Giuseppe Penno1, Anna Solini2, Emanuela Orsi3, Enzo Bonora4, Cecilia Fondelli5, Roberto Trevisan6, Monica Vedovato7, Franco Cavalot8, Gianpaolo Zerbini9, Olga Lamacchia10, Antonio Nicolucci11, Giuseppe Pugliese12. 1. Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy. 2. Department of Surgical, Medical, Molecular and Critical Area Pathology, University of Pisa, Pisa, Italy. 3. Diabetes Unit, IRCCS "Cà Granda - Ospedale Maggiore Policlinico" Foundation, Milan, Italy. 4. Division of Endocrinology, Diabetes and Metabolism, University and Hospital Trust of Verona, Verona, Italy. 5. Diabetes Unit, University of Siena, Siena, Italy. 6. Endocrinology and Diabetes Unit, Azienda Ospedaliera Papa Giovanni XXIII, Bergamo, Italy. 7. Department of Clinical and Experimental Medicine, University of Padua, Padua, Italy. 8. Department of Clinical and Biological Sciences, University of Turin, Orbassano, Italy. 9. Complications of Diabetes Unit, Division of Metabolic and Cardiovascular Sciences, San Raffaele Scientific Institute, Milan, Italy. 10. Department of Medical Sciences, University of Foggia, Foggia, Italy. 11. Centre for Outcomes Research and Clinical Epidemiology (CORESEARCH), Pescara, Italy. 12. Department of Clinical and Molecular Medicine, "La Sapienza" University, Via di Grottarossa, 1035-1039, 00189, Rome, Italy. giuseppe.pugliese@uniroma1.it.
Abstract
BACKGROUND: It is unclear whether insulin resistance (IR) contributes to excess mortality in patients with type 2 diabetes independent of diabetic kidney disease (DKD), which is strongly associated with IR and is a major risk factor for cardiovascular disease (CVD), the main cause of death in these individuals. We tested this hypothesis in patients with type 2 diabetes from the Renal Insufficiency And Cardiovascular Events Italian Multicentre Study. METHODS: This observational, prospective, cohort study enrolled 15,773 patients with type 2 diabetes attending 19 Italian Diabetes Clinics in 2006-2008. Insulin sensitivity was assessed as estimated glucose disposal rate (eGDR), which was validated against the euglycaemic-hyperinsulinemic clamp technique. Vital status on October 31, 2015, was retrieved for 15,656 patients (99.3%). Participants were stratified by eGDR tertiles from T1 (≥ 5.35 mg/kg/min) to T3 (≤ 4.14 mg/kg/min, highest IR). RESULTS: CVD risk profile was worse in T2 and T3 vs T1. eGDR tertiles were independently associated with micro- and macroalbuminuria and the albuminuric DKD phenotypes (albuminuria with preserved or reduced estimated glomerular filtration rate [eGFR]) as well as with eGFR categories or the nonalbuminuric DKD phenotype. Over a 7.4-year follow-up, unadjusted death rates and mortality risks increased progressively across eGDR tertiles, but remained significantly elevated after adjustment only in T3 vs T1 (age- and gender- adjusted death rate, 22.35 vs 16.74 per 1000 person-years, p < 0.0001, and hazard ratio [HR] adjusted for multiple confounders including DKD, 1.140 [95% confidence interval [CI], 1.049-1.238], p = 0.002). However, eGDR was independently associated with mortality in participants with no DKD (adjusted HR, 1.214 [95% CI, 1.072-1.375], p = 0.002) and in those with nonalbuminuric DKD (1.276 [1.034-1.575], p = 0.023), but not in those with the albuminuric DKD phenotypes. Moreover, the association was stronger in males and in younger individuals and was observed in those without but not with prior CVD, though interaction was significant only for age. CONCLUSIONS: The proxy of insulin sensitivity eGDR predicts all-cause mortality in type 2 diabetes, independent of confounders including DKD. However, the impact of IR in individuals with albuminuric DKD may be mediated by its relationship with albuminuria. TRIAL REGISTRATION: ClinicalTrials.gov , NCT00715481, retrospectively registered 15 July 2008.
BACKGROUND: It is unclear whether insulin resistance (IR) contributes to excess mortality in patients with type 2 diabetes independent of diabetic kidney disease (DKD), which is strongly associated with IR and is a major risk factor for cardiovascular disease (CVD), the main cause of death in these individuals. We tested this hypothesis in patients with type 2 diabetes from the Renal Insufficiency And Cardiovascular Events Italian Multicentre Study. METHODS: This observational, prospective, cohort study enrolled 15,773 patients with type 2 diabetes attending 19 Italian Diabetes Clinics in 2006-2008. Insulin sensitivity was assessed as estimated glucose disposal rate (eGDR), which was validated against the euglycaemic-hyperinsulinemic clamp technique. Vital status on October 31, 2015, was retrieved for 15,656 patients (99.3%). Participants were stratified by eGDR tertiles from T1 (≥ 5.35 mg/kg/min) to T3 (≤ 4.14 mg/kg/min, highest IR). RESULTS:CVD risk profile was worse in T2 and T3 vs T1. eGDR tertiles were independently associated with micro- and macroalbuminuria and the albuminuric DKD phenotypes (albuminuria with preserved or reduced estimated glomerular filtration rate [eGFR]) as well as with eGFR categories or the nonalbuminuric DKD phenotype. Over a 7.4-year follow-up, unadjusted death rates and mortality risks increased progressively across eGDR tertiles, but remained significantly elevated after adjustment only in T3 vs T1 (age- and gender- adjusted death rate, 22.35 vs 16.74 per 1000 person-years, p < 0.0001, and hazard ratio [HR] adjusted for multiple confounders including DKD, 1.140 [95% confidence interval [CI], 1.049-1.238], p = 0.002). However, eGDR was independently associated with mortality in participants with no DKD (adjusted HR, 1.214 [95% CI, 1.072-1.375], p = 0.002) and in those with nonalbuminuric DKD (1.276 [1.034-1.575], p = 0.023), but not in those with the albuminuric DKD phenotypes. Moreover, the association was stronger in males and in younger individuals and was observed in those without but not with prior CVD, though interaction was significant only for age. CONCLUSIONS: The proxy of insulin sensitivity eGDR predicts all-cause mortality in type 2 diabetes, independent of confounders including DKD. However, the impact of IR in individuals with albuminuric DKD may be mediated by its relationship with albuminuria. TRIAL REGISTRATION: ClinicalTrials.gov , NCT00715481, retrospectively registered 15 July 2008.
Authors: G Penno; A Solini; E Bonora; C Fondelli; E Orsi; G Zerbini; R Trevisan; M Vedovato; G Gruden; L Laviola; A Nicolucci; G Pugliese Journal: J Intern Med Date: 2013-04-22 Impact factor: 8.989
Authors: Stefan Pilz; Femke Rutters; Giel Nijpels; Coen D A Stehouwer; Kurt Højlund; John J Nolan; Beverley Balkau; Jacqueline M Dekker Journal: Diabetes Care Date: 2014-03-12 Impact factor: 19.112