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Rocha GR, de Melo FF. Glucagon-like peptide-1 and impaired counterregulatory responses to hypoglycemia in type 1 diabetes. World J Diabetes 2025; 16:99928. [PMID: 39959274 PMCID: PMC11718485 DOI: 10.4239/wjd.v16.i2.99928] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/04/2024] [Revised: 10/25/2024] [Accepted: 11/04/2024] [Indexed: 12/30/2024] Open
Abstract
This letter comments on a study by Jin et al, published recently in the World Journal of Diabetes. Hypoglycemia is a significant complication of diabetes, with primary defense mechanisms involving the stimulation of glucagon secretion in α-cells and the inhibition of insulin secretion in pancreatic β-cells, which are often compromised in type 1 diabetes mellitus (T1DM) and advanced type 2 diabetes mellitus. Recurrent hypoglycemia predisposes the development of impaired hypoglycemia awareness, a condition underpinned by complex pathophysiological processes, encompassing central nervous system adaptations and several hormonal interactions, including a potential role for glucagon-like peptide-1 (GLP-1) in paracrine and endocrine vias. Experimental evidence indicates that GLP-1 may impair hypoglycemic counterregulation by disrupting the sympathoadrenal system and promoting somatostatin release in pancreatic δ-cells, which inhibits glucagon secretion from neighboring α-cells. However, current trials evaluating GLP-1 receptor agonists (GLP-1 RAs) in T1DM patients have shown promising benefits in reducing insulin requirements and body weight, without increasing the risk of hypoglycemia. Further research is essential to elucidate the specific roles of GLP-1 and GLP-1 RAs in modulating glucagon secretion and the sympathetic-adrenal reflex, and their impact on hypoglycemia unawareness in T1DM patients.
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Affiliation(s)
- Gabriel Reis Rocha
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45065-430, Bahia, Brazil
| | - Fabrício Freire de Melo
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45065-430, Bahia, Brazil
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2
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Shibib L, Al-Qaisi M, Guess N, Miras AD, Greenwald SE, Pelling M, Ahmed A. Manipulation of Post-Prandial Hyperglycaemia in Type 2 Diabetes: An Update for Practitioners. Diabetes Metab Syndr Obes 2024; 17:3111-3130. [PMID: 39206417 PMCID: PMC11350065 DOI: 10.2147/dmso.s458894] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2024] [Accepted: 07/23/2024] [Indexed: 09/04/2024] Open
Abstract
This review paper explores post-prandial glycemia in type 2 diabetes. Post-prandial glycemia is defined as the period of blood glucose excursion from immediately after the ingestion of food or drink to 4 to 6 hours after the end of the meal. Post-prandial hyperglycemia is an independent risk factor for cardiovascular disease with glucose "excursions" being more strongly associated with markers of oxidative stress than the fasting or pre-prandial glucose level. High blood glucose is a major promoter of enhanced free radical production and is associated with the onset and progression of type 2 diabetes. Oxidative stress impairs insulin action creating a vicious cycle where repeated post-prandial glucose spikes are key drivers in the pathogenesis of the vascular complications of type 2 diabetes, both microvascular and macrovascular. Some authors suggest post-prandial hyperglycemia is the major cause of death in type 2 diabetes. Proper management of post-prandial hyperglycemia could yield up to a 35% cut in overall cardiovascular events, and a 64% cut in myocardial infarction. The benefits of managing post-prandial hyperglycemia are similar in magnitude to those seen in type 2 diabetes patients receiving secondary prevention with statins - prevention which today is regarded as fundamental by all practitioners. Given all the evidence surrounding the impact of post-prandial glycemia on overall outcome, it is imperative that any considered strategy for the management of type 2 diabetes should include optimum dietary, pharma, and lifestyle interventions that address glucose excursion. Achieving a low post-prandial glucose response is key to prevention and progression of type 2 diabetes and cardiometabolic diseases. Further, such therapeutic interventions should be sustainable and must benefit patients in the short and long term with the minimum of intrusion and side effects. This paper reviews the current literature around dietary manipulation of post-prandial hyperglycemia, including novel approaches. A great deal of further work is required to optimize and standardize the dietary management of post-prandial glycemia in type 2 diabetes, including consideration of novel approaches that show great promise.
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Affiliation(s)
- Lina Shibib
- Department of Surgery and Cancer, Imperial College London, London, UK
| | - Mo Al-Qaisi
- Department of Surgery and Cancer, Imperial College London, London, UK
| | - Nicola Guess
- Nuffield Department of Primary Care Health Sciences, Oxford University, Oxford, UK
| | | | - Steve E Greenwald
- Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Marc Pelling
- Department of Surgery and Cancer, Imperial College London, London, UK
| | - Ahmed Ahmed
- Department of Surgery and Cancer, Imperial College London, London, UK
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Huang WK, Jalleh RJ, Rayner CK, Wu TZ. Management of gestational diabetes mellitus via nutritional interventions: The relevance of gastric emptying. World J Diabetes 2024; 15:1394-1397. [PMID: 39099817 PMCID: PMC11292344 DOI: 10.4239/wjd.v15.i7.1394] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/25/2024] [Revised: 04/09/2024] [Accepted: 04/18/2024] [Indexed: 07/08/2024] Open
Abstract
Gestational diabetes mellitus (GDM) represents one of the most common medical complications of pregnancy and is important to the well-being of both mothers and offspring in the short and long term. Lifestyle intervention remains the mainstay for the management of GDM. The efficacy of nutritional approaches (e.g. calorie restriction and small frequent meals) to improving the maternal-neonatal outcomes of GDM was attested to by Chinese population data, discussed in two articles in recent issues of this journal. However, a specific focus on the relevance of postprandial glycaemic control was lacking. Postprandial rather than fasting hyperglycaemia often represents the predominant manifestation of disordered glucose homeostasis in Chinese women with GDM. There is now increasing appreciation that the rate of gastric emptying, which controls the delivery of nutrients for digestion and absorption in the small intestine, is a key determinant of postprandial glycaemia in both health, type 1 and 2 diabetes. It remains to be established whether gastric emptying is abnormally rapid in GDM, particularly among Chinese women, thus contributing to a predisposition to postprandial hyperglycaemia, and if so, how this influences the therapeutic response to nutritional interventions. It is essential that we understand the role of gastric emptying in the regulation of postprandial glycaemia during pregnancy and the potential for its modulation by nutritional strategies in order to improve post-prandial glycaemic control in GDM.
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Affiliation(s)
- Wei-Kun Huang
- Adelaide Medical School and Centre of Research Excellence in Translating Nutritional Science to Good Health, The University of Adelaide, Adelaide 5000, Australia
| | - Ryan J Jalleh
- Adelaide Medical School and Centre of Research Excellence in Translating Nutritional Science to Good Health, The University of Adelaide, Adelaide 5000, Australia
| | - Christopher K Rayner
- Adelaide Medical School and Centre of Research Excellence in Translating Nutritional Science to Good Health, The University of Adelaide and Department of Gastroenterology and Hepatology, Royal Adelaide Hospital, Adelaide 5000, Australia
| | - Tong-Zhi Wu
- Adelaide Medical School and Centre of Research Excellence in Translating Nutritional Science to Good Health, The University of Adelaide, Adelaide 5000, Australia
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Frykholm P, Disma N, Andersson H, Beck C, Bouvet L, Cercueil E, Elliott E, Hofmann J, Isserman R, Klaucane A, Kuhn F, de Queiroz Siqueira M, Rosen D, Rudolph D, Schmidt AR, Schmitz A, Stocki D, Sümpelmann R, Stricker PA, Thomas M, Veyckemans F, Afshari A, překladu: A, Harazim H, Ťoukálková M, Valouchová V, Štourač P. Předoperační lačnění u dětí - Doporučený postup Evropské společnosti pro anesteziologii a intenzivní péči. ANESTEZIOLOGIE A INTENZIVNÍ MEDICÍNA 2024; 35:58-80. [DOI: 10.36290/aim.2024.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Salman UA, Schwartz JG, McMahan AC, Michalek JE, Phillips WT. Rapid Gastric emptying in spontaneously hypertensive rats. J Hypertens 2024; 42:572-578. [PMID: 38088427 DOI: 10.1097/hjh.0000000000003640] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/01/2024]
Abstract
OBJECTIVE To assess the rate of gastric emptying in spontaneously hypertensive rats (SHR) and to evaluate rapid gastric emptying as a possible predisposing factor for hypertension. Rapid gastric emptying of carbohydrates, known to elevate postprandial serum glucose, has been reported to occur in many insulin-resistant states, including hypertension. SHR exhibit insulin resistance similar to human hypertensive patients. No prior studies have assessed gastric emptying of an oral glucose solution in SHR as compared with control Wistar Kyoto rats (WKY). METHODS Using scintigraphic imaging, gastric emptying of a physiologic, orally consumed glucose solution was assessed in 12 SHR and 12 control WKY at 5 weeks of age, prior to the development of hypertension, and at 12 weeks of age after hypertension was fully established. RESULTS At 5 weeks, the gastric half-emptying time (GHET) was 67.8 ± 9.8 min for the SHR vs. 109.3 ± 18 ( P = 0.042) minutes for the WKY controls. At 12 weeks, the GHET was 37.29 ± 10.3 min for the SHR vs. 138.53 ± 37.6 ( P = 0.016) min for the WKY controls. CONCLUSION Gastric emptying was significantly more rapid in the SHR before and after the development of hypertension. Even though SHR are known to have increased sympathetic activity associated with their development of hypertension, this increased sympathetic activity does not inhibit gastric emptying. SHR are a promising animal model for investigating therapeutic agents for treating hypertension aimed at slowing the rate of gastric emptying.
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Affiliation(s)
| | | | | | - Joel E Michalek
- Department of Population Health Sciences, UT Health San Antonio, San Antonio, Texas, USA
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Caturano A, Cavallo M, Nilo D, Vaudo G, Russo V, Galiero R, Rinaldi L, Marfella R, Monda M, Luca G, Sasso FC. Diabetic Gastroparesis: Navigating Pathophysiology and Nutritional Interventions. GASTROINTESTINAL DISORDERS 2024; 6:214-229. [DOI: 10.3390/gidisord6010016] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/04/2025] Open
Abstract
Diabetic gastroparesis (DGP) delays gastric emptying in diabetes patients, notably impacting those with type 1 and long-standing type 2 diabetes. Symptoms include early satiety, fullness, appetite loss, bloating, abdominal pain, and vomiting, arising from slow stomach-to-intestine food movement. DGP’s unpredictable nature complicates diagnosis and blood glucose management, leading to severe complications like dehydration, malnutrition, and bezoar formation. Understanding DGP’s mechanisms is crucial for effective management. Vagal dysfunction, disturbances in the interstitial cells of Cajal, reduced neural nitric oxide synthase, and increased oxidative stress contribute to the complex pathophysiology. Accurate diagnosis demands a comprehensive approach, utilizing tools like gastric scintigraphy and the Gastric Emptying Breath Test. Considering the complex relationship between DGP and glycemia, managing blood glucose levels becomes paramount. Nutritional interventions, tailored to each patient, address malnutrition risks, emphasizing smaller, more frequent meals and liquid consistency. DGP’s complex nature necessitates collaborative efforts for enhanced diagnostic strategies, improved pathophysiological understanding, and compassionate management approaches. This comprehensive approach offers hope for a future where individuals with DGP can experience improved well-being and quality of life.
