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Capuccio S, Scilletta S, La Rocca F, Miano N, Di Marco M, Bosco G, Di Giacomo Barbagallo F, Scicali R, Piro S, Di Pino A. Implications of GLP-1 Receptor Agonist on Thyroid Function: A Literature Review of Its Effects on Thyroid Volume, Risk of Cancer, Functionality and TSH Levels. Biomolecules 2024; 14:687. [PMID: 38927090 PMCID: PMC11202033 DOI: 10.3390/biom14060687] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2024] [Revised: 06/10/2024] [Accepted: 06/11/2024] [Indexed: 06/28/2024] Open
Abstract
The increasing utilization of Glucagon-like Peptide-1 receptor agonists (GLP-1 RAs) in managing type 2 diabetes mellitus has raised interest regarding their impact on thyroid function. In fact, while these agents are well known for their efficacy in glycemic control and weight management, their association with thyroid disorders requires clarification due to the complex interplay between thyroid hormones and metabolic pathways. Thyroid dysfunction commonly co-occurs with metabolic conditions such as diabetes and obesity, suggesting a profound interconnection between these systems. This review aims to contribute to a deeper understanding of the interaction between GLP-1 RAs and thyroid dysfunction and to clarify the safety of GLP-1 RAs in diabetic patients with thyroid disorders. By synthesizing existing evidence, this review highlights that, despite various studies exploring this topic, current evidence is inconclusive, with conflicting results. It is important to note that these drugs are relatively recent, and longer-term studies with larger sample sizes are likely needed to draw clearer conclusions. Currently, no existing guidelines provide definitive directions on this clinical issue; however, it is advisable to include thyroid function tests in the routine screening of diabetic patients, particularly those treated with GLP-1 Ras, with the goal of optimizing patient care and management.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | - Antonino Di Pino
- Department of Clinical and Experimental Medicine, University of Catania, 95122 Catania, Italy; (S.C.); (S.S.); (F.L.R.)
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Lizarzaburu-Robles JC, Herman WH, Garro-Mendiola A, Galdón Sanz-Pastor A, Lorenzo O. Prediabetes and Cardiometabolic Risk: The Need for Improved Diagnostic Strategies and Treatment to Prevent Diabetes and Cardiovascular Disease. Biomedicines 2024; 12:363. [PMID: 38397965 PMCID: PMC10887025 DOI: 10.3390/biomedicines12020363] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2023] [Revised: 01/15/2024] [Accepted: 01/18/2024] [Indexed: 02/25/2024] Open
Abstract
The progression from prediabetes to type-2 diabetes depends on multiple pathophysiological, clinical, and epidemiological factors that generally overlap. Both insulin resistance and decreased insulin secretion are considered to be the main causes. The diagnosis and approach to the prediabetic patient are heterogeneous. There is no agreement on the diagnostic criteria to identify prediabetic subjects or the approach to those with insufficient responses to treatment, with respect to regression to normal glycemic values or the prevention of complications. The stratification of prediabetic patients, considering the indicators of impaired fasting glucose, impaired glucose tolerance, or HbA1c, can help to identify the sub-phenotypes of subjects at risk for T2DM. However, considering other associated risk factors, such as impaired lipid profiles, or risk scores, such as the Finnish Diabetes Risk Score, may improve classification. Nevertheless, we still do not have enough information regarding cardiovascular risk reduction. The sub-phenotyping of subjects with prediabetes may provide an opportunity to improve the screening and management of cardiometabolic risk in subjects with prediabetes.
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Affiliation(s)
- Juan Carlos Lizarzaburu-Robles
- Endocrinology Unit, Hospital Central de la Fuerza Aérea del Perú, 15046 Lima, Peru;
- Doctorate Program, Universidad Autónoma de Madrid, 28049 Madrid, Spain
| | - William H. Herman
- Department of Internal Medicine and Epidemiology, University of Michigan, Ann Arbor, MI 48109, USA;
| | | | | | - Oscar Lorenzo
- Laboratory of Diabetes and Vascular Pathology, IIS-Fundación Jiménez Díaz, Universidad Autónoma, 28049 Madrid, Spain;
- Biomedical Research Network on Diabetes and Associated Metabolic Disorders (CIBERDEM), Carlos III National Health Institute, 28029 Madrid, Spain
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Meling S, Tjora E, Eichele H, Nedergaard RB, Knop FK, Ejskjaer N, Carlsen S, Njølstad PR, Brock C, Søfteland E. Rectal sensitivity correlated with gastrointestinal-mediated glucose disposal, but not the incretin effect. Endocrinol Diabetes Metab 2024; 7:e463. [PMID: 38059537 PMCID: PMC10782140 DOI: 10.1002/edm2.463] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2023] [Revised: 11/08/2023] [Accepted: 11/19/2023] [Indexed: 12/08/2023] Open
Abstract
OBJECTIVE The mechanisms behind the diminished incretin effect in type 2 diabetes are uncertain, but impaired vagal transmission has been suggested. We aimed to investigate the association between the incretin effect and autonomic neuropathy, and the degree of dysglycaemia and duration of diabetes. DESIGN AND METHODS For a cross-sectional study, we included participants with either longstanding type 2 diabetes, recent onset, untreated diabetes and controls without diabetes matched for age, sex and body mass index. Autonomic nerve function was assessed with cardiovascular reflex tests, heart rate variability and sudomotor function. Visceral afferent nerves in the gut were tested performing rapid rectal balloon distention. An oral glucose tolerance test and an intravenous isoglycaemic glucose infusion were performed to calculate the incretin effect and gastrointestinal-mediated glucose disposal (GIGD). RESULTS Sixty-five participants were recruited. Participants with diabetes had rectal hyposensitivity for earliest sensation (3.7 ± 1.1 kPa in longstanding, 4.0 ± 1.3 in early), compared to controls (3.0 ± 0.9 kPa), p = .005. Rectal hyposensitivity for earliest sensation was not associated with the incretin effect (rho = -0.204, p = .106), but an association was found with GIGD (rho -0.341, p = .005). Incretin effect and GIGD were correlated with all glucose values, HbA1c and duration of diabetes. CONCLUSIONS Rectal hyposensitivity was uncovered in both longstanding and early type 2 diabetes, and was not associated with the incretin effect, but with GIGD, implying a potential link between visceral neuropathy and gastrointestinal handling of glucose. Both the incretin effect and GIGD were associated with the degree of dysglycaemia and the duration of diabetes. PREVIOUSLY PUBLISHED Some of the data have previously been published and presented as a poster on the American Diabetes Association 83rd Scientific Sessions: Meling et al; 1658-P: Rectal Hyposensitivity, a Potential Marker of Enteric Autonomic Nerve Dysfunction, Is Significantly Associated with Gastrointestinally Mediated Glucose Disposal in Persons with Type 2 Diabetes. Diabetes 20 June 2023; 72 (Supplement_1): 1658-P. https://doi.org/10.2337/db23-1658-P.
