Eleni Rebelos1, Marta Seghieri1, Andrea Natali1, Beverly Balkau2, Alain Golay3, Pier Marco Piatti4, Nebojsa M Lalic5, Markku Laakso6, Andrea Mari7, Ele Ferrannini8,9. 1. Department of Clinical & Experimental Medicine, University of Pisa, Via Roma, 67, 56126, Pisa, Italy. 2. Inserm Unit 1018, Villejuif, France. 3. Division of Therapeutical Teaching for Chronic Diseases, University Hospital, Geneva, Switzerland. 4. Cardio-Metabolism and Clinical Trials Unit, Department of Internal Medicine, IRCCS Ospedale San Raffaele, Milan, Italy. 5. Clinic for Endocrinology, Diabetes and Metabolic Diseases, CCS, Faculty of Medicine, University of Belgrade, Belgrade, Serbia. 6. Department of Medicine, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland. 7. CNR Institute of Neuroscience, Padova, Italy. 8. Department of Clinical & Experimental Medicine, University of Pisa, Via Roma, 67, 56126, Pisa, Italy. ferranni@ifc.cnr.it. 9. CNR Institute of Clinical Physiology, Pisa, Italy. ferranni@ifc.cnr.it.
Abstract
AIMS/HYPOTHESIS: It is a commonly held view that chronically elevated NEFA levels adversely affect insulin secretion and insulin action (lipotoxicity). However, the effect of NEFA on beta cell function has only been explored using acute NEFA elevations. Our aim was to analyse the relationship between endogenous NEFA levels and beta cell function. METHODS: In 1,267 individuals followed-up for 3 years, we measured insulin sensitivity (by clamp) and beta cell function (by C-peptide modelling during OGTT and as the acute insulin response [AIR] to IVGTT). RESULTS: At baseline, both fasting and insulin-suppressed NEFA levels were higher across glucose tolerance groups, while insulin sensitivity was lower, insulin output was higher, and beta cell glucose sensitivity and AIR were lower (all p < 0.0001). In multiple logistic analyses adjusting for age, BMI, WHR and glucose tolerance, both fasting and insulin-suppressed NEFA levels were inversely related to insulin sensitivity, as expected (both p < 0.0001). Furthermore, after adjusting for insulin sensitivity, insulin-suppressed NEFA were positively associated with total insulin output (p = 0.0042). In contrast, neither fasting nor insulin-suppressed NEFA were related to beta cell glucose sensitivity or AIR. At follow-up, worsening of glucose tolerance (n = 126) was predicted by lower insulin and beta cell glucose sensitivity. In this model, baseline NEFA were not significant predictors of progression. CONCLUSIONS/ INTERPRETATION: In the non-diabetic state and in subjects with impaired glucose tolerance, circulating endogenous NEFA are not independently associated measures of beta cell function, and do not predict deterioration of glucose tolerance. Thus, in the Relationship Between Insulin Sensitivity and Cardiovascular Disease (RISC) cohort there is no evidence for beta cell lipotoxicity of endogenous total NEFA concentrations.
AIMS/HYPOTHESIS: It is a commonly held view that chronically elevated NEFA levels adversely affect insulin secretion and insulin action (lipotoxicity). However, the effect of NEFA on beta cell function has only been explored using acute NEFA elevations. Our aim was to analyse the relationship between endogenous NEFA levels and beta cell function. METHODS: In 1,267 individuals followed-up for 3 years, we measured insulin sensitivity (by clamp) and beta cell function (by C-peptide modelling during OGTT and as the acute insulin response [AIR] to IVGTT). RESULTS: At baseline, both fasting and insulin-suppressed NEFA levels were higher across glucose tolerance groups, while insulin sensitivity was lower, insulin output was higher, and beta cell glucose sensitivity and AIR were lower (all p < 0.0001). In multiple logistic analyses adjusting for age, BMI, WHR and glucose tolerance, both fasting and insulin-suppressed NEFA levels were inversely related to insulin sensitivity, as expected (both p < 0.0001). Furthermore, after adjusting for insulin sensitivity, insulin-suppressed NEFA were positively associated with total insulin output (p = 0.0042). In contrast, neither fasting nor insulin-suppressed NEFA were related to beta cell glucose sensitivity or AIR. At follow-up, worsening of glucose tolerance (n = 126) was predicted by lower insulin and beta cell glucose sensitivity. In this model, baseline NEFA were not significant predictors of progression. CONCLUSIONS/ INTERPRETATION: In the non-diabetic state and in subjects with impaired glucose tolerance, circulating endogenous NEFA are not independently associated measures of beta cell function, and do not predict deterioration of glucose tolerance. Thus, in the Relationship Between Insulin Sensitivity and Cardiovascular Disease (RISC) cohort there is no evidence for beta cell lipotoxicity of endogenous total NEFA concentrations.
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