Improving Insulin Sensitivity in Patients With Type 2 Diabetes Via Repeated Cold-induced Shivering Thermogenesis

Type 2 Diabetes Mellitus (T2DM) is a widespread health condition characterized by impaired ability of the body to maintain glucose homeostasis. This impairment often leads to secondary complications, including heart disease, high blood pressure, and poor quality of life. While exercise and healthy eating are effective strategies in managing and preventing T2DM, data shows that long-term adherence to these methods are poor - especially among elderly, individuals with obesity and/or with physical limitations.

This clinical study explores cold exposure with shivering as a novel strategy to improve blood sugar control and heart health. In earlier research, spending time in mildly cold environments (around 15-17°C) for a few hours a day improved insulin sensitivity of T2DM patients. Interestingly, these benefits only occurred when the cold caused mild shivering. In a recent 10-day cold acclimation study with overt shivering for minimally 1 hour/day, we observed improved glucose tolerance in participants with overweight/obesity, as well as improved fasting lipid profiles. These results indicate that when accompanied with sufficient level of muscle activation, repeated exposure to cold can beneficially affect both glucose and lipid levels - both of which are impaired in people with T2DM.

In this study, we hypothesise that a 10-day cold acclimation with shivering will improve the (peripheral) insulin sensitivity of patients with T2DM, accompanied by enhanced skeletal muscle FA uptake and oxidation as assessed via the 11C palmitate uptake.

Study Overview

• Status: Recruiting
• Conditions: Type 2 Diabetes
• Intervention / Treatment: Behavioral: Cold exposure with shivering

Detailed Description

In a longitudinal design, participants will be exposed to a 10-day cold acclimation with daily shivering. Several metabolic read-out parameters will be evaluated before, during and after the intervention.

On their first visit (Visit 1) participants will arrive to the research facility to receive a physical activity, ambulatory blood pressure and continuous glucose monitors. Around 48 hours following Visit 1, participants will return (Visit 2) for the baseline two-step hyperinsulinaemic-euglycaemic clamp (HEC) measurement, used to assess their hepatic and peripheral insulin sensitivity. Within 1 week after Visit 2 the acclimation period with 10 consecutive daily shivering sessions will start (Visits 3 - 12). During the first (Visit 3) and last (Visit 12) cold exposure sessions organ-specific fatty acid uptake, and oxidative vs. non-oxidative metabolism will be determined using [11C]-palmitate PET/CT. Additionally, indirect calorimetry and regular blood sampling will be performed. During cold exposures 2 to 9, heat loss will be assessed by measuring change in water temperature perfused through the cold exposure suit. In addition, skin temperature, as well as surface electromyography and blood pressure measurements will be performed on days 3, 5, 7 and 9 (Visits 5, 7, 9 and 11) during the acclimation period. On the last cold exposure day participants will be provided a standard dinner to be consumed in the evening before Visit 13. Around 16h following Visit 12, i.e. the day after, participant will return for the post-intervention HEC (Visit 13). At the end of Visit 13, participants will be supplied with an activity and ABP monitors for the post-intervention measuremends. Finally, participants will return to the research centre ~42-45h after Visit 13 for the close-out visit (Visit 14) during which the two monitors will be collected.

• Study Type: Interventional
• Enrollment (Estimated): 15
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Frédérique Frisch; Phone Number: 12394 819-346-1110; Email: frederique.frisch@usherbrooke.ca

Study Locations

• Canada
  • Quebec
    • Sherbrooke, Quebec, Canada, J1H 5N4
      • Recruiting
      • Centre de Recherche du CHUS
      • Contact: Frédérique Frisch; Phone Number: 12394 819-346-1110; Email: frederique.frisch@usherbrooke.ca
      • Sub-Investigator: André Carpentier

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Patients are able to provide signed and dated written informed consent prior to any study specific procedures
• Women are post-menopausal (defined as at least 1 year post cessation of menses)
• Aged ≥ 40 years and ≤ 75 years
• Patients should have suitable veins for cannulation or repeated venipuncture
• Body mass index (BMI) 25-38 kg/m2
• Stable dietary habits (no weight loss or gain >5kg in the past 3 months)
• Diagnosed with T2D at least 1.5 years before the start of the study
• Relatively well-controlled T2D: HbA1c < 8.5%
• Oral glucose-lowering medication: metformin alone or in combination with sulfonylurea agents and/or on stable dose of a DPPIV inhibitor treatment for at least the last 3 months. In case of GLP-1 agonist medication treatment inclusion will be discussed with the dependent physician.
• No signs of active diabetes-related co-morbidities like active cardiovascular diseases, active diabetic foot, polyneuropathy or retinopathy
• No signs of active liver or kidney malfunction

Exclusion Criteria:

• Previous enrolment in a clinical study with an investigational product during the last 3 months or as judged by the Investigator
• Participate in sports of physical activity at a moderate- to high-intensity more than 3 times a week, or as judged by the investigator
• Being cold-acclimated, e.g. having taken daily extended cold baths, working in a refrigerated environment, or practicing regular cold-water swimming/ showering within 1 month of starting the study
• Unstable body weight (weight gain or loss > 5 kg in the last three months)
• Alcohol consumption of >2 servings per day for man and >1 servings per day for women
• Smoking
• Being insulin-dependent and/or using SGLT2 inhibitor medications
• Patients with congestive heart failure and and/or severe renal and or liver insufficiency
• Men: Hb <8.4 mmol/L, Women: Hb <7.8 mmol/l
• A medical doctor will judge participation eligibility based on the medical history questionnaire, medication use and fasting blood parameters. If the medical doctor advises that a patient cannot participate, the patient will be excluded from enrolment.
• Being pregnant
• Having participated in another study involving PET/CT scanning in the past 1 year