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Affiliation(s)
- Sondre Meling
- Department of MedicineStavanger University HospitalStavangerNorway
- Department of Clinical ScienceUniversity of BergenBergenNorway
| | - Erling Tjora
- Department of Clinical ScienceUniversity of BergenBergenNorway
- Children and Youth ClinicHaukeland University HospitalBergenNorway
| | - Heike Eichele
- Department of Biological and Medical Psychology, Faculty of PsychologyUniversity of BergenBergenNorway
- Regional resource Centre for Autism, ADHD and Tourette Syndrome Western Norway, Division of PsychiatryHaukeland University HospitalBergenNorway
| | - Rasmus B. Nedergaard
- Mech‐Sense, Department of Gastroenterology and HepatologyAalborg University HospitalAalborgDenmark
| | - Filip K. Knop
- Center for Clinical Metabolic ResearchCopenhagen University Hospital—Herlev and GentofteCopenhagenDenmark
- Department of Clinical Medicine, Faculty of Health and Medical SciencesUniversity of CopenhagenCopenhagenDenmark
- Steno Diabetes Center CopenhagenGentofteDenmark
- Novo Nordisk Foundation Center for Basic Metabolic ResearchUniversity of CopenhagenCopenhagenDenmark
| | - Niels Ejskjaer
- Department of Clinical Medicine, Faculty of MedicineAalborg University HospitalAalborgDenmark
- Steno Diabetes Center North DenmarkAalborg University HospitalAalborgDenmark
- Department of EndocrinologyAalborg University HospitalAalborgDenmark
| | - Siri Carlsen
- Department of MedicineStavanger University HospitalStavangerNorway
| | - Pål R. Njølstad
- Department of Clinical ScienceUniversity of BergenBergenNorway
- Children and Youth ClinicHaukeland University HospitalBergenNorway
- Mohn Center for Diabetes Precision Medicine, Department of Clinical ScienceUniversity of BergenBergenNorway
| | - Christina Brock
- Mech‐Sense, Department of Gastroenterology and HepatologyAalborg University HospitalAalborgDenmark
- Department of Clinical Medicine, Faculty of MedicineAalborg University HospitalAalborgDenmark
- Steno Diabetes Center North DenmarkAalborg University HospitalAalborgDenmark
| | - Eirik Søfteland
- Department of Clinical ScienceUniversity of BergenBergenNorway
- Department of MedicineHaukeland University HospitalBergenNorway
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Di Marco M, Scilletta S, Miano N, Marrano N, Natalicchio A, Giorgino F, Di Mauro S, Filippello A, Scamporrino A, Tribulato P, Bosco G, Di Giacomo Barbagallo F, Scicali R, Milluzzo A, Ballirò T, Frittitta L, Castellino P, Purrello F, Piro S, Di Pino A. Cardiovascular risk and renal injury profile in subjects with type 2 diabetes and non-albuminuric diabetic kidney disease. Cardiovasc Diabetol 2023; 22:344. [PMID: 38093293 PMCID: PMC10720121 DOI: 10.1186/s12933-023-02065-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/14/2023] [Accepted: 11/13/2023] [Indexed: 12/17/2023] Open
Abstract
BACKGROUND In the last years, the classical pattern of diabetic kidney disease (DKD) has been partially overcome, because of the uncovering of a new DKD phenotype with significant renal dysfunction without presence of albuminuria: the non-albuminuric DKD (NA-DKD). To date, the cardiovascular risk associated with this phenotype is still debated. We investigated the cardiovascular risk and renal injury profile of NA-DKD subjects in comparison with other DKD phenotypes. METHODS Pulse wave velocity (PWV), intima-media thickness, presence of carotid atherosclerotic plaque, renal resistive index (RRI), and a panel of urinary biomarkers of kidney injury were evaluated in 160 subjects with type 2 diabetes, stratified according to estimated glomerular filtration rate (eGFR) and urinary albumin to creatinine ratio (UACR) into four groups: controls (UACR < 30 mg/g and eGFR ≥ 60 mL/min/1.73 m2), A-DKD (Albuminuric-DKD, UACR ≥ 30 mg/g and eGFR ≥ 60 mL/min/1.73 m2), NA-DKD (UACR < 30 mg/g and eGFR < 60 mL/min/1.73 m2), AL-DKD (Albuminuric and Low eGFR-DKD; UACR ≥ 30 mg/g and eGFR < 60 mL/min/1.73 m2). RESULTS Subjects with NA-DKD showed a higher PWV (11.83 ± 3.74 m/s vs. 10.24 ± 2.67 m/s, P = 0.045), RRI (0.76 ± 0.11 vs. 0.71 ± 0.09, P = 0.04), and prevalence of carotid atherosclerotic plaque (59% vs. 31%, P = 0.009) compared with controls. These characteristics were similar to those of subjects with AL-DKD, whereas the profile of A-DKD subjects was closer to controls. After multiple regression analyses, we found that RRI, that is in turn influenced by eGFR (β = - 0.01, P = 0.01), was one of the major determinants of PWV (β = 9.4, P = 0.02). Urinary TreFoil Factor 3, a marker of tubular damage, was higher in NA-DKD subjects vs. controls (1533.14 ± 878.31 ng/mL vs. 1253.84 ± 682.17 ng/mL, P = 0.047). Furthermore, after multiple regression analyses, we found that urinary osteopontin was independently associated with PWV (β = 2.6, P = 0.049) and RRI (β = 0.09, P = 0.006). CONCLUSIONS Our data showed a worse cardiovascular and renal injury profile in NA-DKD subjects. This finding emphasizes the central role of eGFR in the definition of cardiovascular risk profile of diabetic subjects together with albuminuria.
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Affiliation(s)
- Maurizio Di Marco
- Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy
| | - Sabrina Scilletta
- Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy
| | - Nicoletta Miano
- Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy
| | - Nicola Marrano
- Department of Precision and Regenerative Medicine and Ionian Area, Section of Internal Medicine, Endocrinology, Andrology and Metabolic Diseases, University of Bari Aldo Moro, 70124, Bari, Italy
| | - Annalisa Natalicchio
- Department of Precision and Regenerative Medicine and Ionian Area, Section of Internal Medicine, Endocrinology, Andrology and Metabolic Diseases, University of Bari Aldo Moro, 70124, Bari, Italy
| | - Francesco Giorgino
- Department of Precision and Regenerative Medicine and Ionian Area, Section of Internal Medicine, Endocrinology, Andrology and Metabolic Diseases, University of Bari Aldo Moro, 70124, Bari, Italy
| | - Stefania Di Mauro
- Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy
| | - Agnese Filippello
- Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy
| | | | - Paola Tribulato
- Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy
| | - Giosiana Bosco
- Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy
| | | | - Roberto Scicali
- Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy
| | - Agostino Milluzzo
- Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy
| | - Teresa Ballirò
- Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy
| | - Lucia Frittitta
- Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy
| | - Pietro Castellino
- Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy
| | - Francesco Purrello
- Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy
| | - Salvatore Piro
- Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy.
| | - Antonino Di Pino
- Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy
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Grespan E, Guolo A, Muscelli E, Ferrannini E, Mari A. Loss of the Incretin Effect in Type 2 Diabetes: A Systematic Review and Meta-analysis. J Clin Endocrinol Metab 2022; 107:2092-2100. [PMID: 35397169 DOI: 10.1210/clinem/dgac213] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/19/2022] [Indexed: 11/19/2022]
Abstract
CONTEXT Loss of the incretin effect (IE) in type 2 diabetes (T2D) contributes to hyperglycemia and the mechanisms underlying this impairment are unclear. OBJECTIVE To quantify the IE impairment in T2D and to investigate the factors associated with it using a meta-analytic approach. METHODS PubMed, Scopus, and Web-of-Science were searched. Studies measuring IE by the gold-standard protocol employing an oral glucose tolerance test (OGTT) and an intravenous glucose infusion at matched glucose levels were selected. We extracted IE, sex, age, body mass index (BMI), and hemoglobin A1c, fasting values, and area under curve (AUC) of glucose, insulin, C-peptide, glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide 1 (GLP-1). In subjects with T2D, we also recorded T2D duration, age at diagnosis, and the percentage of subjects taking antidiabetic medications. RESULTS The IE weighted mean difference between subjects with T2D and those with normal glucose tolerance (NGT) was -27.3% (CI -36.5% to -18.1%; P < .001; I2 = 86.6%) and was affected by age (P < .005). By meta-regression of combined NGT and T2D data, IE was inversely associated with glucose tolerance (lower IE in T2D), BMI, and fasting GIP (P < .05). By meta-regression of T2D studies only, IE was associated with the OGTT glucose dose (P < .0001). IE from insulin was larger than IE from C-peptide (weighted mean difference 11.2%, CI 9.2-13.2%; P < .0001; I2 = 28.1%); the IE difference was inversely associated with glucose tolerance and fasting glucose. CONCLUSION The IE impairment in T2D vs NGT is consistent though considerably variable, age being a possible factor affecting the IE difference. Glucose tolerance, BMI, and fasting GIP are independently associated with IE; in subjects with T2D only, the OGTT dose is a significant covariate.
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Affiliation(s)
| | - Annamaria Guolo
- Department of Statistical Sciences, University of Padua, Padua, Italy
| | - Elza Muscelli
- Department of Internal Medicine, School of Medical Sciences, State University of Campinas, Campinas, Brazil
| | | | - Andrea Mari
- C.N.R. Institute of Neuroscience, Padua, Italy
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Wei J, Tian J, Tang C, Fang X, Miao R, Wu H, Wang X, Tong X. The Influence of Different Types of Diabetes on Vascular Complications. J Diabetes Res 2022; 2022:3448618. [PMID: 35242879 PMCID: PMC8888068 DOI: 10.1155/2022/3448618] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/25/2021] [Revised: 01/27/2022] [Accepted: 02/03/2022] [Indexed: 12/12/2022] Open
Abstract
The final outcome of diabetes is chronic complications, of which vascular complications are the most serious, which is the main cause of death for diabetic patients and the direct cause of the increase in the cost of diabetes. Type 1 and type 2 diabetes are the main types of diabetes, and their pathogenesis is completely different. Type 1 diabetes is caused by genetics and immunity to destroy a large number of β cells, and insulin secretion is absolutely insufficient, which is more prone to microvascular complications. Type 2 diabetes is dominated by insulin resistance, leading to atherosclerosis, which is more likely to progress to macrovascular complications. This article explores the pathogenesis of two types of diabetes, analyzes the pathogenesis of different vascular complications, and tries to explain the different trends in the progression of different types of diabetes to vascular complications, in order to better prevent diabetes and its vascular complications.
