Insulin Sensitivity and Renal Hemodynamic Function in Metformin-Treated Adults With Type 2 Diabetes and Preserved Renal Function

Abstract

Impaired insulin sensitivity is associated with hyperfiltration (i.e., elevated glomerular filtration rate [GFR]) in adolescents with type 2 diabetes (T2D) and adults with prediabetes. Yet, these relationships are based on studies that relied on estimated GFR (eGFR), estimates of insulin sensitivity, or both. We aimed to verify the relationship between insulin sensitivity and renal hemodynamic function by gold standard methods in adults with T2D. RESEARCH DESIGN AND METHODSInsulin sensitivity was assessed by hyperinsulinemic-euglycemic clamp (M value) (glucose infusion rate in mg/kg lean /min) and renal hemodynamic function by urinary inulin (GFR) and para-aminohippuric acid (effective renal plasma flow [ERPF]) clearances in participants with T2D without overt kidney disease. Filtration fraction (FF) (GFR/ERPF) was calculated. Relationships between insulin sensitivity and renal hemodynamic parameters were examined by multivariable linear regression. Renal hemodynamic parameters were examined across tertiles of M values. RESULTSWe tested 44 adults with T2D, of whom 77% were male, with mean 6 SD age 63 6 7 years, BMI 31.2 6 4.0 kg/m 2 , and HbA 1c 7.4 6 0.6%. Average GFR was 110 6 26 mL/min, with an FF of 22.1 6 2.8% and median 24-h urinary albumin excretion of 11.3 mg (interquartile range 5.8-17.0). Average M value was 5.6 6 2.9 mg/kg lean / min. Insulin sensitivity inversely correlated with GFR (r 5 20.44, P < 0.01) and FF (r 5 20.40, P < 0.01), and these associations remained significant after multivariable adjustments for age, sex, renin-angiotensin system inhibitor use, and HbA 1c . In addition, GFR, FF, and urinary albumin excretion were highest in the participants in the lowest M value tertile. CONCLUSIONSFor the first time, we demonstrate that impaired insulin sensitivity is associated with intrarenal hemodynamic dysfunction by gold standard techniques in adults with T2D treated with metformin monotherapy.

High glomerular filtration rate is associated with impaired arterial stiffness and subendocardial viability ratio in prediabetic subjects

“…Interestingly, in this study, subjects with prediabetes and HGFR exhibited a lower insulin sensitivity (expressed as Matsuda Index); furthermore, the study demonstrated a significant association between high eGFR and insulin resistance (expressed as HOMA index); in the kidney, insulin-resistance/sensitivity may act at multiple levels and modulate different functions such glomerular filtration, gluconeogenesis, renal sodium handling and others [31]. In agreement with our data, van Bommel et al recently demonstrated that impaired insulin sensitivity is associated with intrarenal hemodynamic dysfunction by gold standard techniques (hyperinsulinemiceeuglycemic clamp and urinary inulin) in adults with type 2 diabetes treated with metformin monotherapy [32]. The association between insulin resistance and cardiovascular disease has been previously reported, however, these results suggest that insulin resistance may be associated with hemodynamic renal dysfunction, including hyperfiltration, and raise the possibility that it may represent one factor linking renal function and cardiovascular disease [33].…”

Sex-specific associations of insulin resistance with chronic kidney disease and kidney function: a bi-directional Mendelian randomisation study

“…Sex hormones may directly affect renal function, for example, testosterone may induce glomerular podocyte apoptosis and activate the reninangiotensin system, whilst oestrogen may have opposite effects [4]. Correspondingly, fasting insulin is associated with renal haemodynamic function [40], is responsive to a highenergy diet [41] and regulates blood pressure possibly through the renin-angiotensin system [42], besides being a potential driver of growth and reproduction [7,8]. Nevertheless, our findings are consistent with differing disease patterns by person, place and time.…”

A synergistic effect of variability in estimated glomerular filtration rate with chronic kidney disease on all-cause mortality prediction in patients with type 2 diabetes: a retrospective cohort study

“…The annual rate of eGFR decline was reported to be greater in patients with type 2 DM than in those without DM [37]. Insulin resistance might be associated with intrarenal hemodynamic dysfunction and predictive of all-cause mortality in patients with type 2 DM [38,39]. Diabetic retinopathy was reported to be associated with eGFR variability and predictive of all-cause mortality in patients with type 2 DM [40,41].…”