The Effects of Weight Loss on Neuroadrenergic Function

Neuroadrenergic Dysfunction Along the Diabetes Continuum: Benefits of Weight Loss Within Different Strata of Metabolic Risk

Elevated subconscious nervous system activity is a characteristic of the obese state and contributes importantly to the risk of heart disease and diabetes. This project will compare sympathetic nervous system activity and function in a group of obese persons with differing levels of sugar tolerance (normal, impaired and type 2 diabetic). Inter-relationships with insulin action, blood pressure, heart and kidney function will be determined before and after a 4-month weight loss and 3-month weight loss maintenance program.

It is hypothesized that the transition from normal sugar tolerance to impaired sugar tolerance to type 2 diabetes will be accompanied by escalating sympathetic nervous system dysfunction. Furthermore, that weight loss will favorably improve sympathetic function, with greatest benefits occurring in those subjects who are insulin resistant with high blood insulin concentration.

Study Overview

• Status: Unknown
• Conditions: Obesity; Metabolic Syndrome; Type 2 Diabetes
• Intervention / Treatment: Other: Dietary weight loss at 25% energy deficit

Detailed Description

The twin epidemics of obesity and diabetes represent a major public health problem worldwide. There is a growing body of evidence to suggest that autonomic dysfunction, comprising elevated sympathetic nervous system (SNS) activity and blunted sympathetic neural responsiveness plays a role in both the pathogenesis and target organ complications of obesity and diabetes. The proposed project will undertake a detailed comparative analysis of neuroadrenergic function along the diabetes continuum, its inter-relationship with insulin sensitivity and secretion, and target organ function, and the benefits of active weight loss and weight loss maintenance within different strata of metabolic risk.

• Study Type: Interventional
• Enrollment (Anticipated): 120
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Australia
  • Victoria
    • Melbourne, Victoria, Australia, 8008
      • Baker IDI Heart & Diabetes Institute

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 45 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

Men and postmenopausal women (n=120), untreated, weight-stable, non-smoking, aged 45-65 years, BMI 27-45 kg/m2, will be recruited. Glucose tolerance status will be determined by a 75-g oral glucose tolerance test (OGTT), using WHO criteria (53): normal glucose tolerance, fasting plasma glucose < 7.0 mmol/L and 2-h plasma glucose < 7.8 mmol/L; IGT, fasting plasma glucose < 7.0 mmol/L and 2-h plasma glucose > 7.8 and < 11.1 mmol/L; T2D, fasting plasma glucose > 7.0 mmol/L or 2-h plasma glucose > 11.1 mmol/L. Hyper-insulinemia will be defined as an insulin area under the curve during OGTT > 8000 mU/L ∙ min-1 and hypo-insulinemia as < 8000 mU/L ∙ min-1.

Exclusion Criteria:

Prior history of cardiovascular disease (previous myocardial infarction, angina, stroke, heart failure, secondary hypertension), renal (serum creatinine >0.12 mmol/L or estimated GFR <60 ml/min/1.73 m2) or hepatic disease or diseases which may affect measured parameters (e.g. thyroid disease); severe hypertension; a history of surgical weight loss; CPAP therapy; and >4 alcoholic drinks/day. T2D individuals with moderate hyperglycemia (HbA1c >9%) will be excluded so that hypoglycaemic pharmacotherapy may be instituted (54). Participants will be sought through newspaper advertising and poster displays in primary health care centres (General Practices). Newly diagnosed T2D subjects