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Affiliation(s)
- Jiahua Wei
- Changchun University of Chinese Medicine, Changchun 130117, China
| | - Jiaxing Tian
- Department of Endocrinology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, China
| | - Cheng Tang
- Changchun University of Chinese Medicine, Changchun 130117, China
| | - Xinyi Fang
- Department of Endocrinology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, China
- Beijing University of Traditional Chinese Medicine, Beijing 100029, China
| | - Runyu Miao
- Department of Endocrinology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, China
- Beijing University of Traditional Chinese Medicine, Beijing 100029, China
| | - Haoran Wu
- Beijing University of Traditional Chinese Medicine, Beijing 100029, China
| | - Xiuge Wang
- Affiliated Hospital of Changchun University of Traditional Chinese Medicine, Changchun 130021, China
| | - Xiaolin Tong
- Changchun University of Chinese Medicine, Changchun 130117, China
- Department of Endocrinology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, China
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Di Pino A, Scicali R, Marchisello S, Zanoli L, Ferrara V, Urbano F, Filippello A, Di Mauro S, Scamporrino A, Piro S, Castellino P, Purrello F, Rabuazzo AM. High glomerular filtration rate is associated with impaired arterial stiffness and subendocardial viability ratio in prediabetic subjects. Nutr Metab Cardiovasc Dis 2021; 31:3393-3400. [PMID: 34625357 DOI: 10.1016/j.numecd.2021.08.030] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/17/2021] [Revised: 07/08/2021] [Accepted: 08/04/2021] [Indexed: 11/27/2022]
Abstract
BACKGROUND AND AIMS High glomerular filtration rate (HGFR) is associated with cardiovascular damage in the setting of various conditions such as obesity and diabetes. Prediabetes was also associated with increased GFR, however, the association between prediabetes, HGFR and cardiovascular damage has not been investigated. In this study, we investigated the association between HGFR and early markers of cardiovascular disease in subjects with prediabetes. METHODS AND RESULTS Augmentation pressure (Aug), augmentation index (AIx), subendocardial viability ratio (SEVR), pulse wave velocity (PWV), intima-media thickness (IMT) and estimated GFR (eGFR) were evaluated in 230 subjects with prediabetes. The eGFR was assessed using the Chronic Kidney Disease Epidemiology Collaboration formula. HGFR was defined as an eGFR above the 75th percentile. Prediabetic subjects were divided into two groups according to presence/absence of HGFR: 61 subjects with HGFR and 169 subjects without HGFR. Subjects with HGFR showed higher Aug, AIx and lower SEVR compared with prediabetic subjects with lower eGFR (14.1 ± 7.2 vs 10.8 ± 6.2, 32.9 ± 12.7 vs 27.6 ± 11.7, 153.5 ± 27.8 vs 162 ± 30.2, p < 0.05). No differences were found in PWV and IMT values between the two groups. Then, we performed multiple regression analysis to test the relationship between Aug, SEVR and several cardiovascular risk factors. In multiple regression analysis Aug was associated with age, systolic blood pressure (BP), HOMA-IR and eGFR; the major determinants of SEVR were systolic BP, HOMA-IR and eGFR. CONCLUSION Subjects with prediabetes and HGFR exhibited an increased Aug, AIx and a reduced SEVR. These alterations are associated with eGFR, insulin resistance and systolic BP.
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Affiliation(s)
- Antonino Di Pino
- Department of Clinical and Experimental Medicine, University of Catania, Torre Biologica F. Latteri, S. Sofia Street 89, 9512, Catania, Italy
| | - Roberto Scicali
- Department of Clinical and Experimental Medicine, University of Catania, Torre Biologica F. Latteri, S. Sofia Street 89, 9512, Catania, Italy
| | - Simona Marchisello
- Department of Clinical and Experimental Medicine, University of Catania, Torre Biologica F. Latteri, S. Sofia Street 89, 9512, Catania, Italy
| | - Luca Zanoli
- Department of Clinical and Experimental Medicine, University of Catania, Torre Biologica F. Latteri, S. Sofia Street 89, 9512, Catania, Italy
| | - Viviana Ferrara
- Department of Clinical and Experimental Medicine, University of Catania, Torre Biologica F. Latteri, S. Sofia Street 89, 9512, Catania, Italy
| | - Francesca Urbano
- Department of Clinical and Experimental Medicine, University of Catania, Torre Biologica F. Latteri, S. Sofia Street 89, 9512, Catania, Italy
| | - Agnese Filippello
- Department of Clinical and Experimental Medicine, University of Catania, Torre Biologica F. Latteri, S. Sofia Street 89, 9512, Catania, Italy
| | - Stefania Di Mauro
- Department of Clinical and Experimental Medicine, University of Catania, Torre Biologica F. Latteri, S. Sofia Street 89, 9512, Catania, Italy
| | - Alessandra Scamporrino
- Department of Clinical and Experimental Medicine, University of Catania, Torre Biologica F. Latteri, S. Sofia Street 89, 9512, Catania, Italy
| | - Salvatore Piro
- Department of Clinical and Experimental Medicine, University of Catania, Torre Biologica F. Latteri, S. Sofia Street 89, 9512, Catania, Italy
| | - Pietro Castellino
- Department of Clinical and Experimental Medicine, University of Catania, Torre Biologica F. Latteri, S. Sofia Street 89, 9512, Catania, Italy
| | - Francesco Purrello
- Department of Clinical and Experimental Medicine, University of Catania, Torre Biologica F. Latteri, S. Sofia Street 89, 9512, Catania, Italy.
| | - Agata M Rabuazzo
- Department of Clinical and Experimental Medicine, University of Catania, Torre Biologica F. Latteri, S. Sofia Street 89, 9512, Catania, Italy
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8
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Yang T, Alessandri-Haber N, Fury W, Schaner M, Breese R, LaCroix-Fralish M, Kim J, Adler C, Macdonald LE, Atwal GS, Bai Y. AdRoit is an accurate and robust method to infer complex transcriptome composition. Commun Biol 2021; 4:1218. [PMID: 34686758 PMCID: PMC8536787 DOI: 10.1038/s42003-021-02739-1] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2021] [Accepted: 10/04/2021] [Indexed: 12/31/2022] Open
Abstract
Bulk RNA sequencing provides the opportunity to understand biology at the whole transcriptome level without the prohibitive cost of single cell profiling. Advances in spatial transcriptomics enable to dissect tissue organization and function by genome-wide gene expressions. However, the readout of both technologies is the overall gene expression across potentially many cell types without directly providing the information of cell type constitution. Although several in-silico approaches have been proposed to deconvolute RNA-Seq data composed of multiple cell types, many suffer a deterioration of performance in complex tissues. Here we present AdRoit, an accurate and robust method to infer the cell composition from transcriptome data of mixed cell types. AdRoit uses gene expression profiles obtained from single cell RNA sequencing as a reference. It employs an adaptive learning approach to alleviate the sequencing technique difference between the single cell and the bulk (or spatial) transcriptome data, enhancing cross-platform readout comparability. Our systematic benchmarking and applications, which include deconvoluting complex mixtures that encompass 30 cell types, demonstrate its preferable sensitivity and specificity compared to many existing methods as well as its utilities. In addition, AdRoit is computationally efficient and runs orders of magnitude faster than most methods.
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Affiliation(s)
- Tao Yang
- Regeneron Pharmaceuticals, Inc., Tarrytown, NY, 10591, USA
| | | | - Wen Fury
- Regeneron Pharmaceuticals, Inc., Tarrytown, NY, 10591, USA
| | | | - Robert Breese
- Regeneron Pharmaceuticals, Inc., Tarrytown, NY, 10591, USA
| | | | - Jinrang Kim
- Regeneron Pharmaceuticals, Inc., Tarrytown, NY, 10591, USA
| | | | | | | | - Yu Bai
- Regeneron Pharmaceuticals, Inc., Tarrytown, NY, 10591, USA.
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9
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Kumpatla S, Parveen R, Murugan P, Juttada U, Devarajan A, Viswanathan V. Hyperglucagonemia and impaired insulin sensitivity are associated with development of prediabetes and type 2 diabetes - A study from South India. Diabetes Metab Syndr 2021; 15:102199. [PMID: 34265492 DOI: 10.1016/j.dsx.2021.102199] [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: 04/02/2021] [Revised: 07/01/2021] [Accepted: 07/04/2021] [Indexed: 11/23/2022]
Abstract
BACKGROUND AND AIMS Glucagon levels and glucagon suppression in response to oral glucose load has not been elucidated at different stages of glucose intolerance in India. METHODS A total of 81 subjects underwent OGTT and were classified into three groups as having normal glucose tolerance (NGT) (n = 23), prediabetes (PreDM) (n = 33), newly diagnosed diabetes (NDM) (n = 25). Insulin and glucagon at fasting, 30 and 120 min was measured by ELISA. HOMA-IR, measures of insulin sensitivity, early, late and overall glucagon suppression during OGTT was calculated. RESULTS Plasma glucagon levels were higher at all-time points in the PreDM and NDM groups. Fasting glucagon levels were higher than post glucose load glucagon in all groups. There was a significant difference in the fasting(p = 0.001), 30 min(p = 0.004) and 120 min(p = 0.032) glucagon between the groups. HOMA-IR increased and insulin sensitivity decreased with worsening of glucose intolerance(p < 0.0001). The groups did not differ in terms of early glucagon suppression(p = 0.094). NDM group suppressed glucagon more than NGT from 30 to 120 min after glucose intake. CONCLUSION This study demonstrated higher fasting glucagon levels. Prediabetes and newly diagnosed diabetes individuals had higher glucagon levels, high insulin resistance and lower insulin sensitivity. Hyperglucagonemia may contribute to type 2 diabetes.
