Clinical trial NCT01771042: The Effects of Weight Loss on Neuroadrenergic Function
Official title: Neuroadrenergic Dysfunction Along the Diabetes Continuum: Benefits of Weight Loss Within Different Strata of Metabolic Risk
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: NA
Conditions: Obesity
Type 2 Diabetes
Metabolic Syndrome
Keywords: weight loss
metabolic syndrome
sympathetic nervous system
insulin resistance
glucose tolerance
Lead sponsor: Baker Heart Research Institute
Sponsor class: OTHER
First posted: 2013-01-18
Enrollment: 120
Sex: ALL
Minimum age (years): 45
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

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.

Eligibility criteria: 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

Primary outcomes:
measure: Change in whole-body norepinephrine kinetics
timeFrame: 4 months and 7 months
Secondary outcomes:
measure: Change in muscle sympathetic nerve activity
timeFrame: 4 months and 7 months
Other outcomes:
measure: Change in insulin sensitivity
timeFrame: 4 months and 7 months
Locations:
city: Melbourne
country: Australia
facility: Baker IDI Heart & Diabetes Institute
state: Victoria
Study officials:
affiliation: Baker IDI Heart & Diabetes Institute
name: Dr Nora E Straznicky, PhD MPH
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.