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Cold acclimation with shivering; This is a single-arm longitudinal study with a 10-day cold acclimation intervention period. Pre- and post-intervention measurements will be obtained before and after the 10-day period.	Behavioral: Cold exposure with shivering; Cold exposure which elicits a minimally 80% increase in the baseline metabolic rate of participants.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Whole-body insulin sensitivity measured as glucose infusion rate (GIR) in µmol/kg/min during the stable period of the low- and high-insulin phase of the clamp.	1) Hepatic insulin sensitivity measured as percent EGP suppression in µmol/kg/min; 2) Peripheral insulin sensitivity measured as Rd in µmol/kg/min. Determined by means of a hyperinsulinaemic-euglycaemic clamp.	At baseline and Day 13.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
11-C palmitate uptake and oxidation in liver and skeletal muscle, expressed in µmol/g/min	Determined by means of PET-CT scanning with a cervico-thoracic dynamic acquisition with 1-[11C]-palmitate (175 MBq).	At Day 3 and Day 12.

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
24-hour systolic and diastolic blood pressure and heart rate	24-hour ambulatory blood pressure before and after the 10-day cold acclimation	24-hour period before the baseline clamp (i.e. visit 2) and 24-hour period after the post-acclimation clamp (i.e. visit 13).
Plasma metabolites	In the fasted state plasma metabolites such as glucose, insulin, free fatty acids, triglycerides, inflammatory markers, liver enzymes, etc. will be measured; Under cold- and insulin-stimulated conditions circulating metabolites and hormones during the first and last cold exposure, as well as during the hyperinsulinaemic euglycaemic clamp will be measured	Day 2 and Day 13 for insulin stimulated conditions, and Day 3 and Day 12 for cold-stimulated conditions.
Average 24-hour interstitial glucose concentrations	24-hour interstitial glucose values measured under normal living conditions via continuous glucose monitors	24-hour period before Day 2 and after Day 13.
Energy expenditure	Energy expenditure will be assessed via indirect calorimetry before and after the 10-day acclimation during: Baseline (room temperature); Cold exposure; Baseline phase of the hyperinsulinaemic euglycaemic clamp; Low- and high-insulin phase of the hyperinsulinaemic euglycaemic clamp	During hyperinsulinaemic euglycaemic clamp: at baseline and day 13 During cold exposure: Day 3 and Day 12
Substrate (CHO and fat) oxidation	CHO and fat oxidation will be assessed via indirect calorimetry before and after the 10-day acclimation during: Baseline (room temperature); Cold exposure - Baseline phase of the hyperinsulinaemic euglycaemic clamp; Low- and high-insulin phase of the hyperinsulinaemic euglycaemic clamp	During hyperinsulinaemic euglycaemic clamp: at baseline and day 13 During cold exposure: Day 3 and Day 12
Skin temperature	Skin temperature will be assessed via skin thermistors attached to 12 different locations around the body	Day 3, Day 5, Day 7, Day 9, Day 11 and Day 12
Shivering intensity	Muscle activity at baseline and during cold exposure will be assessed via electromyography sensors placed on up to 8 different muscle groups.	Day 3, Day 5, Day 7, Day 9, Day 11 and Day 12
Morning blood pressure	Systolic and diastolic blood pressure will be assessed by means of an automated office blood pressure device.	Day 3, Day 5, Day 7, Day 9, Day 11 and Day 12
Morning heart rate	Morning heart rate will be assessed by means of an automated office blood pressure device.	Day 3, Day 5, Day 7, Day 9, Day 11 and Day 12

Collaborators and Investigators

• Sponsor: Université de Sherbrooke
• Collaborators: Maastricht University Medical Center
• Investigators: Principal Investigator: Denis P. Blondin, PhD, Universite de Sherbrooke

Study record dates

Study Major Dates

• Study Start (Actual): September 24, 2025
• Primary Completion (Estimated): October 31, 2026
• Study Completion (Estimated): May 31, 2027

Study Registration Dates

• First Submitted: September 9, 2025
• First Submitted That Met QC Criteria: May 4, 2026
• First Posted (Actual): May 7, 2026

Study Record Updates

• Last Update Posted (Actual): May 7, 2026
• Last Update Submitted That Met QC Criteria: May 4, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Keywords: Insulin sensitivity; Substrate metabolism; cardiometabolic health; shivering thermogensis
• Additional Relevant MeSH Terms: Endocrine System Diseases; Metabolic Diseases; Glucose Metabolism Disorders; Diabetes Mellitus; Hyperinsulinism; Nutritional and Metabolic Diseases; Diabetes Mellitus, Type 2; Insulin Resistance; Physiological Phenomena; Biological Phenomena; Adaptation, Physiological; Adaptation, Biological; Homeostasis; Thermogenesis; Body Temperature Regulation; Body Temperature; Shivering
• Other Study ID Numbers: 2025-5718

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: IPD from published manuscript will be provided upon reasonable request and dependent upon specific permission from the Comité d'éthique de la recherche du CIUSSS de l'Estrie-CHUS. In addition, the study protocol, statistical analysis plan and informed consent form may also be available upon reasonable request and approval from the Comité d'ethique de la recherche du CIUSSS de l'Estrie-CHUS.

Drug and device information, study documents

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