Insulin Sensitivity After Breast Cancer

Study of Molecular Causes of Metabolic Disorders in Obese Premenopausal Women After Breast Cancer

Epidemiological studies have revealed that 60-80% of women with breast cancer (BC) develop metabolic disorders that are similar to those observed in conditions like type 2 diabetes. These metabolic disorders, including insulin resistance, obesity, hyperinsulinemia, and glucose intolerance, are associated with increased BC recurrence and mortality. Skeletal muscle is the major site of glucose uptake in humans. The aims of the present project are to 1) determine the involvement of insulin resistance in skeletal muscle in the metabolic disorders prevalent in BC survivors, 2) identify BC-and/or treatment-induced molecular changes in skeletal muscle from BC survivors .

Study Overview

• Status: Recruiting
• Conditions: Breast Cancer; Insulin Sensitivity/Resistance; Metabolic Disturbance; Survivorship
• Intervention / Treatment: Drug: Insulin

Detailed Description

Up to 80% of women with breast cancer (BC) develop metabolic disorders, such as insulin resistance, obesity, hyperinsulinemia, and glucose intolerance, during or after their treatment. Such disorders increase BC mortality and the likelihood of relapse 2- and 3-fold, respectively. However, it is not known why BC and/or the treatment hereof causes metabolic disorders and very few studies have investigated the underlying biological causes.

Aims:

1. determine the involvement of insulin resistance in skeletal muscle in the metabolic disorders prevalent in BC survivors
2. identify BC-and/or treatment-induced molecular changes in skeletal muscle

BC is a common cancer with 2.1 million new cases each year, and BC also causes the largest number of cancer-related deaths among women worldwide. Fortunately, more people are now surviving their cancer. In Denmark, the majority of the 300.000 cancer survivors, constitute a group of ~ 70,000 women who have survived BC. However, there is a severe lack of research into the physiological sequelae of cancer and/or treatment, including the metabolic health consequences of BC. Recent epidemiological studies have revealed that 60-80% of women with BC develop metabolic disorders that are similar to those observed in conditions such as type 2 diabetes (T2D) during or following their treatment. However, unlike T2D, the underlying biological causes for the development of metabolic disorders with BC and/or the treatment are poorly investigated. It is important to address this knowledge gap, as metabolic disorders increase mortality among women with BC 2-fold and increase the likelihood of BC recurrence up to 3-fold.

The investigators hypothesize that metabolic disorders in BC survivors are due to cancer and/or treatment-mediated molecular rewiring of skeletal muscle, which causes insulin resistance.

Scientific breakthroughs in obesity and diabetes research have shown that hyperinsulinemia and hyperglycemia are most often caused by insulin resistance in skeletal muscle, fat, and liver. In particular, skeletal muscle is essential for maintaining a normal metabolism as it is responsible for up to 75% of the uptake of glucose from the blood in response to insulin. It is thus likely that skeletal muscle insulin resistance causes metabolic perturbations in BC survivors but this has not been investigated directly. Insulin-resistant skeletal muscle does not respond normally to insulin, causing severe metabolic disorders. These include hyperglycemia, hyperinsulinemia, dyslipidemia and hypertension; all conditions that are increasingly being documented in women with BC and BC survivors It is likely that insulin resistance in skeletal muscle is causing the metabolic disorders often present in BC survivors. Since muscle plays key roles in metabolic regulation by keeping blood glucose and insulin levels normal, it is extremely relevant to clarify the precise involvement of skeletal muscle in BC-related metabolic disorders.

