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Jansson Sigfrids F, Groop PH. Progression and regression of kidney disease in type 1 diabetes. FRONTIERS IN NEPHROLOGY 2023; 3:1282818. [PMID: 38192517 PMCID: PMC10773897 DOI: 10.3389/fneph.2023.1282818] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 08/24/2023] [Accepted: 11/27/2023] [Indexed: 01/10/2024]
Abstract
Diabetic kidney disease is distinguished by the presence of albuminuria, hypertension, declining kidney function, and a markedly elevated cardiovascular disease risk. This constellation of clinical features drives the premature mortality associated with type 1 diabetes. The first epidemiological investigations concerning type 1 diabetes-related albuminuria date back to the 1980s. The early studies found that proteinuria - largely equivalent to severe albuminuria - developed in 35 to 45% of individuals with type 1 diabetes, with the diabetes duration-specific incidence rate pattern portraying one or two peaks. Furthermore, moderate albuminuria, the first detectable sign of diabetic kidney disease, was found to nearly inexorably progress to overt kidney disease within a short span of time. Since the early reports, studies presenting more updated incidence rates have appeared, although significant limitations such as study populations that lack broad generalizability, study designs vulnerable to substantive selection bias, and constrained follow-up times have been encountered by many. Nevertheless, the most recent reports estimate that in modern times, moderate - instead of severe - albuminuria develops in one-third of individuals with type 1 diabetes; yet, a considerable part (up to 40% during the first ten years after the initial albuminuria diagnosis) progresses to more advanced stages of the disease over time. An alternative pathway to albuminuria progression is its regression, which affects up to 60% of the individuals, but notably, the relapse rate to a more advanced disease stage is high. Whether albuminuria regression translates into a decline in cardiovascular disease and premature mortality risk is an area of debate, warranting more detailed research in the future. Another unclear but alarming feature is that although the incidence of severe albuminuria has fallen since the 1930s, the decline seems to have reached a plateau after the 1980s. This stagnation may be due to the lack of kidney-protective medicines since the early 1980s, as the recent breakthroughs in type 2 diabetes have not been applicable to type 1 diabetes. Therefore, novel treatment strategies are at high priority within this patient population.
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Affiliation(s)
- Fanny Jansson Sigfrids
- Folkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland
- Department of Nephrology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
- Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Per-Henrik Groop
- Folkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland
- Department of Nephrology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
- Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, Finland
- Department of Diabetes, Central Clinical School, Monash University, Melbourne, VIC, Australia
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Khadilkar A, Oza C, Mondkar SA. Insulin Resistance in Adolescents and Youth With Type 1 Diabetes: A Review of Problems and Solutions. Clin Med Insights Endocrinol Diabetes 2023; 16:11795514231206730. [PMID: 37901890 PMCID: PMC10604500 DOI: 10.1177/11795514231206730] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2022] [Accepted: 09/21/2023] [Indexed: 10/31/2023] Open
Abstract
Though insulin resistance (IR) was previously considered a feature of only type 2 Diabetes (T2DM), its development in type 1 Diabetes (T1DM) is not an uncommon occurrence, the causes of which are multifactorial (gender, pubertal status, diabetes duration, ethnicity, genetics, adiposity, glycemic control, chronic inflammation). Despite improvements in glucose, blood pressure and lipid profile, vascular complications (coronary artery disease and nephropathy) continue to remain common causes of morbidity and mortality in T1DM. Aggressive glycemic control reduces but does not eliminate the risk of IR. IR accelerates the development of micro and macrovascular complications, many of which can be potentially reversed if diagnosed and managed early. Lack of endogenous insulin production makes estimation of insulin sensitivity in T1DM difficult. As hyperinsulinemic-euglycemic clamp studies are cumbersome and invasive, the use of prediction equations for calculating estimated insulin sensitivity may prove to be useful. Along with intensive insulin therapy, dietary modifications and increasing physical activity, the role of Metformin in managing IR in T1DM is becoming increasingly popular. Metformin adjunct therapy in T1DM has been shown to improve insulin sensitivity, glycemic control, lipid profile, body composition, vascular smooth muscle function, thereby reducing the risk of vascular complications, as well as reversal of early vascular dysfunction. However, further studies to assess long-term efficacy and safety of Metformin use in adolescents and youth with T1DM are needed. This review aims at revisiting the pathophysiology of IR in T1DM and techniques of identifying those at risk so as to put into action various strategies for management of the same.
