High Intensity Interval Training and Insulin Sensitivity in Type 2 Diabetes (T2D-HIIT)

Effects of High Intensity Interval Training on Skeletal Muscle Insulin Sensitivity in Type 2 Diabetes Patients

A recognized driver for cardiovascular complications of type 2 diabetes mellitus (T2DM) is impaired plasma glucose homeostasis as consequence of skeletal muscle insulin resistance. Insulin-mediated plasma glucose disposal in skeletal muscle comprises oxidative glucose disposal (cellular glucose uptake for oxidation) and non-oxidative glucose disposal (NOGD; cellular glucose uptake for storage as glycogen), both processes being impaired in T2DM patients. Excessive intrahepatic fat accumulation (particularly monounsaturated (MUFA) and saturated (SFA)) is commonly observed in T2DM patients and tightly associates with plasma glucose dysregulation. It has been hypothesized that skeletal muscle insulin resistance redistributes circulating glucose away from muscle which together with hyperinsulinemia promotes intrahepatic lipid accretion via de novo lipogenesis (DNL). As saturated lipids is the final product of DNL, improving skeletal muscle insulin sensitivity, next to enhance plasma glucose homeostasis, might lower intrahepatic lipid content particularly intrahepatic saturated lipids.

Regular exercise is a cornerstone in the treatment of T2DM and to improve skeletal muscle insulin sensitivity. Interestingly, a conventional exercise program (aerobic-type combined with strength-type exercise) restores insulin-stimulated oxidative glucose disposal in T2DM patients to levels observed in age-matched normoglycemic subjects. Non-oxidative glucose disposal (NOGD), however, does not improve upon such conventional exercise programs. In this regard, for full restoration of compromised glucose disposal, it is pivotal to come up with effective training methods to target NOGD. High intensity interval training (HIIT) has the potential to expands the glycogen synthesis capacity in athletes by repetitive cycles of glycogen depletion/repletion, hence holds promise to improve NOGD in T2DM patients. Of note, HIIT also lowers the intrahepatic fat content in pre-diabetes individuals. Nevertheless, whether HIIT reduces the intrahepatic fat content and modifies its composition in T2DM patients is unknown. In this regard, it is hypothesized that HIIT expands the NOGD capacity in skeletal muscle of overweight/obese type 2 diabetes patients. By doing so, it is postulated that HIIT improves skeletal muscle insulin sensitivity and therefore benefits the 24 hours glycaemic profile in T2DM patients. In line, it is hypothesized that the HIIT-mediated improvements on NOGD and skeletal muscle insulin sensitivity coexist with the reduction of intrahepatic lipid content -particularly reduced saturated lipids- via lowering DNL.

Study Overview

• Status: Recruiting
• Conditions: Type 2 Diabetes; Insulin Sensitivity/Resistance; Lifestyle-related Condition
• Intervention / Treatment: Other: Experimental group: Exercise training

• Study Type: Interventional
• Enrollment (Estimated): 36
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Rodrigo Mancilla, PhD; Phone Number: +56953676588; Email: rmancilla@uft.cl

Study Locations

• Chile
  • Santiago, Chile
    • Recruiting
    • Finis Terrae University
    • Contact: Rodrigo Mancilla, PhD

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Participants are able to provide signed and dated written informed consent prior to any study specific procedures
• Aged ≥ 45 and ≤ 75 years
• BMI: 25-35 kg/m2
• Diagnosed as T2DM patients for at least 1 year and not longer than 5 years
• HbA1c ≥ 6.5% and ≤ 8.5%
• Fasting blood glucose <130 mg/dL
• Women are post-menopausal (>1 year cessation of menses),
• Being stable on medication use of metformin and/or sulfonylurea derivatives for the previous 3 months or more and other medication naïve.

