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.

Figures

Fig. 1

Changes in insulin sensitivity and insulin clearance in control and hypocaloric diet (HCD) groups (week 16 minus baseline measurements). a Homeostasis model assessment of insulin resistance (HOMA-IR): group × time interaction, P < 0.001. b Matsuda insulin sensitivity index (ISI): group × time interaction, P < 0.001. c Steady state glucose utilization during euglycemic clamp (M): group × time interaction, P = 0.02. d Fasting C-peptide to insulin ratio: group × time interaction, P = 0.06. e Insulin clearance: group × time interaction, P = 0.03. *P < 0.05 and ***P < 0.001 versus control group

Fig. 2

Change in sympathetic nervous system parameters in relation to change in body weight and insulin status in control and hypocaloric diet (HCD) groups (week 16 minus baseline measurements). HCD sub-groups are indicated by the hashed bars and include hyperinsulinemic (Hyper, n = 10) and normo-insulinemic (Normo, n = 7) subjects. a Body weight. b Insulin area under the curve during oral glucose tolerance test (AUC0–120). c Muscle sympathetic nerve activity (MSNA) burst incidence. d Arterial plasma norepinephrine (NE) concentration. e Norepinephrine plasma clearance. f Whole-body norepinephrine spillover rate. *P < 0.05, **P < 0.01 and ***P < 0.001 versus control group

Fig. 3

Calf vascular resistance during 75-g oral glucose tolerance test in a control and b HCD groups. *P < 0.05 versus baseline. Change in the area under the curve (AUC0–120) averaged 927 ± 555 units per min and −712 ± 526 units per min in control and HCD groups, respectively (P = 0.045)

Fig. 4

Univariate correlates of change in whole-body insulin clearance and hepatic insulin extraction (fasting C-peptide to insulin ratio) in the HCD group (n = 17). a Change in fasting calf vascular resistance (r = −0.63, 0.007). b Change in steady state glucose utilization during euglycemic hyperinsulinemic clamp (M) (r = 0.45, P = 0.07). c Change in plasma HDL-cholesterol concentration (r = 0.53, P = 0.03). d Change in finger reactive hyperaemic index (r = 0.49 P = 0.04). e Change in Matsuda insulin sensitivity index (ISI) (r = 0.52, P = 0.03). f Change in glucose area under the curve (AUC0–120) during oral glucose tolerance test (r = −0.61, P = 0.009)