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Affiliation(s)
- Satyavani Kumpatla
- Department of Biochemistry, M.V. Hospital for Diabetes and Prof. M. Viswanathan Diabetes Research Centre (WHO Collaborating Centre for Research, Education and Training in Diabetes) (IDF Centre for Excellence in Diabetes Care), Royapuram, Chennai, Tamil Nadu, India
| | - Rizwana Parveen
- Department of Primary Prevention of Diabetes, M.V. Hospital for Diabetes and Prof. M. Viswanathan Diabetes Research Centre (WHO Collaborating Centre for Research, Education and Training in Diabetes) (IDF Centre for Excellence in Diabetes Care), Royapuram, Chennai, Tamil Nadu, India
| | - Premalatha Murugan
- Department of Primary Prevention of Diabetes, M.V. Hospital for Diabetes and Prof. M. Viswanathan Diabetes Research Centre (WHO Collaborating Centre for Research, Education and Training in Diabetes) (IDF Centre for Excellence in Diabetes Care), Royapuram, Chennai, Tamil Nadu, India
| | - Udyama Juttada
- Departments of Genetics, M.V. Hospital for Diabetes and Prof. M. Viswanathan Diabetes Research Centre (WHO Collaborating Centre for Research, Education and Training in Diabetes) (IDF Centre for Excellence in Diabetes Care), Royapuram, Chennai, Tamil Nadu, India
| | - Arutselvi Devarajan
- Department of Epidemiology, M.V. Hospital for Diabetes and Prof. M. Viswanathan Diabetes Research Centre (WHO Collaborating Centre for Research, Education and Training in Diabetes) (IDF Centre for Excellence in Diabetes Care), Royapuram, Chennai, Tamil Nadu, India
| | - Vijay Viswanathan
- Department of Diabetology, M.V. Hospital for Diabetes and Prof. M. Viswanathan Diabetes Research Center (WHO Collaborating Center for Research Education and Training in Diabetes) (IDF Centre for Excellence in Diabetes Care), Royapuram, Chennai, Tamil Nadu, India.
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Roy A, Kamalanathan S, Sahoo J, Kar SS, Naik D, Narayanan N, Merugu C, Patel D. Comparison of islet cell function, insulin sensitivity, and incretin axis between Asian-Indians with either impaired fasting glucose or impaired glucose tolerance, and normal healthy controls. Diabetes Res Clin Pract 2021; 176:108846. [PMID: 33951481 DOI: 10.1016/j.diabres.2021.108846] [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: 03/07/2021] [Revised: 04/24/2021] [Accepted: 04/28/2021] [Indexed: 01/06/2023]
Abstract
AIMS The objective of this study was to compare the islet cell function, insulin sensitivity, and incretin axis between Asian-Indian subjects with either impaired fasting glucose (IFG), or impaired glucose tolerance (IGT), and normal glucose tolerance (NGT). MATERIALS AND METHODS Prediabetes subjects underwent a mixed meal tolerance test(MMTT) after overnight fasting. Samples for glucose, insulin, glucagon, and glucagon-like peptide-1 (GLP-1) were collected at 0, 30, 60, and 120 min. Insulin secretion sensitivity index -2 (ISSI-2) for beta-cell function and Matsuda index for insulin sensitivity were assessed. Alpha cell function was assessed by measuring the area under the curve (AUC) 0-120 glucagon/AUC0-120 glucose. RESULTS A total of sixty subjects were recruited with 20 in each group. The beta-cell function represented by ISSI-2 was impaired in prediabetes subjects as compared to NGT group (IFG: 2.09 ± 0.44 vs. NGT: 3.04 ± 0.80, P < 0.0001, and IGT: 2.33 ± 0.59 vs. NGT: 3.04 ± 0.80, P = 0.002). Similarly, AUC0-120 glucagon/AUC0-120 glucose was also lower in prediabetes group as compared to healthy controls (IFG: 0.41(0.54) vs. NGT: 1.07(0.39), P = 0.003 and IGT: 0.57(0.38) vs. NGT: 1.07(0.39), P = 0.001). CONCLUSION Asian-Indian prediabetes subjects have reduced beta-cell function with lesser glucagon secretion during MMTT as compared to normal healthy controls.
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Affiliation(s)
- Ayan Roy
- Department of Endocrinology, Jawaharlal Institute of Post Graduate Medical Education and Research (JIPMER), Puducherry, India; Department of Endocrinology and Metabolism, All India Institute of Medical Sciences, Jodhpur, Rajasthan, 342005, India
| | - Sadishkumar Kamalanathan
- Department of Endocrinology, Jawaharlal Institute of Post Graduate Medical Education and Research (JIPMER), Puducherry, India
| | - Jayaprakash Sahoo
- Department of Endocrinology, Jawaharlal Institute of Post Graduate Medical Education and Research (JIPMER), Puducherry, India.
| | - Sitanshu Sekhar Kar
- Department of Preventive and Social Medicine, Jawaharlal Institute of Post Graduate Medical Education and Research (JIPMER), Puducherry, India
| | - Dukhabandhu Naik
- Department of Endocrinology, Jawaharlal Institute of Post Graduate Medical Education and Research (JIPMER), Puducherry, India
| | - Niya Narayanan
- Department of Endocrinology, Jawaharlal Institute of Post Graduate Medical Education and Research (JIPMER), Puducherry, India
| | - Chandhana Merugu
- Department of Endocrinology, Jawaharlal Institute of Post Graduate Medical Education and Research (JIPMER), Puducherry, India
| | - Deepika Patel
- Department of Endocrinology, Jawaharlal Institute of Post Graduate Medical Education and Research (JIPMER), Puducherry, India
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Scicali R, Giral P, D'Erasmo L, Cluzel P, Redheuil A, Di Pino A, Rabuazzo AM, Piro S, Arca M, Béliard S, Purrello F, Bruckert E, Gallo A. High TG to HDL ratio plays a significant role on atherosclerosis extension in prediabetes and newly diagnosed type 2 diabetes subjects. Diabetes Metab Res Rev 2021; 37:e3367. [PMID: 32558162 DOI: 10.1002/dmrr.3367] [Citation(s) in RCA: 46] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2020] [Revised: 06/10/2020] [Accepted: 06/11/2020] [Indexed: 12/30/2022]
Abstract
AIMS We investigated the role of TG to HDL ratio (TG/HDL) on atherosclerosis extension, defined as presence of coronary artery calcium (CAC), carotid and femoral plaque, in prediabetes or newly diagnosed type 2 diabetes (T2D). METHODS We performed a retrospective, cross-sectional, single centre study involving 440 prediabetes or newly diagnosed controlled T2D subjects. Participants underwent CAC analysis by computed tomography and carotid and femoral plaque evaluation by ultrasonography and were stratified in high TG/HDL (H-TG/HDL) or low TG/HDL (L-TG/HDL) group according to TG/HDL median value. We estimated atherosclerosis extension according to the number of involved vascular districts. RESULTS CAC was higher in the H-TG/HDL group than L-TG/HDL group (29.15 [0.0-95.68] vs 0.0 [0.0-53.97] AU, P < .01) and CAC > 0 was more prevalent in the H-TG/HDL group than L-TG/HDL group (64.5% vs 45%, P < .001). Femoral atherosclerosis was higher in the H-TG/HDL group than L-TG/HDL group (57.3% vs 43.6%, P < .01). H-TG/HDL group exhibited a lower prevalence of subjects with 0-TWP compared to L-TG/HDL group (21.8% vs 38.6%, P < .01) and higher percentages of subjects with 2-TWP or 3-TWP than L-TG/HDL group (for 2-TWP 29.5% vs 21.5%, P < .05; for 3-TWP 32.7% vs 20.9%, P < .01). Multiple logistic regression analysis showed that a H-TG/HDL was inversely associated to 0-TWP (P < .05) and positively associated with 2-TWP (P < .05) and 3-TWP (P < .01). CONCLUSIONS Our data suggest that TG/HDL is a marker of increased atherosclerotic extension in prediabetes and newly diagnosed T2D and may be useful to identify subjects with a higher cardiovascular risk profile.
