Normal-weight Diabetes: Adipocyte-directed Therapy With Pioglitazone or Tirzepatide

NCT06657209 | Recruiting Phase 4 FDA Drug

• 1 other identifier: 77199
• Study Type: interventional
• Target: 104
• Locations: 1 country
• Sites: 2

Brief Summary

This study is to investigate how adipocyte (fat cell) function and fat distribution differ between individuals with normal-weight type 2 diabetes (NWD), those with overweight type 2 diabetes (OWD), and normal-weight controls without diabetes (NWC). The study will assess whether adipocyte-directed therapies, specifically pioglitazone and tirzepatide, can improve insulin resistance, adipocyte function, and fat distribution in individuals with NWD. By analyzing the biological mechanisms underlying adipocyte dysfunction, the study aims to provide insights into novel treatment strategies for improving metabolic health in normal-weight individuals with type 2 diabetes.

Conditions

Diabetes Mellitus, Type 2; Diabetes; Type 2 Diabetes; Pre Diabetes

Keywords

metabolism; diabetes; pre-diabetes; insulin sensitivity; insulin resistance; insulin resistant; insulin sensitive; adipocyte

Outcome Measures

Primary Outcomes (3)

• Insulin resistance in normal weight women with diabetes compared to those with no diabetes

  Insulin resistance will be measured by a Steady State Plasma Glucose test (SSPG). Results will be measured by glucose levels at steady state in mg/dL.

  Baseline measures comparison between the groups

• Adipocyte function in women with normal weight diabetes as compared with those without diabetes

  Adipocyte function will be measured as percent small adipocytes and peak diameter adipocytes from the fat biopsies.

  Baseline comparisons

• Fat storage in women with normal weight diabetes compared to those without diabetes

  Fat storage will be measured by MRI. Quantification of subcutaneous and visceral abdominal fat will be obtained by MRI using a fat-water imaging sequence (parameters: IDEAL-IQ: 3D GRE, 160x160 matrix, 6 echoes, 4 degree flip angle, minimum TR = 7.3 ms, 28 slices, 10 mm slice thickness.

  Baseline comparisons between the groups

Secondary Outcomes (6)

• Effect of adipose-directed therapy pioglitazone on HbA1c in both men and women with normal weight diabetes

  16 weeks

• Effect of pioglitazone in insulin resistance in both men and women.

  16 weeks

• Fat storage in men with normal weight diabetes (NWD) compared to those without diabetes (NWC).

  Baseline comparisons between the groups

• Adipocyte function in men with normal weight diabetes as compared with those without diabetes

  Baseline comparisons

• Insulin resistance in normal weight men with diabetes compared to those with no diabetes

  Baseline measures comparison between the groups

Other Outcomes (1)

• Effect of adipose-directed therapy with tirzepatide on insulin resistance in men and women with normal weight diabetes (NWD).

  16 weeks

Study Arms (3)

Normal weight controls

OTHER

Control

Procedure: Insulin resistance testing; Procedure: OGTT; Procedure: Fat biopsy; Radiation: DXA scan; Procedure: MRI; Procedure: 1H-MRS

Normal weight with diabetes tirzepatide first pioglitazone second

EXPERIMENTAL

Baseline testing Intervention with tirzepatide for 16 weeks Retesting Washout for 5 weeks Intervention with pioglitazone for 16 weeks Retesting

Procedure: Insulin resistance testing; Procedure: OGTT; Procedure: Fat biopsy; Radiation: DXA scan; Procedure: MRI; Procedure: 1H-MRS; Drug: Tirzepatide; Drug: Pioglitazone

Normal weight with diabetes pioglitazone first, tirzepatide second

EXPERIMENTAL

Baseline testing Intervention with pioglitazone for 16 weeks Retesting Washout for 5 weeks Intervention with tirzepatide for 16 weeks Retesting

Procedure: Insulin resistance testing; Procedure: OGTT; Procedure: Fat biopsy; Radiation: DXA scan; Procedure: MRI; Procedure: 1H-MRS; Drug: Tirzepatide; Drug: Pioglitazone

Interventions

Insulin resistance testing PROCEDURE

Steady state Plasma Glucose test

Also known as: SSPG

Normal weight controls; Normal weight with diabetes pioglitazone first, tirzepatide second; Normal weight with diabetes tirzepatide first pioglitazone second

OGTT PROCEDURE

Will collect 5 blood draws during the test to measure insulin secretion

Also known as: Oral glucose tolerance test

Normal weight controls; Normal weight with diabetes pioglitazone first, tirzepatide second; Normal weight with diabetes tirzepatide first pioglitazone second

Fat biopsy PROCEDURE

Needle biopsy to gather a sample of abdominal subcutaneous fat

Normal weight controls; Normal weight with diabetes pioglitazone first, tirzepatide second; Normal weight with diabetes tirzepatide first pioglitazone second

DXA scan RADIATION

Whole body DXA scan

Normal weight controls; Normal weight with diabetes pioglitazone first, tirzepatide second; Normal weight with diabetes tirzepatide first pioglitazone second

MRI PROCEDURE

Abdominal MRI

Normal weight controls; Normal weight with diabetes pioglitazone first, tirzepatide second; Normal weight with diabetes tirzepatide first pioglitazone second

1H-MRS PROCEDURE

Spectroscopy of the abdominal region

Also known as: proton magnetic resonance spectroscopy

Normal weight controls; Normal weight with diabetes pioglitazone first, tirzepatide second; Normal weight with diabetes tirzepatide first pioglitazone second

