title: Reduction in peripheral vascular resistance predicts improvement in insulin clearance following weight loss.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  Insulin clearance is independently and reciprocally associated with changes in vascular function during weight loss intervention. Trial registration ClinicalTrials.gov: NCT01771042 and NCT00408850.
authors: Laboratory of Human Neurotransmitters, Baker IDI Heart and Diabetes Institute, P.O. Box 6492, St Kilda Road Central, Melbourne, VIC, 8008, Australia. nora.straznicky@bakeridi.edu.au.
authors: Nora E
authors: NE
authors: Straznicky
authors: Laboratory of Human Neurotransmitters, Baker IDI Heart and Diabetes Institute, P.O. Box 6492, St Kilda Road Central, Melbourne, VIC, 8008, Australia. mariee.grima@bakeridi.edu.au.
authors: Mariee T
authors: MT
authors: Grima
authors: Laboratory of Human Neurotransmitters, Baker IDI Heart and Diabetes Institute, P.O. Box 6492, St Kilda Road Central, Melbourne, VIC, 8008, Australia. carolina.ikasari@bakeridi.edu.au.
authors: Carolina I
authors: CI
authors: Sari
authors: Laboratory of Human Neurotransmitters, Baker IDI Heart and Diabetes Institute, P.O. Box 6492, St Kilda Road Central, Melbourne, VIC, 8008, Australia. elisabeth.lambert@bakeridi.edu.au.|Department of Physiology, Monash University, Melbourne, VIC, Australia. elisabeth.lambert@bakeridi.edu.au.|Department of Physiology, University of Melbourne, Melbourne, VIC, Australia. elisabeth.lambert@bakeridi.edu.au.
authors: Elisabeth A
authors: EA
authors: Lambert
authors: Laboratory of Human Neurotransmitters, Baker IDI Heart and Diabetes Institute, P.O. Box 6492, St Kilda Road Central, Melbourne, VIC, 8008, Australia. sarah.phillips@bakeridi.edu.au.
authors: Sarah E
authors: SE
authors: Phillips
authors: Laboratory of Human Neurotransmitters, Baker IDI Heart and Diabetes Institute, P.O. Box 6492, St Kilda Road Central, Melbourne, VIC, 8008, Australia. nina.eikelis@bakeridi.edu.au.
authors: Nina
authors: N
authors: Eikelis
authors: Laboratory of Human Neurotransmitters, Baker IDI Heart and Diabetes Institute, P.O. Box 6492, St Kilda Road Central, Melbourne, VIC, 8008, Australia. daisuke.kobayashi@bakeridi.edu.au.
authors: Daisuke
authors: D
authors: Kobayashi
authors: Laboratory of Neurovascular Hypertension and Kidney Disease, Baker IDI Heart and Diabetes Institute, Melbourne, VIC, Australia. dagmara.hering@bakeridi.edu.au.
authors: Dagmara
authors: D
authors: Hering
authors: Heart Failure Research Group, Baker IDI Heart and Diabetes Institute, Melbourne, VIC, Australia. justin.mariani@me.com.|Faculty of Medicine, Nursing and Health Sciences, Monash University, Melbourne, VIC, Australia. justin.mariani@me.com.
authors: Justin A
authors: JA
authors: Mariani
authors: Laboratory of Human Neurotransmitters, Baker IDI Heart and Diabetes Institute, P.O. Box 6492, St Kilda Road Central, Melbourne, VIC, 8008, Australia. john.dixon@bakeridi.edu.au.|Department of Primary Health Care, Monash University, Melbourne, VIC, Australia. john.dixon@bakeridi.edu.au.
authors: John B
authors: JB
authors: Dixon
authors: Laboratory of Cardiovascular Nutrition, Baker IDI Heart and Diabetes Institute, Melbourne, VIC, Australia. paul.nestel@bakeridi.edu.au.
authors: Paul J
authors: PJ
authors: Nestel
authors: Alfred Baker Medical Unit, Baker IDI Heart and Diabetes Institute, Melbourne, VIC, Australia. s.karapanagiotidis@alfred.org.au.
authors: Sofie
authors: S
authors: Karapanagiotidis
authors: Laboratory of Neurovascular Hypertension and Kidney Disease, Baker IDI Heart and Diabetes Institute, Melbourne, VIC, Australia. markus.schlaich@bakeridi.edu.au.|Faculty of Medicine, Nursing and Health Sciences, Monash University, Melbourne, VIC, Australia. markus.schlaich@bakeridi.edu.au.|Department of Physiology, Monash University, Melbourne, VIC, Australia. markus.schlaich@bakeridi.edu.au.
authors: Markus P
authors: MP
authors: Schlaich
authors: Laboratory of Human Neurotransmitters, Baker IDI Heart and Diabetes Institute, P.O. Box 6492, St Kilda Road Central, Melbourne, VIC, 8008, Australia. gavin.lambert@bakeridi.edu.au.|Faculty of Medicine, Nursing and Health Sciences, Monash University, Melbourne, VIC, Australia. gavin.lambert@bakeridi.edu.au.
authors: Gavin W
authors: GW
authors: Lambert
mesh_terms: D000368:Aged; D015415:Biomarkers / Q000097:blood; D001786:Blood Glucose / Q000378:metabolism; D015992:Body Mass Index; D002096:C-Peptide / Q000097:blood; D031204:Caloric Restriction; D005260:Female; D005385:Fingers / Q000098:blood supply*; D015309:Glucose Clamp Technique; D005951:Glucose Tolerance Test; D006801:Humans; D006946:Hyperinsulinism / Q000097:blood / Q000175:diagnosis / Q000178:diet therapy* / Q000209:etiology / Q000503:physiopathology; D007328:Insulin / Q000097:blood*; D007700:Kinetics; D008099:Liver / Q000378:metabolism*; D008297:Male; D008365:Manometry; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000294:innervation; D009638:Norepinephrine / Q000097:blood; D009765:Obesity / Q000097:blood / Q000150:complications / Q000175:diagnosis / Q000178:diet therapy* / Q000503:physiopathology; D010991:Plethysmography; D013564:Sympathetic Nervous System / Q000378:metabolism / Q000503:physiopathology; D016896:Treatment Outcome; D014655:Vascular Resistance; D014739:Victoria; D015431:Weight Loss
chemical_list: D015415:Biomarkers; D001786:Blood Glucose; D002096:C-Peptide; D007328:Insulin; D009638:Norepinephrine