12 premenopausal women (Body Mass Index = 25-30) who were operated for BC (stage I-III) will be included. Especially overweight premenopausal women develop markedly metabolic dysfunction as determined by an oral glucose tolerance test. The subjects will be studied 3-10 weeks after completing adjuvant chemotherapy. Twelve healthy weight-, activity- and age-matched subjects will be recruited as controls (matched by bicycle exercise test, grip strength, dual x-ray absorptiometry, and using the international physical activity questionnaire). Exclusion criteria are as follows: Post-menopause at the time of BC diagnosis, metastatic cancer, < 4 or > 5 series of paclitaxel treatment, alcohol intake of > 7 items/week, smoking, known T2D or metabolic syndrome, known cardiovascular disease and medical treatment thereof, or impaired mobility. Insulin sensitivity will be measured via the hyperinsulinemic-euglycemic clamp method. In short, basal muscle (from the vastus lateralus muscle) biopsies are taken after 1 hour rest after which insulin (1.4 mU/kg/min) is administered while maintaining euglycemia by continuous glucose infusion. Insulin-stimulated biopsies are taken after 1.5 hours.

• Study Type: Interventional
• Enrollment (Anticipated): 24
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Lykke Sylow, PhD; Phone Number: 20955250; Email: Lykkesylow@sund.ku.dk

Study Locations

• Denmark
  • DK
    • Copenhagen, DK, Denmark, 2100
      • Recruiting
      • University of Copenhagen
      • Contact: Lykke Sylow, PhD; Phone Number: 0045 20955250; Email: Lykkesylow@sund.ku.dk

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 20 years to 45 years (Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: Female

Description

Inclusion Criteria:

• Premenopausal women operated for breast cancer and after completing adjuvant chemotherapy and no earlier than 3 weeks after its termination
• BMI: 25-30
• Healthy controls will be included matched by gender, weight, age, and level of physical activity to the patient group included as subjects

Exclusion Criteria:

• Known postmenopause occurred at the time of diagnosis of breast cancer
• Alcohol intake of> 7 items / week
• Smoker
• Already known Type 2 diabetes mellitus or metabolic syndrome and medical treatment thereof.
• Cardiovascular disease and its medical treatment
• Impaired mobility

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Healthy control subjects; Healthy control subjects undergoing a hyperinsulinemic euglycemic clamp	Drug: Insulin; Hyperinsulinemic euglycemic clamp; Other Names: Hyperinsulinemic euglycemic clamp
Experimental: Breast cancer survivors; Breast cancer survivors undergoing a hyperinsulinemic euglycemic clamp	Drug: Insulin; Hyperinsulinemic euglycemic clamp; Other Names: Hyperinsulinemic euglycemic clamp

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Insulin sensitivity status	Glucose infusion rate during the hyperinsulinemic euglycemic clamp to ascertain the insulin sensitivity	2 years
Hepatic glucose production	Measurements from the Hyperinsulinemic Euglycemic Clamp will be used to assess insulin effects on hepatic glucose production	2 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proteomic changes in skeletal muscle	Skeletal muscle biopsies from the vastus lateralis muscle will be analysez using mass spectometry to determine proteomic chances in response to breast cancer in skeletal muscle	4 years
Insulin signaling	Intracellular insulin signaling will be determined using western blotting technique	4 years

Collaborators and Investigators

• Sponsor: University of Copenhagen
• Investigators: Principal Investigator: Lykke Sylow, PhD, University of Copenhagen

Study record dates

Study Major Dates

• Study Start (Anticipated): August 1, 2021
• Primary Completion (Anticipated): December 1, 2022
• Study Completion (Anticipated): September 1, 2026

Study Registration Dates

• First Submitted: June 23, 2021
• First Submitted That Met QC Criteria: August 10, 2021
• First Posted (Actual): August 18, 2021

Study Record Updates

• Last Update Posted (Actual): August 18, 2021
• Last Update Submitted That Met QC Criteria: August 10, 2021
• Last Verified: August 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Skin Diseases; Immune System Diseases; Neoplasms; Neoplasms by Site; Breast Diseases; Hyperinsulinism; Hypersensitivity; Breast Neoplasms; Insulin Resistance; Hypoglycemic Agents; Physiological Effects of Drugs; Insulin
• Other Study ID Numbers: 514-0213/21-5000

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No