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Affiliation(s)
- Anuradha Khadilkar
- Hirabai Cowasji Jehangir Medical Research Institute, Jehangir Hospital, Pune, Maharashtra, India
- Interdisciplinary School of Health Sciences, Savitribai Phule University, Pune, Maharashtra, India
| | - Chirantap Oza
- Hirabai Cowasji Jehangir Medical Research Institute, Jehangir Hospital, Pune, Maharashtra, India
| | - Shruti A Mondkar
- Hirabai Cowasji Jehangir Medical Research Institute, Jehangir Hospital, Pune, Maharashtra, India
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Oza C, Khadilkar A, Karguppikar M, Gondhalekar K, Khadilkar V. Comparison of insulin sensitivity indices for detection of double diabetes in Indian adolescents with type 1 diabetes. J Pediatr Endocrinol Metab 2022; 35:1010-1019. [PMID: 35705059 DOI: 10.1515/jpem-2022-0076] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/10/2022] [Accepted: 05/24/2022] [Indexed: 11/15/2022]
Abstract
OBJECTIVES The role of insulin sensitivity (IS) in the development and progression of metabolic syndrome (MS) in subjects with type-1 diabetes (T1D) is being increasingly recognized. As patients with T1D lack endogenous insulin secretion, measurement of insulin concentration by immunoassay or by indices such as homeostasis model of assessment for insulin resistance (HOMA-IR) is not helpful in assessing IS. Hence, some equations have been developed and validated against data from euglycemic-hyper-insulinemic clamp tests (the gold standard) to estimate IS. 1) To assess IS using available equations (EDC, SEARCH and CACTI) and relationship of IS with MS and microalbuminuria in adolescents with T1D, (2) To compare the predictive value of these equations for detection of MS and derive a cut-off to predict the future risk of development of MS and microalbuminuria and (3) To identify the most accurate non-invasive and easy-to-use equation for detecting patients with double diabetes (DD) in a clinical setting. METHODS This cross-sectional study included 181 adolescents aged 12-18 years with T1D. Demographic data and laboratory measurements were performed using standard protocols. IS was calculated using following equations:(1) EDC=24.31-12.22×(WHR)-3.29×(hypertension)-0.57×(HbA1c), (2) SEARCH=exp(4.64725-0.02032(waist)-0.09779(HbA1c)-0.00235(Triglycerides), (3)CACTI-exA=exp(4.1075-0.01299×(waist)-1.05819×(insulin dose)-0.00354×(Triglycerides)-0.00802×(DBP)). RESULTS IS determined by all three methods had significant negative correlation (p<0.05) with MS as well as with microalbuminuria. The cut-off value of 5.485 mg/kg/min by SEARCH method for determining IS had the highest sensitivity and specificity in identifying MS. CONCLUSIONS IS by SEARCH equation may be used in routine clinical practice to detect DD in Indian adolescents with T1D at risk of developing metabolic as well as microvascular complications.
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Affiliation(s)
- Chirantap Oza
- Hirabai Cowasji Jehangir Medical Research Institute, Pune, India
| | - Anuradha Khadilkar
- Hirabai Cowasji Jehangir Medical Research Institute, Pune, India.,Senior Pediatric Endocrinologist, Jehangir Hospital, Pune, India.,Department of Health Sciences, Savitribai Phule Pune University, Pune, Maharashtra, India
| | | | | | - Vaman Khadilkar
- Senior Pediatric Endocrinologist, Jehangir Hospital, Pune, India.,Department of Health Sciences, Savitribai Phule Pune University, Pune, Maharashtra, India
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Elbarbary NS, Ismail EAR, Ghallab MA. Effect of metformin as an add-on therapy on neuregulin-4 levels and vascular-related complications in adolescents with type 1 diabetes: A randomized controlled trial. Diabetes Res Clin Pract 2022; 186:109857. [PMID: 35351535 DOI: 10.1016/j.diabres.2022.109857] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/06/2022] [Revised: 03/06/2022] [Accepted: 03/24/2022] [Indexed: 12/13/2022]
Abstract
BACKGROUND Inflammation is closely associated with atherosclerosis and plays a crucial role in the development of cardiovascular disease. Metformin sensitizes body cells to insulin, which may cause a reduction of atherogenic lipid fractions. Low neuregulin-4 (Nrg-4) levels, an adipokine, are linked to obesity, insulin resistance, impaired glucose tolerance and type 2 diabetes. OBJECTIVES We assessed the effect of oral supplementation with metformin on glycemic control, neuregulin-4 levels and carotid intima media thickness (CIMT) as a marker for subclinical atherosclerosis in adolescents with type 1 diabetes mellitus (T1DM) and microvascular complications. METHODS This randomized placebo-controlled trial included 80 type 1 diabetic patients with microvascular complications who were randomly divided to receive either 24 weeks of metformin 500 mg/day or matching placebo. Fasting blood glucose (FBG), HbA1c, C-reactive protein (CRP), urinary albumin creatinine ratio (UACR), lipid profile, Nrg-4 and CIMT were assessed at baseline and study end. RESULTS Both groups were well-matched as regards baseline clinical and laboratory data (p greater than 0.05). After 24-weeks, metformin therapy for the intervention group resulted in a significant decrease of HbA1c, CRP, UACR, total cholesterol and CIMT while Nrg-4 levels were increased compared with baseline levels (p < 0.001) and with placebo group(p < 0.001). Baseline Nrg-4 levels were negatively correlated to FBG, HbA1c, total cholesterol, CRP and CIMT. Metformin was well-tolerated. CONCLUSIONS Oral metformin supplementation once daily for 24 weeks as an adjuvant therapy to intensive insulin in pediatric T1DM was safe and effective in improving glycemic control, dyslipidemia and Nrg-4 levels; hence, it decreased inflammation, microvascular complications and subclinical atherosclerosis.