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Affiliation(s)
- Alfredo Caturano
- Department of Advanced Medical and Surgical Sciences, University of Campania Luigi Vanvitelli, I-80138 Naples, Italy
- Department of Experimental Medicine, University of Campania Luigi Vanvitelli, I-80138 Naples, Italy
| | - Massimiliano Cavallo
- Internal Medicine Unit, Santa Maria Terni Hospital, I-05100 Terni, Italy
- Medical Andrology and Reproductive Endocrinology Unit, Santa Maria Hospital, I-05100 Terni, Italy
| | - Davide Nilo
- Department of Advanced Medical and Surgical Sciences, University of Campania Luigi Vanvitelli, I-80138 Naples, Italy
| | - Gaetano Vaudo
- Internal Medicine Unit, Santa Maria Terni Hospital, I-05100 Terni, Italy
| | - Vincenzo Russo
- Department of Biology, College of Science and Technology, Sbarro Institute for Cancer Research and Molecular Medicine, Temple University, Philadelphia, PA 19122, USA
- Division of Cardiology, Department of Medical Translational Sciences, University of Campania Luigi Vanvitelli, I-80138 Naples, Italy
| | - Raffaele Galiero
- Department of Advanced Medical and Surgical Sciences, University of Campania Luigi Vanvitelli, I-80138 Naples, Italy
| | - Luca Rinaldi
- Department of Medicine and Health Sciences “Vincenzo Tiberio”, University of Molise, I-86100 Campobasso, Italy
| | - Raffaele Marfella
- Department of Advanced Medical and Surgical Sciences, University of Campania Luigi Vanvitelli, I-80138 Naples, Italy
| | - Marcellino Monda
- Department of Experimental Medicine, University of Campania Luigi Vanvitelli, I-80138 Naples, Italy
| | - Giovanni Luca
- Medical Andrology and Reproductive Endocrinology Unit, Santa Maria Hospital, I-05100 Terni, Italy
| | - Ferdinando Carlo Sasso
- Department of Advanced Medical and Surgical Sciences, University of Campania Luigi Vanvitelli, I-80138 Naples, Italy
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Maguolo A, Mazzuca G, Smart CE, Maffeis C. Postprandial glucose metabolism in children and adolescents with type 1 diabetes mellitus: potential targets for improvement. Eur J Clin Nutr 2024; 78:79-86. [PMID: 37875611 DOI: 10.1038/s41430-023-01359-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2023] [Revised: 10/05/2023] [Accepted: 10/11/2023] [Indexed: 10/26/2023]
Abstract
The main goal of therapeutic management of type 1 Diabetes Mellitus (T1DM) is to maintain optimal glycemic control to prevent acute and long-term diabetes complications and to enable a good quality of life. Postprandial glycemia makes a substantial contribution to overall glycemic control and variability in diabetes and, despite technological advancements in insulin treatments, optimal postprandial glycemia is difficult to achieve. Several factors influence postprandial blood glucose levels in children and adolescents with T1DM, including nutritional habits and adjustment of insulin doses according to meal composition. Additionally, hormone secretion, enteroendocrine axis dysfunction, altered gastrointestinal digestion and absorption, and physical activity play important roles. Meal-time routines, intake of appropriate ratios of macronutrients, and correct adjustment of the insulin dose for the meal composition have positive impacts on postprandial glycemic variability and long-term cardiometabolic health of the individual with T1DM. Further knowledge in the field is necessary for management of all these factors to be part of routine pediatric diabetes education and clinical practice. Thus, the aim of this report is to review the main factors that influence postprandial blood glucose levels and metabolism, focusing on macronutrients and other nutritional and lifestyle factors, to suggest potential targets for improving postprandial glycemia in the management of children and adolescents with T1DM.
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Affiliation(s)
- Alice Maguolo
- Section of Pediatric Diabetes and Metabolism, Department of Surgery, Dentistry, Pediatrics, and Gynecology, University of Verona, Verona, Italy.
| | - Giorgia Mazzuca
- Section of Pediatric Diabetes and Metabolism, Department of Surgery, Dentistry, Pediatrics, and Gynecology, University of Verona, Verona, Italy
| | - Carmel E Smart
- School of Health Sciences, University of Newcastle, Callaghan, NSW, Australia
- Department of Paediatric Diabetes and Endocrinology, John Hunter Children's Hospital, Newcastle, NSW, Australia
| | - Claudio Maffeis
- Section of Pediatric Diabetes and Metabolism, Department of Surgery, Dentistry, Pediatrics, and Gynecology, University of Verona, Verona, Italy
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Arunachala Murthy T, Chapman M, Jones KL, Horowitz M, Marathe CS. Inter-relationships between gastric emptying and glycaemia: Implications for clinical practice. World J Diabetes 2023; 14:447-459. [PMID: 37273253 PMCID: PMC10236995 DOI: 10.4239/wjd.v14.i5.447] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/24/2022] [Revised: 12/09/2022] [Accepted: 04/07/2023] [Indexed: 05/15/2023] Open
Abstract
Gastric emptying (GE) exhibits a wide inter-individual variation and is a major determinant of postprandial glycaemia in health and diabetes; the rise in blood glucose following oral carbohydrate is greater when GE is relatively more rapid and more sustained when glucose tolerance is impaired. Conversely, GE is influenced by the acute glycaemic environment acute hyperglycaemia slows, while acute hypoglycaemia accelerates it. Delayed GE (gastroparesis) occurs frequently in diabetes and critical illness. In diabetes, this poses challenges for management, particularly in hospitalised individuals and/or those using insulin. In critical illness it compromises the delivery of nutrition and increases the risk of regurgitation and aspiration with consequent lung dysfunction and ventilator dependence. Substantial advances in knowledge relating to GE, which is now recognised as a major determinant of the magnitude of the rise in blood glucose after a meal in both health and diabetes and, the impact of acute glycaemic environment on the rate of GE have been made and the use of gut-based therapies such as glucagon-like peptide-1 receptor agonists, which may profoundly impact GE, in the management of type 2 diabetes, has become commonplace. This necessitates an increased understanding of the complex inter-relationships of GE with glycaemia, its implications in hospitalised patients and the relevance of dysglycaemia and its management, particularly in critical illness. Current approaches to management of gastroparesis to achieve more personalised diabetes care, relevant to clinical practice, is detailed. Further studies focusing on the interactions of medications affecting GE and the glycaemic environment in hospitalised patients, are required.
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Affiliation(s)
- Tejaswini Arunachala Murthy
- Adelaide Medical School, University of Adelaide, Adelaide 5000, SA, Australia
- Intensive Care Unit, Royal Adelaide Hospital, Adelaide 5000, SA, Australia
| | - Marianne Chapman
- Adelaide Medical School, University of Adelaide, Adelaide 5000, SA, Australia
- Intensive Care Unit, Royal Adelaide Hospital, Adelaide 5000, SA, Australia
- NHMRC Centre of Clinical Research Excellence in Nutritional Physiology, Interventions and Outcomes, University of Adelaide, Adelaide 5000, SA, Australia
| | - Karen L Jones
- Adelaide Medical School, University of Adelaide, Adelaide 5000, SA, Australia
- NHMRC Centre of Clinical Research Excellence in Nutritional Physiology, Interventions and Outcomes, University of Adelaide, Adelaide 5000, SA, Australia
| | - Michael Horowitz
- Adelaide Medical School, University of Adelaide, Adelaide 5000, SA, Australia
- NHMRC Centre of Clinical Research Excellence in Nutritional Physiology, Interventions and Outcomes, University of Adelaide, Adelaide 5000, SA, Australia
- Endocrine and Metabolic Unit, Royal Adelaide Hospital, Adelaide 5000, SA, Australia
| | - Chinmay S Marathe
- Adelaide Medical School, University of Adelaide, Adelaide 5000, SA, Australia
- NHMRC Centre of Clinical Research Excellence in Nutritional Physiology, Interventions and Outcomes, University of Adelaide, Adelaide 5000, SA, Australia
- Endocrine and Metabolic Unit, Royal Adelaide Hospital, Adelaide 5000, SA, Australia
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Mashali G, Kaul A, Khoury J, Corsiglia J, Dolan LM, Shah AS. Screening for Gastric Sensory Motor Abnormalities in Pediatric Patients With Type 1 Diabetes. Endocr Pract 2023; 29:168-173. [PMID: 36572278 DOI: 10.1016/j.eprac.2022.12.014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/19/2022] [Revised: 12/14/2022] [Accepted: 12/19/2022] [Indexed: 12/24/2022]
Abstract
OBJECTIVE To determine the frequency of gastric sensory motor symptoms in youth with type 1 diabetes. METHODS A prospective cross-sectional study was performed to evaluate symptoms of delayed gastric emptying in participants with type 1 diabetes, aged 12 to 25 years, using the Gastroparesis Cardinal Symptom Index (GCSI) questionnaire. In addition, a 5-year (January 2015 to December 2019), a retrospective study was completed on all gastric emptying scans performed in youth at our institution. RESULTS A total of 359 participants (mean age, 17.7 ± 3.33 years) with type 1 diabetes completed the GCSI questionnaire. Compared with nonresponders, responders were more likely to be non-Hispanic White (90% vs 86%; P =.003) and female patients (58% vs 44%; P <.0001), with a lower HbA1c (8.1 ± 1.8 vs 9.0 ± 2.1; P <.0001). At least 1 gastrointestinal symptom was reported in 270 (75%) of responders, of which nausea was the most common (71%). A GCSI score of ≥1.9 suggestive of more severe gastrointestinal symptoms was reported in 17% of responders. Participants with scores ≥1.9 were older (19.1 ± 3.0 vs 17.8 ± 3.3 years; P =.01). In the retrospective study, 778 underwent gastric emptying scan, 29 participants had type 1 diabetes and 11 (38%) showed delayed gastric emptying. CONCLUSION Gastrointestinal symptoms related to gastric sensory motor abnormalities are seen in youth and young adults with type 1 diabetes. In particular, for those with higher GCSI scores, earlier recognition and referral may be warranted.
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Affiliation(s)
- Gamal Mashali
- Division of Pediatric Endocrine, Cincinnati Children's Hospital Medical Center and the University of Cincinnati, Cincinnati, Ohio.
| | - Ajay Kaul
- Division of Pediatric Gastroenterology, Cincinnati Children's Hospital Medical Center and the University of Cincinnati, Cincinnati, Ohio
| | - Jane Khoury
- Division of Biostatistics and Epidemiology, Cincinnati Children's Hospital Medical Center and the University of Cincinnati, Cincinnati, Ohio
| | - Joshua Corsiglia
- Xavier University, College of Arts and Sciences, Cincinnati, Ohio
| | - Lawrence M Dolan
- Division of Pediatric Endocrine, Cincinnati Children's Hospital Medical Center and the University of Cincinnati, Cincinnati, Ohio
| | - Amy S Shah
- Division of Pediatric Endocrine, Cincinnati Children's Hospital Medical Center and the University of Cincinnati, Cincinnati, Ohio
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Early Gastrointestinal Neuropathy Assessed by Wireless Motility Capsules in Adolescents with Type 1 Diabetes. J Clin Med 2023; 12:jcm12051925. [PMID: 36902712 PMCID: PMC10003990 DOI: 10.3390/jcm12051925] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2022] [Revised: 02/03/2023] [Accepted: 02/20/2023] [Indexed: 03/06/2023] Open
Abstract
BACKGROUND To assess the prevalence of objective signs of gastrointestinal (GI) autonomic neuropathy (AN) in adolescents with type 1 diabetes (T1D). In addition, to investigate associations between objective GI findings and self-reported symptoms or other findings of AN. METHODS Fifty adolescents with T1D and 20 healthy adolescents were examined with a wireless motility capsule to assess the total and regional GI transit times and motility index. GI symptoms were evaluated with the GI Symptom Rating Scale questionnaire. AN was evaluated with cardiovascular and quantitative sudomotor axon reflex tests. RESULTS There was no difference in GI transit times in adolescents with T1D and healthy controls. Adolescents with T1D had a higher colonic motility index and peak pressure than the controls, and GI symptoms were associated with low gastric and colonic motility index (all p < 0.05). Abnormal gastric motility was associated with the duration of T1D, while a low colonic motility index was inversely associated with "time in target range" for blood glucose (all p < 0.01). No associations were found between signs of GI neuropathy and other measures of AN. CONCLUSIONS Objective signs of GI neuropathy are common in adolescents with T1D and it seems to require early interventions in patients at high risk of developing GI neuropathy.
