Reduction in peripheral vascular resistance predicts improvement in insulin clearance following weight loss

• DOI: 10.1186/s12933-015-0276-2
• Publication Date: 2015-08-21T10:14:59Z
• Authors: Nora E. Straznicky; Mariee T. Grima; Carolina I. Sari; Elisabeth A. Lambert; Sarah E. Phillips; Nina Eikelis; Daisuke Kobayashi; Dagmara Hering; Justin A. Mariani; John B. Dixon; Paul J. Nestel; Sofie Karapanagio...; Markus P. Schlaich; Gavin W. Lambert
• Keywords: Blood Glucose; Male; Manometry; Endocrinology, Diabetes and Metabolism; 630; Body Mass Index; Fingers; Norepinephrine; 03 medical and health sciences; 0302 clinical medicine; Hyperinsulinism; Humans; Insulin; Muscle, Skeletal; Original Investigation; Aged; Caloric Restriction; 2. Zero hunger; C-Peptide; Glucose Tolerance Test; Middle Aged; 3. Good health; Kinetics; Liver; Glucose Clamp Technique; Female; Cardiology and Cardiovascular Medicine; Biomarkers

The hyperinsulinemia of obesity is a function of both increased pancreatic insulin secretion and decreased insulin clearance, and contributes to cardiovascular risk. Whilst weight loss is known to enhance insulin clearance, there is a paucity of data concerning the underlying mechanisms. This study was conducted to examine the inter-relationships between changes in sympathetic nervous system (SNS) activity, vascular function and insulin clearance during a weight loss program. Seventeen non-smoking, un-medicated individuals aged 55 ± 1 years (mean ± SEM), body mass index (BMI) 33.9 ± 1.7 kg/m(2), underwent a 4-month hypocaloric diet (HCD), using a modified Dietary Approaches to Stop Hypertension diet, whilst seventeen age- and BMI-matched subjects acted as controls. Insulin sensitivity and insulin clearance were assessed via euglycemic hyperinsulinemic clamp (exogenous insulin clearance); hepatic insulin extraction was calculated as fasting C-peptide to insulin ratio (endogenous insulin clearance); SNS activity was quantified by microneurographic nerve recordings of muscle sympathetic nerve activity (MSNA) and whole-body norepinephrine kinetics; and vascular function by calf venous occlusion plethysmography and finger arterial tonometry. Weight loss averaged -8.3 ± 0.6 % of body weight in the HCD group and was accompanied by increased clamp-derived glucose utilization (by 20 ± 9 %, P = 0.04) and exogenous insulin clearance (by 12 ± 5 %, P = 0.02). Hepatic insulin extraction increased from 6.3 ± 0.8 to 7.1 ± 0.9 (P = 0.09). Arterial norepinephrine concentration decreased by -12 ± 5 %, whole-body norepinephrine spillover rate by -14 ± 8 %, and MSNA by -9 ± 5 bursts per 100 heartbeats in the HCD group (P all >0.05 versus control group). Step-wise regression analysis revealed a bidirectional relationship between enhanced exogenous insulin clearance post weight loss and reduction in calf vascular resistance (r = -0.63, P = 0.01) which explained 40 % of the variance. Increase in hepatic insulin extraction was predicted by enhanced finger reactive hyperaemic response (P = 0.006) and improvement in oral glucose tolerance (P = 0.002) which together explained 64 % of the variance. Insulin clearance is independently and reciprocally associated with changes in vascular function during weight loss intervention. Trial registration ClinicalTrials.gov: NCT01771042 and NCT00408850.