Brown Fat Activation Treatments for Type 2 Diabetes

(GB8 Trial)

Overseen By Frédérique Frisch

Age: 18+

Sex: Any

Trial Phase: Academic

Sponsor: Université de Sherbrooke

Must not be taking: Fibrates, Thiazolidinediones, Insulin, others

Disqualifiers: Cardiovascular, Liver, Renal, Smoking, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 3

40 Participants Needed

Trial Summary

What is the purpose of this trial?

Activation of brown adipose tissue (BAT) by cold exposure. BAT thermogenesis and BAT volume of metabolic activity will be assessed by Positron-Emitting-Tomography (PET/CT) and MRI/MRS imaging and new pharmacological methods to modulate BAT thermogenesis. All previous data on the functioning of Brown Adipose Tissue (BAT) were obtained by Positron-Emitting-Tomography (PET) imaging studies using fluorodeoxyglucose F18 ( \[18F\]- FDG). This approach underestimates the actual activity of the BAT. In this study, the investigator is going to use a new PET tracer (C11-palmitate) which is a fat molecule. This will allow to quantify more accurately the activity of brown fat.

Will I have to stop taking my current medications?

The trial requires that you stop taking certain medications that affect lipid or carbohydrate metabolism, except for statins, metformin, sulfonylurea, DPP-IV inhibitors, and some antihypertensive agents, which can be temporarily stopped safely before the study.

What data supports the effectiveness of the treatment for activating brown fat in type 2 diabetes?

Research shows that short-term cold exposure can improve insulin sensitivity in people with type 2 diabetes by activating brown fat, which helps the body use sugar more effectively. This suggests that cold treatments might be beneficial for managing diabetes. ^{1 2 3 4 5}

Is cold exposure treatment safe for humans?

Cold exposure, used to activate brown fat, has been studied in humans and generally appears safe, with some studies showing improved insulin sensitivity and glucose metabolism. However, more research is needed to fully understand its long-term safety and effects. ^{1 2 4 6 7}

How does cold exposure treatment for type 2 diabetes differ from other treatments?

Cold exposure treatment is unique because it activates brown fat, which can improve insulin sensitivity and glucose metabolism by increasing the activity of brown adipose tissue and enhancing glucose uptake in skeletal muscle, unlike traditional treatments that primarily focus on medication or lifestyle changes. ^{1 2 3 6 8}

Research Team

André Carpentier

Principal Investigator

Université de Sherbrooke

Eligibility Criteria

This trial is for 20 individuals with Type 2 Diabetes (T2D) and 20 non-diabetic individuals, both groups balanced in terms of sex, body mass index (BMI), and age. Participants should not have serious heart, liver or kidney conditions, be on certain diabetes or lipid-altering medications except for some like statins or metformin, smoke heavily, drink more than two alcoholic beverages daily, have had radiation exposure from research within the last two years, have MRI contraindications or significant weight/lifestyle changes recently.

Inclusion Criteria

I am a non-diabetic person matched in sex, BMI, and age with a Type 2 diabetes participant.

I am a man/woman with type 2 diabetes.

I am a non-diabetic person matched in sex, BMI, and age with a Type 2 diabetes participant.

Exclusion Criteria

You have been in another research study involving radiation in the past two years.

You have a medical reason that makes it unsafe for you to have an MRI scan.

I have a serious heart, liver, kidney, or other medical condition.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

1 visit

1 visit (in-person)

Imaging Studies

Participants undergo PET/MRI imaging studies with and without nicotinic acid, including acute cold exposure to stimulate brown adipose tissue.

2 visits over 2-4 weeks

2 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after imaging studies

4 weeks

Treatment Details

Interventions

• Cold exposure
• Oral Nicotinic acid

Trial Overview The study tests how brown adipose tissue (BAT) metabolism can be activated in people with T2D using cold exposure and oral Nicotinic acid. It will use advanced imaging techniques like PET/CT scans with a new tracer C11-palmitate to measure BAT activity more accurately compared to traditional methods.

Participant Groups

Group I: Subject without type 2 Diabetes- cold exposure and nicotinic acid Experimental Treatment 2 Interventions

3-hour cold exposure with oral nicotinic acid: Protocol A

Group II: Subject with type 2 Diabetes- cold exposure and nicotinic acid Experimental Treatment 2 Interventions

3-hour cold exposure with oral nicotinic acid: Protocol A

Group III: Subject without Type 2 Diabetes- cold exposure Active Control 1 Intervention

3-hour cold exposure: Protocol B

Group IV: Subject with Type 2 Diabetes- cold exposure Active Control 1 Intervention

3-hour cold exposure: Protocol B

Who Is Running the Clinical Trial?

Université de Sherbrooke

Lead Sponsor

Trials

317

Recruited

79,300+

Findings from Research

Cold acclimation for 10 days at temperatures of 14-15 °C significantly improved insulin sensitivity by approximately 43% in eight subjects with type 2 diabetes.