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Jin BY, Kim HJ, Oh MJ, Ha NH, Jeong YT, Choi SH, Lee JS, Kim NH, Kim DH. Metformin acts as a dual glucose regulator in mouse brain. Front Pharmacol 2023; 14:1108660. [PMID: 37153803 PMCID: PMC10157063 DOI: 10.3389/fphar.2023.1108660] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2022] [Accepted: 04/12/2023] [Indexed: 05/10/2023] Open
Abstract
Aims: Metformin improves glucose regulation through various mechanisms in the periphery. Our previous study revealed that oral intake of metformin activates several brain regions, including the hypothalamus, and directly activates hypothalamic S6 kinase in mice. In this study, we aimed to identify the direct effects of metformin on glucose regulation in the brain. Materials and methods: We investigated the role of metformin in peripheral glucose regulation by directly administering metformin intracerebroventricularly in mice. The effect of centrally administered metformin (central metformin) on peripheral glucose regulation was evaluated by oral or intraperitoneal glucose, insulin, and pyruvate tolerance tests. Hepatic gluconeogenesis and gastric emptying were assessed to elucidate the underlying mechanisms. Liver-specific and systemic sympathetic denervation were performed. Results: Central metformin improved the glycemic response to oral glucose load in mice compared to that in the control group, and worsened the response to intraperitoneal glucose load, indicating its dual role in peripheral glucose regulation. It lowered the ability of insulin to decrease serum glucose levels and worsened the glycemic response to pyruvate load relative to the control group. Furthermore, it increased the expression of hepatic G6pc and decreased the phosphorylation of STAT3, suggesting that central metformin increased hepatic glucose production. The effect was mediated by sympathetic nervous system activation. In contrast, it induced a significant delay in gastric emptying in mice, suggesting its potent role in suppressing intestinal glucose absorption. Conclusion: Central metformin improves glucose tolerance by delaying gastric emptying through the brain-gut axis, but at the same time worsens it by increasing hepatic glucose production via the brain-liver axis. However, with its ordinary intake, central metformin may effectively enhance its glucose-lowering effect through the brain-gut axis, which could surpass its effect on glucose regulation via the brain-liver axis.
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Affiliation(s)
- Bo-Yeong Jin
- Department of Pharmacology, Korea University College of Medicine, Seoul, Republic of Korea
- Graduate School of Medicine, Korea University, Seoul, Republic of Korea
| | - Hyun-Ju Kim
- Department of Pharmacology, Korea University College of Medicine, Seoul, Republic of Korea
| | - Mi-Jeong Oh
- Department of Pharmacology, Korea University College of Medicine, Seoul, Republic of Korea
- Graduate School of Medicine, Korea University, Seoul, Republic of Korea
| | - Na-Hee Ha
- Department of Pharmacology, Korea University College of Medicine, Seoul, Republic of Korea
- Graduate School of Medicine, Korea University, Seoul, Republic of Korea
| | - Yong Taek Jeong
- Department of Pharmacology, Korea University College of Medicine, Seoul, Republic of Korea
- Graduate School of Medicine, Korea University, Seoul, Republic of Korea
| | - Sang-Hyun Choi
- Department of Pharmacology, Korea University College of Medicine, Seoul, Republic of Korea
| | - Jun-Seok Lee
- Department of Pharmacology, Korea University College of Medicine, Seoul, Republic of Korea
| | - Nam Hoon Kim
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Korea University College of Medicine, Seoul, Republic of Korea
| | - Dong-Hoon Kim
- Department of Pharmacology, Korea University College of Medicine, Seoul, Republic of Korea
- Graduate School of Medicine, Korea University, Seoul, Republic of Korea
- *Correspondence: Dong-Hoon Kim,
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12
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Portincasa P, Bonfrate L, Wang DQH, Frühbeck G, Garruti G, Di Ciaula A. Novel insights into the pathogenic impact of diabetes on the gastrointestinal tract. Eur J Clin Invest 2022; 52:e13846. [PMID: 35904418 DOI: 10.1111/eci.13846] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/28/2022] [Revised: 06/20/2022] [Accepted: 06/26/2022] [Indexed: 11/09/2022]
Abstract
Type 2 and type 1 diabetes are common endocrine disorders with a progressively increasing incidence worldwide. These chronic, systemic diseases have multiorgan implications, and the whole gastrointestinal (GI) tract represents a frequent target in terms of symptom appearance and interdependent pathophysiological mechanisms. Metabolic alterations linked with diabetic complications, neuropathy and disrupted hormone homeostasis can lead to upper and/or lower GI symptoms in up to 75% of diabetic patients, with multifactorial involvement of the oesophagus, stomach, upper and lower intestine, and of the gallbladder. On the other hand, altered gastrointestinal motility and/or secretions are able to affect glucose and lipid homeostasis in the short and long term. Finally, diabetes has been linked with increased cancer risk at different levels of the GI tract. The presence of GI symptoms and a comprehensive assessment of GI function should be carefully considered in the management of diabetic patients to avoid further complications and to ameliorate the quality of life. Additionally, the presence of gastrointestinal dysfunction should be adequately managed to improve metabolic homeostasis, the efficacy of antidiabetic treatments and secondary prevention strategies.
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Affiliation(s)
- Piero Portincasa
- Clinica Medica "A. Murri", Department of Biomedical Sciences and Human Oncology, University of Bari Aldo Moro, Bari, Italy
| | - Leonilde Bonfrate
- Clinica Medica "A. Murri", Department of Biomedical Sciences and Human Oncology, University of Bari Aldo Moro, Bari, Italy
| | - David Q-H Wang
- Department of Medicine and Genetics, Division of Gastroenterology and Liver Diseases, Marion Bessin Liver Research Center, Einstein-Mount Sinai Diabetes Research Center, Albert Einstein College of Medicine, Bronx, New York, USA
| | - Gema Frühbeck
- Department of Endocrinology & Nutrition, Clínica Universidad de Navarra, Pamplona, Spain Metabolic Research Laboratory, Clínica Universidad de Navarra, Pamplona, Spain.,CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), ISCIII, Pamplona, Spain.,Obesity and Adipobiology Group, Instituto de Investigación Sanitaria de Navarra (IdiSNA), Pamplona, Spain
| | - Gabriella Garruti
- Department of Emergency and Organ Transplants, Unit of Endocrinology, University of Bari Medical School, Bari, Italy
| | - Agostino Di Ciaula
- Clinica Medica "A. Murri", Department of Biomedical Sciences and Human Oncology, University of Bari Aldo Moro, Bari, Italy
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13
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Thakur V, Bashashati M, Enriquez J, Chattopadhyay M. Inhibiting Fatty Acid Amide Hydrolase Ameliorates Enteropathy in Diabetic Mice: A Cannabinoid 1 Receptor Mediated Mechanism. Vet Sci 2022; 9:364. [PMID: 35878381 PMCID: PMC9319435 DOI: 10.3390/vetsci9070364] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2022] [Revised: 07/09/2022] [Accepted: 07/13/2022] [Indexed: 11/16/2022] Open
Abstract
Gastrointestinal (GI) dysmotility in diabetics exhibits fecal incontinence or constipation which affects patients' quality of life. In this study, we aimed to understand the pattern of GI transit in type 1 diabetic (T1D) mice and whether inhibiting endocannabinoid degradation would exhibit therapeutic effect. Whole gut-transit time and fecal-pellet output were measured at 16 week post-diabetes. T1D mice treated with fatty acid amide hydrolase (FAAH) inhibitor URB597 showed reduced fecal output as well as improved gut transit time. Cannabinoid 1 receptor antagonist, AM251 blocked the effects of URB597, which may demonstrate that FAAH inhibitor is a potential remedial strategy for GI dysmotility.
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Affiliation(s)
- Vikram Thakur
- Center of Emphasis in Diabetes and Metabolism, Department of Molecular and Translational Medicine, Texas Tech University Health Sciences Center El Paso, El Paso, TX 79905, USA;
| | - Mohammad Bashashati
- Division of Gastroenterology, Department of Internal Medicine, Texas Tech University Health Sciences Center El Paso, El Paso, TX 79905, USA;
| | - Josue Enriquez
- Graduate School of Biomedical Sciences, Texas Tech University Health Sciences Center El Paso, El Paso, TX 79905, USA;
| | - Munmun Chattopadhyay
- Center of Emphasis in Diabetes and Metabolism, Department of Molecular and Translational Medicine, Texas Tech University Health Sciences Center El Paso, El Paso, TX 79905, USA;
- Graduate School of Biomedical Sciences, Texas Tech University Health Sciences Center El Paso, El Paso, TX 79905, USA;
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14
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De Melo EN, Clarke ABM, McDonald C, Saibil F, Lochnan HA, Punthakee Z, Assor E, Marcon MA, Mahmud FH. Gastrointestinal Symptoms in Type 1 Diabetes: Relationship With Autoimmune and Microvascular Complications. J Clin Endocrinol Metab 2022; 107:e2431-e2437. [PMID: 35176765 DOI: 10.1210/clinem/dgac093] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/24/2021] [Indexed: 02/13/2023]
Abstract
PURPOSE To assess reported rates of gastrointestinal (GI) symptoms and their association with autoimmune diseases and microvascular complications in adults and children with type 1 diabetes. METHODS The Gastrointestinal Symptom Scale was used to assess GI symptom type and severity in 2370 patients with type 1 diabetes aged 8 to 45 years evaluated as part of a clinical trial screening for celiac disease (CD). The presence and severity of GI symptoms and relationships with demographic, clinical, and other diabetes-related factors were evaluated. RESULTS Overall, 1368 adults (57.7%) aged 19 to 45 years and 1002 (42.3%) pediatric patients aged 8 to 18 years were studied. At least 1 GI symptom was reported in 34.1% of adults as compared with 21.7% of children (P < 0.0001). Common symptoms in children included upper and lower abdominal pain while adults more frequently reported lower GI symptoms. Participants with GI symptoms had higher hemoglobin A1c (HbA1c) levels (68 ± 14mmol/mol; 8.35 ± 1.37%) than those without symptoms (66 ± 15mmol/mol; 8.22 ± 1.40%; P = 0.041). Patients with microvascular complications (nephropathy, retinopathy, and/or neuropathy) were 1.8 times more likely to report GI symptoms (95% CI: 1.26-2.60; P < 0.01) after adjusting for age and sex. No association was observed between GI symptoms and the presence of autoimmune conditions, including thyroid and biopsy-confirmed CD (odds ratio = 1.1; 95% CI: 0.86-1.42; P = 0.45). MAIN CONCLUSIONS These results highlight that GI symptoms are an important clinical morbidity and are associated with increasing age, duration of type 1 diabetes, HbA1c, and microvascular complications but not with autoimmune comorbidities including CD.