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Adeva-Andany MM, Fernández-Fernández C, Funcasta-Calderón R, Ameneiros-Rodríguez E, Adeva-Contreras L, Castro-Quintela E. Insulin Resistance is Associated with Clinical Manifestations of Diabetic Kidney Disease (Glomerular Hyperfiltration, Albuminuria, and Kidney Function Decline). Curr Diabetes Rev 2022; 18:e171121197998. [PMID: 34789129 DOI: 10.2174/1573399818666211117122604] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/06/2021] [Revised: 09/13/2021] [Accepted: 09/15/2021] [Indexed: 11/22/2022]
Abstract
Clinical features of diabetic kidney disease include glomerular hyperfiltration, albuminuria, and kidney function decline towards End-Stage Kidney Disease (ESKD). There are presently neither specific markers of kidney involvement in patients with diabetes nor strong predictors of rapid progression to ESKD. Serum-creatinine-based equations used to estimate glomerular filtration rate are notoriously unreliable in patients with diabetes. Early kidney function decline, reduced glomerular filtration rate, and proteinuria contribute to identifying diabetic patients at higher risk for rapid kidney function decline. Unlike proteinuria, the elevation of urinary albumin excretion in the range of microalbuminuria is frequently transient in patients with diabetes and does not always predict progression towards ESKD. Although the rate of progression of kidney function decline is usually accelerated in the presence of proteinuria, histological lesions of diabetes and ESKD may occur with normal urinary albumin excretion. No substantial reduction in the rate of ESKD associated with diabetes has been observed during the last decades despite intensified glycemic control and reno-protective strategies, indicating that existing therapies do not target underlying pathogenic mechanisms of kidney function decline. Very long-term effects of sodium-glucose transporters- 2 inhibitors and glucagon-like peptide-1 analogs remain to be defined. In patients with diabetes, glucagon secretion is typically elevated and induces insulin resistance. Insulin resistance is consistently and strongly associated with clinical manifestations of diabetic kidney disease, suggesting that reduced insulin sensitivity participates in the pathogenesis of the disease and may represent a therapeutic objective. Amelioration of insulin sensitivity in patients with diabetes is associated with cardioprotective and kidney-protective effects.
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Affiliation(s)
- María M Adeva-Andany
- Nephrology Division, Hospital General Juan Cardona, c/ Pardo Bazán s/n, 15406 Ferrol, Spain
| | | | | | | | | | - Elvira Castro-Quintela
- Nephrology Division, Hospital General Juan Cardona, c/ Pardo Bazán s/n, 15406 Ferrol, Spain
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Adeva-Andany MM, Fernández-Fernández C, Carneiro-Freire N, Vila-Altesor M, Ameneiros-Rodríguez E. The differential effect of animal versus vegetable dietary protein on the clinical manifestations of diabetic kidney disease in humans. Clin Nutr ESPEN 2022; 48:21-35. [DOI: 10.1016/j.clnesp.2022.01.030] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2022] [Accepted: 01/25/2022] [Indexed: 10/19/2022]
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Tommerdahl KL, Nadeau KJ, Bjornstad P. Mechanisms of Cardiorenal Protection of Glucagon-Like Peptide-1 Receptor Agonists. Adv Chronic Kidney Dis 2021; 28:337-346. [PMID: 34922690 DOI: 10.1053/j.ackd.2021.06.001] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2020] [Revised: 05/03/2021] [Accepted: 06/01/2021] [Indexed: 11/11/2022]
Abstract
The worldwide prevalence of type 2 diabetes (T2D) is steadily increasing, and it remains a challenging public health problem for populations in both developing and developed countries around the world. Despite the recent advances in novel antidiabetic agents, diabetic kidney disease and cardiovascular disease remain the leading causes of morbidity and mortality in T2D. Glucagon-like peptide-1 (GLP-1) receptor agonists (RAs), incretin hormones that stimulate postprandial insulin secretion, serve as a promising avenue for treatment of T2D as they result in a variety of antihyperglycemic effects including increased endogenous insulin secretion, decreased gluconeogenesis, inhibition of pancreatic α-cell glucagon production, decreased pancreatic β-cell apoptosis, and increased β-cell proliferation. GLP-1RAs have also been found to delay gastric emptying, promote weight loss, increase satiety, decrease hypertension, improve dyslipidemia, reduce inflammation, improve albuminuria, induce natriuresis, improve cardiovascular function, and prevent thrombogenesis. In this review, we will present risk factors for the development of cardiac and kidney disease in individuals with T2D and discuss possible mechanisms for the cardiorenal protective effects seen with GLP-1RAs. We will also present the possibility of dual- and tri-receptor agonist therapies with GLP-1, gastric inhibitory peptide, and glucagon RAs as an area of possible mechanistic synergy in the treatment of T2D and the prevention of cardiorenal complications.
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van Raalte DH, Bjornstad P. Role of sodium-glucose cotransporter 2 inhibition to mitigate diabetic kidney disease risk in type 1 diabetes. Nephrol Dial Transplant 2020; 35:i24-i32. [PMID: 32003832 PMCID: PMC6993198 DOI: 10.1093/ndt/gfz228] [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: 06/25/2019] [Indexed: 12/17/2022] Open
Abstract
Diabetic kidney disease (DKD) is a common complication of type 1 diabetes (T1D) and a major risk factor for premature death from cardiovascular disease (CVD). Current treatments, such as control of hyperglycaemia and hypertension, are beneficial, but only partially protect against DKD. Finding new, safe and effective therapies to halt nephropathy progression has proven to be challenging. Sodium-glucose cotransporter 2 (SGLT2) inhibitors have demonstrated, in addition to glycaemic lowering, impressive protection against DKD and CVD progression in people with type 2 diabetes. Although these beneficial cardiorenal effects may also apply to people with T1D, supporting data are lacking. Furthermore, the increased rates of euglycaemic diabetic ketoacidosis may limit the use of this class in people with T1D. In this review we highlight the pathophysiology of DKD in T1D and the unmet need that exists. We further detail the beneficial and adverse effects of SGLT2 inhibitors based on their mechanism of action. Finally, we balance the effects in people with T1D and indicate future lines of research.
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Affiliation(s)
- Daniël H van Raalte
- Diabetes Center, Department of Internal Medicine, Amsterdam University Medical Center, Amsterdam, The Netherlands
| | - Petter Bjornstad
- Section of Endocrinology, Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO, USA.,Division of Nephrology, Department of Medicine, University of Colorado School of Medicine, Aurora, CO, USA
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Bjornstad P, Cree-Green M, Baumgartner A, Coe G, Reyes YG, Schäfer M, Pyle L, Regensteiner JG, Reusch JE, Nadeau KJ. Achieving ADA/ISPAD clinical guideline goals is associated with higher insulin sensitivity and cardiopulmonary fitness in adolescents with type 1 diabetes: Results from RESistance to InSulin in Type 1 ANd Type 2 diabetes (RESISTANT) and Effects of MEtformin on CardiovasculaR Function in AdoLescents with Type 1 Diabetes (EMERALD) Studies. Pediatr Diabetes 2018; 19:436-442. [PMID: 29082640 PMCID: PMC5918223 DOI: 10.1111/pedi.12598] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/09/2017] [Revised: 08/23/2017] [Accepted: 09/22/2017] [Indexed: 12/12/2022] Open
Abstract
OBJECTIVE Most youth with type 1 diabetes do not meet the American Diabetes Association (ADA) and International Society for Pediatric and Adolescent Diabetes (ISPAD) targets for hemoglobin A1c (HbA1c), blood pressure (BP), lipids, and body mass index (BMI). We hypothesized that ISPAD/ADA goal achievement would be associated with better insulin sensitivity (IS) and cardiopulmonary fitness. METHODS IS was quantified as glucose infusion rate (GIR) from a hyperinsulinemic-euglycemic clamp in youth with type 1 diabetes from the RESistance to InSulin in Type 1 ANd Type 2 diabetes (RESISTANT) (n = 86) and Effects of MEtformin on CardiovasculaR Function in AdoLescents with Type 1 Diabetes (EMERALD) (n = 41) cohorts (n = 127; age 15.7 ± 2.2 years, 52% girls). Cardiopulmonary fitness was measured as peak oxygen consumption (VO2 peak/kg) during upright (RESISTANT) or supine (EMERALD) cycle ergometry and were stratified by cycle type. Goal achievement was defined as HbA1c < 7.5%, BP < 90th percentile, LDL-cholesterol < 100 mg/dL, HDL-cholesterol > 35 mg/dL, triglycerides < 150 mg/dL and BMI < 85th percentile. Participants were stratified into 3 groups: achieving 0-3 goals (n = 52), 4 goals (n = 48), and 5-6 goals (n = 27). Differences between groups were examined with generalized linear models. RESULTS IS was lower in youth who met 0-3 goals (5.2 ± 3.4 mg/kg/min) vs those who met 4 goals (7.4 ± 4.1 mg/kg/min, P = .04) and those who met 5-6 goals (8.5 ± 4.3 mg/kg/min, P = .003), and remained significant after adjustments for sex and diabetes duration. Upright VO2 peak was lower in youth who met 0-3 goals (25.8 ± 4.6 mL/kg/min) vs those who met 4 goals (33.0 ± 7.8 mL/kg/min, P = .01) and those who met 5-6 goals (33.2 ± 4.4 mL/kg/min, P = .004). Similar and significant relationships were observed in EMERALD participants for supine VO2 peak. CONCLUSIONS ADA/ISPAD goal achievement was associated with greater IS and cardiopulmonary fitness.
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Affiliation(s)
- Petter Bjornstad
- Department of Pediatric Endocrinology, University of Colorado School of Medicine, Aurora, Colorado, United States,Barbara Davis Center for Childhood Diabetes, University of Colorado Denver, Aurora, CO
| | - Melanie Cree-Green
- Department of Pediatric Endocrinology, University of Colorado School of Medicine, Aurora, Colorado, United States
| | - Amy Baumgartner
- Department of Pediatric Endocrinology, University of Colorado School of Medicine, Aurora, Colorado, United States
| | - Gregory Coe
- Department of Pediatric Endocrinology, University of Colorado School of Medicine, Aurora, Colorado, United States
| | - Yesenia Garcia Reyes
- Department of Pediatric Endocrinology, University of Colorado School of Medicine, Aurora, Colorado, United States
| | - Michal Schäfer
- Division of Pediatric Cardiology, University of Colorado School of Medicine, Aurora, Colorado, United States
| | - Laura Pyle
- Department of Pediatric Endocrinology, University of Colorado School of Medicine, Aurora, Colorado, United States,Department of Biostatistics and Informatics, Colorado School of Public Health, Aurora, Colorado, United States
| | - Judith G. Regensteiner
- Center for Women’s Health Research, Divisions of General Internal Medicine and Cardiology, University of Colorado School of Medicine, Aurora, Colorado, United States,Divisions of General Internal Medicine and Cardiology, University of Colorado School of Medicine, Aurora, Colorado, United States
| | - Jane E.B. Reusch
- Center for Women’s Health Research, Divisions of General Internal Medicine and Cardiology, University of Colorado School of Medicine, Aurora, Colorado, United States,Division of Endocrinology, Veterans Administration Hospital, University of Colorado School of Medicine, Aurora, Colorado, United States
| | - Kristen J. Nadeau
- Department of Pediatric Endocrinology, University of Colorado School of Medicine, Aurora, Colorado, United States,Barbara Davis Center for Childhood Diabetes, University of Colorado Denver, Aurora, CO
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Sharaf El Din UA, Salem MM, Abdulazim DO. Uric acid in the pathogenesis of metabolic, renal, and cardiovascular diseases: A review. J Adv Res 2017; 8:537-548. [PMID: 28748119 PMCID: PMC5512153 DOI: 10.1016/j.jare.2016.11.004] [Citation(s) in RCA: 227] [Impact Index Per Article: 28.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2016] [Revised: 11/26/2016] [Accepted: 11/27/2016] [Indexed: 02/07/2023] Open
Abstract
The association between uric acid (UA) on one side and systemic hypertension (Htn), dyslipidemia, glucose intolerance, overweight, fatty liver, renal disease and cardiovascular disease (CVD) on the other side is well recognized. However, the causal relationship between UA and these different clinical problems is still debatable. The recent years have witnessed hundreds of experimental and clinical trials that favored the opinion that UA is a probable player in the pathogenesis of these disease entities. These studies disclosed the strong association between hyperuricemia and metabolic syndrome (MS), obesity, Htn, type 2 diabetes mellitus (DM), non-alcoholic fatty liver disease, hypertriglyceridemia, acute kidney injury, chronic kidney disease (CKD), coronary heart disease (CHD), heart failure and increased mortality among cardiac and CKD patients. The association between UA and nephrolithiasis or preeclampsia is a non-debatable association. Recent experimental trials have disclosed different changes in enzyme activities induced by UA. Nitric oxide (NO) synthase, adenosine monophosphate kinase (AMPK), adenosine monophosphate dehydrogenase (AMPD), and nicotinamide adenine dinucleotide phosphate (NADPH)-oxidase are affected by UA. These changes in enzymatic activities can lead to the observed biochemical and pathological changes associated with UA. The recent experimental, clinical, interventional, and epidemiologic trials favor the concept of a causative role of UA in the pathogenesis of MS, renal, and CVDs.
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Affiliation(s)
- Usama A.A. Sharaf El Din
- Nephrology Unit, Internal Medicine Department, School of Medicine, Cairo University, Egypt
- Corresponding author. Fax: +20 222753890.
| | - Mona M. Salem
- Endocrinology Unit, Internal Medicine Department, School of Medicine, Cairo University, Egypt
| | - Dina O. Abdulazim
- Rheumatology and Rehabilitation Department, School of Medicine, Cairo University, Egypt
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Mottl AK, Divers J, Dabelea D, Maahs DM, Dolan L, Pettitt D, Marcovina S, Imperatore G, Pihoker C, Mauer M, Mayer-Davis EJ. The dose-response effect of insulin sensitivity on albuminuria in children according to diabetes type. Pediatr Nephrol 2016; 31:933-40. [PMID: 26754041 PMCID: PMC4841707 DOI: 10.1007/s00467-015-3276-2] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/06/2015] [Revised: 10/25/2015] [Accepted: 10/26/2015] [Indexed: 12/17/2022]
Abstract
BACKGROUND Insulin resistance is associated with microalbuminuria among youth with diabetes mellitus. We sought to determine the dose-response effect of insulin sensitivity (IS) on the magnitude of albuminuria and whether there is a threshold below which urine albumin excretion increases. METHODS These analyses included participants from the SEARCH for Diabetes in Youth Study with incident diabetes who completed a baseline study visit (n = 2988). We estimated IS using a validated equation incorporating waist circumference, HbA1C, and fasting serum triglycerides. Multivariate regression analyses were performed to assess the effect of IS on urine albumin creatinine ratio (UACR), stratified by diabetes type. The IS threshold was then determined using segmented regressions within each diabetes type and incorporated into the multivariate model. RESULTS There was an association between IS and UACR in type 2 diabetes only (beta = -0.39; p < 0.001). There was strong statistical evidence for a threshold effect of IS score on UACR in the group of youth with type 2 (beta = 0.40; p < 0.001) but not type 1 diabetes (p = 0.3). CONCLUSIONS In cross-sectional analyses, there is a negative association between IS and UACR in youth with type 2 but not type 1 diabetes, and this association likely includes a threshold effect of IS on UACR.
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Affiliation(s)
- Amy K Mottl
- UNC Division of Nephrology and Hypertension, University of North Carolina School of Medicine, Chapel Hill, NC, USA.
| | - Jasmin Divers
- Department of Biostatistical Sciences, Wake Forest School of Medicine, Winston-Salem, NC, USA
| | - Dana Dabelea
- Department of Epidemiology, School of Public Health, University of Colorado Denver, Aurora, CO, USA
| | - David M Maahs
- Barbara Davis Center for Childhood Diabetes, University of Colorado Denver, Aurora, CO, USA
| | - Lawrence Dolan
- Division of Endocrinology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
| | | | - Santica Marcovina
- Northwest Lipid Metabolism and Diabetes Research Laboratories, Department of Medicine, University of Washington, Seattle, WA, USA
| | - Giuseppina Imperatore
- Division of Diabetes Translation, National Center for Chronic Disease Prevention and Health Promotion, Centers for Disease Control and Prevention, Atlanta, GA, USA
| | - Catherine Pihoker
- Department of Pediatrics, University of Washington, Seattle, WA, USA
| | - Michael Mauer
- Department of Pediatrics, University of Minnesota Medical School, Minneapolis, MN, USA
- Department of Medicine, University of Minnesota Medical School, Minneapolis, MN, USA
| | - Elizabeth J Mayer-Davis
- Department of Nutrition, University of North Carolina School of Public Health, Chapel Hill, NC, USA
- Department of Medicine, University of North Carolina School of Medicine, Chapel Hill, NC, USA
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12
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Duca LM, Maahs DM, Schauer IE, Bergman BC, Nadeau KJ, Bjornstad P, Rewers M, Snell-Bergeon JK. Development and Validation of a Method to Estimate Insulin Sensitivity in Patients With and Without Type 1 Diabetes. J Clin Endocrinol Metab 2016; 101:686-95. [PMID: 26672636 PMCID: PMC4880115 DOI: 10.1210/jc.2015-3272] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
CONTEXT People with type 1 diabetes (T1D) have markedly reduced insulin sensitivity (IS) compared to their nondiabetic counterparts, and reduced IS is linked to higher cardiovascular risk. OBJECTIVE This study aimed to develop and validate an improved method for estimating IS in people with T1D. DESIGN Prospective cohort. SETTING Adults (36 with T1D, 41 nondiabetic) were recruited from the Coronary Artery Calcification in Type 1 Diabetes (CACTI) study for measurement of IS by hyperinsulinemic-euglycemic clamp to develop a clinically useful IS prediction equation (eIS) for T1D and nondiabetic individuals. These equations were then compared with previously published equations from the SEARCH and Pittsburgh Epidemiology of Diabetes Complications studies for the ability to predict measured IS in test sets of adults and adolescents from independent clamp studies. INTERVENTION None. MAIN OUTCOME MEASURE Comparison of clamp-measured IS to estimated IS. RESULTS The best-fit prediction model (eIS) differed by diabetes status and included waist circumference, triglycerides, adiponectin, and diastolic blood pressure in all CACTI adults and insulin dose in adults with T1D (adjusted R(2) = 0.64) or fasting glucose and hemoglobin A1c (HbA1c) in nondiabetic adults (adjusted R(2) = 0.63). The eIS highly correlated with clamp-measured IS in all of the non-CACTI comparison populations (r = 0.83, P = .0002 in T1D adults; r = 0.71, P = .01 in nondiabetic adults; r = 0.44, P = .008 in T1D adolescents; r = 0.44, P = .006 in nondiabetic adolescents). CONCLUSIONS eIS performed better than previous equations for estimating IS in individuals with and without T1D. These equations could simplify point-of-care assessment of IS to identify patients who could benefit from targeted intervention.