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Affiliation(s)
- Roberto Scicali
- Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy
| | - Philippe Giral
- Cardiovascular Prevention Unit, Department of Endocrinology and Metabolism, Paris Hospital Public Assistance, Pitié-Salpêtrière Hospital Group - Sorbonne University, Paris, France
- Dyslipoproteinemia and Atherosclerosis Research Unit, National Institute for Health and Medical Research (INSERM) and Pierre et Marie Curie University (UPMC - Paris VI), Paris, France
| | - Laura D'Erasmo
- Cardiovascular Prevention Unit, Department of Endocrinology and Metabolism, Paris Hospital Public Assistance, Pitié-Salpêtrière Hospital Group - Sorbonne University, Paris, France
- Department of Translational and Precision Medicine, Sapienza Università di Roma, Rome, Italy
| | - Philippe Cluzel
- Laboratoire d'imagerie Biomédicale, INSERM 1146, - CNRS 7371, Sorbonne University, Paris, France
- Département d'imagerie cardiovasculaire et de radiologie interventionnelle, Pôle Imagerie-Groupe Hospitalier Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris, Paris, France
| | - Alban Redheuil
- Laboratoire d'imagerie Biomédicale, INSERM 1146, - CNRS 7371, Sorbonne University, Paris, France
- Département d'imagerie cardiovasculaire et de radiologie interventionnelle, Pôle Imagerie-Groupe Hospitalier Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris, Paris, France
| | - Antonino Di Pino
- Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy
| | - Agata Maria Rabuazzo
- Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy
| | - Salvatore Piro
- Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy
| | - Marcello Arca
- Department of Translational and Precision Medicine, Sapienza Università di Roma, Rome, Italy
| | - Sophie Béliard
- Aix Marseille Univ, INSERM, INRAE, C2VN, Marseille, France
| | - Francesco Purrello
- Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy
| | - Eric Bruckert
- Cardiovascular Prevention Unit, Department of Endocrinology and Metabolism, Paris Hospital Public Assistance, Pitié-Salpêtrière Hospital Group - Sorbonne University, Paris, France
- Dyslipoproteinemia and Atherosclerosis Research Unit, National Institute for Health and Medical Research (INSERM) and Pierre et Marie Curie University (UPMC - Paris VI), Paris, France
| | - Antonio Gallo
- Cardiovascular Prevention Unit, Department of Endocrinology and Metabolism, Paris Hospital Public Assistance, Pitié-Salpêtrière Hospital Group - Sorbonne University, Paris, France
- Laboratoire d'imagerie Biomédicale, INSERM 1146, - CNRS 7371, Sorbonne University, Paris, France
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12
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Abstract
OBJECTIVES The present study aimed to investigate the dynamic change of α cells and β cells, and their ratios in prediabetes and type 2 diabetes in the Chinese population. METHODS Pancreata from 27 nondiabetic (ND), 8 prediabetic (PreD), and 19 type 2 diabetic (T2D) organ donors were subjected to immunofluorescence staining with insulin and glucagon. RESULTS The β to α ratio in islets (β/α) in PreD was significantly higher than that in ND, resulting from an increase of β cells and a decrease of α cells per islet, but that in T2D was significantly lower than that in ND, resulting from a decrease of β cells and an increase of α cells per islet. The β-cell percentage and β/α ratio positively correlated and α-cell percentage negatively correlated with HbA1c (glycated hemoglobin) in ND and PreD, but these correlations disappeared when T2D subjects were included. CONCLUSIONS The islet β to α ratio increased in PreD individuals because of a relative α-cell loss and β-cell compensation and decreased after T2D onset because of both β-cell loss and α-cell reexpansion.
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13
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Gasbjerg LS, Bergmann NC, Stensen S, Christensen MB, Rosenkilde MM, Holst JJ, Nauck M, Knop FK. Evaluation of the incretin effect in humans using GIP and GLP-1 receptor antagonists. Peptides 2020; 125:170183. [PMID: 31693916 DOI: 10.1016/j.peptides.2019.170183] [Citation(s) in RCA: 59] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/03/2019] [Revised: 10/22/2019] [Accepted: 10/24/2019] [Indexed: 02/07/2023]
Abstract
Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) potentiate glucose-induced insulin secretion and are therefore thought to be responsible for the incretin effect. The magnitude of the incretin effect, defined as the fraction of postprandial insulin secretion stimulated by intestinal factors, has been reported to be up to ∼60% in healthy individuals. In several pathological conditions but especially in patients with type 2 diabetes, the incretin effect is severely reduced or even absent. In line with this, the insulinotropic effects of GIP and GLP-1 are impaired in patients with type 2 diabetes, even when administered in supraphysiological doses. In healthy individuals, GIP has been proposed to be the most important incretin hormone of the two, but the individual contribution of the two is difficult to determine. However, using incretin hormone receptor antagonists: the novel GIP receptor antagonist GIP(3-30)NH2 and the widely used GLP-1 receptor antagonist exendin(9-39)NH2, we can now distinguish between the effects of the two hormones. In this review, we present and discuss studies in which the individual contribution of GIP and GLP-1 to the incretin effect in healthy individuals have been estimated and discuss the limitations of using incretin hormone receptor antagonists.
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Affiliation(s)
- Lærke S Gasbjerg
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark; Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
| | - Natasha C Bergmann
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark
| | - Signe Stensen
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark
| | - Mikkel B Christensen
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Department of Clinical Pharmacology, Bispebjerg Hospital, University of Copenhagen, Copenhagen, Denmark
| | - Mette M Rosenkilde
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Jens J Holst
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Michael Nauck
- Diabetes Division, St. Josef Hospital, Ruhr-University Bochum, Bochum, Germany
| | - Filip K Knop
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark; Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Steno Diabetes Center Copenhagen, Gentofte, Denmark
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14
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Analysis of HDL-microRNA panel in heterozygous familial hypercholesterolemia subjects with LDL receptor null or defective mutation. Sci Rep 2019; 9:20354. [PMID: 31889114 PMCID: PMC6937253 DOI: 10.1038/s41598-019-56857-2] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2019] [Accepted: 12/06/2019] [Indexed: 12/18/2022] Open
Abstract
In the last years increasing attention has been given to the connection between genotype/phenotype and cardiovascular events in subjects with familial hypercholesterolemia (FH). MicroRNAs (miRs) bound to high-density lipoprotein (HDL) may contribute to better discriminate the cardiovascular risk of FH subjects. Our aim was to evaluate the HDL-miR panel in heterozygous FH (HeFH) patients with an LDLR null or defective mutation and its association with pulse wave velocity (PWV). We evaluated lipid panel, HDL-miR panel and PWV in 32 LDLR null mutation (LDLR-null group) and 35 LDLR defective variant (LDLR-defective group) HeFH patients. HDL-miR-486 and HDL-miR-92a levels were more expressed in the LDLR-null group than the LDLR-defective group. When we further stratified the study population into three groups according to both the LDLR genotype and history of ASCVD (LDLR-null/not-ASCVD, LDLR-defective/not-ASCVD and LDLR/ASCVD groups), both the LDLR/ASCVD and the LDLR-null/not-ASCVD groups had a higher expression of HDL-miR-486 and HDL-miR-92a than the LDLR-defective/not-ASCVD group. Finally, HDL-miR-486 and HDL-miR-92a were independently associated with PWV. In conclusion, the LDLR-null group exhibited HDL-miR-486 and HDL-miR-92a levels more expressed than the LDLR-defective group. Further studies are needed to evaluate these HDL-miRs as predictive biomarkers of cardiovascular events in FH.
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Urbano F, Di Pino A, Scicali R, Filippello A, Di Mauro S, Scamporrino A, Marchisello S, Rabuazzo AM, Purrello F, Piro S. Impaired glucagon suppression and reduced insulin sensitivity in subjects with prediabetes undergoing atorvastatin therapy. Eur J Endocrinol 2019; 181:579-590. [PMID: 31546230 PMCID: PMC6977939 DOI: 10.1530/eje-19-0173] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2019] [Accepted: 09/23/2019] [Indexed: 12/30/2022]
Abstract
OBJECTIVE Statin therapy has been linked to an increased risk of type 2 diabetes in high-risk populations; however, the pathophysiology of this association remains to be clarified. We investigated glucagon suppression and its relationship with insulin resistance in prediabetic subjects undergoing atorvastatin therapy; in addition, we studied molecular insulin signaling in pancreatic α-cells exposed to atorvastatin in vitro. DESIGN AND METHODS Fifty subjects with prediabetes were divided into two groups based on atorvastatin therapy. All subjects underwent an oral glucose tolerance test. Early (0-30 min), late (30-120 min) and overall (0-120 min) glucagon suppression were evaluated. Insulin sensitivity was estimated by the insulin sensitivity index (ISI0-120). Insulin signaling pathway and insulin-mediated glucagon suppression were investigated in pancreatic αTC1-6 cells chronically exposed (24 or 48 h) to atorvastatin (100 ng/mL). RESULTS Individuals on statin therapy (n = 26) showed a significantly reduced early (0-30 min) (P = 0.003) and overall (0-120 min) (P = 0.01) glucagon suppression compared with controls (n = 24). In multivariate regression analysis, early glucagon suppression (0-30 min) exhibited a significant correlation with statin therapy. Regression analysis showed a significant association between ISI 0-120 and early0-30 (r = 0.33, P < 0.05) and overall0-120 (r = 0.38, P < 0.05) glucagon suppression. Moreover, in αTC1-6 cells atorvastatin treatment affected insulin-mediated glucagon suppression, insulin receptor phosphorylation and IRS-1-AKT pathway signaling. CONCLUSIONS Prediabetic patients undergoing statin therapy exhibit impaired glucagon suppression associated with lower insulin sensitivity. Our data revealed a new molecular aspect behind the deregulation of insulin sensitivity secondary to statin exposure.