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Affiliation(s)
- Emilia N De Melo
- Division of Endocrinology, Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Toronto, Canada
| | - Antoine B M Clarke
- Division of Endocrinology, Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Toronto, Canada
| | - Charlotte McDonald
- Division of Endocrinology and Metabolism, St. Joseph's Health Care, Western University, London, Canada
| | - Fred Saibil
- Division of Gastroenterology, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Canada
| | | | - Zubin Punthakee
- Department of Endocrinology, McMaster University, Hamilton, Canada
| | - Esther Assor
- Division of Endocrinology, Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Toronto, Canada
| | - Margaret A Marcon
- Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Toronto, Canada
| | - Farid H Mahmud
- Division of Endocrinology, Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Toronto, Canada
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15
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Wollmer E, Ungell AL, Nicolas JM, Klein S. Review of paediatric gastrointestinal physiology relevant to the absorption of orally administered medicines. Adv Drug Deliv Rev 2022; 181:114084. [PMID: 34929252 DOI: 10.1016/j.addr.2021.114084] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2021] [Revised: 11/13/2021] [Accepted: 12/13/2021] [Indexed: 12/11/2022]
Abstract
Despite much progress in regulations to improve paediatric drug development, there remains a significant need to develop better medications for children. For the design of oral dosage forms, a detailed understanding of the specific gastrointestinal (GI) conditions in children of different age categories and how they differ from GI conditions in adults is essential. Several review articles have been published addressing the ontogeny of GI characteristics, including luminal conditions in the GI tract of children. However, the data reported in most of these reviews are of limited quality because (1) information was cited from very old publications and sometimes low quality sources, (2) data gaps in the original data were filled with textbook knowledge, (3) data obtained on healthy and sick children were mixed, (4) average data obtained on groups of patients were mixed with data obtained on individual patients, and (5) results obtained using investigative techniques that may have altered the outcome of the respective studies were considered. Consequently, many of these reviews draw conclusions that may be incorrect. The aim of the present review was to provide a comprehensive and updated overview of the available original data on the ontogeny of GI luminal conditions relevant to oral drug absorption in the paediatric population. To this end, the PubMed and Web of Science metadatabases were searched for appropriate studies that examined age-related conditions in the oral cavity, esophagus, stomach, small intestine, and colon. Maturation was observed for several GI parameters, and corresponding data sets were identified for each paediatric age group. However, it also became clear that the ontogeny of several GI traits in the paediatric population is not yet known. The review article provides a robust and valuable data set for the development of paediatric in vitro and in silico biopharmaceutical tools to support the development of age-appropriate dosage forms. In addition, it provides important information on existing data gaps and should provide impetus for further systematic and well-designed in vivo studies on GI physiology in children of specific age groups in order to close existing knowledge gaps and to sustainably improve oral drug therapy in children.
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16
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Harray AJ, Binkowski S, Keating BL, Horowitz M, Standfield S, Smith G, Paramalingam N, Jones T, King BR, Smart CEM, Davis EA. Effects of Dietary Fat and Protein on Glucoregulatory Hormones in Adolescents and Young Adults With Type 1 Diabetes. J Clin Endocrinol Metab 2022; 107:e205-e213. [PMID: 34410410 DOI: 10.1210/clinem/dgab614] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/01/2021] [Indexed: 11/19/2022]
Abstract
CONTEXT Dietary fat and protein impact postprandial hyperglycemia in people with type 1 diabetes, but the underlying mechanisms are poorly understood. Glucoregulatory hormones are also known to modulate gastric emptying and may contribute to this effect. OBJECTIVE Investigate the effects of fat and protein on glucagon-like peptide (GLP-1), glucagon-dependent insulinotropic polypeptide (GIP) and glucagon secretion. METHODS 2 crossover euglycemic insulin clamp clinical trials at 2 Australian pediatric diabetes centers. Participants were 12-21 years (n = 21) with type 1 diabetes for ≥1 year. Participants consumed a low-protein (LP) or high-protein (HP) meal in Study 1, and low-protein/low-fat (LPLF) or high-protein/high-fat (HPHF) meal in Study 2, all containing 30 g of carbohydrate. An insulin clamp was used to maintain postprandial euglycemia and plasma glucoregulatory hormones were measured every 30 minutes for 5 hours. Data from both cohorts (n = 11, 10) were analyzed separately. The main outcome measure was area under the curve of GLP-1, GIP, and glucagon. RESULTS Meals low in fat and protein had minimal effect on GLP-1, while there was sustained elevation after HP (80.3 ± 16.8 pmol/L) vs LP (56.9 ± 18.6), P = .016, and HPHF (103.0 ± 26.9) vs LPLF (69.5 ± 31.9) meals, P = .002. The prompt rise in GIP after all meals was greater after HP (190.2 ± 35.7 pmol/L) vs LP (152.3 ± 23.3), P = .003, and HPHF (258.6 ± 31.0) vs LPLF (151.7 ± 29.4), P < .001. A rise in glucagon was also seen in response to protein, and HP (292.5 ± 88.1 pg/mL) vs LP (182.8 ± 48.5), P = .010. CONCLUSION The impact of fat and protein on postprandial glucose excursions may be mediated by the differential secretion of glucoregulatory hormones. Further studies to better understand these mechanisms may lead to improved personalized postprandial glucose management.
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Affiliation(s)
- Amelia J Harray
- Telethon Kids Institute, University of Western Australia, Perth, Western Australia, Australia
- School of Population Health, Curtin University, Bentley, Perth, Western Australia, Australia
| | - Sabrina Binkowski
- Telethon Kids Institute, University of Western Australia, Perth, Western Australia, Australia
| | - Barbara L Keating
- Department of Endocrinology and Diabetes, Perth Children's Hospital, Perth, Western Australia, Australia
| | | | | | - Grant Smith
- Telethon Kids Institute, University of Western Australia, Perth, Western Australia, Australia
| | - Nirubasini Paramalingam
- Telethon Kids Institute, University of Western Australia, Perth, Western Australia, Australia
- Department of Endocrinology and Diabetes, Perth Children's Hospital, Perth, Western Australia, Australia
- Division of Paediatrics, School of Medicine, The University of Western Australia, Perth, Western Australia, Australia
| | - Timothy Jones
- Telethon Kids Institute, University of Western Australia, Perth, Western Australia, Australia
- Department of Endocrinology and Diabetes, Perth Children's Hospital, Perth, Western Australia, Australia
- Division of Paediatrics, School of Medicine, The University of Western Australia, Perth, Western Australia, Australia
| | - Bruce R King
- John Hunter Children's Hospital, New Lambton Heights, New South Wales, Australia
- Faculty of Health and Medicine, University of Newcastle, Callaghan, New South Wales, Australia
- Hunter Medical Research Institute, New Lambton Heights, New South Wales, Australia
| | - Carmel E M Smart
- John Hunter Children's Hospital, New Lambton Heights, New South Wales, Australia
- Faculty of Health and Medicine, University of Newcastle, Callaghan, New South Wales, Australia
- Hunter Medical Research Institute, New Lambton Heights, New South Wales, Australia
| | - Elizabeth A Davis
- Telethon Kids Institute, University of Western Australia, Perth, Western Australia, Australia
- Department of Endocrinology and Diabetes, Perth Children's Hospital, Perth, Western Australia, Australia
- Division of Paediatrics, School of Medicine, The University of Western Australia, Perth, Western Australia, Australia
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17
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Pre-operative fasting in children: A guideline from the European Society of Anaesthesiology and Intensive Care. Eur J Anaesthesiol 2022; 39:4-25. [PMID: 34857683 DOI: 10.1097/eja.0000000000001599] [Citation(s) in RCA: 91] [Impact Index Per Article: 30.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Current paediatric anaesthetic fasting guidelines have recommended conservative fasting regimes for many years and have not altered much in the last decades. Recent publications have employed more liberal fasting regimes with no evidence of increased aspiration or regurgitation rates. In this first solely paediatric European Society of Anaesthesiology and Intensive Care (ESAIC) pre-operative fasting guideline, we aim to present aggregated and evidence-based summary recommendations to assist clinicians, healthcare providers, patients and parents. We identified six main topics for the literature search: studies comparing liberal with conservative regimens; impact of food composition; impact of comorbidity; the use of gastric ultrasound as a clinical tool; validation of gastric ultrasound for gastric content and gastric emptying studies; and early postoperative feeding. The literature search was performed by a professional librarian in collaboration with the ESAIC task force. Recommendations for reducing clear fluid fasting to 1 h, reducing breast milk fasting to 3 h, and allowing early postoperative feeding were the main results, with GRADE 1C or 1B evidence. The available evidence suggests that gastric ultrasound may be useful for clinical decision-making, and that allowing a 'light breakfast' may be well tolerated if the intake is well controlled. More research is needed in these areas as well as evaluation of how specific patient or treatment-related factors influence gastric emptying.
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18
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Dai F, Guo J, Wang Y, Jiang T, Chen H, Hu Y, Du J, Xia X, Zhang Q, Shen B. Enhanced Store-Operated Ca 2+ Signal of Small Intestinal Smooth Muscle Cells Accelerates Small Bowel Transit Speed in Type 1 Diabetic Mouse. Front Physiol 2021; 12:691867. [PMID: 34744757 PMCID: PMC8564290 DOI: 10.3389/fphys.2021.691867] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2021] [Accepted: 09/27/2021] [Indexed: 11/26/2022] Open
Abstract
Aims: The underlying mechanism of diabetic enteropathy, a common complication of type 1 diabetes, remains unclear. Store-operated Ca2+ entry (SOCE) is a ubiquitous type of Ca2+ influx involved in various cellular functions. Here, we show that SOCE-related stromal interaction molecule 1 (STIM1) and Orai1 participate in inappropriate cellular Ca2+ homeostasis, augmenting agonist-induced small intestinal smooth muscle contraction and small bowel transit speed in a mouse model of type 1 diabetes. Methods and Results: We used small interfering (si)RNA to suppress STIM1 and Orai1 proteins, and employed intracellular Ca2+, small intestinal contraction and intestinal transit speed measurement to investigate the functional change. We found that SOCE activity and Orai1 and STIM1 expression levels of small intestinal smooth muscle were significantly increased in cells cultured in high glucose medium or in diabetic mice. Gastrointestinal transit speed and SOCE-mediated contractions were markedly increased in diabetic mice; Knocking down Orai1 or STIM1 with siRNA rescued both alterations in diabetic mice. However, the Orai1-large conductance Ca2+-activated K+ (BKCa) channel interaction was decreased in diabetic mice, and suppressing Orai1 expression or inhibiting the BKCa channel increased agonist-induced small intestinal contractions in normal mice. Conclusion: We concluded that the increased SOCE caused by excessive STIM1 and Orai1 expression and decreased Orai1-BKCa interaction augmented small intestinal smooth muscle contraction and accelerated small bowel transit speed in diabetic mice. This finding demonstrates a pathological role for SOCE in diabetic enteropathy and provides a potential therapeutic target for diabetic enteropathy.
