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.

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.

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

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.