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Affiliation(s)
- Francesca Urbano
- Department of Clinical and Experimental Medicine, Internal Medicine, Garibaldi-Nesima Hospital, University of Catania, Catania, Italy
| | - Antonino Di Pino
- Department of Clinical and Experimental Medicine, Internal Medicine, Garibaldi-Nesima Hospital, University of Catania, Catania, Italy
| | - Roberto Scicali
- Department of Clinical and Experimental Medicine, Internal Medicine, Garibaldi-Nesima Hospital, University of Catania, Catania, Italy
| | - Agnese Filippello
- Department of Clinical and Experimental Medicine, Internal Medicine, Garibaldi-Nesima Hospital, University of Catania, Catania, Italy
| | - Stefania Di Mauro
- Department of Clinical and Experimental Medicine, Internal Medicine, Garibaldi-Nesima Hospital, University of Catania, Catania, Italy
| | - Alessandra Scamporrino
- Department of Clinical and Experimental Medicine, Internal Medicine, Garibaldi-Nesima Hospital, University of Catania, Catania, Italy
| | - Simona Marchisello
- Department of Clinical and Experimental Medicine, Internal Medicine, Garibaldi-Nesima Hospital, University of Catania, Catania, Italy
| | - Agata Maria Rabuazzo
- Department of Clinical and Experimental Medicine, Internal Medicine, Garibaldi-Nesima Hospital, University of Catania, Catania, Italy
| | - Francesco Purrello
- Department of Clinical and Experimental Medicine, Internal Medicine, Garibaldi-Nesima Hospital, University of Catania, Catania, Italy
- Correspondence should be addressed to F Purrello;
| | - Salvatore Piro
- Department of Clinical and Experimental Medicine, Internal Medicine, Garibaldi-Nesima Hospital, University of Catania, Catania, Italy
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16
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Di Pino A, Urbano F, Scicali R, Di Mauro S, Filippello A, Scamporrino A, Piro S, Purrello F, Rabuazzo AM. 1 h Postload Glycemia Is Associated with Low Endogenous Secretory Receptor for Advanced Glycation End Product Levels and Early Markers of Cardiovascular Disease. Cells 2019; 8:cells8080910. [PMID: 31426413 PMCID: PMC6721743 DOI: 10.3390/cells8080910] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2019] [Revised: 08/13/2019] [Accepted: 08/14/2019] [Indexed: 12/30/2022] Open
Abstract
We investigated the correlation of the soluble receptor for advanced glycation end products (sRAGE) and endogenous secretory RAGE (esRAGE) with markers of cardiovascular disease in subjects with normal glucose tolerance (NGT) and 1 h postload glucose ≥155 mg/dL after an oral glucose tolerance test. We stratified 282 subjects without a previous diagnosis of diabetes into three groups: 123 controls (NGT and 1 h postload glycemia <155 mg/dL), 84 NGT and 1 h postload glycemia ≥155 mg/dL (NGT 1 h high), and 75 subjects with impaired fasting glucose and/or impaired glucose tolerance (IFG/IGT). NGT 1 h high subjects exhibited lower esRAGE (0.36 ± 0.18 vs. 0.4 5 ± 0.2, p < 0.05) and higher S100A12 levels than controls (5684 (3193.2–8295.6) vs. 3960.1 (2101.8–7419), p < 0.05). Furthermore, they showed an increased pulse wave velocity (PWV) and intima–media thickness (IMT). No differences were found between the NGT 1 h high group and the IFG/IGT group regarding cardiometabolic profiles. After multiple regression analyses, esRAGE was associated with glycated hemoglobin (HbA1c) and high-sensitivity C-reactive protein (hs-CRP). Age, HbA1c, and esRAGE were the determinants of IMT, whereas S100A12 and systolic pressure were the determinants of PWV. The NGT 1 h high group exhibited low esRAGE levels and an altered cardiometabolic profile. HbA1c, S100A12, and hs-CRP were associated with these alterations. In conclusion, subjects with NGT are not a homogeneous population, and they present different cardiovascular and glycometabolic risks.
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18
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Mandaliya DK, Seshadri S. Short Chain Fatty Acids, pancreatic dysfunction and type 2 diabetes. Pancreatology 2019; 19:280-284. [PMID: 30713129 DOI: 10.1016/j.pan.2019.01.021] [Citation(s) in RCA: 69] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/22/2018] [Revised: 01/10/2019] [Accepted: 01/25/2019] [Indexed: 02/07/2023]
Abstract
The microbiota living in gut influence the immune response, metabolism, mood and behavior. The diet plays a pivotal role in maintaining healthy gut microbiota composition and its fermentation leads to production of Short Chain Fatty Acids (SCFAs) mainly acetate, propionate and butyrate. During pancreatic dysfunction, insulin mediated suppression of glucagon is impaired leading to uncontrolled glucose production by liver and state of hyperglycemia. Insulin and glucagon balance is as important as insulin sensitivity which is reduced during Type 2 Diabetes (T2D). Glucagon like peptide-1 (GLP1) produced by Intestinal epithelial cells regulates insulin and glucagon secretion directly via GLP1 receptor on pancreatic cells or via nervous system. But half-life period of GLP1 is very short i.e. about 2 min, after which it is cleaved and inactivated. SCFAs are well documented to induce GLP1 but its direct effect on pancreatic dysfunction has not been reported. This review opens a new avenue to study the role of SCFAs as treatment to pancreatic dysfunction and T2D.
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Affiliation(s)
| | - Sriram Seshadri
- Institute of Science, Nirma University, Ahmedabad, Gujarat, 382481, India.
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Goboza M, Aboua YG, Chegou N, Oguntibeju OO. Vindoline effectively ameliorated diabetes-induced hepatotoxicity by docking oxidative stress, inflammation and hypertriglyceridemia in type 2 diabetes-induced male Wistar rats. Biomed Pharmacother 2019; 112:108638. [PMID: 30784928 DOI: 10.1016/j.biopha.2019.108638] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2018] [Revised: 01/09/2019] [Accepted: 01/28/2019] [Indexed: 12/14/2022] Open
Abstract
Vindoline, an indole alkaloid present in the leaves of Catharanthus roseus plant, has been recently reported to have insulotropic effects. This present study evaluated the possible hepatoprotective effects of vindoline in a type 2 diabetes mellitus rat model. Diabetes mellitus was induced by exposing rats to 10% fructose water for two weeks followed by a single intraperitoneal injection of 40 mg/kg body weight of streptozotocin (STZ). Rats were randomly divided into six groups (n = 8) and treated daily for 6 weeks with the vehicle via oral gavage, vindoline (20 mg/kg) or glibenclamide (5 mg/kg). Weekly fasting blood glucose (FBG) levels and body weight were measured and recorded. Administration of vindoline significantly (p < 0.05) reduced FBG by 15% when compared to the diabetic controls. Vindoline significantly (p < 0.05) decreased diabetes-induced hepatic injury shown by decreased levels of serum alanine transferase (ALT) (-42%), aspartate aminotransferase (AST) (-42%) and alkaline phosphatase (-62%) compared to the diabetic controls. The oxygen radical absorbance capacity and the activities of superoxide dismutase (SOD) and catalase (CAT) were also improved following treatment with vindoline. The results also showed decreased levels of pro-inflammatory cytokines such as TNF-ɑ by (-41%) and IL-6 (-28%) which may have also contributed to the reduction of serum triglycerides (-65%) in the diabetic group treated with vindoline. Histopathological findings showed improvement of both the hepatic and pancreatic tissues following vindoline treatment. Overall, these findings suggest that vindoline may protect the diabetic hepatic tissue from injury via antioxidant, anti-inflammatory and anti-hypertriglyceredemia mechanisms thereby retarding the development of diabetic complications.
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Affiliation(s)
- Mediline Goboza
- Department of Biomedical Sciences, Phytomedicine and Phytochemistry Research Group, Oxidative Stress Research Centre, Faculty of Health & Wellness Sciences, Cape Peninsula University of Technology, P.O. Box 1906, Bellville, 7535, South Africa
| | - Yapo G Aboua
- Department of Health Sciences, Faculty of Health and Applied Sciences, Namibia University of Science and Technology, Private Bag, 13388, Windhoek, Namibia
| | - Novel Chegou
- Department of Biomedical Sciences, Division of Molecular Biology and Human Genetics, DST/NRF Centre of Excellence for Biomedical Tuberculosis Research and SAMRC Centre for Tuberculosis Research, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa
| | - Oluwafemi O Oguntibeju
- Department of Biomedical Sciences, Phytomedicine and Phytochemistry Research Group, Oxidative Stress Research Centre, Faculty of Health & Wellness Sciences, Cape Peninsula University of Technology, P.O. Box 1906, Bellville, 7535, South Africa.