The increase in insulin sensitivity was associated with enhanced GLUT4 translocation in skeletal muscle, suggesting a mechanism of action that does not rely on changes in insulin signaling or AMPK activation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Short-term cold acclimation improves insulin sensitivity in patients with type 2 diabetes mellitus. Hanssen, MJ., Hoeks, J., Brans, B., et al.[2022]

Cold acclimation and exercise training both lead to significant changes in gene expression in human skeletal muscle, with cold acclimation affecting 756 genes and exercise training affecting 665 genes, indicating a potential overlap in their adaptive responses.

However, the overlapping genes primarily relate to tissue remodeling rather than insulin signaling or glucose metabolism, suggesting that while both interventions improve insulin sensitivity, they may do so through different molecular mechanisms.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparative transcriptome analysis of human skeletal muscle in response to cold acclimation and exercise training in human volunteers. Nascimento, EBM., Hangelbroek, RWJ., Hooiveld, GJEJ., et al.[2021]

Humans have active brown adipose tissue (BAT), which is gaining attention as a potential target for preventing and treating obesity and metabolic disorders.

Cold exposure is currently the most effective way to activate BAT, but researchers are exploring other methods to stimulate this tissue, with ongoing studies investigating the long-term effects of BAT activation on metabolic health.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The future of brown adipose tissues in the treatment of type 2 diabetes. Schrauwen, P., van Marken Lichtenbelt, WD., Spiegelman, BM.[2018]

In a clinical trial with 19 healthy adults, just 20 minutes of cooling was found to activate brown adipose tissue (BAT) similarly to the standard 60 minutes, suggesting that BAT can be quickly stimulated for potential metabolic benefits.

After cold exposure ends, the active volume of BAT decreases significantly, indicating that while BAT activation is rapid, its deactivation is slower, which could inform strategies for using cold exposure in obesity treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Kinetics of human brown adipose tissue activation and deactivation. Leitner, BP., Weiner, LS., Desir, M., et al.[2020]

In a case study of a patient with an insulin receptor mutation, discontinuing levothyroxine therapy led to a decrease in brown adipose tissue (BAT) volume and activity, as evidenced by reduced FDG uptake on PET-CT scans.

The findings suggest a relationship between thyroid hormone levels and BAT activity, indicating that thyroid hormones may play a role in glucose metabolism and diabetic control, although further research is needed to confirm this association.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Thyroid hormone induced brown adipose tissue and amelioration of diabetes in a patient with extreme insulin resistance. Skarulis, MC., Celi, FS., Mueller, E., et al.[2022]

A 10-day cold acclimation in 10 metabolically healthy obese men increased glucose uptake in brown adipose tissue (BAT), suggesting potential benefits for glucose metabolism and obesity management.

The study found that cold acclimation also improved glucose uptake in skeletal muscle, likely due to increased GLUT4 localization, which may help prevent insulin resistance and hyperglycemia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Short-term Cold Acclimation Recruits Brown Adipose Tissue in Obese Humans. Hanssen, MJ., van der Lans, AA., Brans, B., et al.[2018]

Brown adipose tissue (BAT) is a unique type of fat that can burn energy and produce heat, which is important for regulating body temperature and metabolism, and can be activated by cold exposure and certain compounds.

The ability of white adipose tissue (WAT) to transform into a BAT-like state, known as 'browning', is linked to increased energy expenditure and protection against obesity and type 2 diabetes, highlighting the potential for therapeutic strategies targeting BAT in humans.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Brown adipose tissue and thermogenesis. Fenzl, A., Kiefer, FW.[2018]

A 10-day cold acclimation protocol in humans significantly increased the activity of brown adipose tissue (BAT) and nonshivering thermogenesis (NST), suggesting a potential method to enhance energy expenditure and combat obesity.

The study found no significant changes in skeletal muscle mitochondrial uncoupling or 'browning' of white adipose tissue, indicating that the increased energy expenditure was primarily due to BAT activation rather than changes in muscle metabolism.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cold acclimation recruits human brown fat and increases nonshivering thermogenesis. van der Lans, AA., Hoeks, J., Brans, B., et al.[2021]

References

1. United States pubmed.ncbi.nlm.nih.gov

Short-term cold acclimation improves insulin sensitivity in patients with type 2 diabetes mellitus. [2022]

2. England pubmed.ncbi.nlm.nih.gov

Comparative transcriptome analysis of human skeletal muscle in response to cold acclimation and exercise training in human volunteers. [2021]

3. Germany pubmed.ncbi.nlm.nih.gov

The future of brown adipose tissues in the treatment of type 2 diabetes. [2018]

4. England pubmed.ncbi.nlm.nih.gov

Kinetics of human brown adipose tissue activation and deactivation. [2020]

5. United States pubmed.ncbi.nlm.nih.gov

Thyroid hormone induced brown adipose tissue and amelioration of diabetes in a patient with extreme insulin resistance. [2022]

6. United States pubmed.ncbi.nlm.nih.gov

Short-term Cold Acclimation Recruits Brown Adipose Tissue in Obese Humans. [2018]

7. Germany pubmed.ncbi.nlm.nih.gov

Brown adipose tissue and thermogenesis. [2018]

8. United States pubmed.ncbi.nlm.nih.gov

Cold acclimation recruits human brown fat and increases nonshivering thermogenesis. [2021]