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Normal glucose tolerant; Weight loss attained by 25% caloric restriction. This arm will be both a glycemic and time control. Initially they will undergo a 4-month weight maintenance phase (acting as time control), followed by 4 month weight loss.	Other: Dietary weight loss at 25% energy deficit; Dietary weight loss at 25% energy deficit. Dietary macronutrient content will comprise 25% protein, 30% fat and 45% carbohydrate.
Experimental: Impaired glucose tolerant; Weight loss using 25% caloric restriction. Impaired glucose tolerant subjects will undergo 4 months weight loss (25% caloric deficit) followed by 3 months weight loss maintenance	Other: Dietary weight loss at 25% energy deficit; Dietary weight loss at 25% energy deficit. Dietary macronutrient content will comprise 25% protein, 30% fat and 45% carbohydrate.
Experimental: Type 2 diabetic hyperinsulinemic; Weight loss using 25% caloric restriction. This group will undergo 4 months weight loss (25% caloric deficit) followed by 3 months weight loss maintenance	Other: Dietary weight loss at 25% energy deficit; Dietary weight loss at 25% energy deficit. Dietary macronutrient content will comprise 25% protein, 30% fat and 45% carbohydrate.
Experimental: Type 2 diabetic hypoinsulinemic; Weight loss via 25% caloric restriction. This group will undergo 4 months weight loss (25% caloric deficit) followed by 3 months weight loss maintenance	Other: Dietary weight loss at 25% energy deficit; Dietary weight loss at 25% energy deficit. Dietary macronutrient content will comprise 25% protein, 30% fat and 45% carbohydrate.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in whole-body norepinephrine kinetics	The study will examine the dynamic processes of norepinephrine spillover into and removal from the central plasma compartment using the isotope dilution technique.Measurements will be made at baseline, after 4 months active weight loss, and again after 3 months weight loss maintenance. The weight loss maintenance phase will permit differentiation of the effects of active weight loss (incorporating both negative energy balance and weight loss per se) and stable lower body weight on sympathetic neural parameters.	4 months and 7 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in muscle sympathetic nerve activity	Muscle sympathetic nerve firing will be quantified by the technique of mirconeurography at baseline and after 4 months active weight loss and 3 months weight loss maintenance. The weight loss maintenance phase will permit differentiation of the effects of active weight loss (incorporating both negative energy balance and weight loss per se) and stable lower body weight on sympathetic nerve firing and pattern.	4 months and 7 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in insulin sensitivity	Insulin sensitivity will be assessed by the gold standard euglycemic hyperinsulinemic clamp method at baseline and after 4 months active weight loss and 3 months weight loss maintenance. The weight loss maintenance phase will permit differentiation of the effects of active weight loss (incorporating both negative energy balance and weight loss per se) and stable lower body weight on insulin sensitivity.	4 months and 7 months

Collaborators and Investigators

• Sponsor: Baker Heart Research Institute
• Investigators: Principal Investigator: Dr Nora E Straznicky, PhD MPH, Baker IDI Heart & Diabetes Institute

Publications and helpful links

General Publications

• Straznicky NE, Grima MT, Sari CI, Lambert EA, Phillips SE, Eikelis N, Kobayashi D, Hering D, Mariani JA, Dixon JB, Nestel PJ, Karapanagiotidis S, Schlaich MP, Lambert GW. Reduction in peripheral vascular resistance predicts improvement in insulin clearance following weight loss. Cardiovasc Diabetol. 2015 Aug 22;14:113. doi: 10.1186/s12933-015-0276-2.
• Straznicky NE, Grima MT, Lambert EA, Sari CI, Eikelis N, Nestel PJ, Phillips SE, Hering D, Karapanagiotidis S, Dixon JB, Schlaich MP, Lambert GW. Arterial norepinephrine concentration is inversely and independently associated with insulin clearance in obese individuals with metabolic syndrome. J Clin Endocrinol Metab. 2015 Apr;100(4):1544-50. doi: 10.1210/jc.2014-3796. Epub 2015 Jan 15.

Study record dates

Study Major Dates

• Study Start: April 1, 2013
• Primary Completion (Anticipated): April 1, 2017
• Study Completion (Anticipated): April 1, 2017

Study Registration Dates

• First Submitted: January 15, 2013
• First Submitted That Met QC Criteria: January 16, 2013
• First Posted (Estimate): January 18, 2013

Study Record Updates

• Last Update Posted (Estimate): January 18, 2013
• Last Update Submitted That Met QC Criteria: January 16, 2013
• Last Verified: January 1, 2013

More Information

Terms related to this study

• Keywords: insulin resistance; weight loss; metabolic syndrome; glucose tolerance; sympathetic nervous system
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Body Weight; Insulin Resistance; Hyperinsulinism; Body Weight Changes; Metabolic Syndrome; Weight Loss
• Other Study ID Numbers: 1/13 (Other Grant/Funding Number: Diabetes Australia Millenium Grant)