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Parrinello CM, Rudolph BJ, Lazo M, Gallo LC, Thyagarajan B, Cotler SJ, Qi Q, Seeherunvong T, Vidot DC, Strickler HD, Kaplan RC, Isasi CR. Associations of Insulin Resistance and Glycemia With Liver Enzymes in Hispanic/Latino Youths: Results From the Hispanic Community Children's Health Study/Study of Latino Youth (SOL Youth). J Clin Gastroenterol 2019; 53:e46-e53. [PMID: 29099463 PMCID: PMC5934331 DOI: 10.1097/mcg.0000000000000946] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Abstract
BACKGROUND Associations of insulin resistance and hyperglycemia with a panel of liver enzymes have not been well studied in a young, heterogenous Hispanic/Latino population. We aimed to assess the associations of insulin resistance and glycemia with nonalcoholic fatty liver disease (NAFLD), as measured by liver enzymes and the pediatric NAFLD fibrosis index (PNFI), and whether these associations are modified by body mass index and mediated by inflammation or endothelial dysfunction. MATERIALS AND METHODS We conducted a cross-sectional study of 1317 boys and girls aged 8 to 16 years from the Hispanic Community Children's Health Study/Study of Latino Youth. We used Poisson regression to assess the associations of fasting glucose, hemoglobin A1c, and homeostasis model assessment of insulin resistance (HOMA-IR) with elevated alanine aminotransferase (ALT) (>25 U/L in boys, >22 U/L in girls), aspartate aminotransferase (AST) (≥37 U/L), gamma-glutamyl transpeptidase (GGT) (≥17 U/L), and PNFI (≥9; a function of age, waist circumference, and triglyceride level). RESULTS HOMA-IR was associated with elevated ALT, AST, GGT, and PNFI [prevalence ratios (95% confidence intervals) for each 1-unit increase in the natural log of HOMA-IR: 1.99 (1.40-2.81), 2.15 (1.12-4.12), 1.70 (1.26-2.30), and 1.98 (1.43-2.74), respectively]. Associations were observed in overweight/obese children, but not in normal weight children (P-interaction=0.04 for AST and P-interaction=0.07 for GGT). After further adjustment for adiponectin, high-sensitivity C-reactive protein, e-selectin, and PAI-1, associations of HOMA-IR with liver enzymes and PNFI were attenuated, but remained statistically significant for AST and PNFI. CONCLUSION Insulin resistance was associated with NAFLD in overweight/obese Hispanic/Latino youth, and this association may be partially mediated by inflammation and endothelial dysfunction.
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Affiliation(s)
- Christina M. Parrinello
- Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Bryan J. Rudolph
- Department of Pediatrics, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Mariana Lazo
- Johns Hopkins School of Medicine and the Welch Center for Prevention, Epidemiology, and Clinical Research, Baltimore, MD, USA
| | - Linda C. Gallo
- Department of Psychology, San Diego State University, San Diego, CA, USA
| | - Bharat Thyagarajan
- Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, USA
| | - Scott J. Cotler
- The Program for Experimental and Theoretical Modeling, Division of Hepatology, Department of Medicine, Loyola University Chicago, Medical Center, Maywood, IL, USA
| | - Qibin Qi
- Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Tossaporn Seeherunvong
- Division of Pediatric Endocrinology, University of Miami Leonard M. Miller School of Medicine, Miami, FL, USA
| | - Denise C. Vidot
- Department of Psychology, University of Miami, Coral Gables, FL, USA
| | - Howard D. Strickler
- Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Robert C. Kaplan
- Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Carmen R. Isasi
- Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY, USA
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Di Pino A, Mangiafico S, Urbano F, Scicali R, Scandura S, D'Agate V, Piro S, Tamburino C, Purrello F, Rabuazzo AM. HbA1c Identifies Subjects With Prediabetes and Subclinical Left Ventricular Diastolic Dysfunction. J Clin Endocrinol Metab 2017; 102:3756-3764. [PMID: 28973588 DOI: 10.1210/jc.2017-00954] [Citation(s) in RCA: 43] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/21/2017] [Accepted: 07/27/2017] [Indexed: 02/07/2023]
Abstract
CONTEXT Prediabetes is associated with subclinical cardiac changes associated with heart failure development. OBJECTIVE We investigated diastolic function and its association with markers of glycation and inflammation related to cardiovascular disease in patients with prediabetes. We focused on individuals with prediabetes identified only by glycated hemoglobin A1c [HbA1c; 5.7% to 6.4% and normal fasting glucose (NFG) and normal glucose tolerance (NGT) after an oral glucose tolerance test (OGTT)]. DESIGN Cross-sectional study. SETTING Departments of Clinical and Experimental Medicine and Cardiology, University of Catania, Catania, Italy. MAIN OUTCOME MEASURES HbA1c, OGTT, Doppler echocardiography, soluble receptor for advanced glycation end products (sRAGEs), and endogenous secretory RAGE (esRAGE) were evaluated. PATIENTS We recruited 167 subjects with NFG/NGT who were stratified according to HbA1c level: controls (HbA1c <5.7%) and HbA1c prediabetes (HbA1c 5.7% to 6.4%). RESULTS Patients with HbA1c prediabetes (n = 106) showed a lower peak mitral inflow in early diastole (E wave) to late diastolic atrial filling velocity (A wave) ratio (E/A ratio) than controls (n = 61) (1.10 ± 0.24 vs 1.18 ± 0.23; P < 0.05). They showed a higher left atrium volume (LAV) (28.4 ± 5 vs 22.1 ± 3; P < 0.05) and sphericity index (SI) (0.6 ± 0.06 vs 0.5 ± 0.05; P < 0.05). After multiple regression analyses, HbA1c, sRAGE, and esRAGE were the major determinants of E/A ratio, LAV, and SI. CONCLUSIONS Subjects with HbA1c prediabetes exhibited subclinical cardiac alterations associated with sRAGE, esRAGE, and HbA1c. These subjects would not have been classified as having prediabetes on the basis of fasting glycemia or post-OGTT values.
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Affiliation(s)
- Antonino Di Pino
- Department of Clinical and Experimental Medicine, Garibaldi Hospital, University of Catania, 95122 Catania, Italy
| | - Sarah Mangiafico
- Division of Cardiology, Ferrarotto Hospital, University of Catania, 95100 Catania, Italy
| | - Francesca Urbano
- Department of Clinical and Experimental Medicine, Garibaldi Hospital, University of Catania, 95122 Catania, Italy
| | - Roberto Scicali
- Department of Clinical and Experimental Medicine, Garibaldi Hospital, University of Catania, 95122 Catania, Italy
| | - Salvatore Scandura
- Division of Cardiology, Ferrarotto Hospital, University of Catania, 95100 Catania, Italy
| | - Veronica D'Agate
- Division of Cardiology, Ferrarotto Hospital, University of Catania, 95100 Catania, Italy
| | - Salvatore Piro
- Department of Clinical and Experimental Medicine, Garibaldi Hospital, University of Catania, 95122 Catania, Italy
| | - Corrado Tamburino
- Division of Cardiology, Ferrarotto Hospital, University of Catania, 95100 Catania, Italy
| | - Francesco Purrello
- Department of Clinical and Experimental Medicine, Garibaldi Hospital, University of Catania, 95122 Catania, Italy
| | - Agata Maria Rabuazzo
- Department of Clinical and Experimental Medicine, Garibaldi Hospital, University of Catania, 95122 Catania, Italy
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Bertran EA, Berlie HD, Taylor A, Divine G, Jaber LA. Diagnostic performance of HbA 1c for diabetes in Arab vs. European populations: a systematic review and meta-analysis. Diabet Med 2017; 34:156-166. [PMID: 26996656 DOI: 10.1111/dme.13118] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 03/14/2016] [Indexed: 12/16/2022]
Abstract
AIM To examine differences in the performance of HbA1c for diagnosing diabetes in Arabs compared with Europeans. METHODS The PubMed, Embase and Cochrane library databases were searched for records published between 1998 and 2015. Estimates of sensitivity, specificity and log diagnostic odds ratios for an HbA1c cut-point of 48 mmol/mol (6.5%) were compared between Arabs and Europeans, using a bivariate linear mixed-model approach. For studies reporting multiple cut-points, population-specific summary receiver operating characteristic (SROC) curves were constructed. In addition, sensitivity, specificity and Youden Index were estimated for strata defined by HbA1c cut-point and population type. Database searches yielded 1912 unique records; 618 full-text articles were reviewed. Fourteen studies met the inclusion criteria; hand-searching yielded three additional eligible studies. Three Arab (N = 2880) and 16 European populations (N = 49 127) were included in the analysis. RESULTS Summary sensitivity and specificity for a HbA1c cut-point of 48 mmol/mol (6.5%) in both populations were 42% (33-51%), and 97% (95-98%). There was no difference in area under SROC curves between Arab and European populations (0.844 vs. 0.847; P = 0.867), suggesting no difference in HbA1c diagnostic accuracy between populations. Multiple cut-point summary estimates stratified by population suggest that Arabs have lower sensitivity and higher specificity at a HbA1c cut-point of 44 mmol/mol (6.2%) compared with European populations. Estimates also suggest similar test performance at cut-points of 44 mmol/mol (6.2%) and 48 mmol/mol (6.5%) for Arabs. CONCLUSIONS Given the low sensitivity of HbA1c in the high-risk Arab American population, we recommend a combination of glucose-based and HbA1c testing to ensure an accurate and timely diagnosis of diabetes.