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Affiliation(s)
- Lindsey M Duca
- Barbara Davis Center for Diabetes (L.M.D., D.M.M., P.B., M.R., J.K.S.-B.), School of Medicine, University of Colorado, Aurora, Colorado 80045; Colorado School of Public Health (L.M.D., D.M.M., J.K.S.-B.), University of Colorado, Aurora, Colorado 80045; Division of Endocrinology, Metabolism, and Diabetes (I.E.S., B.C.B.), Department of Medicine, School of Medicine, University of Colorado, Aurora, Colorado 80045; Division of Pediatric Endocrinology (K.J.N.), Department of Pediatrics, University of Colorado School of Medicine, Aurora, Colorado 80045; and Denver VA Medical Center (I.E.S.), Denver, Colorado 80220
| | - David M Maahs
- Barbara Davis Center for Diabetes (L.M.D., D.M.M., P.B., M.R., J.K.S.-B.), School of Medicine, University of Colorado, Aurora, Colorado 80045; Colorado School of Public Health (L.M.D., D.M.M., J.K.S.-B.), University of Colorado, Aurora, Colorado 80045; Division of Endocrinology, Metabolism, and Diabetes (I.E.S., B.C.B.), Department of Medicine, School of Medicine, University of Colorado, Aurora, Colorado 80045; Division of Pediatric Endocrinology (K.J.N.), Department of Pediatrics, University of Colorado School of Medicine, Aurora, Colorado 80045; and Denver VA Medical Center (I.E.S.), Denver, Colorado 80220
| | - Irene E Schauer
- Barbara Davis Center for Diabetes (L.M.D., D.M.M., P.B., M.R., J.K.S.-B.), School of Medicine, University of Colorado, Aurora, Colorado 80045; Colorado School of Public Health (L.M.D., D.M.M., J.K.S.-B.), University of Colorado, Aurora, Colorado 80045; Division of Endocrinology, Metabolism, and Diabetes (I.E.S., B.C.B.), Department of Medicine, School of Medicine, University of Colorado, Aurora, Colorado 80045; Division of Pediatric Endocrinology (K.J.N.), Department of Pediatrics, University of Colorado School of Medicine, Aurora, Colorado 80045; and Denver VA Medical Center (I.E.S.), Denver, Colorado 80220
| | - Bryan C Bergman
- Barbara Davis Center for Diabetes (L.M.D., D.M.M., P.B., M.R., J.K.S.-B.), School of Medicine, University of Colorado, Aurora, Colorado 80045; Colorado School of Public Health (L.M.D., D.M.M., J.K.S.-B.), University of Colorado, Aurora, Colorado 80045; Division of Endocrinology, Metabolism, and Diabetes (I.E.S., B.C.B.), Department of Medicine, School of Medicine, University of Colorado, Aurora, Colorado 80045; Division of Pediatric Endocrinology (K.J.N.), Department of Pediatrics, University of Colorado School of Medicine, Aurora, Colorado 80045; and Denver VA Medical Center (I.E.S.), Denver, Colorado 80220
| | - Kristen J Nadeau
- Barbara Davis Center for Diabetes (L.M.D., D.M.M., P.B., M.R., J.K.S.-B.), School of Medicine, University of Colorado, Aurora, Colorado 80045; Colorado School of Public Health (L.M.D., D.M.M., J.K.S.-B.), University of Colorado, Aurora, Colorado 80045; Division of Endocrinology, Metabolism, and Diabetes (I.E.S., B.C.B.), Department of Medicine, School of Medicine, University of Colorado, Aurora, Colorado 80045; Division of Pediatric Endocrinology (K.J.N.), Department of Pediatrics, University of Colorado School of Medicine, Aurora, Colorado 80045; and Denver VA Medical Center (I.E.S.), Denver, Colorado 80220
| | - Petter Bjornstad
- Barbara Davis Center for Diabetes (L.M.D., D.M.M., P.B., M.R., J.K.S.-B.), School of Medicine, University of Colorado, Aurora, Colorado 80045; Colorado School of Public Health (L.M.D., D.M.M., J.K.S.-B.), University of Colorado, Aurora, Colorado 80045; Division of Endocrinology, Metabolism, and Diabetes (I.E.S., B.C.B.), Department of Medicine, School of Medicine, University of Colorado, Aurora, Colorado 80045; Division of Pediatric Endocrinology (K.J.N.), Department of Pediatrics, University of Colorado School of Medicine, Aurora, Colorado 80045; and Denver VA Medical Center (I.E.S.), Denver, Colorado 80220
| | - Marian Rewers
- Barbara Davis Center for Diabetes (L.M.D., D.M.M., P.B., M.R., J.K.S.-B.), School of Medicine, University of Colorado, Aurora, Colorado 80045; Colorado School of Public Health (L.M.D., D.M.M., J.K.S.-B.), University of Colorado, Aurora, Colorado 80045; Division of Endocrinology, Metabolism, and Diabetes (I.E.S., B.C.B.), Department of Medicine, School of Medicine, University of Colorado, Aurora, Colorado 80045; Division of Pediatric Endocrinology (K.J.N.), Department of Pediatrics, University of Colorado School of Medicine, Aurora, Colorado 80045; and Denver VA Medical Center (I.E.S.), Denver, Colorado 80220
| | - Janet K Snell-Bergeon
- Barbara Davis Center for Diabetes (L.M.D., D.M.M., P.B., M.R., J.K.S.-B.), School of Medicine, University of Colorado, Aurora, Colorado 80045; Colorado School of Public Health (L.M.D., D.M.M., J.K.S.-B.), University of Colorado, Aurora, Colorado 80045; Division of Endocrinology, Metabolism, and Diabetes (I.E.S., B.C.B.), Department of Medicine, School of Medicine, University of Colorado, Aurora, Colorado 80045; Division of Pediatric Endocrinology (K.J.N.), Department of Pediatrics, University of Colorado School of Medicine, Aurora, Colorado 80045; and Denver VA Medical Center (I.E.S.), Denver, Colorado 80220
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Bjornstad P, Cherney DZ, Maahs DM, Nadeau KJ. Diabetic Kidney Disease in Adolescents With Type 2 Diabetes: New Insights and Potential Therapies. Curr Diab Rep 2016; 16:11. [PMID: 26803647 PMCID: PMC5841446 DOI: 10.1007/s11892-015-0708-0] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Diabetic kidney disease (DKD) is the leading cause of end-stage renal disease (ESRD) and dialysis in the Western world. Early DKD, including microalbuminuria and renal hyperfiltration, is common in adolescents with type 2 diabetes (T2D). Furthermore, youth-onset T2D carries a higher risk of progressive DKD than adult-onset T2D of similar diabetes duration. DKD is characterized by a long clinically silent period without signs of disease. Therefore, a major challenge in preventing DKD is the difficulty in identifying high-risk T2D patients at an early stage. The Type 2 Diabetes in Adolescents and Youth (TODAY) study demonstrated a high initial prevalence that increased over time, irrespective of treatment arm. This key observation underscores the importance of discovering new therapeutic targets to supplement conventional management, in order to reduce DKD risk. In this review, we focus on early DKD in T2D and summarize potential novel biomarkers and therapeutic targets.
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Affiliation(s)
- Petter Bjornstad
- Department of Pediatric Endocrinology, University of Colorado School of Medicine, Aurora, CO, USA.
- Barbara Davis Center for Diabetes, University of Colorado School of Medicine, 13123 East 16th Ave, Box B265, Aurora, CO, 80045, USA.
| | - David Z Cherney
- Department of Medicine, Division of Nephrology, Toronto General Hospital, University of Toronto, Toronto, ON, Canada
| | - David M Maahs
- Department of Pediatric Endocrinology, University of Colorado School of Medicine, Aurora, CO, USA
- Barbara Davis Center for Diabetes, University of Colorado School of Medicine, 13123 East 16th Ave, Box B265, Aurora, CO, 80045, USA
- Department of Medicine, Division of Nephrology, University of Colorado, Aurora, CO, USA
| | - Kristen J Nadeau
- Department of Pediatric Endocrinology, University of Colorado School of Medicine, Aurora, CO, USA
- Barbara Davis Center for Diabetes, University of Colorado School of Medicine, 13123 East 16th Ave, Box B265, Aurora, CO, 80045, USA
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Bjornstad P, Snell-Bergeon JK, Nadeau KJ, Maahs DM. Insulin sensitivity and complications in type 1 diabetes: New insights. World J Diabetes 2015; 6:8-16. [PMID: 25685274 PMCID: PMC4317319 DOI: 10.4239/wjd.v6.i1.8] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/22/2014] [Revised: 09/24/2014] [Accepted: 12/01/2014] [Indexed: 02/05/2023] Open
Abstract
Despite improvements in glucose, lipids and blood pressure control, vascular complications remain the most important cause of morbidity and mortality in patients with type 1 diabetes. For that reason, there is a need to identify additional risk factors to utilize in clinical practice or translate to novel therapies to prevent vascular complications. Reduced insulin sensitivity is an increasingly recognized component of type 1 diabetes that has been linked with the development and progression of both micro- and macrovascular complications. Adolescents and adults with type 1 diabetes have reduced insulin sensitivity, even when compared to their non-diabetic counterparts of similar adiposity, serum triglycerides, high-density lipoprotein cholesterol, level of habitual physical activity, and in adolescents, pubertal stage. Reduced insulin sensitivity is thought to contribute both to the initiation and progression of macro- and microvascular complications in type 1 diabetes. There are currently clinical trials underway examining the benefits of improving insulin sensitivity with regards to vascular complications in type 1 diabetes. Reduced insulin sensitivity is an increasingly recognized component of type 1 diabetes, is implicated in the pathogenesis of vascular complications and is potentially an important therapeutic target to prevent vascular complications. In this review, we will focus on the pathophysiologic contribution of insulin sensitivity to vascular complications and summarize related ongoing clinical trials.
