Insulin sensitivity measured with euglycemic clamp is independently associated with glomerular filtration rate in a community-based cohort

OBJECTIVE—To investigate the association between insulin sensitivity and glomerular filtration rate (GFR) in the community, with prespecified subgroup analyses in normoglycemic individuals with normal GFR.RESEARCH DESIGN AND METHODS—We investigated the cross-sectional association between insulin sensitivity (M/I, assessed using euglycemic clamp) and cystatin C–based GFR in a community-based cohort of elderly men (Uppsala Longitudinal Study of Adult Men [ULSAM], n = 1,070). We also investigated whether insulin sensitivity predicted the incidence of renal dysfunction at a follow-up examination after 7 years.RESULTS—Insulin sensitivity was directly related to GFR (multivariable-adjusted regression coefficient for 1-unit higher M/I 1.19 [95% CI 0.69–1.68]; P < 0.001) after adjusting for age, glucometabolic variables (fasting plasma glucose, fasting plasma insulin, and 2-h glucose after an oral glucose tolerance test), cardiovascular risk factors (hypertension, dyslipidemia, and smoking), and lifestyle factors (BMI, physical activity, and consumption of tea, coffee, and alcohol). The positive multivariable-adjusted association between insulin sensitivity and GFR also remained statistically significant in participants with normal fasting plasma glucose, normal glucose tolerance, and normal GFR (n = 443; P < 0.02). In longitudinal analyses, higher insulin sensitivity at baseline was associated with lower risk of impaired renal function (GFR <50 ml/min per 1.73 m²) during follow-up independently of glucometabolic variables (multivariable-adjusted odds ratio for 1-unit higher of M/I 0.58 [95% CI 0.40–0.84]; P < 0.004).CONCLUSIONS—Our data suggest that impaired insulin sensitivity may be involved in the development of renal dysfunction at an early stage, before the onset of diabetes or prediabetic glucose elevations. Further studies are needed in order to establish causality.Reduced insulin sensitivity is a key component in the pathogenesis of diabetes, and diabetic nephropathy is a leading cause of end-stage renal disease (ESRD) (1). However, lower insulin sensitivity has also been suggested to be associated with impaired renal function in individuals without overt diabetes (2). For instance, insulin resistance has been shown to predict ESRD in patients with mild renal impairment due to IgA nephritis (3). Furthermore, the opposite chain of events has also been observed; patients with ESRD without diabetes have been shown to develop insulin resistance in the later stage of the disease (3,4). Based on previous data, we hypothesized that reduced insulin sensitivity could be involved in the development of renal dysfunction via pathways that are not primarily mediated via increased glucose levels.We are aware of a few previous community-based studies that have reported the association of reduced insulin sensitivity to diminished renal function (2,5,6). These studies, however, have been limited by the use of surrogate markers of insulin sensitivity or by the use of creatinine-based glomerular filtration rate (GFR). Furthermore, all previous studies have included patients with impaired fasting glucose and impaired glucose tolerance, making it difficult to fully evaluate whether the association between insulin sensitivity and GFR is independent of elevated fasting and postload glucose levels. Moreover, most previous studies (2,5) have included patients with impaired renal function at baseline, and our knowledge of the relationship between insulin sensitivity and GFR within the normal range in the community is limited.Thus, we investigated the association between insulin sensitivity, evaluated by euglycemic clamp, and cystatin C–based GFR in a community-based cohort of elderly men with prespecified subgroup analyses in individuals with normal fasting glucose, normal glucose tolerance, and normal GFR. We also investigated the longitudinal association between insulin sensitivity and renal dysfunction during follow-up and evaluated whether this association was independent of other glucometabolic factors.