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Affiliation(s)
- E A Bertran
- Eugene Applebaum College of Pharmacy and Health Sciences, Department of Pharmacy Practice, Wayne State University, Detroit
| | - H D Berlie
- Eugene Applebaum College of Pharmacy and Health Sciences, Department of Pharmacy Practice, Wayne State University, Detroit
| | - A Taylor
- Henry Ford Health System, Department of Public Health Sciences, Detroit, MI, USA
| | - G Divine
- Henry Ford Health System, Department of Public Health Sciences, Detroit, MI, USA
| | - L A Jaber
- Eugene Applebaum College of Pharmacy and Health Sciences, Department of Pharmacy Practice, Wayne State University, Detroit
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Di Pino A, Urbano F, Piro S, Purrello F, Rabuazzo AM. Update on pre-diabetes: Focus on diagnostic criteria and cardiovascular risk. World J Diabetes 2016; 7:423-432. [PMID: 27795816 PMCID: PMC5065662 DOI: 10.4239/wjd.v7.i18.423] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/07/2016] [Revised: 06/24/2016] [Accepted: 08/15/2016] [Indexed: 02/05/2023] Open
Abstract
Pre-diabetes, which is typically defined as blood glucose concentrations higher than normal but lower than the diabetes threshold, is a high-risk state for diabetes and cardiovascular disease development. As such, it represents three groups of individuals: Those with impaired fasting glucose (IFG), those with impaired glucose tolerance (IGT) and those with a glycated haemoglobin (HbA1c) between 39-46 mmol/mol. Several clinical trials have shown the important role of IFG, IGT and HbA1c-pre-diabetes as predictive tools for the risk of developing type 2 diabetes. Moreover, with regard to cardiovascular disease, pre-diabetes is associated with more advanced vascular damage compared with normoglycaemia, independently of confounding factors. In view of these observations, diagnosis of pre-diabetes is mandatory to prevent or delay the development of the disease and its complications; however, a number of previous studies reported that the concordance between pre-diabetes diagnoses made by IFG, IGT or HbA1c is scarce and there are conflicting data as to which of these methods best predicts cardiovascular disease. This review highlights recent studies and current controversies in the field. In consideration of the expected increased use of HbA1c as a screening tool to identify individuals with alteration of glycaemic homeostasis, we focused on the evidence regarding the ability of HbA1c as a diagnostic tool for pre-diabetes and as a useful marker in identifying patients who have an increased risk for cardiovascular disease. Finally, we reviewed the current evidence regarding non-traditional glycaemic biomarkers and their use as alternatives to or additions to traditional ones.
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Gyldenløve M, Vilsbøll T, Zachariae C, Holst JJ, Knop FK, Skov L. Impaired incretin effect is an early sign of glucose dysmetabolism in nondiabetic patients with psoriasis. J Intern Med 2015; 278:660-70. [PMID: 26174490 DOI: 10.1111/joim.12388] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND Patients with psoriasis have an increased risk of type 2 diabetes. The gastrointestinal system plays a major role in normal glucose metabolism, and in healthy individuals, postprandial insulin secretion is largely mediated by the gut incretin hormones. This potentiation is termed the incretin effect and is reduced in type 2 diabetes. The impact of psoriasis on gastrointestinal factors involved in glucose metabolism has not previously been examined. OBJECTIVE To investigate whether the incretin effect, gastrointestinal-mediated glucose disposal (GIGD) and/or secretion of glucagon and gut incretin hormones are impaired in normal glucose-tolerant patients with psoriasis. METHODS Oral glucose tolerance tests and intravenous isoglycaemic glucose infusions were performed in 12 patients with moderate-to-severe psoriasis and 12 healthy matched control subjects. RESULTS In patients with psoriasis, the incretin effect (39% vs. 57%, P = 0.02) and GIGD (53% vs. 61%, P = 0.04) were significantly reduced compared to control subjects. In addition, patients were glucose intolerant and showed exaggerated glucose-dependent insulinotropic polypeptide responses. CONCLUSION These novel findings support the notion that psoriasis is a prediabetic condition and suggest that gastrointestinal-related mechanisms are involved in the increased susceptibility to type 2 diabetes in patients with psoriasis.
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Affiliation(s)
- M Gyldenløve
- Department of Dermato-Allergology, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark
| | - T Vilsbøll
- Center for Diabetes Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark
| | - C Zachariae
- Department of Dermato-Allergology, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark
| | - J J Holst
- NNF Centre for Basic Metabolic Research, Department of Biomedicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - F K Knop
- Center for Diabetes Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark.,NNF Centre for Basic Metabolic Research, Department of Biomedicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - L Skov
- Department of Dermato-Allergology, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark
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Abstract
PURPOSE OF REVIEW Autoimmune destruction of the β cells is considered the key abnormality in type 1 diabetes mellitus and insulin replacement the primary therapeutic strategy. However, a lack of insulin is accompanied by disturbances in glucagon release, which is excessive postprandially, but insufficient during hypoglycaemia. In addition, replacing insulin alone appears insufficient for adequate glucose control. This review focuses on the growing body of evidence that glucagon abnormalities contribute significantly to the pathophysiology of diabetes and on recent efforts to target the glucagon axis as adjunctive therapy to insulin replacement. RECENT FINDINGS This review discusses recent (since 2013) advances in abnormalities of glucagon regulation and their link to the pathophysiology of diabetes; new mechanisms of glucagon action and regulation; manipulation of glucagon in diabetes treatment; and analytical and systems biology tools to study glucagon regulation. SUMMARY Recent efforts 'resurrected' glucagon as a key hormone in the pathophysiology of diabetes. New studies target its abnormal regulation and action that is key for improving diabetes treatment. The progress is promising, but major questions remain, including unravelling the mechanism of loss of glucagon counterregulation in type 1 diabetes mellitus and how best to manipulate glucagon to achieve more efficient and safer glycaemic control.
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Affiliation(s)
- Leon S Farhy
- Division of Endocrinology and Metabolism, Department of Medicine and Center for Diabetes Technology, University of Virginia, Charlottesville, Virginia, USA
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26
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Færch K, Johansen NB, Witte DR, Lauritzen T, Jørgensen ME, Vistisen D. Relationship between insulin resistance and β-cell dysfunction in subphenotypes of prediabetes and type 2 diabetes. J Clin Endocrinol Metab 2015; 100:707-16. [PMID: 25387263 DOI: 10.1210/jc.2014-2853] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
CONTEXT There is little overlap between diabetes diagnosed by glycated hemoglobin (HbA1c) and blood glucose, and it is unclear which pathophysiological defects are captured when using HbA1c for diagnosis. OBJECTIVE We examined and compared the relationship between insulin sensitivity and β-cell function in different subphenotypes of prediabetes and type 2 diabetes (T2D). DESIGN, SETTING, AND PARTICIPANTS A cross-sectional analysis of the Danish ADDITION-PRO study was performed (n = 1713). Participants without known diabetes were classified into subgroups of prediabetes and T2D based on fasting or 2-hour glucose criteria or HbA1c. Insulin sensitivity and insulin release were determined from glucose and insulin concentrations during the oral glucose tolerance test, and disposition indices were calculated. RESULTS Individuals with prediabetes or T2D diagnosed by fasting glucose had lower absolute insulin release (P ≤ .01) and higher insulin sensitivity in response to glucose intake (P ≤ .01) but a similar disposition index (P ≥ .36), compared with individuals with elevated 2-hour glucose concentrations. Individuals with HbA1c-defined T2D or prediabetes had a mixture of the pathophysiological defects observed in the glucose-defined subgroups, and individuals with normoglycemia by HbA1c had worse pathophysiological abnormalities than individuals with normoglycemia by the glucose criteria. CONCLUSIONS On average, the diagnostic HbA1c criteria for diabetes and prediabetes identified individuals with a mixture of the pathophysiological characteristics found when using the glucose criteria, but the diversity and pathophysiology captured by the oral glucose tolerance test cannot be captured when applying the more simple HbA1c criteria. Whether the disease progression and prognosis will differ in individuals diagnosed by fasting glucose, 2-hour glucose, or HbA1c should be examined in longitudinal studies.
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Affiliation(s)
- Kristine Færch
- Steno Diabetes Center (K.F., N.B.J., M.E.J., D.V.), 2820 Gentofte, Denmark; Danish Diabetes Academy (N.B.J.), 5000 Odense, Denmark; Centre de Recherche Public de la Santé (D.R.W.), 1445 Strassen, Luxembourg; and Institute of Public Health (T.L.), Section of General Practice, University of Aarhus, 8000 Aarhus, Denmark
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Worsley R, Jane F, Robinson PJ, Bell RJ, Davis SR. Metformin for overweight women at midlife: a double-blind, randomized, controlled trial. Climacteric 2014; 18:270-7. [DOI: 10.3109/13697137.2014.954997] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
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