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Affiliation(s)
- Fang Dai
- Department of Endocrinology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Jizheng Guo
- School of Basic Medicine, Anhui Medical University, Hefei, China
| | - Yang Wang
- School of Basic Medicine, Anhui Medical University, Hefei, China
| | - Tian Jiang
- Department of Endocrinology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Hongbo Chen
- Department of Obstetrics and Gynecology, Maternal and Child Health Hospital Affiliated to Anhui Medical University, Hefei, China
| | - Ying Hu
- School of Basic Medicine, Anhui Medical University, Hefei, China
| | - Juan Du
- School of Basic Medicine, Anhui Medical University, Hefei, China
| | - Xianming Xia
- Digestive Medicine Center, Department of General Practice, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, China
| | - Qiu Zhang
- Department of Endocrinology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Bing Shen
- School of Basic Medicine, Anhui Medical University, Hefei, China
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19
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Rasmussen VF, Jensen TS, Tankisi H, Karlsson P, Vestergaard ET, Kristensen K, Nyengaard JR, Terkelsen AJ. Large fibre, small fibre and autonomic neuropathy in adolescents with type 1 diabetes: A systematic review. J Diabetes Complications 2021; 35:108027. [PMID: 34429229 DOI: 10.1016/j.jdiacomp.2021.108027] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/21/2021] [Revised: 05/27/2021] [Accepted: 08/14/2021] [Indexed: 01/23/2023]
Abstract
AIMS To estimate the prevalence of neuropathy in adolescents with type 1 diabetes. METHODS Systematic collection of published studies exploring the prevalence of large fibre neuropathy (LFN), small fibre neuropathy (SFN), and autonomic neuropathy in adolescents with type 1 diabetes. Following prospective registration (Prospero CRD42020206093), PubMed, EMBASE, and Cochrane Library were searched for studies from 2000 to 2020. PICO framework was used in the selection process (Population: adolescents aged 10-19 years with type 1 diabetes; Intervention: diagnostic methods for neuropathy; Comparison: reference data; Outcome: data on prevalence or comparison). Data were extracted concerning study quality based on available data and established methods for determining and diagnosing various neuropathy types. RESULTS From 2,017 initial citations, 27 studies (7589 participants) fulfilled eligibility criteria. The study population (47% males) had a diabetes duration between 4.0 and 10.6 years, and HbA1c level between 7.3 and 10.8%, 56-95 mmol/mol. The prevalence of LFN, based on nerve conduction studies, was 10-57%. Based on other tests for neuropathy, the prevalence of LFN and SFN was 12-62%, and that of cardiac autonomic neuropathy was 12-75%. CONCLUSION The described prevalence of neuropathy in adolescents with type 1 diabetes varied, which can be methodological due to different screening methods and classifications of neuropathy.
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Affiliation(s)
- Vinni Faber Rasmussen
- Danish Pain Research Center, Department of Clinical Medicine, Aarhus University, Aarhus, Denmark; Department of Paediatrics, Randers Regional Hospital, Randers, Denmark.
| | - Troels Staehelin Jensen
- Danish Pain Research Center, Department of Clinical Medicine, Aarhus University, Aarhus, Denmark; International Diabetic Neuropathy Consortium, Aarhus University, Denmark
| | - Hatice Tankisi
- Department of Neurophysiology, Department of Clinical Medicine, Aarhus University, Denmark
| | - Páll Karlsson
- Danish Pain Research Center, Department of Clinical Medicine, Aarhus University, Aarhus, Denmark; Core Centre for Molecular Morphology, Section for Stereology and Microscopy, Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
| | - Esben Thyssen Vestergaard
- Department of Paediatrics, Randers Regional Hospital, Randers, Denmark; Steno Diabetes Center Aarhus, Aarhus University Hospital, Denmark
| | - Kurt Kristensen
- Steno Diabetes Center Aarhus, Aarhus University Hospital, Denmark
| | - Jens Randel Nyengaard
- Core Centre for Molecular Morphology, Section for Stereology and Microscopy, Department of Clinical Medicine, Aarhus University, Aarhus, Denmark; Department of Pathology, Aarhus University Hospital, Aarhus, Denmark
| | - Astrid Juhl Terkelsen
- Danish Pain Research Center, Department of Clinical Medicine, Aarhus University, Aarhus, Denmark; Department of Neurology, Aarhus University Hospital, Aarhus, Denmark
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20
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Keller J, Hammer HF, Afolabi PR, Benninga M, Borrelli O, Dominguez-Munoz E, Dumitrascu D, Goetze O, Haas SL, Hauser B, Pohl D, Salvatore S, Sonyi M, Thapar N, Verbeke K, Fox MR. European guideline on indications, performance and clinical impact of 13 C-breath tests in adult and pediatric patients: An EAGEN, ESNM, and ESPGHAN consensus, supported by EPC. United European Gastroenterol J 2021; 9:598-625. [PMID: 34128346 PMCID: PMC8259225 DOI: 10.1002/ueg2.12099] [Citation(s) in RCA: 44] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/08/2021] [Accepted: 04/06/2021] [Indexed: 12/20/2022] Open
Abstract
Introduction 13C‐breath tests are valuable, noninvasive diagnostic tests that can be widely applied for the assessment of gastroenterological symptoms and diseases. Currently, the potential of these tests is compromised by a lack of standardization regarding performance and interpretation among expert centers. Methods This consensus‐based clinical practice guideline defines the clinical indications, performance, and interpretation of 13C‐breath tests in adult and pediatric patients. A balance between scientific evidence and clinical experience was achieved by a Delphi consensus that involved 43 experts from 18 European countries. Consensus on individual statements and recommendations was established if ≥ 80% of reviewers agreed and <10% disagreed. Results The guideline gives an overview over general methodology of 13C‐breath testing and provides recommendations for the use of 13C‐breath tests to diagnose Helicobacter pylori infection, measure gastric emptying time, and monitor pancreatic exocrine and liver function in adult and pediatric patients. Other potential applications of 13C‐breath testing are summarized briefly. The recommendations specifically detail when and how individual 13C‐breath tests should be performed including examples for well‐established test protocols, patient preparation, and reporting of test results. Conclusion This clinical practice guideline should improve pan‐European harmonization of diagnostic approaches to symptoms and disorders, which are very common in specialist and primary care gastroenterology practice, both in adult and pediatric patients. In addition, this guideline identifies areas of future clinical research involving the use of 13C‐breath tests.
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Affiliation(s)
- Jutta Keller
- Department of Internal Medicine, Israelitic Hospital, Academic Hospital University of Hamburg, Hamburg, Germany
| | - Heinz F Hammer
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, Medical University of Graz, Graz, Austria
| | - Paul R Afolabi
- NIHR Southampton Biomedical Research Centre, University Hospital Southampton NHS Foundation Trust and University of Southampton, Southampton, UK
| | - Marc Benninga
- Department of Pediatric Gastroenterology, Hepatology and Nutrition, Emma Children's Hospital, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
| | - Osvaldo Borrelli
- UCL Great Ormond Street Institute of Child Health and Department of Gastroenterology, Neurogastroenterology and Motility, Great Ormond Street Hospital, London, UK
| | - Enrique Dominguez-Munoz
- Department of Gastroenterology and Hepatology, University Hospital of Santiago de Compostela, Santiago, Spain
| | | | - Oliver Goetze
- Department of Medicine II, Division of Hepatology, University Hospital Würzburg, Würzburg, Germany
| | - Stephan L Haas
- Department of Upper GI Diseases, Karolinska University Hospital, Stockholm, Sweden
| | - Bruno Hauser
- Department of Paediatric Gastroenterology, Hepatology and Nutrition, KidZ Health Castle UZ Brussels, Brussels, Belgium
| | - Daniel Pohl
- Division of Gastroenterology and Hepatology, University Hospital Zürich, Zürich, Switzerland
| | - Silvia Salvatore
- Pediatric Department, Hospital "F. Del Ponte", University of Insubria, Varese, Italy
| | - Marc Sonyi
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, Medical University of Graz, Graz, Austria.,Clinic for General Medicine, Gastroenterology, and Infectious Diseases, Augustinerinnen Hospital, Cologne, Germany
| | - Nikhil Thapar
- UCL Great Ormond Street Institute of Child Health and Department of Gastroenterology, Neurogastroenterology and Motility, Great Ormond Street Hospital, London, UK.,Department of Gastroenterology, Hepatology and Liver Transplantation, Queensland Children's Hospital, Brisbane, Australia
| | - Kristin Verbeke
- Translational Research Center for Gastrointestinal Disorders, KU Leuven, Leuven, Belgium
| | - Mark R Fox
- Division of Gastroenterology and Hepatology, University Hospital Zürich, Zürich, Switzerland.,Digestive Function: Basel, Laboratory and Clinic for Motility Disorders and Functional Gastrointestinal Diseases, Centre for Integrative Gastroenterology, Klinik Arlesheim, Arlesheim, Switzerland
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21
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Keller J, Hammer HF, Hauser B. 13 C-gastric emptying breath tests: Clinical use in adults and children. Neurogastroenterol Motil 2021; 33:e14172. [PMID: 33998745 DOI: 10.1111/nmo.14172] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/21/2021] [Accepted: 04/27/2021] [Indexed: 12/28/2022]
Abstract
13 C-gastric emptying breath tests (13 C-GEBT) are validated, reliable, and non-invasive tools for measurement of gastric emptying (GE) velocity of solids and liquids without radiation exposure or risk of toxicity. They are recommended and routinely used for clinical purposes in adult as well as pediatric patients and can be readily performed onsite or even at the patient's home. However, the underlying methodology is rather complex and test results can be influenced by dietary factors, physical activity, concurrent diseases, and medication. Moreover, epidemiological factors can influence gastric emptying as well as production and exhalation of 13 CO2 , which is the ultimate metabolic product measured for all 13 C-breath tests. Accordingly, in this issue of Neurogastroenterology & Motility, Kovacic et al. report performance of the 13 C-Spirulina breath test in a large group of healthy children and show significant effects of gender, pubertal status, and body size on test results. The purpose of this mini-review is to evaluate the clinical use of 13 C-GEBT in adults and children, exploring available protocols, analytical methods, and essential prerequisites for test performance, as well as the role of GE measurements in the light of the current discussion on relevance of delayed GE for symptom generation.
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Affiliation(s)
- Jutta Keller
- Department of Internal Medicine, Israelitic Hospital, Academic Hospital University of Hamburg, Hamburg, Germany
| | - Heinz F Hammer
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University Graz, Graz, Austria
| | - Bruno Hauser
- Department of Paediatric Gastroenterology, Hepatology and Nutrition, KidZ Health Castle UZ Brussel, Brussels, Belgium
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22
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Petri M, Singh I, Baker C, Underkofler C, Rasouli N. Diabetic gastroparesis: An overview of pathogenesis, clinical presentation and novel therapies, with a focus on ghrelin receptor agonists. J Diabetes Complications 2021; 35:107733. [PMID: 32948398 DOI: 10.1016/j.jdiacomp.2020.107733] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2020] [Revised: 08/29/2020] [Accepted: 08/29/2020] [Indexed: 12/19/2022]
Abstract
Diabetic gastroparesis is defined as delayed gastric emptying without mechanical obstruction in the setting of diabetes. Symptoms range from mild bloating to severe vomiting episodes and can result in frequent hospitalizations and poor quality of life. It is suspected that diabetic gastroparesis is underdiagnosed due to its similar presentation to other conditions such as gastroesophageal reflux disease. The pathogenesis of diabetic gastroparesis remains unclear, but proposed mechanisms include vagal dysfunction, hyperglycemia, interstitial cells of Cajal network disturbances, loss of neural nitric oxide synthase expression in the myenteric plexus, and oxidative stress. Current management for diabetic gastroparesis focuses on dietary and lifestyle changes as well as improved glycemic control. Limited options for medical therapies are available that include prokinetic and antiemetic medications. Metoclopramide is the only FDA-approved medication for the treatment of gastroparesis. Metoclopramide improves symptoms of gastroparesis although extended treatment presents challenges such as decreased efficacy over time and increased risks for adverse events. We summarize the current knowledge of the pathophysiology of diabetic gastroparesis and review current and investigational treatments for diabetes gastroparesis.
