenterology. J. Clin. Invest. 123, 4111–4120 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  203. Ejskjaer, N. et al. Ghrelin receptor agonist (TZP-101) accelerates gastric emptying in adults with diabetes and symptomatic gastroparesis. Aliment. Pharmacol. Ther. 29, 1179–1187 (2009).

    CAS  PubMed  Google Scholar 

  204. Ejskjaer, N. et al. Safety and efficacy of ghrelin agonist TZP-101 in relieving symptoms in patients with diabetic gastroparesis: a randomized, placebo-controlled study. Neurogastroenterol. Motil. 22, 1069-e281 (2010).

    PubMed  Google Scholar 

  205. Shin, A. et al. Randomized controlled phase Ib study of ghrelin agonist, RM-131, in type 2 diabetic women with delayed gastric emptying: pharmacokinetics and pharmacodynamics. Diabetes Care 36, 41–48 (2013).

    CAS  PubMed  Google Scholar 

  206. Shin, A. et al. The ghrelin agonist RM-131 accelerates gastric emptying of solids and reduces symptoms in patients with type 1 diabetes mellitus. Clin. Gastroenterol. Hepatol. 11, 1453–1459 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  207. Kusunoki, H. et al. Therapeutic efficacy of acotiamide in patients with functional dyspepsia based on enhanced postprandial gastric accommodation and emptying: randomized controlled study evaluation by real-time ultrasonography. Neurogastroenterol. Motil. 24, 540–545, e250–e251 (2012).

    CAS  PubMed  Google Scholar 

  208. Tack, J., Janssen, P., Masaoka, T., Farre, R. & Van Oudenhove, L. Efficacy of buspirone, a fundus-relaxing drug, in patients with functional dyspepsia. Clin. Gastroenterol. Hepatol. 10, 1239–1245 (2012).

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Contributions

L.K.P. researched data for the article. L.K.P and M.H. wrote the article. All authors contributed equally to substantial discussions of the content and reviewed and/or edited the manuscript before submission.

Corresponding author

Correspondence to Michael Horowitz.

Ethics declarations

Competing interests

K.L.J. has received research funding from Merck Sharp & Dohme and Sanofi. C.K.R. has received funding from AstraZeneca, Merck Sharp & Dohme and Novartis. M.H. has participated on advisory boards and/or symposia for AstraZeneca, Boehringer Ingelheim, Eli Lilly, Merck Sharp & Dohme, Novartis, Novo Nordisk and Sanofi and has received honoraria for this activity. L.K.P. and A.M.D. declare no competing interests.

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Phillips, L., Deane, A., Jones, K. et al. Gastric emptying and glycaemia in health and diabetes mellitus. Nat Rev Endocrinol 11, 112–128 (2015). https://doi.org/10.1038/nrendo.2014.202

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrendo.2014.202

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing