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Dakroub A, Dbouk A, Asfour A, Nasser SA, El-Yazbi AF, Sahebkar A, Eid AA, Iratni R, Eid AH. C-peptide in diabetes: A player in a dual hormone disorder? J Cell Physiol 2024; 239:e31212. [PMID: 38308646 DOI: 10.1002/jcp.31212] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2023] [Revised: 01/16/2024] [Accepted: 01/22/2024] [Indexed: 02/05/2024]
Abstract
C-peptide, a byproduct of insulin synthesis believed to be biologically inert, is emerging as a multifunctional molecule. C-peptide serves an anti-inflammatory and anti-atherogenic role in type 1 diabetes mellitus (T1DM) and early T2DM. C-peptide protects endothelial cells by activating AMP-activated protein kinase α, thus suppressing the activity of NAD(P)H oxidase activity and reducing reactive oxygen species (ROS) generation. It also prevents apoptosis by regulating hyperglycemia-induced p53 upregulation and mitochondrial adaptor p66shc overactivation, as well as reducing caspase-3 activity and promoting expression of B-cell lymphoma-2. Additionally, C-peptide suppresses platelet-derived growth factor (PDGF)-beta receptor and p44/p42 mitogen-activated protein (MAP) kinase phosphorylation to inhibit vascular smooth muscle cells (VSMC) proliferation. It also diminishes leukocyte adhesion by virtue of its capacity to abolish nuclear factor kappa B (NF-kB) signaling, a major pro-inflammatory cascade. Consequently, it is envisaged that supplementation of C-peptide in T1DM might ameliorate or even prevent end-organ damage. In marked contrast, C-peptide increases monocyte recruitment and migration through phosphoinositide 3-kinase (PI-3 kinase)-mediated pathways, induces lipid accumulation via peroxisome proliferator-activated receptor γ upregulation, and stimulates VSMC proliferation and CD4+ lymphocyte migration through Src-kinase and PI-3K dependent pathways. Thus, it promotes atherosclerosis and microvascular damage in late T2DM. Indeed, C-peptide is now contemplated as a potential biomarker for insulin resistance in T2DM and linked to increased coronary artery disease risk. This shift in the understanding of the pathophysiology of diabetes from being a single hormone deficiency to a dual hormone disorder warrants a careful consideration of the role of C-peptide as a unique molecule with promising diagnostic, prognostic, and therapeutic applications.
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Affiliation(s)
- Ali Dakroub
- St. Francis Hospital and Heart Center, Roslyn, New York, USA
| | - Ali Dbouk
- Department of Medicine, Saint-Joseph University Medical School, Hotel-Dieu de France Hospital, Beirut, Lebanon
| | - Aref Asfour
- Leeds Teaching Hospitals NHS Trust, West Yorkshire, United Kingdom
| | | | - Ahmed F El-Yazbi
- Faculty of Pharmacy, Alamein International University (AIU), Alamein City, Egypt
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Alexandria University, Alexandria, Egypt
| | - Amirhossein Sahebkar
- Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Assaad A Eid
- Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine, American University of Beirut, Beirut, Lebanon
| | - Rabah Iratni
- Department of Biology, College of Science, United Arab Emirates University, Al Ain, UAE
| | - Ali H Eid
- Department of Basic Medical Sciences, College of Medicine, QU Health, Qatar University, Doha, Qatar
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Toprak K. Effect of Serum C-Peptide Levels on the Development of Contrast-Induced Nephropathy in Diabetic Patients Undergoing Coronary Angiography. Angiology 2024; 75:139-147. [PMID: 36303403 DOI: 10.1177/00033197221132359] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2023]
Abstract
Contrast-induced nephropathy (CIN) is an important cause of morbidity and mortality, in patients with diabetes who undergo coronary angiography (CAG). It is known that serum C-peptide has renoprotective effects in diabetic nephropathy. Patients with diabetes (n = 552) who underwent CAG in our center between January 2020 and December 2021 were included, retrospectively. The patients were divided into 2 groups: not-developing CIN (group 1) and developing CIN (group 2). CIN developed in 128 (23.1%) of the patients with diabetes who underwent CAG. C-peptide, albumin, hemoglobin, hematocrit, initial creatinine, ejection fraction (EF), were significantly lower in the group that developed CIN compared with the group that did not (P < .05, for all). In correlation analysis, creatinine increase rate (ΔCr) was negatively correlated with C-peptide, hematocrit, and ejection fraction (r = -.241, P < .001; r = -.135, P < .001; r = -.194, P = .001; respectively). In logistic regression analysis, C-peptide level (Odds Ratio: .404, 95% Confidence Interval: .286-.571, P < .001) was an independent predictor of CIN. In the present study, C-peptide level was an independent predictor of CIN in patients with diabetes. This study suggests that low levels of C-peptide are associated with a greater risk of CIN.
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Affiliation(s)
- Kenan Toprak
- Siverek State Hospital and Department of Cardiology, Faculty of Medicine, Harran University, Sanliurfa, Turkey
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3
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Spallone V. Diabetic neuropathy: Current issues in diagnosis and prevention. CHRONIC COMPLICATIONS OF DIABETES MELLITUS 2024:117-163. [DOI: 10.1016/b978-0-323-88426-6.00016-6] [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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Chen J, Huang Y, Liu C, Chi J, Wang Y, Xu L. The role of C-peptide in diabetes and its complications: an updated review. Front Endocrinol (Lausanne) 2023; 14:1256093. [PMID: 37745697 PMCID: PMC10512826 DOI: 10.3389/fendo.2023.1256093] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/10/2023] [Accepted: 08/18/2023] [Indexed: 09/26/2023] Open
Abstract
Worldwide, diabetes and its complications have seriously affected people's quality of life and become a serious public health problem. C-peptide is not only an indicator of pancreatic β-cell function, but also a biologically active peptide that can bind to cell membrane surface signaling molecules and activate downstream signaling pathways to play antioxidant, anti-apoptotic and inflammatory roles, or regulate cellular transcription through internalization. It is complex how C-peptide is related to diabetic complications. Both deficiencies and overproduction can lead to complications, but their mechanisms of action may be different. C-peptide replacement therapy has shown beneficial effects on diabetic complications in animal models when C-peptide is deficient, but results from clinical trials have been unsatisfactory. The complex pattern of the relationship between C-peptide and diabetic chronic complications has not yet been fully understood. Future basic and clinical studies of C-peptide replacement therapies will need to focus on baseline levels of C-peptide in addition to more attention also needs to be paid to post-treatment C-peptide levels to explore the optimal range of fasting C-peptide and postprandial C-peptide maintenance.
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Affiliation(s)
| | | | | | | | - Yangang Wang
- Department of Endocrinology, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Lili Xu
- Department of Endocrinology, The Affiliated Hospital of Qingdao University, Qingdao, China
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Lian X, Qi J, Yuan M, Li X, Wang M, Li G, Yang T, Zhong J. Study on risk factors of diabetic peripheral neuropathy and establishment of a prediction model by machine learning. BMC Med Inform Decis Mak 2023; 23:146. [PMID: 37533059 PMCID: PMC10394817 DOI: 10.1186/s12911-023-02232-1] [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: 04/20/2023] [Accepted: 07/12/2023] [Indexed: 08/04/2023] Open
Abstract
BACKGROUND Diabetic peripheral neuropathy (DPN) is a common complication of diabetes. Predicting the risk of developing DPN is important for clinical decision-making and designing clinical trials. METHODS We retrospectively reviewed the data of 1278 patients with diabetes treated in two central hospitals from 2020 to 2022. The data included medical history, physical examination, and biochemical index test results. After feature selection and data balancing, the cohort was divided into training and internal validation datasets at a 7:3 ratio. Training was made in logistic regression, k-nearest neighbor, decision tree, naive bayes, random forest, and extreme gradient boosting (XGBoost) based on machine learning. The k-fold cross-validation was used for model assessment, and the accuracy, precision, recall, F1-score, and the area under the receiver operating characteristic curve (AUC) were adopted to validate the models' discrimination and clinical practicality. The SHapley Additive exPlanation (SHAP) was used to interpret the best-performing model. RESULTS The XGBoost model outperformed other models, which had an accuracy of 0·746, precision of 0·765, recall of 0·711, F1-score of 0·736, and AUC of 0·813. The SHAP results indicated that age, disease duration, glycated hemoglobin, insulin resistance index, 24-h urine protein quantification, and urine protein concentration were risk factors for DPN, while the ratio between 2-h postprandial C-peptide and fasting C-peptide(C2/C0), total cholesterol, activated partial thromboplastin time, and creatinine were protective factors. CONCLUSIONS The machine learning approach helped established a DPN risk prediction model with good performance. The model identified the factors most closely related to DPN.
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Affiliation(s)
- Xiaoyang Lian
- Affiliated Hospital of Nanjing University of Chinese Medicine，Jiangsu Province Hospital of Chinese Medicine, Nanjing, Jiangsu, 210029, China
| | - Juanzhi Qi
- School of Artificial Intelligence and Information Technology, Nanjing University of Chinese Medicine, Nanjing, 210023, Jiangsu, China
| | - Mengqian Yuan
- Affiliated Hospital of Nanjing University of Chinese Medicine，Jiangsu Province Hospital of Chinese Medicine, Nanjing, Jiangsu, 210029, China
| | - Xiaojie Li
- Jiangsu Health Vocational College, Nanjing, 210036, Jiangsu, China
| | - Ming Wang
- Geriatric Hospital of Nanjing Medical University, Jiangsu Province Official Hospital, Nanjing, Jiangsu, 210036, China
| | - Gang Li
- School of Artificial Intelligence and Information Technology, Nanjing University of Chinese Medicine, Nanjing, 210023, Jiangsu, China
| | - Tao Yang
- School of Artificial Intelligence and Information Technology, Nanjing University of Chinese Medicine, Nanjing, 210023, Jiangsu, China.
| | - Jingchen Zhong
- Affiliated Hospital of Nanjing University of Chinese Medicine，Jiangsu Province Hospital of Chinese Medicine, Nanjing, Jiangsu, 210029, China.
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Li X, Chen M. Correlation of hemoglobin levels with diabetic retinopathy in US adults aged ≥40 years: the NHANES 2005-2008. Front Endocrinol (Lausanne) 2023; 14:1195647. [PMID: 37600684 PMCID: PMC10433903 DOI: 10.3389/fendo.2023.1195647] [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: 03/28/2023] [Accepted: 07/14/2023] [Indexed: 08/22/2023] Open
Abstract
Purpose The aim of this study was to explore the connection between hemoglobin levels and diabetic retinopathy (DR). Methods Cross-sectional research used data from the National Health and Nutrition Examination Survey (NHANES) 2005-2008. A multiple logistic regression analysis was performed to investigate the association between DR and hemoglobin levels. Additionally, generalized additivity models and smoothed curve fitting were carried out. Results After adjusting for several covariates, there was a negative association between hemoglobin levels and DR in the study, which included 837 participants. The negative association between hemoglobin levels and DR was present in men and women, the obese (BMI > 30), and 60- to 69-year-olds in subgroup analyses stratified by sex, BMI, and age. The association between hemoglobin levels and DR in the normal weight group (BMI < 25) displayed an inverted U-shaped curve with an inflection point of 13.7 (g/dL). Conclusion In conclusion, our research reveals that high hemoglobin levels are related to a decreased risk of DR. Ascertaining the hemoglobin levels ought to be regarded as an integral facet of the monitoring regimen for patients with diabetic complications and that the risk of DR is reduced through the detection and management of hemoglobin levels.
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Affiliation(s)
- Xiao Li
- First Clinical Medical College, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Meirong Chen
- Ophthalmology Department, Shandong Hospital of Traditional Chinese Medicine, Jinan, China
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Sharma A, Behl T, Sharma L, Shah OP, Yadav S, Sachdeva M, Rashid S, Bungau SG, Bustea C. Exploring the molecular pathways and therapeutic implications of angiogenesis in neuropathic pain. Biomed Pharmacother 2023; 162:114693. [PMID: 37062217 DOI: 10.1016/j.biopha.2023.114693] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2023] [Revised: 03/26/2023] [Accepted: 04/10/2023] [Indexed: 04/18/2023] Open
Abstract
Recently, much attention has been paid to chronic neuro-inflammatory condition underlying neuropathic pain. It is generally linked with thermal hyperalgesia and tactile allodynia. It results due to injury or infection in the nervous system. The neuropathic pain spectrum covers a variety of pathophysiological states, mostly involved are ischemic injury viral infections associated neuropathies, chemotherapy-induced peripheral neuropathies, autoimmune disorders, traumatic origin, hereditary neuropathies, inflammatory disorders, and channelopathies. In CNS, angiogenesis is evident in inflammation of neurons and pain in bone cancer. The role of chemokines and cytokines is dualistic; their aggressive secretion produces detrimental effects, leading to neuropathic pain. However, whether the angiogenesis contributes and exists in neuropathic pain remains doubtful. In the present review, we elucidated summary of diverse mechanisms of neuropathic pain associated with angiogenesis. Moreover, an overview of multiple targets that have provided insights on the VEGF signaling, signaling through Tie-1 and Tie-2 receptor, erythropoietin pathway promoting axonal growth are also discussed. Because angiogenesis as a result of these signaling, results in inflammation, we focused on the mechanisms of neuropathic pain. These factors are mainly responsible for the activation of post-traumatic regeneration of the PNS and CNS. Furthermore, we also reviewed synthetic and herbal treatments targeting angiogenesis in neuropathic pain.
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Affiliation(s)
- Aditi Sharma
- School of Pharmaceutical Sciences, Shoolini University, Solan 173211, Himachal Pradesh, India
| | - Tapan Behl
- School of Health Sciences and Technology, University of Petroleum and Energy Studies, Bidholi, 248007 Dehradun, Uttarakhand, India.
| | - Lalit Sharma
- School of Pharmaceutical Sciences, Shoolini University, Solan 173211, Himachal Pradesh, India
| | - Om Prakash Shah
- School of Pharmaceutical Sciences, Shoolini University, Solan 173211, Himachal Pradesh, India
| | - Shivam Yadav
- Department of Pharmaceutical Sciences, School of Pharmaceutical Sciences, Chhatrapati Shahu ji Maharaj University, Kanpur 208024, Uttar Pradesh, India
| | - Monika Sachdeva
- Fatima College of Health Sciences, Al Ain 00000, United Arab Emirates
| | - Summya Rashid
- Department of Pharmacology & Toxicology, College of Pharmacy, Prince Sattam Bin Abdulaziz University, Al-Kharj 11942, Saudi Arabia
| | - Simona Gabriela Bungau
- Department of Pharmacy, Faculty of Medicine and Pharmacy, University of Oradea, Oradea 410028, Romania; Doctoral School of Biomedical Sciences, University of Oradea, Oradea 410028, Romania.
| | - Cristiana Bustea
- Department of Preclinical Disciplines, Faculty of Medicine and Pharmacy, University of Oradea, Oradea 410073, Romania
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Dai FC, Wang P, Li Q, Zhang L, Yu LJ, Wu L, Tao RX, Zhu P. Mediterranean diet during pregnancy and infant neurodevelopment: A prospective birth cohort study. Front Nutr 2023; 9:1078481. [PMID: 36726814 PMCID: PMC9885498 DOI: 10.3389/fnut.2022.1078481] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2022] [Accepted: 12/28/2022] [Indexed: 01/18/2023] Open
Abstract
Background Embryonic neural development is associated with intrauterine nutritional status. However, few cohort studies estimated the relationship between maternal dietary patterns during pregnancy and offspring's early neurodevelopment. Objective To examine the impact of the Mediterranean diet (MD) during pregnancy on infant neurodevelopment, including the potential mediating role of cord blood metabolites. Methods Among 1,471 mother-child pairs in a prospective birth cohort study in Hefei, China, we investigated the associations between maternal MD score [calculated based on a validated food frequency questionnaire (FFQ)] and child neurodevelopment at infancy [assessed using Ages and Stages Questionnaires, Third Edition (ASQ-3)]. The cord blood metabolic markers (including C-peptide, high-density lipoprotein-cholesterol, low-density lipoprotein-cholesterol, total cholesterol, and triglycerides) were measured. Results The MD score was negatively associated with communication domain developmental delays in infants [relative risk (RR) with 95% CI: 0.34 (0.16, 0.72)]. Compared with girls, boys born from mothers with lower MD scores during pregnancy were inclined to the failure of the communication domain [RRs with 95% CI for boys: 0.34 (0.14, 0.84); for girls: 0.26 (0.06, 1.18)]. Mediation analysis showed that the association between the maternal MD score and failure of communication domain mediated by C-peptide was 19.4% in boys but not in girls. Conclusion Adhering to the MD during pregnancy was associated with a decreased risk of poor neurodevelopment, possibly mediated by lower levels of cord blood C-peptide.
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Affiliation(s)
- Fei-cai Dai
- Department of Maternal, Child and Adolescent Health, School of Public Health, Anhui Medical University, Hefei, China,MOE Key Laboratory of Population Health Across Life Cycle, Hefei, China,NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract, Anhui Medical University, Hefei, China,Anhui Provincial Key Laboratory of Population Health and Aristogenics, Anhui Medical University, Hefei, China
| | - Peng Wang
- Department of Maternal, Child and Adolescent Health, School of Public Health, Anhui Medical University, Hefei, China,MOE Key Laboratory of Population Health Across Life Cycle, Hefei, China,NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract, Anhui Medical University, Hefei, China,Anhui Provincial Key Laboratory of Population Health and Aristogenics, Anhui Medical University, Hefei, China
| | - Qiong Li
- Department of Maternal, Child and Adolescent Health, School of Public Health, Anhui Medical University, Hefei, China,MOE Key Laboratory of Population Health Across Life Cycle, Hefei, China,NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract, Anhui Medical University, Hefei, China,Anhui Provincial Key Laboratory of Population Health and Aristogenics, Anhui Medical University, Hefei, China
| | - Lei Zhang
- Department of Maternal, Child and Adolescent Health, School of Public Health, Anhui Medical University, Hefei, China,MOE Key Laboratory of Population Health Across Life Cycle, Hefei, China,NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract, Anhui Medical University, Hefei, China,Anhui Provincial Key Laboratory of Population Health and Aristogenics, Anhui Medical University, Hefei, China
| | - Li-jun Yu
- Department of Maternal, Child and Adolescent Health, School of Public Health, Anhui Medical University, Hefei, China,MOE Key Laboratory of Population Health Across Life Cycle, Hefei, China,NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract, Anhui Medical University, Hefei, China,Anhui Provincial Key Laboratory of Population Health and Aristogenics, Anhui Medical University, Hefei, China
| | - Lin Wu
- Department of Maternal, Child and Adolescent Health, School of Public Health, Anhui Medical University, Hefei, China,MOE Key Laboratory of Population Health Across Life Cycle, Hefei, China,NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract, Anhui Medical University, Hefei, China,Anhui Provincial Key Laboratory of Population Health and Aristogenics, Anhui Medical University, Hefei, China
| | - Rui-xue Tao
- Department of Gynecology and Obstetrics, Hefei First People's Hospital, Hefei, China,*Correspondence: Rui-xue Tao ✉
| | - Peng Zhu
- Department of Maternal, Child and Adolescent Health, School of Public Health, Anhui Medical University, Hefei, China,MOE Key Laboratory of Population Health Across Life Cycle, Hefei, China,NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract, Anhui Medical University, Hefei, China,Anhui Provincial Key Laboratory of Population Health and Aristogenics, Anhui Medical University, Hefei, China,Peng Zhu ✉
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Wang P, Xie J, Jiao XC, Ma SS, Liu Y, Yin WJ, Tao RX, Hu HL, Zhang Y, Chen XX, Tao FB, Zhu P. Maternal Glycemia During Pregnancy and Early Offspring Development: A Prospective Birth Cohort Study. J Clin Endocrinol Metab 2021; 106:2279-2290. [PMID: 33982055 DOI: 10.1210/clinem/dgab331] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/05/2021] [Indexed: 12/18/2022]
Abstract
CONTEXT The association of maternal gestational diabetes mellitus (GDM) with neurodevelopmental outcomes remains controversial and evidence that maternal increasing levels of glucose during pregnancy associated with the risk for impaired neurodevelopment were limited. OBJECTIVE To identify the continuous association of increasing maternal glucose levels with neurodevelopmental disorders in offspring and explore the potential contribution of cord metabolites to this association. METHODS The prospective birth cohort study included 1036 mother-child pairs. Primary predictors were maternal exposure GDM and maternal glucose values at a 75-g oral-glucose-tolerance test at 24 to 28 weeks during pregnancy. Primary neurodevelopmental outcomes at 12 months in offspring were assessed by the Ages and Stages Questionnaires, Third Edition (ASQ-3). RESULTS Maternal GDM was associated with failing the communication domain in offspring in the adjusted models [relative risk (RR) with 95% CI: 1.97 (1.11, 3.52)]. Increasing levels of fasting plasma glucose (FPG), 1-h plasma glucose (1-h PG) and 2-h plasma glucose (2-h PG) with 1 SD change were at higher risks in failing the personal social domain of ASQ-3 [RRs with 95% CI for FPG: 1.49 (1.09, 2.04); for 1-h PG: 1.70 (1.27, 2.29); for 2-h PG: 1.36 (1.01, 1.84)]. The linear association was also demonstrated. Compared with girls, boys exposed to higher maternal glucose levels were inclined to the failure of the personal social domain. Mediation analysis showed the contribution of maternal GDM to failure of communication domain mediated by C-peptide. CONCLUSIONS Maternal glucose levels below those diagnostic of diabetes are continuously associated with impaired neurodevelopment in offspring at 12 months.
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Affiliation(s)
- Peng Wang
- Department of Maternal, Child & Adolescent Health, School of Public Health, Anhui Medical University, Hefei, China
- MOE Key Laboratory of Population Health Across Life Cycle, Hefei, China
- NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract, Hefei, China
| | - Jun Xie
- Department of Maternal, Child & Adolescent Health, School of Public Health, Anhui Medical University, Hefei, China
- MOE Key Laboratory of Population Health Across Life Cycle, Hefei, China
- NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract, Hefei, China
| | - Xue-Chun Jiao
- Department of Maternal, Child & Adolescent Health, School of Public Health, Anhui Medical University, Hefei, China
| | - Shuang-Shuang Ma
- Department of Maternal, Child & Adolescent Health, School of Public Health, Anhui Medical University, Hefei, China
| | - Yang Liu
- Department of Maternal, Child & Adolescent Health, School of Public Health, Anhui Medical University, Hefei, China
| | - Wan-Jun Yin
- Department of Maternal, Child & Adolescent Health, School of Public Health, Anhui Medical University, Hefei, China
| | - Rui-Xue Tao
- Department of Obstetrics and Gynecology, the First People's Hospital of Hefei City, Hefei, China
| | - Hong-Lin Hu
- Department of endocrinology, the First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Ying Zhang
- Department of Obstetrics and Gynecology, the First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Xian-Xia Chen
- Department of Obstetrics and Gynecology, Anhui Women and Child Health Care Hospital, Hefei, China
| | - Fang-Biao Tao
- Department of Maternal, Child & Adolescent Health, School of Public Health, Anhui Medical University, Hefei, China
- MOE Key Laboratory of Population Health Across Life Cycle, Hefei, China
- NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract, Hefei, China
- Anhui Provincial Key Laboratory of Population Health and Aristogenics, Hefei, China
| | - Peng Zhu
- Department of Maternal, Child & Adolescent Health, School of Public Health, Anhui Medical University, Hefei, China
- MOE Key Laboratory of Population Health Across Life Cycle, Hefei, China
- NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract, Hefei, China
- Anhui Provincial Key Laboratory of Population Health and Aristogenics, Hefei, China
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Keshavarz H, Meints LM, Geiger MK, R Zinn K, Spence DM. Specific Binding of Leptin to Red Blood Cells Delivers a Pancreatic Hormone and Stimulates ATP Release. Mol Pharm 2021; 18:2438-2447. [PMID: 33939443 DOI: 10.1021/acs.molpharmaceut.1c00300] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Since its discovery in 1994, leptin continues to have new potential physiological roles uncovered, including a role in the regulation of blood flow. Leptin's role in regulating blood flow is not completely understood. Red blood cell (RBC)-derived ATP is a recognized stimulus of blood flow, and multiple studies suggest that C-peptide, a hormone secreted in equimolar amounts with insulin from the pancreatic β-cells, can stimulate that release when delivered by albumin and in combination with Zn2+. Here, we report leptin delivers C-peptide and Zn2+ to RBCs in a saturable and specific manner. We labeled leptin with technetium-99 m (99mTc) to perform binding studies while using albumin to block the specific binding of 99mTc-leptin in the presence or absence of C-peptide. Our results suggest that leptin has a saturable and specific binding site on the RBC ((Kd = 1.79 ± 0.46) × 10-7 M) that is statistically equal to the binding affinity in the presence of 20 nM C-peptide ((Kd = 2.05 ± 0.20) × 10-7 M). While the binding affinity between leptin and the RBC did not change with C-peptide, the moles of bound leptin did increase with C-peptide, suggesting a separate binding site on the cell for a leptin/C-peptide complex. The RBC-derived ATP increased in the presence of a leptin/C-peptide/Zn2+ addition, in a concentration-dependent manner. Control RBCs ATP release increased (71 ± 5.6%) in the presence of C-peptide and Zn2+, which increased further to (94 ± 5.6%) in the presence of Zn2+, C-peptide, and leptin.
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Affiliation(s)
- Hamideh Keshavarz
- Department of Chemistry, Michigan State University, East Lansing, Michigan 48824, United States
| | - Lisa M Meints
- Department of Chemistry, Michigan State University, East Lansing, Michigan 48824, United States.,Institute for Quantitative Health Science & Engineering, Michigan State University, East Lansing, Michigan 48824, United States
| | - Morgan K Geiger
- Department of Chemistry, Michigan State University, East Lansing, Michigan 48824, United States.,Department of Biomedical Engineering, Michigan State University, East Lansing, Michigan 48824, United States
| | - Kurt R Zinn
- Institute for Quantitative Health Science & Engineering, Michigan State University, East Lansing, Michigan 48824, United States.,Department of Biomedical Engineering, Michigan State University, East Lansing, Michigan 48824, United States
| | - Dana M Spence
- Institute for Quantitative Health Science & Engineering, Michigan State University, East Lansing, Michigan 48824, United States.,Department of Biomedical Engineering, Michigan State University, East Lansing, Michigan 48824, United States
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Prospects for the Personalized Multimodal Therapy Approach to Pain Management via Action on NO and NOS. Molecules 2021; 26:molecules26092431. [PMID: 33921984 PMCID: PMC8122598 DOI: 10.3390/molecules26092431] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Revised: 04/17/2021] [Accepted: 04/19/2021] [Indexed: 12/15/2022] Open
Abstract
Chronic pain syndromes are an important medical problem generated by various molecular, genetic, and pathophysiologic mechanisms. Back pain, neuropathic pain, and posttraumatic pain are the most important pathological processes associated with chronic pain in adults. Standard approaches to the treatment of them do not solve the problem of pain chronicity. This is the reason for the search for new personalized strategies for the prevention and treatment of chronic pain. The nitric oxide (NO) system can play one of the key roles in the development of peripheral pain and its chronicity. The purpose of the study is to review publications devoted to changes in the NO system in patients with peripheral chronical pain syndromes. We have carried out a search for the articles published in e-Library, PubMed, Oxford Press, Clinical Case, Springer, Elsevier, and Google Scholar databases. The search was carried out using keywords and their combinations. The role of NO and NO synthases (NOS) isoforms in peripheral pain development and chronicity was demonstrated primarily from animal models to humans. The most studied is the neuronal NOS (nNOS). The role of inducible NOS (iNOS) and endothelial NOS (eNOS) is still under investigation. Associative genetic studies have shown that single nucleotide variants (SNVs) of NOS1, NOS2, and NOS3 genes encoding nNOS, iNOS, and eNOS may be associated with acute and chronic peripheral pain. Prospects for the use of NOS inhibitors to modulate the effect of drugs used to treat peripheral pain syndrome are discussed. Associative genetic studies of SNVs NOS1, NOS2, and NOS3 genes are important for understanding genetic predictors of peripheral pain chronicity and development of new personalized pharmacotherapy strategies.
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C-Peptide as a Therapy for Type 1 Diabetes Mellitus. Biomedicines 2021; 9:biomedicines9030270. [PMID: 33800470 PMCID: PMC8000702 DOI: 10.3390/biomedicines9030270] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2021] [Revised: 03/02/2021] [Accepted: 03/03/2021] [Indexed: 12/13/2022] Open
Abstract
Diabetes mellitus (DM) is a complex metabolic disease affecting one-third of the United States population. It is characterized by hyperglycemia, where the hormone insulin is either not produced sufficiently or where there is a resistance to insulin. Patients with Type 1 DM (T1DM), in which the insulin-producing beta cells are destroyed by autoimmune mechanisms, have a significantly increased risk of developing life-threatening cardiovascular complications, even when exogenous insulin is administered. In fact, due to various factors such as limited blood glucose measurements and timing of insulin administration, only 37% of T1DM adults achieve normoglycemia. Furthermore, T1DM patients do not produce C-peptide, a cleavage product from insulin processing. C-peptide has potential therapeutic effects in vitro and in vivo on many complications of T1DM, such as peripheral neuropathy, atherosclerosis, and inflammation. Thus, delivery of C-peptide in conjunction with insulin through a pump, pancreatic islet transplantation, or genetically engineered Sertoli cells (an immune privileged cell type) may ameliorate many of the cardiovascular and vascular complications afflicting T1DM patients.
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Abstract
BACKGROUND Diabetic neuropathy is a multifaceted condition affecting up to 50% of individuals with long standing diabetes. The most common presentation is peripheral diabetic sensory neuropathy (DPN). METHODS We carried out a systematic review of papers dealing with diabetic neuropathy on Pubmed in addition to a targeted Google search.Search terms included small fiber neuropathy,diffuse peripheral neuropathy, quantitative sensory testing, nerve conduction testing, intra-epidermal nerve fiber density, corneal confocal reflectance microscopy, aldose reductase inhbitors, nerve growth factor, alpha-lipoic acid, ruboxistaurin, nerve growth factor antibody, and cibinetide. RESULTS Over the past half century, there have been a number of agents undergoing unsuccessful trials for treatment of DPN.There are several approved agents for relief of pain caused by diabetic neuropathy, but these do not affect the pathologic process. EXPERT OPINION The failure to find treatments for diabetic neuropathy can be ascribed to (1) the complexity of design of studies and (2) the slow progression of the condition, necessitating long duration trials to prove efficacy.We propose a modification of the regulatory process to permit early introduction of agents with demonstrated safety and suggestion of benefit as well as prolongation of marketing exclusivity while long term trials are in progress to prove efficacy.
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Affiliation(s)
- Marc S Rendell
- The Association for Diabetes Investigators , Newport Coast, California. USA
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14
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Biological Activity of c-Peptide in Microvascular Complications of Type 1 Diabetes-Time for Translational Studies or Back to the Basics? Int J Mol Sci 2020; 21:ijms21249723. [PMID: 33419247 PMCID: PMC7766542 DOI: 10.3390/ijms21249723] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2020] [Revised: 12/15/2020] [Accepted: 12/16/2020] [Indexed: 12/15/2022] Open
Abstract
People with type 1 diabetes have an increased risk of developing microvascular complications, which have a negative impact on the quality of life and reduce life expectancy. Numerous studies in animals with experimental diabetes show that c-peptide supplementation exerts beneficial effects on diabetes-induced damage in peripheral nerves and kidneys. There is substantial evidence that c-peptide counteracts the detrimental changes caused by hyperglycemia at the cellular level, such as decreased activation of endothelial nitric oxide synthase and sodium potassium ATPase, and increase in formation of pro-inflammatory molecules mediated by nuclear factor kappa-light-chain-enhancer of activated B cells: cytokines, chemokines, cell adhesion molecules, vascular endothelial growth factor, and transforming growth factor beta. However, despite positive results from cell and animal studies, no successful c-peptide replacement therapies have been developed so far. Therefore, it is important to improve our understanding of the impact of c-peptide on the pathophysiology of microvascular complications to develop novel c-peptide-based treatments. This article aims to review current knowledge on the impact of c-peptide on diabetic neuro- and nephropathy and to evaluate its potential therapeutic role.
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Chan KH, Lim J, Jee JE, Aw JH, Lee SS. Peptide-Peptide Co-Assembly: A Design Strategy for Functional Detection of C-peptide, A Biomarker of Diabetic Neuropathy. Int J Mol Sci 2020; 21:ijms21249671. [PMID: 33352955 PMCID: PMC7766332 DOI: 10.3390/ijms21249671] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2020] [Revised: 12/07/2020] [Accepted: 12/14/2020] [Indexed: 12/29/2022] Open
Abstract
Diabetes-related neuropathy is a debilitating condition that may be averted if it can be detected early. One possible way this can be achieved at low cost is to utilise peptides to detect C-peptide, a biomarker of diabetic neuropathy. This depends on peptide-peptide co-assembly, which is currently in a nascent stage of intense study. Instead, we propose a bead-based triple-overlay combinatorial strategy that can preserve inter-residue information during the screening process for a suitable complementary peptide to co-assemble with C-peptide. The screening process commenced with a pentapeptide general library, which revealed histidine to be an essential residue. Further screening with seven tetrapeptide focused libraries led to a table of self-consistent peptide sequences that included tryptophan and lysine at high frequencies. Three complementary nonapeptides (9mer com-peptides), wpkkhfwgq (Trp-D), kwkkhfwgq (Lys-D), and KWKKHFWGQ (Lys-L) (as a negative control) were picked from this table for co-assembly studies with C-peptide. Attenuated total reflectance Fourier transform infrared (ATR-FTIR) and circular dichroism (CD) spectroscopies were utilized to study inter-peptide interactions and changes in secondary structures respectively. ATR-FTIR studies showed that there is indeed inter-peptide interaction between C-peptide and the tryptophan residues of the 9mer com-peptides. CD studies of unaggregated and colloidal C-peptide with the 9mer com-peptides suggest that the extent of co-assembly of C-peptide with Trp-D is greatest, followed by Lys-D and Lys-L. These results are promising and indicate that the presented strategy is viable for designing and evaluating longer complementary peptides, as well as complementary peptides for co-assembly with other polypeptides of interest and importance. We discuss the possibility of designing complementary peptides to inhibit toxic amyloidosis with this approach.
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Affiliation(s)
- Kiat Hwa Chan
- Division of Science, Yale-NUS College, 16 College Avenue West, Singapore 138527, Singapore;
- Correspondence: (K.H.C.); (S.S.L.)
| | - Jaehong Lim
- Institute of Bioengineering and Nanotechnology, 31 Biopolis Way, The Nanos, Singapore 138669, Singapore; (J.L.); (J.E.J.)
| | - Joo Eun Jee
- Institute of Bioengineering and Nanotechnology, 31 Biopolis Way, The Nanos, Singapore 138669, Singapore; (J.L.); (J.E.J.)
| | - Jia Hui Aw
- Division of Science, Yale-NUS College, 16 College Avenue West, Singapore 138527, Singapore;
| | - Su Seong Lee
- Institute of Bioengineering and Nanotechnology, 31 Biopolis Way, The Nanos, Singapore 138669, Singapore; (J.L.); (J.E.J.)
- Correspondence: (K.H.C.); (S.S.L.)
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16
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A C-peptide complex with albumin and Zn 2+ increases measurable GLUT1 levels in membranes of human red blood cells. Sci Rep 2020; 10:17493. [PMID: 33060722 PMCID: PMC7566639 DOI: 10.1038/s41598-020-74527-6] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2020] [Accepted: 09/28/2020] [Indexed: 12/11/2022] Open
Abstract
People with type 1 diabetes (T1D) require exogenous administration of insulin, which stimulates the translocation of the GLUT4 glucose transporter to cell membranes. However, most bloodstream cells contain GLUT1 and are not directly affected by insulin. Here, we report that C-peptide, the 31-amino acid peptide secreted in equal amounts with insulin in vivo, is part of a 3-component complex that affects red blood cell (RBC) membranes. Multiple techniques were used to demonstrate saturable and specific C-peptide binding to RBCs when delivered as part of a complex with albumin. Importantly, when the complex also included Zn2+, a significant increase in cell membrane GLUT1 was measured, thus providing a cellular effect similar to insulin, but on a transporter on which insulin has no effect.
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17
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Poteryaeva ON, Usynin IF. [Molecular mechanisms of action and physiological effects of the proinsulin C-peptide (a systematic review)]. BIOMEDIT︠S︡INSKAI︠A︡ KHIMII︠A︡ 2020; 66:196-207. [PMID: 32588825 DOI: 10.18097/pbmc20206603196] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
The C-peptide is a fragment of proinsulin, the cleavage of which forms active insulin. In recent years, new information has appeared on the physiological effects of the C-peptide, indicating its positive effect on many organs and tissues, including the kidneys, nervous system, heart, vascular endothelium and blood microcirculation. Studies on experimental models of diabetes mellitus in animals, as well as clinical trials in patients with diabetes, have shown that the C-peptide has an important regulatory effect on the early stages of functional and structural disorders caused by this disease. The C-peptide exhibits its effects through binding to a specific receptor on the cell membrane and activation of downstream signaling pathways. Intracellular signaling involves G-proteins and Ca2+-dependent pathways, resulting in activation and increased expression of endothelial nitric oxide synthase, Na+/K+-ATPase and important transcription factors involved in apoptosis, anti-inflammatory and other intracellular defense mechanisms. This review gives an idea of the C-peptide as a bioactive endogenous peptide that has its own biological activity and therapeutic potential.
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Affiliation(s)
- O N Poteryaeva
- Institute of Biochemistry, Federal Research Center of Fundamental and Translation Medicine, Novosibirsk, Russia
| | - I F Usynin
- Institute of Biochemistry, Federal Research Center of Fundamental and Translation Medicine, Novosibirsk, Russia
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Souto SB, Campos JR, Fangueiro JF, Silva AM, Cicero N, Lucarini M, Durazzo A, Santini A, Souto EB. Multiple Cell Signalling Pathways of Human Proinsulin C-Peptide in Vasculopathy Protection. Int J Mol Sci 2020; 21:E645. [PMID: 31963760 PMCID: PMC7013900 DOI: 10.3390/ijms21020645] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2019] [Revised: 01/15/2020] [Accepted: 01/16/2020] [Indexed: 12/19/2022] Open
Abstract
A major hallmark of diabetes is a constant high blood glucose level (hyperglycaemia), resulting in endothelial dysfunction. Transient or prolonged hyperglycemia can cause diabetic vasculopathy, a secondary systemic damage. C-Peptide is a product of cleavage of proinsulin by a serine protease that occurs within the pancreatic β-cells, being secreted in similar amounts as insulin. The biological activity of human C-peptide is instrumental in the prevention of diabetic neuropathy, nephropathy and other vascular complications. The main feature of type 1 diabetes mellitus is the lack of insulin and of C-peptide, but the progressive β-cell loss is also observed in later stage of type 2 diabetes mellitus. C-peptide has multifaceted effects in animals and diabetic patients due to the activation of multiple cell signalling pathways, highlighting p38 mitogen-activated protein kinase and extracellular signal-regulated kinase ½, Akt, as well as endothelial nitric oxide production. Recent works highlight the role of C-peptide in the prevention and amelioration of diabetes and also in organ-specific complications. Benefits of C-peptide in microangiopathy and vasculopathy have been shown through conservation of vascular function, and also in the prevention of endothelial cell death, microvascular permeability, neointima formation, and in vascular inflammation. Improvement of microvascular blood flow by replacing a physiological amount of C-peptide, in several tissues of diabetic animals and humans, mainly in nerve tissue, myocardium, skeletal muscle, and kidney has been described. A review of the multiple cell signalling pathways of human proinsulin C-peptide in vasculopathy protection is proposed, where the approaches to move beyond the state of the art in the development of innovative and effective therapeutic options of diabetic neuropathy and nephropathy are discussed.
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Affiliation(s)
- Selma B. Souto
- Department of Endocrinology, Hospital de São João, Alameda Prof. Hernâni Monteiro, 4200-319 Porto, Portugal;
| | - Joana R. Campos
- Department of Pharmaceutical Technology, Faculty of Pharmacy, University of Coimbra (FFUC), Pólo das Ciências da Saúde, 3000-548 Coimbra, Portugal; (J.R.C.); (J.F.F.)
| | - Joana F. Fangueiro
- Department of Pharmaceutical Technology, Faculty of Pharmacy, University of Coimbra (FFUC), Pólo das Ciências da Saúde, 3000-548 Coimbra, Portugal; (J.R.C.); (J.F.F.)
| | - Amélia M. Silva
- Department of Biology and Environment, University of Trás-os-Montes e Alto Douro, UTAD, Quinta de Prados, P-5001-801 Vila Real, Portugal;
- Centre for Research and Technology of Agro-Environmental and Biological Sciences, CITAB, UTAD, Quinta de Prados, P-5001-801 Vila Real, Portugal
| | - Nicola Cicero
- Dipartimento di Scienze biomediche, odontoiatriche e delle immagini morfologiche e funzionali, Università degli Studi di Messina, Polo Universitario Annunziata, 98168 Messina, Italy;
| | - Massimo Lucarini
- CREA—Research Centre for Food and Nutrition, Via Ardeatina 546, 00178 Rome, Italy; (M.L.); (A.D.)
| | - Alessandra Durazzo
- CREA—Research Centre for Food and Nutrition, Via Ardeatina 546, 00178 Rome, Italy; (M.L.); (A.D.)
| | - Antonello Santini
- Department of Pharmacy, University of Napoli Federico II, Via D. Montesano 49, 80131 Napoli, Italy
| | - Eliana B. Souto
- Department of Pharmaceutical Technology, Faculty of Pharmacy, University of Coimbra (FFUC), Pólo das Ciências da Saúde, 3000-548 Coimbra, Portugal; (J.R.C.); (J.F.F.)
- CEB—Centre of Biological Engineering, University of Minho, Campus de Gualtar, 4710-057 Braga, Portugal
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Zuo A, Wang C, Li L, Qu J, Cao J, Chen L, Tesfaye S, Li W, Hou X. The Association of Fasting C-peptide with Corneal Neuropathy in Patients with Type 2 Diabetes. J Diabetes Res 2020; 2020:8883736. [PMID: 33344652 PMCID: PMC7725581 DOI: 10.1155/2020/8883736] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/06/2020] [Revised: 11/17/2020] [Accepted: 11/18/2020] [Indexed: 12/13/2022] Open
Abstract
PURPOSE Damage to corneal nerve fibers has been demonstrated in people with type 2 diabetes mellitus (T2DM) that further progresses with increasing severity of diabetic peripheral neuropathy. However, the role of C-peptide in corneal nerve damage has not been reported in T2DM. The present study investigated the relationship of fasting C-peptide levels with corneal neuropathy evaluated by corneal confocal microscopy (CCM) in patients with T2DM. METHODS 160 T2DM patients (72 females) aged 34-78 with duration ranging from 0 to 40 years underwent CCM to measure corneal nerve fiber length (CNFL), corneal nerve fiber density (CNFD), and corneal nerve branch density (CNBD). Pearson correlation analysis and multiple linear regression analysis were used to explore the association of fasting C-peptide levels with corneal nerve parameters. Partial correlation analysis (adjusted for age and gender) was also conducted to analyze the correlation of metabolic indexes with these three corneal nerve parameters. The relationship between fasting C-peptide levels and duration of diabetes was also explored by Pearson correlation analysis. RESULTS With an increase in fasting C-peptide levels, the values of CNFL, CNFD, and CNBD also showed a corresponding trend for an increase. Partial correlation analysis revealed that fasting C-peptide levels were positively associated with CNFL (r = 0.245, P = 0.002), CNFD (r = 0.180, P = 0.024), and CNBD (r = 0.214, P = 0.008) after adjusting for age and gender. Using multiple linear regression analysis, fasting C-peptide levels were also closely associated with CNFL (P = 0.047) and CNBD (P = 0.038) after multiple adjustments. However, this association disappeared after further adjusting for duration of diabetes. Further analysis indicated that fasting C-peptide levels declined with duration of diabetes (r = -0.267, P = 0.001). CONCLUSIONS C-peptide was closely associated with corneal neuropathy and disease duration in T2DM. C-peptide levels might be both an indicator of beta-cell function and a marker of disease severity (such as diabetic corneal neuropathy) and duration.
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Affiliation(s)
- Anju Zuo
- Department of Endocrinology, Qilu Hospital of Shandong University, Jinan, Shandong, China 250012
- Department of General Practice, Qilu Hospital of Shandong University, Jinan, Shandong, China 250012
- Institute of Endocrine and Metabolic Diseases of Shandong University, Jinan, Shandong, China 250012
- Key Laboratory of Endocrine and Metabolic Diseases, Shandong Province Medicine & Health, Jinan, Shandong, China 250012
- Jinan Clinical Research Center for Endocrine and Metabolic Diseases, Shandong Province Medicine & Health, Jinan, Shandong, China 250012
| | - Chuan Wang
- Department of Endocrinology, Qilu Hospital of Shandong University, Jinan, Shandong, China 250012
- Institute of Endocrine and Metabolic Diseases of Shandong University, Jinan, Shandong, China 250012
- Key Laboratory of Endocrine and Metabolic Diseases, Shandong Province Medicine & Health, Jinan, Shandong, China 250012
- Jinan Clinical Research Center for Endocrine and Metabolic Diseases, Shandong Province Medicine & Health, Jinan, Shandong, China 250012
| | - Lili Li
- Department of Endocrinology, Qilu Hospital of Shandong University, Jinan, Shandong, China 250012
- Department of Ultrasound, Qilu Hospital of Shandong University, Qingdao, Shandong, China 266000
| | - Jingru Qu
- Department of Endocrinology, Qilu Hospital of Shandong University, Jinan, Shandong, China 250012
- Institute of Endocrine and Metabolic Diseases of Shandong University, Jinan, Shandong, China 250012
- Key Laboratory of Endocrine and Metabolic Diseases, Shandong Province Medicine & Health, Jinan, Shandong, China 250012
- Jinan Clinical Research Center for Endocrine and Metabolic Diseases, Shandong Province Medicine & Health, Jinan, Shandong, China 250012
| | - Juan Cao
- Department of Endocrinology, Qilu Hospital of Shandong University, Jinan, Shandong, China 250012
- Department of Health Management Center, Qilu Hospital of Shandong University, Jinan, Shandong, China 250012
| | - Li Chen
- Department of Endocrinology, Qilu Hospital of Shandong University, Jinan, Shandong, China 250012
- Institute of Endocrine and Metabolic Diseases of Shandong University, Jinan, Shandong, China 250012
- Key Laboratory of Endocrine and Metabolic Diseases, Shandong Province Medicine & Health, Jinan, Shandong, China 250012
- Jinan Clinical Research Center for Endocrine and Metabolic Diseases, Shandong Province Medicine & Health, Jinan, Shandong, China 250012
| | - Solomon Tesfaye
- Diabetes Research Department, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK
| | - Wenjuan Li
- Department of Endocrinology, Qilu Hospital of Shandong University, Jinan, Shandong, China 250012
- Institute of Endocrine and Metabolic Diseases of Shandong University, Jinan, Shandong, China 250012
- Key Laboratory of Endocrine and Metabolic Diseases, Shandong Province Medicine & Health, Jinan, Shandong, China 250012
- Jinan Clinical Research Center for Endocrine and Metabolic Diseases, Shandong Province Medicine & Health, Jinan, Shandong, China 250012
| | - Xinguo Hou
- Department of Endocrinology, Qilu Hospital of Shandong University, Jinan, Shandong, China 250012
- Institute of Endocrine and Metabolic Diseases of Shandong University, Jinan, Shandong, China 250012
- Key Laboratory of Endocrine and Metabolic Diseases, Shandong Province Medicine & Health, Jinan, Shandong, China 250012
- Jinan Clinical Research Center for Endocrine and Metabolic Diseases, Shandong Province Medicine & Health, Jinan, Shandong, China 250012
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Wilmshurst JM, Ouvrier RA, Ryan MM. Peripheral nerve disease secondary to systemic conditions in children. Ther Adv Neurol Disord 2019; 12:1756286419866367. [PMID: 31447934 PMCID: PMC6691669 DOI: 10.1177/1756286419866367] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2019] [Accepted: 07/07/2019] [Indexed: 12/17/2022] Open
Abstract
This review is an overview of systemic conditions that can be associated with peripheral nervous system dysfunction. Children may present with neuropathic symptoms for which, unless considered, a causative systemic condition may not be recognized. Similarly, some systemic conditions may be complicated by comorbid peripheral neuropathies, surveillance for which is indicated. The systemic conditions addressed in this review are critical illness polyneuropathy, chronic renal failure, endocrine disorders such as insulin-dependent diabetes mellitus and multiple endocrine neoplasia type 2b, vitamin deficiency states, malignancies and reticuloses, sickle cell disease, neurofibromatosis, connective tissue disorders, bowel dysmotility and enteropathy, and sarcoidosis. In some disorders presymptomatic screening should be undertaken, while in others there is no benefit from early detection of neuropathy. In children with idiopathic peripheral neuropathies, systemic disorders such as celiac disease should be actively excluded. While management is predominantly focused on symptomatic care through pain control and rehabilitation, some neuropathies improve with effective control of the underlying etiology and in a small proportion a more targeted approach is possible. In conclusion, peripheral neuropathies can be associated with a diverse range of medical conditions and unless actively considered may not be recognized and inadequately managed.
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Affiliation(s)
- Jo M. Wilmshurst
- Department of Paediatric Neurology, Department of Paediatrics and Child Health, Red Cross War Memorial Children’s, Hospital Neuroscience Institute, University of Cape Town, Klipfontein Road, Cape Town, Western Cape, 7700, South Africa
| | - Robert A. Ouvrier
- The Institute of Neuroscience and Muscle Research, The Children’s Hospital at Westmead, Sydney, Australia
| | - Monique M. Ryan
- Department of Neurology, Royal Children’s Hospital, Murdoch Children’s Research Institute and University of Melbourne, Melbourne, Victoria, Australia
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Chahbi Z, Lahmar B, Hadri SE, Abainou L, Kaddouri S, Qacif H, Baizri H, Zyani M. The prevalence of painful diabetic neuropathy in 300 Moroccan diabetics. Pan Afr Med J 2018; 31:158. [PMID: 31086614 PMCID: PMC6488236 DOI: 10.11604/pamj.2018.31.158.14687] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2017] [Accepted: 04/11/2018] [Indexed: 12/18/2022] Open
Abstract
Painful diabetic neuropathy is a frequent complication of diabetes. Its diagnosis is clinical. Our goal is to determine the prevalence of painful diabetic neuropathy in this population. We also analyzed the relationship between this neuropathy and certain parameters, concerning the patient and his diabetes. It is a cross sectional study conducted at the department of endocrinology and internal medicine of Avicenne hospital Marrakech-Morocco, among a cohort of 300 diabetic outpatients. We used the DN4 questionnaire (Douleur Neuropathique en 4 questions), for diagnosis. The results showed a prevalence of 15%. In this study: advanced age, female gender, duration of diabetes greater than 10 years, and the lack of medical follow up were found to be statistically significant risk factors for painful diabetic neuropathy, in addition to some diabetes-related comorbidities such as hypertension, dyslipidemia, sedentary life style and diabetic retinopathy. Painful diabetic neuropathy remains undertreated, in fact 74% of our patients did not receive any specific treatment, knowing that the progress in developing effective and well-tolerated therapies has been disappointing.
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Affiliation(s)
- Zakaria Chahbi
- Internal Medicine Department, Avicenne Military Hospital, Marrakech, Morocco
| | - Bouchra Lahmar
- Internal Medicine Department, Avicenne Military Hospital, Marrakech, Morocco
| | - Sanae El Hadri
- Endocrinology Department, Avicenne Military Hospital, Marrakech, Morocco
| | | | - Said Kaddouri
- Internal Medicine Department, Avicenne Military Hospital, Marrakech, Morocco
| | - Hassan Qacif
- Internal Medicine Department, Avicenne Military Hospital, Marrakech, Morocco
| | - Hicham Baizri
- Endocrinology Department, Avicenne Military Hospital, Marrakech, Morocco
| | - Mohamed Zyani
- Internal Medicine Department, Avicenne Military Hospital, Marrakech, Morocco
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22
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Fensom B, Harris C, Thompson SE, Al Mehthel M, Thompson DM. Islet cell transplantation improves nerve conduction velocity in type 1 diabetes compared with intensive medical therapy over six years. Diabetes Res Clin Pract 2016; 122:101-105. [PMID: 27825059 DOI: 10.1016/j.diabres.2016.10.011] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/13/2016] [Revised: 10/02/2016] [Accepted: 10/12/2016] [Indexed: 11/21/2022]
Abstract
BACKGROUND Neuropathy is a common diabetic complication that can result in significant disability. Few treatment options exist to reverse this process. METHODS We conducted a one-way crossover cohort study comparing intensive medical treatment and islet cell transplantation for type 1 diabetes on the change in nerve conduction velocity over six years. FINDINGS For subjects with some neuropathy at baseline (Z score below -1), nerve conduction velocity significantly improved post-transplant (slope (0.073±0.042) while it worsened in medically treated patients (-0.136±0.081) (p<.05). INTERPRETATION Islet cell transplantation improves nerve conduction velocity and could be further investigated as a treatment for neuropathy in type 1 diabetes.
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Affiliation(s)
- Blake Fensom
- Department of Medicine, Vancouver General Hospital and University of British Columbia, Canada
| | - Claire Harris
- Department of Medicine, Vancouver General Hospital and University of British Columbia, Canada
| | - Sharon E Thompson
- Department of Medicine, Vancouver General Hospital and University of British Columbia, Canada
| | - Mohammed Al Mehthel
- Department of Medicine, Vancouver General Hospital and University of British Columbia, Canada
| | - David M Thompson
- Department of Medicine, Vancouver General Hospital and University of British Columbia, Canada.
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Affiliation(s)
- Johnny Ludvigsson
- Department of Clinical and Experimental Medicine, University Hospital, Linkoping University, Linköping, Sweden
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24
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Wahren J, Foyt H, Daniels M, Arezzo JC. Long-Acting C-Peptide and Neuropathy in Type 1 Diabetes: A 12-Month Clinical Trial. Diabetes Care 2016; 39:596-602. [PMID: 26884473 DOI: 10.2337/dc15-2068] [Citation(s) in RCA: 54] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/22/2015] [Accepted: 01/04/2016] [Indexed: 02/03/2023]
Abstract
OBJECTIVE Lack of C-peptide in type 1 diabetes may be an important contributing factor in the development of microvascular complications. Replacement of native C-peptide has been shown to exert a beneficial influence on peripheral nerve function in type 1 diabetes. The aim of this study was to evaluate the efficacy and safety of a long-acting C-peptide in subjects with type 1 diabetes and mild to moderate peripheral neuropathy. RESEARCH DESIGN AND METHODS A total of 250 patients with type 1 diabetes and peripheral neuropathy received long-acting (pegylated) C-peptide in weekly dosages of 0.8 mg (n = 71) or 2.4 mg (n = 73) or placebo (n = 106) for 52 weeks. Bilateral sural nerve conduction velocity (SNCV) and vibration perception threshold (VPT) on the great toe were measured on two occasions at baseline, at 26 weeks, and at 52 weeks. The modified Toronto Clinical Neuropathy Score (mTCNS) was used to grade the peripheral neuropathy. RESULTS Plasma C-peptide rose during the study to 1.8-2.2 nmol/L (low dose) and to 5.6-6.8 nmol/L (high dose). After 52 weeks, SNCV had increased by 1.0 ± 0.24 m/s (P < 0.001 within group) in patients receiving C-peptide (combined groups), but the corresponding value for the placebo group was 1.2 ± 0.29 m/s. Compared with basal, VPT had improved by 25% after 52 weeks of C-peptide therapy (Δ for combined C-peptide groups: -4.5 ± 1.0 μm, placebo group: -0.1 ± 0.9 μm; P < 0.001). mTCNS was unchanged during the study. CONCLUSIONS Once-weekly subcutaneous administration of long-acting C-peptide for 52 weeks did not improve SNCV, other electrophysiological variables, or mTCNS but resulted in marked improvement of VPT compared with placebo.
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Affiliation(s)
- John Wahren
- Cebix Inc., San Diego, CA Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
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Li C, Zhang L, Chen Y, Lin X, Li T. Protective role of adenovirus vector-mediated interleukin-10 gene therapy on endogenous islet β-cells in recent-onset type 1 diabetes in NOD mice. Exp Ther Med 2016; 11:1625-1632. [PMID: 27168782 DOI: 10.3892/etm.2016.3169] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2014] [Accepted: 02/11/2016] [Indexed: 12/28/2022] Open
Abstract
The aim of the present study was to provide an animal experimental basis for the protective effect of the adenoviral vector-mediated interleukin-10 (Ad-mIL-10) gene on islet β-cells during the early stages of type 1 diabetes (T1D) in non-obese diabetic (NOD) mice. A total of 24 female NOD mice at the onset of diabetes were allocated at random into three groups (n=8 per group): Group 1, intraperitoneally injected with 0.1 ml Ad-mIL-10; group 2, intraperitoneally injected with 0.1 ml adenovirus vector; and group 3, was a diabetic control. In addition to groups 1, 2 and 3, 8 age- and gender-matched NOD mice were intraperitoneally injected with 0.1 ml PBS and assigned to group 4 as a normal control. All mice were examined weekly for body weight, urine glucose and blood glucose values prior to onset of diabetes, and at 1, 2 and 3 weeks after that, and all mice were sacrificed 3 weeks after injection. Serum levels of interleukin (IL)-10, interferon (IFN)-γ, IL-4, insulin and C-peptide were evaluated, and in addition the degree of insulitis and the local expression of IL-10 gene in the pancreas were detected. The apoptosis rate of pancreatic β-cells was determined using a TUNEL assay. Compared with groups 2 and 3, IL-10 levels in the serum and pancreas were elevated in group 1. Serum IFN-γ levels were decreased while serum IL-4 levels and IFN-γ/IL-4 ratio were significantly increased in group 1 (P<0.01). C-peptide and insulin levels were higher in group 1 compared with groups 2 and 3, (P<0.01). Furthermore, compared with groups 2 and 3, the degree of insulitis, islet β-cell apoptosis rate and blood glucose values did not change significantly (P>0.05). The administration of the Ad-mIL-10 gene induced limited immune regulatory and protective effects on islet β-cell function in NOD mice with early T1D, while no significant reduction in insulitis, islet β-cell apoptosis rate and blood glucose was observed.
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Affiliation(s)
- Cheng Li
- Department of Pediatrics, Affiliated Hospital of Qingdao University, Qingdao, Shandong 266001, P.R. China; Medical College, Qingdao University, Qingdao, Shandong 266071, P.R. China
| | - Lijuan Zhang
- Department of Pediatrics, Affiliated Hospital of Qingdao University, Qingdao, Shandong 266001, P.R. China
| | - Yanyan Chen
- Department of Pediatrics, People's Hospital of Rizhao, Rizhao, Shandong 276800, P.R. China
| | - Xiaojie Lin
- Department of Pediatrics, Affiliated Hospital of Qingdao University, Qingdao, Shandong 266001, P.R. China
| | - Tang Li
- Department of Pediatrics, Affiliated Hospital of Qingdao University, Qingdao, Shandong 266001, P.R. China
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Jolivalt CG, Rodriguez M, Wahren J, Calcutt NA. Efficacy of a long-acting C-peptide analogue against peripheral neuropathy in streptozotocin-diabetic mice. Diabetes Obes Metab 2015; 17:781-8. [PMID: 25904006 DOI: 10.1111/dom.12477] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/13/2015] [Revised: 03/08/2015] [Accepted: 04/17/2015] [Indexed: 12/28/2022]
Abstract
AIMS To investigate the efficacy of a pegylated C-peptide (Peg-C-peptide) against indices of peripheral neuropathy in a mouse model of type 1 diabetes and to compare efficacy of this C-peptide analogue against that of the native molecule. METHODS C57Bl/6 mice were injected with two consecutive doses of streptozotocin (STZ) to induce type 1 diabetes. Mice were treated twice daily with native C-peptide [0.4-1.3 mg/kg subcutaneously (s.c.)] or twice weekly with Peg-C-peptide (0.1-1.3 mg/kg s.c.) for 20 weeks. Motor and sensory nerve conduction velocities, thermal and tactile responses and rate dependent H-wave depression were assessed after 20 weeks of diabetes. Foot skin intraepidermal fibres and corneal nerves were counted, and sciatic nerve substance P and plasma C-peptide levels were also determined. RESULTS After 5 months of STZ-induced diabetes, mice exhibited significant motor and sensory nerve conduction slowing, thermal hypoalgesia, tactile allodynia and attenuation of rate-dependent depression of the H reflex. These functional disorders were accompanied by nerve substance P depletion but not loss of small sensory fibres in the hind paw epidermis or the cornea. The efficacy of twice-daily treatment with native C-peptide in preventing these disorders was matched or exceeded by twice-weekly treatment with Peg-C-peptide. Both native and Peg-C-peptide also increased corneal nerve occupancy in the sub-basal nerve plexus of control rats. CONCLUSIONS These data identify actions of C-peptide against novel and clinically pertinent aspects of diabetic neuropathy in mice and also establish Peg-C-peptide as a long-acting therapeutic method of potential clinical value.
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Affiliation(s)
- C G Jolivalt
- Department of Pathology, University of California, San Diego, La Jolla, CA, USA
| | - M Rodriguez
- Department of Pathology, University of California, San Diego, La Jolla, CA, USA
| | - J Wahren
- Department of Molecular Medicine, Karolinska Institutet, Stockholm, Sweden
- Cebix AB, Stockholm, Sweden
| | - N A Calcutt
- Department of Pathology, University of California, San Diego, La Jolla, CA, USA
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Wahren J, Larsson C. C-peptide: new findings and therapeutic possibilities. Diabetes Res Clin Pract 2015; 107:309-19. [PMID: 25648391 DOI: 10.1016/j.diabres.2015.01.016] [Citation(s) in RCA: 62] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/15/2014] [Accepted: 01/15/2015] [Indexed: 12/18/2022]
Abstract
Much new information on C-peptide physiology has appeared during the past 20 years. It has been shown that C-peptide binds specifically to cell membranes, elicits intracellular signaling via G-protein and Ca2+ -dependent pathways, resulting in activation and increased expression of endothelial nitric oxide synthase, Na+, K+ -ATPase and several transcription factors of importance for anti-inflammatory, anti-oxidant and cell protective mechanisms. Studies in animal models of diabetes and early clinical trials in patients with type 1 diabetes demonstrate that C-peptide in replacement doses elicits beneficial effects on early stages of diabetes-induced functional and structural abnormalities of the peripheral nerves, the kidneys and the retina. Much remains to be learned about C-peptide's mechanism of action and long-term clinical trials in type 1 diabetes subjects will be required to determine C-peptide's clinical utility. Nevertheless, even a cautious evaluation of the available evidence presents the picture of a bioactive endogenous peptide with therapeutic potential.
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Affiliation(s)
- John Wahren
- Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden; Cebix AB, Stockholm, Sweden.
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Li Y, Li Y, Meng L, Zheng L. Association between serum C-peptide as a risk factor for cardiovascular disease and high-density lipoprotein cholesterol levels in nondiabetic individuals. PLoS One 2015; 10:e112281. [PMID: 25559358 PMCID: PMC4283961 DOI: 10.1371/journal.pone.0112281] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2014] [Accepted: 10/14/2014] [Indexed: 12/22/2022] Open
Abstract
Objective Objective: Although serum C-peptide has increasingly received attention as a new and important risk factor for cardiovascular disease (CVD), the potential mechanisms remain unclear. This study aimed to investigate the association between serum C-peptide as a risk factor for CVD and high-density lipoprotein cholesterol (HDL-C) levels. Methods The present study included 13,185 participants aged ≥20 years. Serum C-peptide and HDL-C levels were measured according to a standard protocol. Stratified analysis of covariance was used to compare serum HDL-C levels between different quartiles of serum C-peptide levels. Logistic regression analysis was used to determine the association between serum C-peptide and HDL-C levels. Cox proportional hazard regression analysis was conducted to determine the hazard ratio of serum HDL-C for CVD-related mortality. Results The results of the ANCOVA analysis showed a significant linear trend between the mean serum HDL-C level and the different quartiles of serum C-peptide. Compared to the first quartile (25th percentile), the second, third, and fourth quartiles had gradual reduction in serum HDL-C levels. Logistic regression analyses showed a strong negative association between serum C-peptide levels and HDL-C levels; the p value for the linear trend was <0.001. In men, compared with the lowest quartile of the serum C-peptide level, the relative risk was 1.75, 2.79, and 3.07 for the upper three quartiles of the serum C-peptide level. The relative risk was 1.60, 2.61, and 3.67 for women. The results of the survival analysis showed that serum HDL-C levels were negatively associated with CVD-related death in both men and women. Conclusion Serum C-peptide as a risk factor for CVD was significantly and negatively associated with serum HDL-C levels in individuals without diabetes. These findings suggest that serum C-peptide levels association with CVD death can be caused, at least in part, by the low serum HDL-C level.
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Affiliation(s)
- Ying Li
- Department of Social Medicine, School of Public Health, Zhejiang University, Zhejiang, China
- * E-mail: (YL); (LSZ)
| | - Yue Li
- School of Basic Medical Sciences, Zhejiang University, Zhejiang, China
| | - Lu Meng
- Department of Social Medicine, School of Public Health, Zhejiang University, Zhejiang, China
| | - LianShun Zheng
- School of Basic Medical Sciences, Zhejiang University, Zhejiang, China
- * E-mail: (YL); (LSZ)
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Javed S, Petropoulos IN, Alam U, Malik RA. Treatment of painful diabetic neuropathy. Ther Adv Chronic Dis 2015; 6:15-28. [PMID: 25553239 DOI: 10.1177/2040622314552071] [Citation(s) in RCA: 134] [Impact Index Per Article: 13.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023] Open
Abstract
Painful diabetic neuropathy (PDN) is a debilitating consequence of diabetes that may be present in as many as one in five patients with diabetes. The objective assessment of PDN is difficult, making it challenging to diagnose and assess in both clinical practice and clinical trials. No single treatment exists to prevent or reverse neuropathic changes or to provide total pain relief. Treatment of PDN is based on three major approaches: intensive glycaemic control and risk factor management, treatments based on pathogenetic mechanisms, and symptomatic pain management. Clinical guidelines recommend pain relief in PDN through the use of antidepressants such as amitriptyline and duloxetine, the γ-aminobutyric acid analogues gabapentin and pregabalin, opioids and topical agents such as capsaicin. Of these medications, duloxetine and pregabalin were approved by the US Food and Drug Administration (FDA) in 2004 and tapentadol extended release was approved in 2012 for the treatment of PDN. Proposed pathogenetic treatments include α-lipoic acid (stems reactive oxygen species formation), benfotiamine (prevents vascular damage in diabetes) and aldose-reductase inhibitors (reduces flux through the polyol pathway). There is a growing need for studies to evaluate the most potent drugs or combinations for the management of PDN to maximize pain relief and improve quality of life. A number of agents are potential candidates for future use in PDN therapy, including Nav 1.7 antagonists, N-type calcium channel blockers, NGF antibodies and angiotensin II type 2 receptor antagonists.
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Affiliation(s)
- Saad Javed
- Centre for Endocrinology and Diabetes, University of Manchester, Core Technology Facility (3rd floor), 46 Grafton Street, Manchester, M13 9NT, UK
| | - Ioannis N Petropoulos
- School of Medicine, Institute of Human Development, Centre for Endocrinology and Diabetes, Manchester, UK
| | - Uazman Alam
- School of Medicine, Institute of Human Development, Centre for Endocrinology and Diabetes, and Central Manchester NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK
| | - Rayaz A Malik
- School of Medicine, Institute of Human Development, Centre for Endocrinology and Diabetes, Central Manchester NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK, and Weill Cornell Medical College, Qatar
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Yosten GLC, Maric-Bilkan C, Luppi P, Wahren J. Physiological effects and therapeutic potential of proinsulin C-peptide. Am J Physiol Endocrinol Metab 2014; 307:E955-68. [PMID: 25249503 PMCID: PMC4254984 DOI: 10.1152/ajpendo.00130.2014] [Citation(s) in RCA: 64] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
Connecting Peptide, or C-peptide, is a product of the insulin prohormone, and is released with and in amounts equimolar to those of insulin. While it was once thought that C-peptide was biologically inert and had little biological significance beyond its role in the proper folding of insulin, it is now known that C-peptide binds specifically to the cell membranes of a variety of tissues and initiates specific intracellular signaling cascades that are pertussis toxin sensitive. Although it is now clear that C-peptide is a biologically active molecule, controversy still remains as to the physiological significance of the peptide. Interestingly, C-peptide appears to reverse the deleterious effects of high glucose in some tissues, including the kidney, the peripheral nerves, and the vasculature. C-peptide is thus a potential therapeutic agent for the treatment of diabetes-associated long-term complications. This review addresses the possible physiologically relevant roles of C-peptide in both normal and disease states and discusses the effects of the peptide on sensory nerve, renal, and vascular function. Furthermore, we highlight the intracellular effects of the peptide and present novel strategies for the determination of the C-peptide receptor(s). Finally, a hypothesis is offered concerning the relationship between C-peptide and the development of microvascular complications of diabetes.
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Affiliation(s)
- Gina L C Yosten
- Department of Pharmacological and Physiological Science, Saint Louis University School of Medicine, St. Louis, Missouri;
| | - Christine Maric-Bilkan
- Division of Cardiovascular Sciences, Vascular Biology and Hypertension Branch, National Heart, Lung and Blood Institute, Bethesda, Maryland; Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, Mississippi
| | - Patrizia Luppi
- Department of Cell Biology, University of Pittsburgh Medical School, Pittsburgh, Pennsylvania
| | - John Wahren
- Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden; and Cebix Inc., Karolinska Institutet Science Park, Solna, Sweden
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Bhatt MP, Lim YC, Ha KS. C-peptide replacement therapy as an emerging strategy for preventing diabetic vasculopathy. Cardiovasc Res 2014; 104:234-44. [PMID: 25239825 DOI: 10.1093/cvr/cvu211] [Citation(s) in RCA: 58] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Lack of C-peptide, along with insulin, is the main feature of Type 1 diabetes mellitus (DM) and is also observed in progressive β-cell loss in later stage of Type 2 DM. Therapeutic approaches to hyperglycaemic control have been ineffective in preventing diabetic vasculopathy, and alternative therapeutic strategies are necessary to target both hyperglycaemia and diabetic complications. End-stage organ failure in DM seems to develop primarily due to vascular dysfunction and damage, leading to two types of organ-specific diseases, such as micro- and macrovascular complications. Numerous studies in diabetic patients and animals demonstrate that C-peptide treatment alone or in combination with insulin has physiological functions and might be beneficial in preventing diabetic complications. Current evidence suggests that C-peptide replacement therapy might prevent and ameliorate diabetic vasculopathy and organ-specific complications through conservation of vascular function, as well as prevention of endothelial cell death, microvascular permeability, vascular inflammation, and neointima formation. In this review, we describe recent advances on the beneficial role of C-peptide replacement therapy for preventing diabetic complications, such as retinopathy, nephropathy, neuropathy, impaired wound healing, and inflammation, and further discuss potential beneficial effects of combined C-peptide and insulin supplement therapy to control hyperglycaemia and to prevent organ-specific complications.
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Affiliation(s)
- Mahendra Prasad Bhatt
- Department of Molecular and Cellular Biochemistry, Kangwon National University School of Medicine, Kangwondaehak-gil 1, Chuncheon, Kangwon-do 200-701, Republic of Korea
| | - Young-Cheol Lim
- Department of Molecular and Cellular Biochemistry, Kangwon National University School of Medicine, Kangwondaehak-gil 1, Chuncheon, Kangwon-do 200-701, Republic of Korea
| | - Kwon-Soo Ha
- Department of Molecular and Cellular Biochemistry, Kangwon National University School of Medicine, Kangwondaehak-gil 1, Chuncheon, Kangwon-do 200-701, Republic of Korea
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Adeghate E, Fehér E, Kalász H. Evaluating the Phase II drugs currently under investigation for diabetic neuropathy. Expert Opin Investig Drugs 2014; 24:1-15. [PMID: 25171371 DOI: 10.1517/13543784.2014.954033] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
Introduction: The worldwide number of patients suffering from diabetes mellitus (DM) is projected to approach 552 million by the year 2030. As diabetic neuropathy (DN) is present in 8% of new diabetic patients at the time of diagnosis and occurs in ∼ 50% of all patients with established DM, the number of patients who will develop painful DN will also increase. The suboptimal efficacies of currently approved drugs have prompted investigators to develop new therapeutic agents for the management of painful DN. Areas covered: In this review, the authors present and elucidate the current status of drugs under investigation for the treatment of painful DN. A short synopsis of currently approved drugs is also given. Literature information and data analysis were retrieved from PubMed, the American Diabetes and Neurological Associations Websites and ClinicalTrials.gov. The keywords used in the search included: DM, DN, painful diabetic neuropathy. Expert opinion: In addition to treating the pain associated with DN, the actual causes of the disease should also be targeted for improved management. It is hoped that drugs which improve vascular blood flow, induce neural regeneration, reduce hyperglycemia, oxidative stress and inflammation can be more effective for the overall treatment of painful DN.
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Affiliation(s)
- Ernest Adeghate
- United Arab Emirates University, College of Medicine and Health Sciences, Department of Anatomy , P.O Box 17666, Al Ain , UAE +971 3 7672033 ;
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Olver TD, Grisé KN, McDonald MW, Dey A, Allen MD, Rice CL, Lacefield JC, Melling CJ, Noble EG, Shoemaker JK. The relationship between blood pressure and sciatic nerve blood flow velocity in rats with insulin-treated experimental diabetes. Diab Vasc Dis Res 2014; 11:281-289. [PMID: 24853907 DOI: 10.1177/1479164114533357] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Peripheral nerve blood flow (NBF) does not autoregulate but, instead, responds passively to changes in mean arterial pressure (MAP). How this relationship is impacted by insulin-treated experimental diabetes (ITED) is unknown. We tested the hypothesis that ITED will reduce NBF across a range of MAP in Sprague Dawley rats. Following 10 weeks of control or ITED conditions, conscious MAP (tail-cuff) was measured, and under anaesthesia, the MAP (carotid artery catheter, pressure transducer) and NBF (Doppler ultrasound, 40 MHz) responses to sodium nitroprusside (60 µg/kg) and phenylephrine (12 µg/kg) infusion were recorded (regression equations for MAP vs NBF were created for each rodent). Thereafter, motor nerve conduction velocity (MNCV) and nerve vascularization (haematoxylin and eosin stain) were determined. Conscious MAP was higher and MNCV was lower in the ITED group (p < 0.01). In response to drug infusions, the ΔMAP and ΔNBF were similar between groups (p ≥ 0.18). Estimated conscious NBF (based on substituting conscious MAP values into each individual regression equation) was greater in the ITED group (p < 0.01). Sciatic nerve vascularization was similar between groups (p ≥ 0.50). In contrast to the hypothesis, NBF was not reduced across a range of MAP. In spite of increased estimated conscious NBF values, MNCV was reduced in rats with ITED.
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Affiliation(s)
- T Dylan Olver
- Neurovascular Research Laboratory, School of Kinesiology, Western University, London, ON, Canada
| | - Kenneth N Grisé
- Exercise Biochemistry Laboratory, School of Kinesiology, Western University, London, ON, Canada
| | - Matthew W McDonald
- Exercise Biochemistry Laboratory, School of Kinesiology, Western University, London, ON, Canada
| | - Adwitia Dey
- Exercise Biochemistry Laboratory, School of Kinesiology, Western University, London, ON, Canada
| | - Matti D Allen
- Neuromuscular Research Laboratory, School of Kinesiology, Western University, London, ON, Canada
| | - Charles L Rice
- Neuromuscular Research Laboratory, School of Kinesiology, Western University, London, ON, Canada
| | - James C Lacefield
- Department of Electrical and Computer Engineering, Western University, London, ON, Canada Department of Medical Biophysics, Western University, London, ON, Canada Robarts Research Institute, Western University, London, ON, Canada
| | - Cw James Melling
- Exercise Biochemistry Laboratory, School of Kinesiology, Western University, London, ON, Canada
| | - Earl G Noble
- Exercise Biochemistry Laboratory, School of Kinesiology, Western University, London, ON, Canada
| | - J Kevin Shoemaker
- Neurovascular Research Laboratory, School of Kinesiology, Western University, London, ON, Canada Department of Physiology and Pharmacology, Western University, London, ON, Canada
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Abstract
More than half of all patients with diabetes develop neuropathic disorders affecting the distal sensory and/or motor nerves, or autonomic or cranial nerve functions. Glycemic control can decrease the incidence of neuropathy but is not adequate alone to prevent or treat the disease. This chapter introduces diabetic neuropathy with a morphological description of the disease then describes our current understanding of metabolic and molecular mechanisms that contribute to neurovascular dysfunctions. Key mechanisms include glucose and lipid imbalances and insulin resistance that are interconnected via oxidative stress, inflammation, and altered gene expression. These complex interactions should be considered for the development of new treatment strategies against the onset or progression of neuropathy. Advances in understanding the combined metabolic stressors and the novel study of epigenetics suggest new therapeutic targets to combat this morbid and intractable disease affecting millions of patients with type 1 or type 2 diabetes.
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Dimitropoulos G, Tahrani AA, Stevens MJ. Cardiac autonomic neuropathy in patients with diabetes mellitus. World J Diabetes 2014; 5:17-39. [PMID: 24567799 PMCID: PMC3932425 DOI: 10.4239/wjd.v5.i1.17] [Citation(s) in RCA: 188] [Impact Index Per Article: 17.1] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/15/2013] [Revised: 12/02/2013] [Accepted: 12/12/2013] [Indexed: 02/05/2023] Open
Abstract
Cardiac autonomic neuropathy (CAN) is an often overlooked and common complication of diabetes mellitus. CAN is associated with increased cardiovascular morbidity and mortality. The pathogenesis of CAN is complex and involves a cascade of pathways activated by hyperglycaemia resulting in neuronal ischaemia and cellular death. In addition, autoimmune and genetic factors are involved in the development of CAN. CAN might be subclinical for several years until the patient develops resting tachycardia, exercise intolerance, postural hypotension, cardiac dysfunction and diabetic cardiomyopathy. During its sub-clinical phase, heart rate variability that is influenced by the balance between parasympathetic and sympathetic tones can help in detecting CAN before the disease is symptomatic. Newer imaging techniques (such as scintigraphy) have allowed earlier detection of CAN in the pre-clinical phase and allowed better assessment of the sympathetic nervous system. One of the main difficulties in CAN research is the lack of a universally accepted definition of CAN; however, the Toronto Consensus Panel on Diabetic Neuropathy has recently issued guidance for the diagnosis and staging of CAN, and also proposed screening for CAN in patients with diabetes mellitus. A major challenge, however, is the lack of specific treatment to slow the progression or prevent the development of CAN. Lifestyle changes, improved metabolic control might prevent or slow the progression of CAN. Reversal will require combination of these treatments with new targeted therapeutic approaches. The aim of this article is to review the latest evidence regarding the epidemiology, pathogenesis, manifestations, diagnosis and treatment for CAN.
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Ke JT, Li M, Xu SQ, Zhang WJ, Jiang YW, Cheng LY, Chen L, Lou JN, Wu W. Gliquidone decreases urinary protein by promoting tubular reabsorption in diabetic Goto-Kakizaki rats. J Endocrinol 2014; 220:129-41. [PMID: 24254365 DOI: 10.1530/joe-13-0199] [Citation(s) in RCA: 8] [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: 01/26/2023]
Abstract
The efficacy of gliquidone for the treatment of diabetic nephropathy was investigated by implanting micro-osmotic pumps containing gliquidone into the abdominal cavities of Goto-Kakizaki (GK) rats with diabetic nephropathy. Blood glucose, 24 h urinary protein, and 24 h urinary albumin levels were measured weekly. After 4 weeks of gliquidone therapy, pathological changes in the glomerular basement membrane (GBM) were examined using an electron microscope. Real-time PCR, western blotting, and immunohistochemistry were employed to detect glomerular expression of receptors for advanced glycation end products (RAGE) (AGER), protein kinase C β (PKCβ), and protein kinase A (PKA) as well as tubular expression of the albumin reabsorption-associated proteins: megalin and cubilin. Human proximal tubular epithelial cells (HK-2 cells) were used to analyze the effects of gliquidone and advanced glycation end products (AGEs) on the expression of megalin and cubilin and on the absorption of albumin. Gliquidone lowered blood glucose, 24 h urinary protein, and 24 h urinary albumin levels in GK rats with diabetic nephropathy. The level of plasma C-peptide increased markedly and GBM and podocyte lesions improved dramatically after gliquidone treatment. Glomerular expression of RAGE and PKCβ decreased after gliquidone treatment, while PKA expression increased. AGEs markedly suppressed the expression of megalin and cubulin and the absorption of albumin in HK-2 cells in vitro, whereas the expression of megalin and cubilin and the absorption of albumin were all increased in these cells after gliquidone treatment. In conclusion, gliquidone treatment effectively reduced urinary protein in GK rats with diabetic nephropathy by improving glomerular lesions and promoting tubular reabsorption.
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Affiliation(s)
- Jian-Ting Ke
- Department of Nephrology, Fifth Affiliated Hospital, Sun Yat-Sen University, Zhuhai 519000, People's Republic of China Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Beijing 100029, People's Republic of China Department of Endocrinology, Qilu Hospital, Shandong University, Jinan 250012, Shandong, China
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Luppi P, Kallas Å, Wahren J. Can C-peptide mediated anti-inflammatory effects retard the development of microvascular complications of type 1 diabetes? Diabetes Metab Res Rev 2013; 29:357-62. [PMID: 23463541 DOI: 10.1002/dmrr.2409] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/06/2012] [Revised: 01/30/2013] [Accepted: 02/28/2013] [Indexed: 02/07/2023]
Abstract
Hyperglycemia is considered to be the major cause of microvascular complications of diabetes. Growing evidence highlights the importance of hyperglycemia-mediated inflammation in the initiation and progression of microvascular complications in type 1 diabetes. We hypothesize that lack of proinsulin C-peptide and lack of its anti-inflammatory properties contribute to the development of microvascular complications. Evidence gathered over the past 20 years shows that C-peptide is a biologically active peptide in its own right. It has been shown to reduce formation of reactive oxygen species and nuclear factor-κB activation induced by hyperglycemia, resulting in inhibition of cytokine, chemokine and cell adhesion molecule formation as well as reduced apoptotic activity. In addition, C-peptide stimulates and induces the expression of both Na⁺, K⁺-ATPase and endothelial nitric oxide synthase. Animal studies and small-scale clinical trials in type 1 diabetes patients suggest that C-peptide replacement combined with regular insulin therapy exerts beneficial effects on kidney and nerve dysfunction. Further clinical trials in patients with microvascular complications including measurements of inflammatory markers are warranted to explore the clinical significance of the aforementioned, previously unrecognized, C-peptide effects.
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Affiliation(s)
- Patrizia Luppi
- Division of Immunogenetics, Department of Pediatrics, Children's Hospital of Pittsburgh of UPMC, Rangos Research Center, Pittsburgh, PA 15201, USA
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Giebink AW, Vogel PA, Medawala W, Spence DM. C-peptide-stimulated nitric oxide production in a cultured pulmonary artery endothelium is erythrocyte mediated and requires Zn(2+). Diabetes Metab Res Rev 2013; 29:44-52. [PMID: 23007928 DOI: 10.1002/dmrr.2359] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/16/2012] [Accepted: 08/23/2012] [Indexed: 12/13/2022]
Abstract
BACKGROUND C-peptide has been shown to stimulate the production of nitric oxide (NO) in aortic endothelial cells via activation of endothelial nitric oxide synthase (eNOS) through an increased calcium influx. Here, results obtained using cultured bovine pulmonary artery endothelial cells (bPAECs) suggest that C-peptide does not induce eNOS activation directly in cultured pulmonary artery endothelium. However, C-peptide has been shown to stimulate the release of ATP from erythrocytes, a well-documented stimulus of eNOS activity in the pulmonary endothelium. Therefore, studies were performed to examine if C-peptide can indirectly stimulate NO production in a cultured pulmonary endothelium that is erythrocyte mediated. METHODS NO production and free intracellular calcium changes were monitored in immobilized bPAECs using specific intracellular fluorescent probes after stimulation with adenosine triphosphate (ATP), calcium ionophore A23187, or C-peptide. A microfluidic device enabled immobilized bPAECs to interact with flowing erythrocytes in the presence and absence of C-peptide to determine the role of the erythrocyte in C-peptide-stimulated NO production in cultured bPAECs. RESULTS ATP and the calcium ionophore stimulate significant increases in both intracellular NO production and influx of free calcium in cultured bPAECs. In contrast, C-peptide, ranging from physiological to above physiological concentrations, was unable to stimulate NO production or calcium influx in the bPAECs. However, when erythrocytes were pre-incubated with a mixture containing physiological concentrations of C-peptide with Zn(2+) and haemodynamically pumped beneath bPAECs cultured on a microfluidic device, an 88.6 ± 7.5% increase in endothelial NO production was observed. CONCLUSIONS C-peptide does not affect NO production in bPAECs directly but can impact NO production through an erythrocyte-mediated mechanism. Furthermore, in the absence of Zn(2+), C-peptide does not stimulate this NO production directly or indirectly. These results suggest that C-peptide, in the presence of Zn(2+), may be a determinant in purinergic receptor signalling via its ability to stimulate the release of ATP from erythrocytes.
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Affiliation(s)
- Adam W Giebink
- Department of Chemistry, Michigan State University, East Lansing, MI 48824, USA
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Affiliation(s)
- John Wahren
- Department of Molecular Medicine and Surgery, Karolinska Institutet,Stockholm, Sweden.
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GLP-1, exendin-4 and C-peptide regulate pancreatic islet microcirculation, insulin secretion and glucose tolerance in rats. Clin Sci (Lond) 2012; 122:375-84. [PMID: 22054347 DOI: 10.1042/cs20090464] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
GLP-1 (glucagon-like peptide 1) and its mimetic exendin-4 are used against Type 2 diabetes. C-peptide has also proven promising to enhance insulin action. Since insulin secretion in vivo can be rapidly tuned by changes in islet microcirculation, we evaluated the influence of GLP-1, exendin-4 and C-peptide on pancreatic IBF (islet blood flow), and dynamic changes in insulin secretion and glycaemia in the rat. Adult male Wistar rats were divided into four groups given intravenous saline, GLP-1, exendin-4 or C-peptide respectively and administered either saline or 30% glucose. Furthermore, we investigated the effect of intravenous infusion of different doses of exendin-4 into either the femoral vein or the portal vein on islet microcirculation. A non-radioactive microsphere technique was adopted to measure the regional blood flow. Both GLP-1 and exendin-4 prevented the glucose-induced PBF (pancreatic blood flow) redistribution into the islets. Infusion of exendin-4 into the portal vein did not alter pancreatic islet microcirculation, while infusion of exendin-4 into femoral vein significantly decreased basal IBF. C-peptide increased basal IBF and the proportion of IBF out of total PBF, but did not affect the islet microcirculation after glucose administration. GLP-1, exendin-4 and C-peptide stimulated insulin secretion and significantly decreased glycaemia. Blocking NO formation did not prevent the decreased IBF and post-load glycaemia evoked by exendin-4, but further decreased IBF and KBF (kidney blood flow) and increased basal glycaemia. Blocking the vagus nerve enhanced pancreatic IBF and further decreased post-load glycaemia and KBF and increased basal glycaemia. The vascular modulatory effect on pancreatic islet microcirculation described herein, with subsequent effects on in vivo insulin secretion and glycaemia, might be one of the mechanisms underlying the anti-diabetic actions of GLP-1 and its long acting mimetic exendin-4, as well as that of C-peptide.
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Kim BY, Jung CH, Mok JO, Kang SK, Kim CH. Association between serum C-peptide levels and chronic microvascular complications in Korean type 2 diabetic patients. Acta Diabetol 2012; 49:9-15. [PMID: 21212993 DOI: 10.1007/s00592-010-0249-6] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/21/2010] [Accepted: 12/20/2010] [Indexed: 12/25/2022]
Abstract
This study evaluated the association between serum C-peptide levels and chronic vascular complications in Korean patients with type 2 diabetes. Data for 1,410 patients with type 2 diabetes were evaluated cross-sectionally. Fasting and postprandial 2-hour serum C-peptide levels were analyzed with respect to diabetic micro- and macrovascular complications. In the group of patients with lower fasting serum C-peptide quartile, the prevalences of diabetic retinopathy and neuropathy were significantly higher (P = 0.035, P < 0.001, respectively). In the group of patients with lower delta C-peptide (postprandial - fasting C-peptide) quartile, the prevalences of diabetic retinopathy, nephropathy, and neuropathy were significantly higher (P < 0.001 for all). Low delta C-peptide quartile was also associated with increased severity of retinopathy and nephropathy. The age- and sex-adjusted odds ratios (ORs) for retinopathy, neuropathy, and nephropathy in the lowest versus the highest delta C-peptide quartile were 6.45 (95% confidence interval 3.41-12.22), 3.01 (2.16-4.19), and 2.65 (1.71-4.12), respectively. After further adjustment for the duration of diabetes, type of antidiabetic therapy, mean hemoglobin A1c, body mass index, and blood pressure, the ORs were reduced to 2.83 (1.32-6.08), 1.68 (1.12-2.53), and 1.61 (1.05-2.47), respectively, but remained significant. No significant difference was observed in the prevalence of macrovascular complications with respect to fasting or delta C-peptide quartiles. These results suggest that low C-peptide level is associated with diabetic microvascular, but not macrovascular complications in patients with type 2 diabetes mellitus.
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Affiliation(s)
- Bo-Yeon Kim
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Bucheon Hospital, Soonchunhyang University College of Medicine, Jung-Dong, Wonmi-Gu, South Korea
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He BB, Wei L, Gu YJ, Han JF, Li M, Liu YX, Bao YQ, Jia WP. Factors associated with diabetic retinopathy in chinese patients with type 2 diabetes mellitus. Int J Endocrinol 2012; 2012:157940. [PMID: 22844279 PMCID: PMC3400337 DOI: 10.1155/2012/157940] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/06/2012] [Accepted: 05/07/2012] [Indexed: 12/11/2022] Open
Abstract
Objective. To investigate the risk factors of DR in Chinese T2DM patients. Methods. 2009 patients with T2DM were included in this cross-sectional study. All patients underwent eye examination, and the DR stage was defined by an ophthalmologist. Correlation analysis was performed to evaluate the relation between DR and clinical variables. Logistic regression models were used to assess risk for those factors associated with DR. Results. A total of 597 T2DM patients (29.7%) had DR, of which 548 (27.3%) were nonproliferative diabetic retinopathy and 49 (2.4%) were proliferative diabetic retinopathy. Positive correlations were found between DR and duration of diabetes, systolic blood pressure (SBP), diastolic blood pressure, glycated hemoglobin, glycated albumin, 24 hurinary albumin excretion, peripheral atherosclerosis (PA), diabetes nephropathy (DN), diabetic peripheral neuropathy, and anemia. Negative correlations were found between DR and C-peptide and glomerular filtration rate. Logistic regression analysis revealed that duration of diabetes, SBP, DN, anemia, PA, and C-peptide were each independent risk factors of DR. Conclusion. The duration of diabetes, SBP, DN, anemia, and PA are positively associated with DR in Chinese T2DM patients, while C-peptide is negatively associated with DR. Monitoring and evaluation of these related factors will likely contribute to the prevention and treatment of DR.
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Affiliation(s)
- Bin-Bin He
- Shanghai Municipal Key Laboratory on Diabetes, Department of Endocrinology and Metabolism, Shanghai Diabetes Institute, and Shanghai Municipal Clinical Center on Diabetes, Shanghai Jiaotong University Affiliated Sixth People's Hospital, Shanghai 200233, China
| | - Li Wei
- Shanghai Municipal Key Laboratory on Diabetes, Department of Endocrinology and Metabolism, Shanghai Diabetes Institute, and Shanghai Municipal Clinical Center on Diabetes, Shanghai Jiaotong University Affiliated Sixth People's Hospital, Shanghai 200233, China
- *Li Wei:
| | - Yun-Juan Gu
- Shanghai Municipal Key Laboratory on Diabetes, Department of Endocrinology and Metabolism, Shanghai Diabetes Institute, and Shanghai Municipal Clinical Center on Diabetes, Shanghai Jiaotong University Affiliated Sixth People's Hospital, Shanghai 200233, China
| | - Jun-Feng Han
- Shanghai Municipal Key Laboratory on Diabetes, Department of Endocrinology and Metabolism, Shanghai Diabetes Institute, and Shanghai Municipal Clinical Center on Diabetes, Shanghai Jiaotong University Affiliated Sixth People's Hospital, Shanghai 200233, China
| | - Ming Li
- Shanghai Municipal Key Laboratory on Diabetes, Department of Endocrinology and Metabolism, Shanghai Diabetes Institute, and Shanghai Municipal Clinical Center on Diabetes, Shanghai Jiaotong University Affiliated Sixth People's Hospital, Shanghai 200233, China
| | - Yu-Xiang Liu
- Shanghai Municipal Key Laboratory on Diabetes, Department of Endocrinology and Metabolism, Shanghai Diabetes Institute, and Shanghai Municipal Clinical Center on Diabetes, Shanghai Jiaotong University Affiliated Sixth People's Hospital, Shanghai 200233, China
| | - Yu-Qian Bao
- Shanghai Municipal Key Laboratory on Diabetes, Department of Endocrinology and Metabolism, Shanghai Diabetes Institute, and Shanghai Municipal Clinical Center on Diabetes, Shanghai Jiaotong University Affiliated Sixth People's Hospital, Shanghai 200233, China
| | - Wei-Ping Jia
- Shanghai Municipal Key Laboratory on Diabetes, Department of Endocrinology and Metabolism, Shanghai Diabetes Institute, and Shanghai Municipal Clinical Center on Diabetes, Shanghai Jiaotong University Affiliated Sixth People's Hospital, Shanghai 200233, China
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Affiliation(s)
- Patrizia Luppi
- Division of Immunogenetics, Department of Pediatrics, Children's Hospital of Pittsburgh of UPMC, Rangos Research Center, 530 45th Street, Pittsburgh, PA 15201, USA
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Rogers SA, Mohanakumar T, Liapis H, Hammerman MR. Engraftment of cells from porcine islets of Langerhans and normalization of glucose tolerance following transplantation of pig pancreatic primordia in nonimmune-suppressed diabetic rats. THE AMERICAN JOURNAL OF PATHOLOGY 2010; 177:854-64. [PMID: 20581052 DOI: 10.2353/ajpath.2010.091193] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
Transplantation therapy for human diabetes is limited by the toxicity of immunosuppressive drugs. However, even if toxicity can be minimalized, there will still be a shortage of human donor organs. Xenotransplantation of porcine islets may be a strategy to overcome these supply problems. Xenotransplantation in mesentery of pig pancreatic primordia obtained very early during organogenesis [embryonic day 28 (E28)] can obviate the need for immune suppression in rats or rhesus macaques. Here, in rats transplanted previously with E28 pig pancreatic primordia in the mesentery, we show normalization of glucose tolerance in nonimmune-suppressed streptozotocin-diabetic LEW rats and insulin and porcine proinsulin mRNA-expressing cell engraftment in the kidney following implantation of porcine islets beneath the renal capsule. Donor cell engraftment was confirmed using fluorescent in situ hybridization for the porcine X chromosome and electron microscopy. In contrast, cells from islets did not engraft in the kidney without prior transplantation of E28 pig pancreatic primordia in the mesentery. This is the first report of prolonged engraftment and sustained normalization of glucose tolerance following transplantation of porcine islets in nonimmune-suppressed, immune-competent rodents. The data are consistent with tolerance induction to a cell component of porcine islets induced by previous transplantation of E28 pig pancreatic primordia.
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Affiliation(s)
- Sharon A Rogers
- Renal Division, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA
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Keltner Z, Meyer JA, Johnson EM, Palumbo AM, Spence DM, Reid GE. Mass spectrometric characterization and activity of zinc-activated proinsulin C-peptide and C-peptide mutants. Analyst 2009; 135:278-88. [PMID: 20098759 DOI: 10.1039/b917600d] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Numerous reports have demonstrated an active role for proinsulin C-peptide in ameliorating chronic complications associated with diabetes mellitus. It has been recently reported that some of these activities are dependent upon activation of C-peptide with certain metal ions, such as Fe(II), Cr(III) or Zn(II). In an effort to gain a greater understanding of the structure/function dependence of the peptide-metal interactions responsible for this activity, a series of experiments involving the use of electrospray ionization (ESI), matrix assisted laser desorption/ionization (MALDI) and collision-induced dissociation-tandem mass spectrometry (CID-MS/MS) of C-peptide in the presence or absence of Zn(II) have been carried out. Additionally, various C-peptide mutants with alanine substitution at individual aspartic acid or glutamic acid residues throughout the C-peptide sequence were analyzed. CID-MS/MS of wild type C-peptide in the presence of Zn(II) indicated multiple sites for metal binding, localized at acidic residues within the peptide sequence. Mutations of individual acidic residues did not significantly affect this fragmentation behavior, suggesting that no single acidic residue is critical for binding. However, ESI-MS analysis revealed an approximately 50% decrease in relative Zn(II) binding for each of the mutants compared to the wild type sequence. Furthermore, a significant decrease in activity was observed for each of the Zn(II)-activated mutant peptides compared to the wild type C-peptide, indicated by measurement of ATP released from erythrocytes, with a 75% decrease observed for the Glu27 mutant. Additional studies on the C-terminal pentapeptide of C-peptide EGSLQ, as well as a mutant C-terminal pentapeptide sequence AGSLQ, revealed that substitution of the glutamic acid residue resulted in a complete loss of activity, implicating a central role for Glu27 in Zn(II)-mediated C-peptide activity.
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Affiliation(s)
- Zachary Keltner
- Department of Chemistry, Michigan State University, East Lansing, MI 48824, USA
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Forst T, Hach T, Kunt T, Weber MM, Pfützner A. Molecular effects of C-Peptide in microvascular blood flow regulation. Rev Diabet Stud 2009; 6:159-67. [PMID: 20039005 DOI: 10.1900/rds.2009.6.159] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
C-Peptide is produced in beta-cells in the pancreas, and secreted into the blood stream in equimolar amounts with insulin. For a long time, C-peptide was considered as an important component in the biosynthesis of insulin, but otherwise believed to possess minimal biological activity. In the recent years, numerous studies demonstrated that lacking C-peptide in type 1 diabetic patients might exert an important role in the development of microvascular complications such as nephropathy or neuropathy. There is increasing evidence that the biological effects of C-peptide are, at least in part, mediated through the modulation of endothelial function and microvascular blood flow. In several tissues, an increase in microvascular and nutritional blood flow could be observed during substitution of physiological amounts of C-peptide. Recent studies confirmed that C-peptide stimulates endothelial NO release by the activation of Ca2+ calmodulin-regulated endothelial NO synthase. A restoration of Na+/K+-ATPase activity during C-peptide supplementation could be observed in erythrocytes and renal tubular cells. The improvement of erythrocyte Na+/K+-ATPase is associated with an increase in erythrocyte deformability, and improved rheological properties. In this article, we consider the role of C-peptide in the context of endothelial function and microvascular blood flow as pathophysiologic components in the development of microvascular complications in patients with diabetes mellitus and loss of beta-cell function.
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Affiliation(s)
- Thomas Forst
- Institute for Clinical Research and Development, Parcusstr. 8, 55116 Mainz, Germany
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Kamiya H, Zhang W, Sima AAF. The beneficial effects of C-Peptide on diabetic polyneuropathy. Rev Diabet Stud 2009; 6:187-202. [PMID: 20039008 DOI: 10.1900/rds.2009.6.187] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
Diabetic polyneuropathy (DPN) is a common complication in diabetes. At present, there is no adequate treatment, and DPN is often debilitating for patients. It is a heterogeneous disorder and differs in type 1 and type 2 diabetes. An important underlying factor in type 1 DPN is insulin deficiency. Proinsulin C-peptide is a critical element in the cascade of events. In this review, we describe the physiological role of C-peptide and how it provides an insulin-like signaling function. Such effects translate into beneficial outcomes in early metabolic perturbations of neural Na+/K+-ATPase and nitric oxide (NO) with subsequent preventive effects on early nerve dysfunction. Further corrective consequences resulting from this signaling cascade have beneficial effects on gene regulation of early gene responses, neurotrophic factors, their receptors, and the insulin receptor itself. This may lead to preventive and corrective results to nerve fiber degeneration and loss, as well as, promotion of nerve fiber regeneration with respect to sensory somatic fibers and small nociceptive nerve fibers. A characteristic abnormality of type 1 DPN is nodal and paranodal degeneration with severe consequences for myelinated fiber function. This review deals in detail with the underlying insulin-deficiency-related molecular changes and their correction by C-peptide. Based on these observations, it is evident that continuous maintenance of insulin-like actions by C-peptide is needed in peripheral nerve to minimize the sequences of metabolic and molecular abnormalities, thereby ameliorating neuropathic complications. There is now ample evidence demonstrating that C-peptide replacement in type 1 diabetes promotes insulin action and signaling activities in a more enhanced, prolonged, and continuous fashion than does insulin alone. It is therefore necessary to replace C-peptide to physiological levels in diabetic patients. This will have substantial beneficial effects on type 1 DPN.
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Affiliation(s)
- Hideki Kamiya
- Department of Pathology, Wayne State University, Detroit, MI, USA
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Vareniuk I, Pacher P, Pavlov IA, Drel VR, Obrosova IG. Peripheral neuropathy in mice with neuronal nitric oxide synthase gene deficiency. Int J Mol Med 2009; 23:571-580. [PMID: 19360314 PMCID: PMC2756471 DOI: 10.3892/ijmm_00000166] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
Evidence for the important role of the potent oxidant peroxynitrite in peripheral diabetic neuropathy and neuropathic pain is emerging. This study evaluated the contribution of neuronal nitric oxide synthase (nNOS) to diabetes-induced nitrosative stress in peripheral nerve and dorsal root ganglia, and peripheral nerve dysfunction and degeneration. Control and nNOS-/- mice were made diabetic with streptozotocin, and maintained for 6 weeks. Peroxynitrite injury was assessed by nitrotyrosine and poly(ADP-ribose) immunoreactivities. Peripheral diabetic neuropathy was evaluated by measurements of sciatic motor and hind-limb digital sensory nerve conduction velocities, thermal algesia, tactile allodynia, and intraepidermal nerve fiber density. Control nNOS-/- mice displayed normal motor nerve conduction velocity and thermal response latency, whereas sensory nerve conduction velocity was slightly lower compared with non-diabetic wild-type mice, and tactile response threshold and intraepidermal nerve fiber density were reduced by 47 and 38%, respectively. Both diabetic wild-type and nNOS-/- mice displayed enhanced nitrosative stress in peripheral nerve. In contrast to diabetic wild-type mice, diabetic nNOS-/- mice had near normal nitrotyrosine and poly(ADP-ribose) immunofluorescence in dorsal root ganglia. Both diabetic wild-type and nNOS-/- mice developed motor and sensory nerve conduction velocity deficits and thermal hypoalgesia although nNOS gene deficiency slightly reduced severity of the three disorders. Tactile response thresholds were similarly decreased in control and diabetic nNOS-/- mice compared with non-diabetic wild-type mice. Intraepidermal nerve fiber density was lower by 27% in diabetic nNOS-/- mice compared with the corresponding non-diabetic group, and by 20% in diabetic nNOS-/- mice compared with diabetic wild-type mice. In conclusion, nNOS is required for maintaining the normal peripheral nerve function and small sensory nerve fibre innervation. nNOS gene deficiency does not protect from development of nerve conduction deficit, sensory neuropathy and intraepidermal nerve fiber loss.
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Affiliation(s)
- Igor Vareniuk
- Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, LA 70808, USA
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Abstract
Type 1 diabetes is diagnosed when the patient's endogenous insulin secretion decreases to a level which results in hyperglycemia. After diagnosis, insulin secretion continues to decline. As a reference for clinical trials trying to preserve endogenous beta-cell function in patients with recently diagnosed type 1 diabetes, in this short review I attempt to summarize the natural history of endogenous beta-cell function after the diagnosis of type 1 diabetes.
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Affiliation(s)
- Jerry P Palmer
- Department of Medicine, Veterans Affairs Puget Sound Health Care System and University of Washington, Seattle, WA, USA.
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