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Affiliation(s)
- Madison Petri
- Department of Medicine, University of Colorado Anschutz Medical Campus, 12401 East 17th Avenue, Aurora, CO, USA
| | - Inderpreet Singh
- Department of Medicine, University of Colorado Anschutz Medical Campus, 12401 East 17th Avenue, Aurora, CO, USA
| | - Chelsea Baker
- Department of Medicine, University of Colorado Anschutz Medical Campus, 12401 East 17th Avenue, Aurora, CO, USA
| | - Chantal Underkofler
- Department of Medicine, University of Colorado Anschutz Medical Campus, 12401 East 17th Avenue, Aurora, CO, USA
| | - Neda Rasouli
- Department of Medicine, University of Colorado Anschutz Medical Campus, 12401 East 17th Avenue, Aurora, CO, USA.
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Enteroendocrine Hormone Secretion and Metabolic Control: Importance of the Region of the Gut Stimulation. Pharmaceutics 2020; 12:pharmaceutics12090790. [PMID: 32825608 PMCID: PMC7559385 DOI: 10.3390/pharmaceutics12090790] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2020] [Revised: 08/19/2020] [Accepted: 08/19/2020] [Indexed: 12/11/2022] Open
Abstract
It is now widely appreciated that gastrointestinal function is central to the regulation of metabolic homeostasis. Following meal ingestion, the delivery of nutrients from the stomach into the small intestine (i.e., gastric emptying) is tightly controlled to optimise their subsequent digestion and absorption. The complex interaction of intraluminal nutrients (and other bioactive compounds, such as bile acids) with the small and large intestine induces the release of an array of gastrointestinal hormones from specialised enteroendocrine cells (EECs) distributed in various regions of the gut, which in turn to regulate gastric emptying, appetite and postprandial glucose metabolism. Stimulation of gastrointestinal hormone secretion, therefore, represents a promising strategy for the management of metabolic disorders, particularly obesity and type 2 diabetes mellitus (T2DM). That EECs are distributed distinctively between the proximal and distal gut suggests that the region of the gut exposed to intraluminal stimuli is of major relevance to the secretion profile of gastrointestinal hormones and associated metabolic responses. This review discusses the process of intestinal digestion and absorption and their impacts on the release of gastrointestinal hormones and the regulation of postprandial metabolism, with an emphasis on the differences between the proximal and distal gut, and implications for the management of obesity and T2DM.
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Haidar A, Tsoukas MA, Bernier-Twardy S, Yale JF, Rutkowski J, Bossy A, Pytka E, El Fathi A, Strauss N, Legault L. A Novel Dual-Hormone Insulin-and-Pramlintide Artificial Pancreas for Type 1 Diabetes: A Randomized Controlled Crossover Trial. Diabetes Care 2020; 43:597-606. [PMID: 31974099 DOI: 10.2337/dc19-1922] [Citation(s) in RCA: 84] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/26/2019] [Accepted: 11/22/2019] [Indexed: 02/03/2023]
Abstract
OBJECTIVE The rapid insulin-alone artificial pancreas improves glycemia in type 1 diabetes but daytime control remains suboptimal. We propose two novel dual-hormone artificial pancreas systems. RESEARCH DESIGN AND METHODS We conducted a randomized crossover trial comparing a rapid insulin-alone artificial pancreas with rapid insulin-and-pramlintide and with regular insulin-and-pramlintide artificial pancreas systems in adults with type 1 diabetes. Participants were assigned to the interventions in random order during three 24-h inpatient visits. Each visit was preceded by an outpatient hormonal open-loop run-in period of 10-14 days. The dual-hormone artificial pancreas delivered pramlintide in a basal-bolus manner, using a novel dosing algorithm, with a fixed ratio relative to insulin. The primary outcome was time in the range 3.9-10.0 mmol/L. RESULTS Compared with the rapid insulin-alone artificial pancreas system, the rapid insulin-and-pramlintide system increased the time in range from 74% (SD 18%) to 84% (13%) (P = 0.0014), whereas the regular insulin-and-pramlintide system did not change the time in range (69% [19%]; P = 0.22). The increased time in range with the rapid insulin-and-pramlintide system was due to improved daytime control (daytime time in range increased from 63% [23%] to 78% [16%], P = 0.0004). There were 11 (1 per 2.5 days) hypoglycemic events (<3.3 mmol/L with symptoms or <3.0 mmol/L irrespective of symptoms) with the rapid insulin-alone system, compared with 12 (1 per 2.3 days) and 18 (1 per 1.4 days) with the rapid and regular insulin-and-pramlintide systems, respectively. Gastrointestinal symptoms were reported after 0% (0 of 112) of meals with the rapid insulin-alone system, compared with 6% (6 of 108) and 11% (11 of 104) with the rapid and regular insulin-and-pramlintide systems, respectively; none of the symptoms were severe. CONCLUSIONS A novel rapid insulin-and-pramlintide artificial pancreas improves glucose control compared with a rapid insulin-alone artificial pancreas (ClinicalTrials.gov number NCT02814123).
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Affiliation(s)
- Ahmad Haidar
- Department of Biomedical Engineering, McGill University, Montréal, Québec, Canada .,The Research Institute of McGill University Health Centre, Montréal, Québec, Canada
| | - Michael A Tsoukas
- The Research Institute of McGill University Health Centre, Montréal, Québec, Canada.,Royal Victoria Hospital, McGill University Health Centre, Montréal, Québec, Canada
| | - Sarah Bernier-Twardy
- Department of Biomedical Engineering, McGill University, Montréal, Québec, Canada
| | - Jean-Francois Yale
- The Research Institute of McGill University Health Centre, Montréal, Québec, Canada.,Royal Victoria Hospital, McGill University Health Centre, Montréal, Québec, Canada
| | - Joanna Rutkowski
- Department of Biomedical Engineering, McGill University, Montréal, Québec, Canada
| | - Anne Bossy
- Department of Biomedical Engineering, McGill University, Montréal, Québec, Canada
| | - Evelyne Pytka
- Department of Biomedical Engineering, McGill University, Montréal, Québec, Canada
| | - Anas El Fathi
- Department of Biomedical Engineering, McGill University, Montréal, Québec, Canada
| | - Natalia Strauss
- Department of Biomedical Engineering, McGill University, Montréal, Québec, Canada
| | - Laurent Legault
- Montreal Children's Hospital, McGill University Health Centre, Montréal, Québec, Canada
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Abstract
PURPOSE OF REVIEW Gastroparesis is an important complication of diabetes that may have a major impact on the quality of life as a result of upper gastrointestinal symptoms and impaired glycaemic control. Current management strategies include optimising blood glucose control, dietary modifications and supportive nutrition. Pharmacologic approaches with drugs that have prokinetic and/or antiemetic effects are also used widely; however, current available treatments have major limitations. There is increasing recognition that the rate of gastric emptying (GE) is a key determinant of the glycaemic response to a meal. RECENT FINDINGS There is ongoing uncertainty regarding the impact of longstanding hyperglycaemia on GE, which requires clarification. New diagnostic techniques have been developed to better characterise the mechanisms underlying gastroparesis in individual patients, and these have the potential to lead to more personalised therapy. Management of gastroparesis is complex and suboptimal; novel approaches are desirable. This review summarises recent advances in the understanding of diabetic gastroparesis, with an emphasis on the current therapies that influence GE, and the bidirectional relationship between glycaemic control and GE.
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Affiliation(s)
- Ryan Jalleh
- Endocrine and Metabolic Unit, Royal Adelaide Hospital, Adelaide, South Australia, Australia.
| | - Chinmay S Marathe
- Endocrine and Metabolic Unit, Royal Adelaide Hospital, Adelaide, South Australia, Australia
- Adelaide Medical School, University of Adelaide, Adelaide, South Australia, Australia
| | - Christopher K Rayner
- Adelaide Medical School, University of Adelaide, Adelaide, South Australia, Australia
- Department of Gastroenterology and Hepatology, Royal Adelaide Hospital, Adelaide, South Australia, Australia
| | - Karen L Jones
- Endocrine and Metabolic Unit, Royal Adelaide Hospital, Adelaide, South Australia, Australia
- Adelaide Medical School, University of Adelaide, Adelaide, South Australia, Australia
| | - Michael Horowitz
- Endocrine and Metabolic Unit, Royal Adelaide Hospital, Adelaide, South Australia, Australia
- Adelaide Medical School, University of Adelaide, Adelaide, South Australia, Australia
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Goyal RK, Cristofaro V, Sullivan MP. Rapid gastric emptying in diabetes mellitus: Pathophysiology and clinical importance. J Diabetes Complications 2019; 33:107414. [PMID: 31439470 PMCID: PMC7707148 DOI: 10.1016/j.jdiacomp.2019.107414] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/05/2019] [Revised: 07/20/2019] [Accepted: 08/07/2019] [Indexed: 12/23/2022]
Abstract
Although slow gastric emptying (gastroparesis) is a well-known complication of chronic hyperglycemia in diabetes mellitus (DM), it recently has become clear that rapid gastric emptying also is a frequent and important diabetic complication. In contrast, acute hyperglycemia causes slow gastric emptying, and acute hypoglycemia causes rapid gastric emptying. Rapid gastric emptying is frequent in T2DM; however, it may also occur in T1DM, particularly in the early stages of the disease, but may persist even into late stages. Recent studies suggest that usually, the stomach restricts the emptying of nutrients to 1-4 kcals/min. This restriction is due to the action of the gastric 'braking' hormones such as GLP-1, leptin, and amylin acting via the gastric inhibitory vagal motor circuit (GIVMC). Disruption of this braking system leads to rapid gastric emptying. Acute hyperglycemia also slows gastric emptying by stimulating the GIVMC, while acute hypoglycemia causes rapid gastric emptying by stimulating the gastric excitatory vagal motor circuit (GEVMC). In contrast, chronic hyperglycemia causes rapid gastric emptying by inducing oxidative stress in the stomach wall that disrupts inhibitory neuromuscular transmission and increases the contractility of the smooth muscle, while chronic hyperglycemia may also cause slow gastric emptying via severe inflammatory stress caused by proinflammatory macrophages and reduce contractility of the smooth muscle. There is a bidirectional relationship between blood glucose and gastric emptying. Thus, rapid gastric emptying may lead to a sizeable postprandial spike, and slow gastric emptying may blunt it. Postprandial hyperglycemia is involved in the development, progression, and complications of DM. Correction of fast gastric emptying involves agents that activate GIVMC and the use of gastric 'braking' hormones or their analogs. Recognition and treatment of rapid gastric emptying may contribute to better management of postprandial hyperglycemia and prevention of some diabetic complications.