Exclusion Criteria:

• Type 1 diabetes
• Patients with congestive heart failure and and/or severe renal and or liver insufficiency
• Contraindications for MRI/MRS examination
• Active diabetic foot
• Polyneuropathy or retinopathy
• Signs of active liver or kidney dysfunction
• BMI >35 kg/m2
• Exogeneous insulin therapy
• Use of antidiabetic medication other than metformin or sulfonylurea derivatives treatment within 3 months before screening
• Use of SGLT2 inhibitors
• Unstable body weight (variations >5kg in the last 3 months)
• Ongoing weight loss diet or use of weight loss agents
• Uncontrolled hypertension
• Engagement in regular exercise program or any other medical condition that will impede the safe performance of the experiments

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: T2D-HIIT; This arm will perform HIIT under supervision. The post training condition of this arm will be compared to an age and BMI matched, normoglycemic non-intervention group.	Other: Experimental group: Exercise training; HIIT program, 3 times per week for 12 weeks
No Intervention: T2D-CON; This corresponds to a non-training, control group, of age-, BMI matched, type 2 diabetes individuals.
No Intervention: NORM; A group of normoglycemic individuals will the reference comparison for the T2D-HIIT arm post-intervention

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Insulin-stimulated non-oxidative plasma glucose disposal (NOGD)	Insulin-stimulated NOGD will be measured upon hyperinsulinemic-euglycemic clamp test	12 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Skeletal muscle insulin sensitivity	Skeletal muscle insulin sensitivity will be measured as the rate of insulin-stimulated plasma glucose disposal (Rd) measured upon hyperinsulinemic-euglycemic clamp test	12 weeks

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maximal aerobic capacity	Maximal aerobic capacity will be measure upon a progressive cycling test	12 weeks
Total muscle mass	total muscle mass will be measured in kilograms and/or percentage	12 weeks
Total fat mass	Total fat mass will be measured in kilograms and/or percentage	12 weeks
Fat-free mass	Fat-free mass will be measured in kilograms and/or percentage	12 weeks
Insulin-stimulated glucose oxidation	Insulin-stimulated glucose oxidation will be measured via indirect calorimetry during clamp test	12 weeks
Liver insulin sensitivity	Liver insulin sensitivity will be measured as the rate of insulin-mediated suppression of endogenous glucose production (EGP) upon hyperinsulinemic-euglycemic clamp test	12 weeks
Intrahepatic lipid content and composition	Intrahepatic lipid content and composition will be measured by magnetic resonance spectroscopy of protons (1H-MRS)	12 weeks
De novo lipogenesis (DNL)	DNL will be measured by the use of deuterated water (D2O)	12 weeks
24 hours glycemic profile	24 hours glycemic profile will be measured by the use of continuous glucose monitoring device	12 weeks
Skeletal muscle glycogen content	Muscle glycogen content will be quantified in muscle biopsies	12 weeks
Proteins that regulate oxidative metabolism	Content of proteins that regulate oxidative phosphorylation system (OXPHOS) will be quantified in muscle biopsies	12 weeks
Body weight	Body weight will be measured in kilograms	12 weeks
Metabolic flexibility	Metabolic flexibility will be measured via indirect calorimetry during the clamp test	12 weeks
Skeletal muscle mutiomics	multiomics will be applied in muscle biopsies	12 weeks

Collaborators and Investigators

• Sponsor: Finis Terrae University
• Investigators: Principal Investigator: Rodrigo Mancilla, PhD, Finis Terrae University

Study record dates

Study Major Dates

• Study Start (Actual): October 1, 2024
• Primary Completion (Estimated): December 31, 2026
• Study Completion (Estimated): December 31, 2026

Study Registration Dates

• First Submitted: November 11, 2024
• First Submitted That Met QC Criteria: November 12, 2024
• First Posted (Actual): November 14, 2024

Study Record Updates

• Last Update Posted (Actual): March 16, 2026
• Last Update Submitted That Met QC Criteria: March 13, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Endocrine System Diseases; Metabolic Diseases; Glucose Metabolism Disorders; Diabetes Mellitus; Hyperinsulinism; Nutritional and Metabolic Diseases; Diabetes Mellitus, Type 2; Mental Disorders; Insulin Resistance
• Other Study ID Numbers: 24-001

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