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Bjornstad P, Maahs DM, Cherney DZ, Cree-Green M, West A, Pyle L, Nadeau KJ. Insulin sensitivity is an important determinant of renal health in adolescents with type 2 diabetes. Diabetes Care 2014; 37:3033-9. [PMID: 25071077 PMCID: PMC4207204 DOI: 10.2337/dc14-1331] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
OBJECTIVE Diabetic nephropathy (DN) remains the most common cause of end-stage renal disease and is a major cause of mortality in type 2 diabetes. Insulin sensitivity is an important determinant of renal health in adults with type 2 diabetes, but limited data exist in adolescents. We hypothesized that measured insulin sensitivity (glucose infusion rate [GIR]) would be associated with early markers of DN reflected by estimated glomerular filtration rate (eGFR) and albumin-creatinine ratio (ACR) in adolescents with type 2 diabetes. RESEARCH DESIGN AND METHODS Type 2 diabetic (n = 46), obese (n = 29), and lean (n = 19) adolescents (15.1 ± 2.2 years) had GIR measured by hyperinsulinemic-euglycemic clamps. ACR was measured and GFR was estimated by the Bouvet equation (combined creatinine and cystatin C). RESULTS Adolescents with type 2 diabetes had significantly lower GIR, and higher eGFR and ACR than obese or lean adolescents. Moreover, 34% of type 2 diabetic adolescents had albuminuria (ACR ≥30 mg/g), and 24% had hyperfiltration (≥135 mL/min/1.73 m2). Stratifying ACR and eGFR into tertiles, adolescents with type 2 diabetes in the highest tertiles of ACR and eGFR had respectively lower GIR than those in the mid and low tertiles, after adjusting for age, sex, Tanner stage, BMI, and HbA1c (P = 0.02 and P = 0.04). GIR, but not HbA1c, LDL, or systolic blood pressure, was also associated with eGFR after adjusting for sex and Tanner stage (β ± SE: -2.23 ± 0.87; P = 0.02). CONCLUSIONS A significant proportion of adolescents with type 2 diabetes showed evidence of early DN, and insulin sensitivity, rather than HbA1c, blood pressure, or lipid control, was the strongest determinant of renal health.
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Affiliation(s)
- Petter Bjornstad
- Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO
| | - David M Maahs
- Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO Barbara Davis Center for Diabetes, University of Colorado School of Medicine, Aurora, CO
| | - David Z Cherney
- Division of Nephrology, Department of Medicine, Toronto General Hospital, University of Toronto, Toronto, Ontario, Canada
| | - Melanie Cree-Green
- Division of Pediatric Endocrinology, Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO
| | - Amy West
- Division of Pediatric Endocrinology, Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO
| | - Laura Pyle
- Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO
| | - Kristen J Nadeau
- Division of Pediatric Endocrinology, Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO
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Bjornstad P, Maahs DM, Rewers M, Johnson RJ, Snell-Bergeon JK. ABC goal achievement predicts microvascular but not macrovascular complications over 6-years in adults with type 1 diabetes: the Coronary Artery Calcification in Type 1 Diabetes Study. J Diabetes Complications 2014; 28:762-6. [PMID: 25270733 PMCID: PMC4252593 DOI: 10.1016/j.jdiacomp.2014.06.017] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/05/2014] [Revised: 06/27/2014] [Accepted: 06/30/2014] [Indexed: 12/14/2022]
Abstract
HYPOTHESIS Vascular complications of type 1 diabetes are thought to cluster. We examined the prevalence and incidence of vascular complications and American Diabetes Association's ABC goal achievements in a prospective cohort of adults with type 1 diabetes. We hypothesized that ABC achievement at baseline would predict both micro- and macrovascular complications over 6-years. METHODS Participants (N=652) were 19-56 year old at baseline and re-examined 6-years later. Microvascular complications included diabetic nephropathy (DN), defined as incident albuminuria (AER≥20 μg/min) or rapid GFR decline (>3.3%/year) by CKD-EPI cystatin C and proliferative diabetic retinopathy (PDR), defined as laser eye-therapy. Macrovascular complications were defined as coronary artery calcium progression (CACp), measured by electron-beam computed-tomography. ABC goals were defined as HbA1c<7.0%, BP<130/80 mmHg and LDL-C<100mg/dL. RESULTS ABC control was suboptimal with only 6% meeting all goals. Meeting no ABC goals at baseline compared to meeting all goals was associated with increased odds of developing microvascular complications (OR: 8.5, 2.3-31.5, p=0.001), but did not reach significance for CACp (OR: 1.7, 0.8-3.9, p=0.19). CONCLUSION ABC achievement at baseline strongly predicted microvascular but not macrovascular complications over 6-years in adults with type 1 diabetes, suggesting a need for novel therapeutic targets to complement conventional risk factors in treating macrovascular complications.
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Affiliation(s)
- Petter Bjornstad
- Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO.
| | - David M Maahs
- Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO; Barbara Davis Center for Diabetes, University of Colorado Denver, Aurora, CO; Department of Nephrology, University of Colorado Denver, Aurora, CO
| | - Marian Rewers
- Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO; Barbara Davis Center for Diabetes, University of Colorado Denver, Aurora, CO
| | | | - Janet K Snell-Bergeon
- Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO; Barbara Davis Center for Diabetes, University of Colorado Denver, Aurora, CO
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