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Affiliation(s)
- Raj K Goyal
- Departments of Medicine and Surgery, VA Boston Healthcare System and Harvard Medical School, Boston, MA, United States of America.
| | - Vivian Cristofaro
- Departments of Medicine and Surgery, VA Boston Healthcare System and Harvard Medical School, Boston, MA, United States of America
| | - Maryrose P Sullivan
- Departments of Medicine and Surgery, VA Boston Healthcare System and Harvard Medical School, Boston, MA, United States of America
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Huang R, Ding X, Fu H, Cai Q. Potential mechanisms of sleeve gastrectomy for reducing weight and improving metabolism in patients with obesity. Surg Obes Relat Dis 2019; 15:1861-1871. [DOI: 10.1016/j.soard.2019.06.022] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2019] [Revised: 06/18/2019] [Accepted: 06/19/2019] [Indexed: 02/07/2023]
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Gomez Cifuentes J, Radetic M, Lopez R, Gabbard S. Clinical Predictors of Rapid Gastric Emptying in Patients Presenting with Dyspeptic Symptoms. Dig Dis Sci 2019; 64:2899-2909. [PMID: 30982211 DOI: 10.1007/s10620-019-05620-8] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/15/2018] [Accepted: 04/08/2019] [Indexed: 12/13/2022]
Abstract
BACKGROUND Rapid gastric emptying (RGE) is defined as less than 30% retention at 1 h of solid meal ingestion. It is unclear whether RGE represents a separated clinical entity or part of the functional dyspepsia spectrum. AIMS To determine clinical predictors of RGE in patients presenting with dyspeptic symptoms. METHODS Retrospective study of patients who underwent solid Gastric Emptying Scintigraphy to evaluate dyspeptic symptoms from January 2011 to September 2012. Patients with delayed gastric emptying (> 10% gastric retention at 4 h) or prior gastric surgery were excluded. Patients with RGE were compared to those with normal gastric emptying (NGE) in a patient ratio of 1:3. Demographic data, symptoms, comorbidities, surgeries, endoscopy findings, medications, HbA1c, and TSH were analyzed. Univariate and multivariate logistic regression analyses were performed. RESULTS A total of 808 patients were included, 202 patients with RGE and 606 patients with NGE. Mean gastric retention at 1 h was 18% [12.0, 24.0] and 65% [52.0, 76.0], respectively. Patient with RGE were more likely to present with nausea/vomiting (OR 2.4, p < 0.001), weight loss (OR 1.7, p = 0.008), and autonomic symptoms (OR 2.8, p = 0.022). Identified clinical predictors of RGE were older age (OR 1.08 [1.01, 1.1], p = 0.018), male gender (OR 2.0 [1.4, 2.9], p ≤ <0.001), higher BMI (OR 1.03 [1.00, 1.05], p = 0.018), diabetes (OR 1.8 [1.2, 2.7], p = 0.05), and fundoplication (OR 4.3 [2.4, 7.7], p ≤ 0.001). CONCLUSION RGE represents a distinct population among patients presenting with dyspepsia in whom fundoplication, diabetes, and male gender were the strongest clinical predictors. RGE was significantly associated with nausea/vomiting, weight loss, and autonomic symptoms.
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Affiliation(s)
| | - Mark Radetic
- Department of Internal Medicine, Cleveland Clinic, Cleveland, OH, USA
| | - Rocio Lopez
- Quantitative Health Sciences, Cleveland Clinic, Cleveland, OH, USA
| | - Scott Gabbard
- Digestive Diseases and Surgery Institute, Cleveland Clinic, Cleveland, OH, USA
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Watson LE, Phillips LK, Wu T, Bound MJ, Jones KL, Horowitz M, Rayner CK. Longitudinal evaluation of gastric emptying in type 2 diabetes. Diabetes Res Clin Pract 2019; 154:27-34. [PMID: 31238060 DOI: 10.1016/j.diabres.2019.06.010] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2019] [Revised: 06/14/2019] [Accepted: 06/18/2019] [Indexed: 02/06/2023]
Abstract
AIMS To evaluate the natural history of gastric emptying in type 2 diabetes. METHODS 12 patients with type 2 diabetes (7 female; age 65.6 ± 1.2 years; duration of known diabetes 22.9 ± 1.5 years) were invited to return for repeat measurements of gastric emptying using the same dual-labelled solid and liquid meal, a mean of 14.0 ± 0.5 years after their initial study. Blood glucose levels, glycated haemoglobin, upper gastrointestinal symptoms and autonomic nerve function at baseline and follow up were also compared. RESULTS Gastric emptying of solids was more rapid at follow up than at baseline (period effect P < 0.05), while emptying of liquids was comparable at baseline and follow up (period effect P = 0.2). Gastric emptying of the solid component was abnormally slow (based on T100min) in 6 subjects at baseline and 1 subject at follow up. Liquid emptying was abnormally slow in 6 subjects at baseline, and 5 subjects at follow up. Two patients were insulin treated at baseline, and 6 at follow up. HbA1c was higher at follow up (P < 0.05); however, fasting blood glucose (P = 0.6), postprandial blood glucose excursions (P = 0.07), autonomic nerve function (P > 0.999), and total upper gastrointestinal symptom score (P = 0.1) did not differ. CONCLUSIONS In patients with long-term type 2 diabetes, gastric emptying of solids and liquids does not usually become more delayed over time, and abnormally slow gastric emptying of solids may improve.
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Affiliation(s)
- Linda E Watson
- Adelaide Medical School, University of Adelaide, Australia; Endocrine Unit, Royal Adelaide Hospital, Australia
| | - Liza K Phillips
- Adelaide Medical School, University of Adelaide, Australia; Endocrine Unit, Royal Adelaide Hospital, Australia
| | - Tongzhi Wu
- Adelaide Medical School, University of Adelaide, Australia; Endocrine Unit, Royal Adelaide Hospital, Australia
| | | | - Karen L Jones
- Adelaide Medical School, University of Adelaide, Australia; Endocrine Unit, Royal Adelaide Hospital, Australia
| | - Michael Horowitz
- Adelaide Medical School, University of Adelaide, Australia; Endocrine Unit, Royal Adelaide Hospital, Australia
| | - Christopher K Rayner
- Adelaide Medical School, University of Adelaide, Australia; Department of Gastroenterology and Hepatology, Royal Adelaide Hospital, Australia.
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Postprandial Glucose Control in Type 1 Diabetes: Importance of the Gastric Emptying Rate. Nutrients 2019; 11:nu11071559. [PMID: 31295897 PMCID: PMC6683017 DOI: 10.3390/nu11071559] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2019] [Revised: 07/05/2019] [Accepted: 07/08/2019] [Indexed: 12/14/2022] Open
Abstract
The achievement of optimal post-prandial (PP) glucose control in patients with type 1 diabetes (T1DM) remains a great challenge. This review summarizes the main factors contributing to PP glucose response and discusses the likely reasons why PP glucose control is rarely achieved in T1DM patients. The macronutrient composition of the meal, the rate of gastric emptying and premeal insulin administration are key factors affecting the PP glucose response in T1DM. Although the use of continuous insulin infusion systems has improved PP glucose control compared to conventional insulin therapy, there is still need for further ameliorations. T1DM patients frequently present a delayed gastric emptying (GE) that produces a lower but more prolonged PP hyperglycemia. In addition, delayed GE is associated with a longer time to reach the glycemic peak, with a consequent mismatch between PP glucose elevation and the timing of premeal insulin action. On this basis, including GE time and meal composition in the algorithms for insulin bolus calculation of the insulin delivery systems could be an important step forward for optimization of PP glucose control in T1DM.
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Porter JA, MacKenzie KE, Darlow BA, Butler R, Day AS. Gastric emptying in children with type 1 diabetes mellitus: A pilot study. J Paediatr Child Health 2019; 55:416-420. [PMID: 30226023 DOI: 10.1111/jpc.14215] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/20/2018] [Revised: 07/11/2018] [Accepted: 08/09/2018] [Indexed: 01/28/2023]
Abstract
AIM Delayed gastric emptying (GE) has been demonstrated in adults with type 1 diabetes mellitus (T1DM). Little is known about GE in children with T1DM. Most methods to measure GE are invasive, that is, scintigraphy, or are only indirectly related to GE, that is, electrogastrography. Carbon-13 breath testing is a non-invasive, very low-risk procedure that accurately correlates with GE time. This was a pilot study to determine the feasibility of using carbon-13 breath testing to measure GE in children with T1DM and healthy controls. METHODS Cases were recruited from children aged 7-15 years presenting to the paediatric diabetic clinic at Christchurch Hospital. Controls were peers of the cases. Children with known gastrointestinal disease were excluded. After an overnight fast, each child ate a standardised pancake labelled with carbon-13 sodium octanoate. Samples of breath were collected over a 4-h period. Samples were analysed by mass spectrometry. GE half time (GET1/2 ) and GE coefficients (GEC) were calculated by linear regression to obtain a measure of GE. RESULTS A total of 19 cases and 15 age- and gender-matched controls underwent testing. The mean GEC in the cases was 3.19 (±0.38) and 2.90 (±0.29) in controls (P = 0.03), with an effect size = 0.86. Mean GET1/2 in the cases was 99 (52.1) min and 103 (27.5) in controls (P = 0.8), with an effect size = 0.1. CONCLUSION The study generated results suggesting that a larger study will be worthwhile to investigate the relationship between GE and T1DM.
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Affiliation(s)
- Jody A Porter
- Paediatric Department, University of Otago, Christchurch, New Zealand
| | - Karen E MacKenzie
- Paediatric Department, University of Otago, Christchurch, New Zealand
| | - Brian A Darlow
- Paediatric Department, University of Otago, Christchurch, New Zealand
| | - Ross Butler
- School of Pharmacy and Medical Science, University of South Australia, Adelaide, South Australia, Australia
| | - Andrew S Day
- Paediatric Department, University of Otago, Christchurch, New Zealand
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Abstract
This article is a comprehensive review of diabetic gastroparesis, defined as delayed or disordered gastric emptying, including basic principles and current trends in management. This review includes sections on anatomy and physiology, diagnosis and differential diagnosis as well as management and current guidelines for treatment of diabetic gastroparesis. Diabetic gastroparesis (DGp) is a component of autonomic neuropathy resulting from long-standing poorly controlled type 1 and type 2 diabetes. The diagnostic workup of DGp first excludes obstruction and other causes including medications that may mimic delayed/disordered gastric emptying. Targeting nutrition, hydration, symptomatic relief and glycemic control are mainstays of treatment for DGp. Additionally, optimal treatment of DGp includes good glycemic management, often involving customizing insulin delivery using basal-bolus insulin and technology, including sensor-augmented pumps and continuous glucose monitoring systems. Prokinetic medications may be helpful in DGp symptoms, although only limited number of medications is currently available in the USA. Selected medication-refractory patients with DGp may benefit from gastric neuromodulation, and some from surgical interventions including pyloric therapies that can also be done endoscopically. As is true of any of the diabetic complications, prevention of DGp by early and optimal glycemic control is more cost-effective.Funding: Hansa Medcell, India.
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Affiliation(s)
- Sathya Krishnasamy
- Division of Endocrinology, Metabolism, and Diabetes, University of Louisville, Louisville, KY, USA
| | - Thomas L Abell
- Division of Gastroenterology, Hepatology, and Nutrition, University of Louisville, Louisville, KY, USA.