Tirzepatide DRUG

16 weeks started at 2.5mg/week and increased to 5mg/week dose

Also known as: Mounjaro

Normal weight with diabetes pioglitazone first, tirzepatide second; Normal weight with diabetes tirzepatide first pioglitazone second

Pioglitazone DRUG

16 weeks at a 45mg/day dose

Also known as: Actos

Normal weight with diabetes pioglitazone first, tirzepatide second; Normal weight with diabetes tirzepatide first pioglitazone second

Eligibility Criteria

• Age: 30 Years - 70 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Normal-Weight Diabetes (NWD) Group:
• Age: 30 to 70 years old.
• Diagnosis of Type 2 Diabetes (T2D): Based on a previous diagnosis or confirmed by laboratory testing at screening (A1c \> 5.7% or fasting glucose \> 100 mg/dL).
• HbA1c Range: Between 5.7% and 8%, with a stable medication or lifestyle regimen for at least 3 months.
• BMI: Between 19 and 24.9 kg/m².
• Diabetes Medications: All diabetes medications are allowed, except insulin and pioglitazone. GLP-1 receptor agonists are permitted if the dose has been stable for 3 months.
• Stable Body Weight: Body weight must have been stable (no more than 2 kg change) over the last 3 months.
• Normal-Weight Control (NWC) Group:
• Age: 30 to 70 years old.
• No Diagnosis of Diabetes: Fasting plasma glucose \< 100 mg/dL and A1c \< 5.7%, with no history of glucose-lowering medications.
• BMI: Between 19 and 24.9 kg/m².
• Stable Body Weight: No more than 2 kg change over the past 3 months. -

You may not qualify if:

• Pregnancy or Lactation: Women who are pregnant, planning to become pregnant, or breastfeeding are excluded due to potential risks to the fetus or infant.
• Prior Use of Pioglitazone: Participants who have previously used pioglitazone are excluded to avoid confounding effects of prior drug exposure.
• Unstable Body Weight: Individuals with a body weight change of more than 2 kg in the last 3 months are excluded to ensure stable metabolic conditions.
• Liver or Kidney Disease: Participants with significant liver disease (ALT \> 3x upper limit of normal) or renal disease (creatinine \> 1.5 mg/dL) are excluded due to potential safety risks.
• Uncontrolled Hypertension: Blood pressure \> 160/90 mmHg excludes participants due to increased cardiovascular risk.
• Active Cancer: Individuals with a diagnosis of cancer in the past 3 years (except for skin cancer) are excluded.
• Chronic Inflammatory Diseases: Excluded due to potential effects on metabolic measurements.
• Use of Weight Loss Medications: Those currently taking weight loss medications are excluded to prevent confounding effects on body weight and metabolic function.
• Bariatric Surgery or Liposuction History: Participants who have had weight-loss surgeries or liposuction are excluded due to alterations in fat tissue and metabolic profiles.
• Insulin Use: Participants using insulin are excluded to focus on non-insulin-dependent diabetes.
• Active Psychiatric Disease or Eating Disorders: Individuals with these conditions are excluded due to potential impacts on study compliance and data integrity.
• Substance Abuse: Participants with a history of substance abuse are excluded for similar reasons.

Sponsors & Collaborators

• Stanford University: lead

Study Sites (2)

Stanford University

Palo Alto, California, 94304, United States

RECRUITING

Stanford University, Clinical and Translational Research Unit (CTRU)

Stanford, California, 94304, United States

NOT YET RECRUITING

MeSH Terms

Conditions

Diabetes Mellitus, Type 2; Diabetes Mellitus; Glucose Intolerance; Insulin Resistance

Interventions

Glucose Tolerance Test; Absorptiometry, Photon; Proton Magnetic Resonance Spectroscopy; Tirzepatide; Pioglitazone

Condition Hierarchy (Ancestors)

Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Endocrine System Diseases; Hyperglycemia; Hyperinsulinism

Intervention Hierarchy (Ancestors)

Blood Chemical Analysis; Clinical Chemistry Tests; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Diagnostic Techniques, Endocrine; Investigative Techniques; Radiography; Diagnostic Imaging; Densitometry; Photometry; Chemistry Techniques, Analytical; Magnetic Resonance Spectroscopy; Spectrum Analysis; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptide Receptors; Receptors, G-Protein-Coupled; Receptors, Cell Surface; Membrane Proteins; Proteins; Amino Acids, Peptides, and Proteins; Receptors, Gastrointestinal Hormone; Receptors, Peptide; Thiazolidinediones; Thiazoles; Sulfur Compounds; Organic Chemicals; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Central Study Contacts

Nina Shenoy, BS

CONTACT

408-896-0134; nshenoy8@stanford.edu

Alisa Turner, BS

CONTACT

650-285-8855; alturner@stanford.edu

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor of Medicine

Model Details: Control groups will undergo baseline testing to provide information about people without diabetes, but will not proceed with treatment.

Study Record Dates

• First Submitted: October 18, 2024
• First Posted: October 24, 2024
• Study Start: January 13, 2025
• Primary Completion (Estimated): December 15, 2027
• Study Completion (Estimated): December 15, 2027
• Last Updated: April 20, 2026

Record last verified: 2026-04

Data Sharing

• IPD Sharing: Will not share

Locations

US (2)