title: Influence of endogenous NEFA on beta cell function in humans.
abstract: OBJECTIVE
  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
  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.
authors.affiliation: Department of Clinical & Experimental Medicine, University of Pisa, Via Roma, 67, 56126, Pisa, Italy.
authors.forename: Eleni
authors.initials: E
authors.lastname: Rebelos
authors.affiliation: Department of Clinical & Experimental Medicine, University of Pisa, Via Roma, 67, 56126, Pisa, Italy.
authors.forename: Marta
authors.initials: M
authors.lastname: Seghieri
authors.affiliation: Department of Clinical & Experimental Medicine, University of Pisa, Via Roma, 67, 56126, Pisa, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Natali
authors.affiliation: Inserm Unit 1018, Villejuif, France.
authors.forename: Beverly
authors.initials: B
authors.lastname: Balkau
authors.affiliation: Division of Therapeutical Teaching for Chronic Diseases, University Hospital, Geneva, Switzerland.
authors.forename: Alain
authors.initials: A
authors.lastname: Golay
authors.affiliation: Cardio-Metabolism and Clinical Trials Unit, Department of Internal Medicine, IRCCS Ospedale San Raffaele, Milan, Italy.
authors.forename: Pier Marco
authors.initials: PM
authors.lastname: Piatti
authors.affiliation: Clinic for Endocrinology, Diabetes and Metabolic Diseases, CCS, Faculty of Medicine, University of Belgrade, Belgrade, Serbia.
authors.forename: Nebojsa M
authors.initials: NM
authors.lastname: Lalic
authors.affiliation: Department of Medicine, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland.
authors.forename: Markku
authors.initials: M
authors.lastname: Laakso
authors.affiliation: CNR Institute of Neuroscience, Padova, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Mari
authors.affiliation: Department of Clinical & Experimental Medicine, University of Pisa, Via Roma, 67, 56126, Pisa, Italy. ferranni@ifc.cnr.it.|CNR Institute of Clinical Physiology, Pisa, Italy. ferranni@ifc.cnr.it.
authors.forename: Ele
authors.initials: E
authors.lastname: Ferrannini
mesh_terms: D000328:Adult; D001786:Blood Glucose / Q000032:analysis*; D005230:Fatty Acids, Nonesterified / Q000097:blood*; D005260:Female; D018149:Glucose Intolerance / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000097:blood*; D007333:Insulin Resistance / Q000502:physiology*; D050417:Insulin-Secreting Cells / Q000502:physiology*; D008297:Male; D008875:Middle Aged
chemical_list: D001786:Blood Glucose; D005230:Fatty Acids, Nonesterified; D007328:Insulin
keywords: Beta cell function; Beta cell glucose sensitivity; Glucose intolerance; Insulin resistance; Lipotoxicity; NEFA