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Simultaneous Blood Glucose Monitoring During Gastric-Emptying Scintigraphy May Identify Unsuspected Abnormalities. Clin Nucl Med 2018; 43:411-419. [DOI: 10.1097/rlu.0000000000002084] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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Lupoli R, Creanza A, Griffo E, Nardone G, Rocco A, Bozzetto L, Annuzzi G, Riccardi G, Capaldo B. Gastric Emptying Impacts the Timing of Meal Glucose Peak in Subjects With Uncomplicated Type 1 Diabetes. J Clin Endocrinol Metab 2018; 103:2269-2276. [PMID: 29659867 DOI: 10.1210/jc.2017-02811] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/03/2018] [Accepted: 04/06/2018] [Indexed: 12/25/2022]
Abstract
CONTEXT Diabetes mellitus is associated with gastrointestinal (GI) motility dysfunction, ranging from delayed to accelerated gastric emptying (GE). OBJECTIVE To evaluate GE in patients with type 1 diabetes mellitus (T1DM) without chronic complications and to investigate its relation with postprandial glucose and GI hormone responses. DESIGN Cross-sectional study. SETTING/PARTICIPANTS Forty-two patients with T1DM free of chronic complications referred to Federico II University and 31 healthy controls similar for age, sex, and body mass index. INTERVENTIONS/MAIN OUTCOME MEASURES GE was assessed by using the 13C-octanoate breath test with a standardized solid meal. During the meal, plasma glucose, ghrelin, and glucagon-like peptide 1 (GLP-1) responses were assessed, and GI symptoms were evaluated by a specific questionnaire. RESULTS Patients with T1DM showed a significantly slower GE half-emptying time (GE t1/2) (113 ± 34 minutes) than did controls (89 ± 17 minutes; P < 0.001). Thirty-six percent of T1DM showed a delayed GE (t1/2 > 120 minutes), whereas all controls showed a normal GE. When patients with T1DM were stratified according to GE t1/2, postmeal glucose response was significantly different between those with delayed and those with normal GE (P = 0.013). In particular, patients with T1DM and delayed GE showed a significantly longer mean time to peak glucose than did patients with normal GE (P = 0.004). In addition, GE t1/2 was an independent predictor of the time to peak glucose (β = 0.329; P = 0.025). GLP-1 and ghrelin responses to the test meal, as well as the prevalence of GI symptoms, were similar between patients with T1DM and controls and between patients with T1DM with normal GE and those with delayed GE. CONCLUSIONS Delayed GE time is associated with a longer time to peak glucose. GE evaluation could be useful for individualizing the timing of preprandial insulin bolus in patients with T1DM.
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Affiliation(s)
- Roberta Lupoli
- Department of Neurosciences, Reproductive and Odontostomatological Sciences, Federico II University, Naples, Italy
| | - Annalisa Creanza
- Department of Clinical Medicine and Surgery, Federico II University, Naples, Italy
| | - Ettore Griffo
- Department of Clinical Medicine and Surgery, Federico II University, Naples, Italy
| | - Gerardo Nardone
- Department of Clinical Medicine and Surgery, Federico II University, Naples, Italy
| | - Alba Rocco
- Department of Clinical Medicine and Surgery, Federico II University, Naples, Italy
| | - Lutgarda Bozzetto
- Department of Clinical Medicine and Surgery, Federico II University, Naples, Italy
| | - Giovanni Annuzzi
- Department of Clinical Medicine and Surgery, Federico II University, Naples, Italy
| | - Gabriele Riccardi
- Department of Clinical Medicine and Surgery, Federico II University, Naples, Italy
| | - Brunella Capaldo
- Department of Clinical Medicine and Surgery, Federico II University, Naples, Italy
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Geyer MC, Rayner CK, Horowitz M, Couper JJ. Targeting postprandial glycaemia in children with diabetes: Opportunities and challenges. Diabetes Obes Metab 2018; 20:766-774. [PMID: 29072820 DOI: 10.1111/dom.13141] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2017] [Revised: 10/02/2017] [Accepted: 10/21/2017] [Indexed: 02/05/2023]
Abstract
Postprandial glycaemia makes a substantial contribution to overall glycaemic control in diabetes, particularly in patients whose preprandial glycaemia is relatively well controlled and glycated haemoglobin (HbA1c) only modestly elevated. Our review addresses the determinants of postprandial glycaemia and how it may be targeted therapeutically in children with diabetes. Postprandial glycaemia is influenced by preprandial glycaemia, macronutrients and their absorption, insulin delivery and sensitivity, the action of the enteroendocrine system, and the rate of gastric emptying. Contemporary continuous glucose monitoring systems reveal patterns of post prandial glycaemia and allow management to be guided more precisely. Delays in blood glucose determination, insulin delivery and its absorption remain challenges in the rapidly evolving closed loop continuous subcutaneous insulin and glucagon delivery systems developed for children with type 1 diabetes. Augmentation of the incretin system through nutritional preloads or incretin mimetics targets postprandial glycaemia by slowing gastric emptying as well as insulinotropic and glucagonostatic effects. These treatments are of particular relevance to children with type 2 diabetes. Following the development of targeted therapies in adults, postprandial blood glucose control will now be increasingly targeted in the treatment of diabetes in children.
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Affiliation(s)
- Myfanwy C Geyer
- Discipline of Paediatrics, University of Adelaide, Adelaide, Australia
- Department of Endocrinology and Diabetes, Women's and Children's Hospital, Adelaide, Australia
| | - Christopher K Rayner
- Discipline of Medicine, University of Adelaide, Adelaide, Australia
- Department of Gastroenterology and Hepatology, Royal Adelaide Hospital, Adelaide, Australia
| | - Michael Horowitz
- Discipline of Medicine, University of Adelaide, Adelaide, Australia
- Endocrine and Metabolic Unit, Royal Adelaide Hospital, Adelaide, Australia
| | - Jennifer J Couper
- Department of Endocrinology and Diabetes, Women's and Children's Hospital, Adelaide, Australia
- Robinson Research Institute, University of Adelaide, Adelaide, Australia
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Marathe CS, Rayner CK, Jones KL, Horowitz M. Gastrointestinal motility in people with type 1 diabetes and peripheral neuropathy. Diabetologia 2017; 60:2312-2313. [PMID: 28801705 DOI: 10.1007/s00125-017-4391-3] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/15/2017] [Accepted: 06/21/2017] [Indexed: 02/07/2023]
Affiliation(s)
- Chinmay S Marathe
- Discipline of Medicine, The University of Adelaide, Royal Adelaide Hospital, Level 6, Eleanor Harrald Building, Adelaide, SA, 5000, Australia.
- Centre of Research Excellence in Translating Nutritional Science to Good Health, The University of Adelaide, Adelaide, SA, Australia.
| | - Christopher K Rayner
- Discipline of Medicine, The University of Adelaide, Royal Adelaide Hospital, Level 6, Eleanor Harrald Building, Adelaide, SA, 5000, Australia
- Centre of Research Excellence in Translating Nutritional Science to Good Health, The University of Adelaide, Adelaide, SA, Australia
| | - Karen L Jones
- Discipline of Medicine, The University of Adelaide, Royal Adelaide Hospital, Level 6, Eleanor Harrald Building, Adelaide, SA, 5000, Australia
- Centre of Research Excellence in Translating Nutritional Science to Good Health, The University of Adelaide, Adelaide, SA, Australia
| | - Michael Horowitz
- Discipline of Medicine, The University of Adelaide, Royal Adelaide Hospital, Level 6, Eleanor Harrald Building, Adelaide, SA, 5000, Australia
- Centre of Research Excellence in Translating Nutritional Science to Good Health, The University of Adelaide, Adelaide, SA, Australia
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Wu T, Rayner CK, Horowitz M. Inter-regulation of gastric emptying and incretin hormone secretion: implications for postprandial glycemic control. Biomark Med 2016; 10:1167-1179. [PMID: 27734721 DOI: 10.2217/bmm-2016-0164] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
The GI tract is central to the regulation of postprandial glycemia, with the rate of gastric emptying and the secretion of the incretin hormones, glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1, being key determinants. Gastric emptying exhibits a large interindividual variation; the latter not only accounts for differences in postprandial glycemia but also determines postprandial incretin profiles. Accordingly, the rate of gastric emptying may affect the glucose-lowering efficacy of dipeptidyl peptidase-4 inhibitors. In contrast, glucagon-like peptide-1 receptor agonists lower postprandial glycemia predominantly by their action to slow gastric emptying. This review discusses the inter-relationship between gastric emptying and the incretin axis in the context of changes in blood glucose, with an emphasis on the relevant clinical implications.
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Affiliation(s)
- Tongzhi Wu
- Discipline of Medicine & Centre of Research Excellence in Translating Nutritional Science to Good Health, The University of Adelaide, Adelaide, South Australia
| | - Christopher K Rayner
- Discipline of Medicine & Centre of Research Excellence in Translating Nutritional Science to Good Health, The University of Adelaide, Adelaide, South Australia
| | - Michael Horowitz
- Discipline of Medicine & Centre of Research Excellence in Translating Nutritional Science to Good Health, The University of Adelaide, Adelaide, South Australia
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Marathe CS, Rayner CK, Jones KL, Horowitz M. Novel insights into the effects of diabetes on gastric motility. Expert Rev Gastroenterol Hepatol 2016; 10:581-93. [PMID: 26647088 DOI: 10.1586/17474124.2016.1129898] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
Recent data from the Diabetes Control and Complications Trial/Epidemiology of Diabetic Interventions and Complications cohort indicate that the disease burden of gastroparesis in diabetes remains high, consistent with the outcome of cross-sectional studies in type 1 and 2 diabetes. An improved understanding of the pathogenesis of diabetic gastroparesis at the cellular level has emerged in the last decade, particularly as a result of initiatives such as the National Institute of Health funded Gastroparesis Clinical Research Consortium in the US. Management of diabetic gastroparesis involves dietary and psychological support, attention to glycaemic control, and the use of prokinetic agents. Given that the relationship between upper gastrointestinal symptoms and the rate of gastric emptying is weak, therapies targeted specifically at symptoms, such as nausea or pain, are important. The relationship between gastric emptying and postprandial glycaemia is complex and inter-dependent. Short-acting glucagon-like peptide-1 agonists, that slow gastric emptying, can be used to reduce postprandial glycaemic excursions and, in combination with basal insulin, result in substantial reductions in glycated haemoglobin in type 2 patients.
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Affiliation(s)
- Chinmay S Marathe
- a Discipline of Medicine , The University of Adelaide, Royal Adelaide Hospital , Adelaide , Australia
- b Centre of Research Excellence in Translating Nutritional Science to Good Health , The University of Adelaide , Adelaide , Australia
| | - Christopher K Rayner
- a Discipline of Medicine , The University of Adelaide, Royal Adelaide Hospital , Adelaide , Australia
- b Centre of Research Excellence in Translating Nutritional Science to Good Health , The University of Adelaide , Adelaide , Australia
| | - Karen L Jones
- a Discipline of Medicine , The University of Adelaide, Royal Adelaide Hospital , Adelaide , Australia
- b Centre of Research Excellence in Translating Nutritional Science to Good Health , The University of Adelaide , Adelaide , Australia
| | - Michael Horowitz
- a Discipline of Medicine , The University of Adelaide, Royal Adelaide Hospital , Adelaide , Australia
- b Centre of Research Excellence in Translating Nutritional Science to Good Health , The University of Adelaide , Adelaide , Australia
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