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

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.

Study Overview

• Status: Recruiting
• Conditions: Diabetes Mellitus, Type 2; Diabetes; Type 2 Diabetes; Pre Diabetes
• Intervention / Treatment: Procedure: Insulin resistance testing; Procedure: OGTT; Procedure: Fat biopsy; Radiation: DXA scan; Procedure: MRI; Procedure: 1H-MRS; Drug: Tirzepatide; Drug: Pioglitazone

Detailed Description

The investigators aim to learn how adipocyte dysfunction and disordered fat distribution contribute to the development of type 2 diabetes in normal-weight individuals. The investigators hope to determine whether adipocyte-directed therapies, such as pioglitazone and tirzepatide, can improve insulin sensitivity, fat distribution, and metabolic health in this population. This study is important because most diabetes research focuses on overweight or obese individuals, and very little is known about how diabetes affects those with normal body weight. Understanding the unique biology of normal-weight diabetes could lead to more personalized and effective treatment strategies, filling a gap in diabetes care for a group that can be overlooked in clinical research.

• Study Type: Interventional
• Enrollment (Estimated): 104
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Nina Shenoy, BS; Phone Number: 408-896-0134; Email: nshenoy8@stanford.edu
• Study Contact Backup: Name: Alisa Turner, BS; Phone Number: 650-285-8855; Email: alturner@stanford.edu

Study Locations

• United States
  • California
    • Palo Alto, California, United States, 94304
      • Recruiting
      • Stanford University
      • Contact: Nina Shenoy, BS; Phone Number: 408-896-0134; Email: nshenoy8@stanford.edu
      • Contact: Alisa Turner, BS; Phone Number: 650-285-8855; Email: alturner@stanford.edu
    • Stanford, California, United States, 94304
      • Not yet recruiting
      • Stanford University, Clinical and Translational Research Unit (CTRU)
      • Principal Investigator: Tracey McLaughlin, MD
      • Contact: Nina Shenoy, BS; Phone Number: 408-896-0134; Email: nshenoy8@stanford.edu
      • Contact: Alisa Turner, BS; Phone Number: 650-285-8855; Email: alturner@stanford.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

Normal-Weight Diabetes (NWD) Group:

1. Age: 30 to 70 years old.
2. 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).
3. HbA1c Range: Between 5.7% and 8%, with a stable medication or lifestyle regimen for at least 3 months.
4. BMI: Between 19 and 24.9 kg/m².
5. 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.
6. 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:

1. Age: 30 to 70 years old.
2. No Diagnosis of Diabetes: Fasting plasma glucose < 100 mg/dL and A1c < 5.7%, with no history of glucose-lowering medications.
3. BMI: Between 19 and 24.9 kg/m².
4. Stable Body Weight: No more than 2 kg change over the past 3 months. -

Exclusion Criteria:

1. Pregnancy or Lactation: Women who are pregnant, planning to become pregnant, or breastfeeding are excluded due to potential risks to the fetus or infant.
2. Prior Use of Pioglitazone: Participants who have previously used pioglitazone are excluded to avoid confounding effects of prior drug exposure.
3. 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.
4. 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.
5. Congestive Heart Failure or Fluid Overload History: These conditions are exclusionary due to the risk of fluid retention with pioglitazone.
6. Uncontrolled Hypertension: Blood pressure > 160/90 mmHg excludes participants due to increased cardiovascular risk.
7. Active Cancer: Individuals with a diagnosis of cancer in the past 3 years (except for skin cancer) are excluded.
8. Chronic Inflammatory Diseases: Excluded due to potential effects on metabolic measurements.
9. Use of Weight Loss Medications: Those currently taking weight loss medications are excluded to prevent confounding effects on body weight and metabolic function.
10. 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.
11. Insulin Use: Participants using insulin are excluded to focus on non-insulin-dependent diabetes.
12. Active Psychiatric Disease or Eating Disorders: Individuals with these conditions are excluded due to potential impacts on study compliance and data integrity.

13. Substance Abuse: Participants with a history of substance abuse are excluded for similar reasons.

    -

Study Plan

How is the study designed?

Design Details

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

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: Normal weight controls; Control	Procedure: Insulin resistance testing; Steady state Plasma Glucose test; Other Names: SSPG; Procedure: OGTT; Will collect 5 blood draws during the test to measure insulin secretion; Other Names: Oral glucose tolerance test; Procedure: Fat biopsy; Needle biopsy to gather a sample of abdominal subcutaneous fat; Radiation: DXA scan; Whole body DXA scan; Procedure: MRI; Abdominal MRI; Procedure: 1H-MRS; Spectroscopy of the abdominal region; Other Names: proton magnetic resonance spectroscopy
Experimental: Normal weight with diabetes tirzepatide first pioglitazone second; Baseline testing Intervention with tirzepatide for 16 weeks Retesting Washout for 5 weeks Intervention with pioglitazone for 16 weeks Retesting	Procedure: Insulin resistance testing; Steady state Plasma Glucose test; Other Names: SSPG; Procedure: OGTT; Will collect 5 blood draws during the test to measure insulin secretion; Other Names: Oral glucose tolerance test; Procedure: Fat biopsy; Needle biopsy to gather a sample of abdominal subcutaneous fat; Radiation: DXA scan; Whole body DXA scan; Procedure: MRI; Abdominal MRI; Procedure: 1H-MRS; Spectroscopy of the abdominal region; Other Names: proton magnetic resonance spectroscopy; Drug: Tirzepatide; 16 weeks started at 2.5mg/week and increased to 5mg/week dose; Other Names: Mounjaro; Drug: Pioglitazone; 16 weeks at a 45mg/day dose; Other Names: Actos
Experimental: Normal weight with diabetes pioglitazone first, tirzepatide second; Baseline testing Intervention with pioglitazone for 16 weeks Retesting Washout for 5 weeks Intervention with tirzepatide for 16 weeks Retesting	Procedure: Insulin resistance testing; Steady state Plasma Glucose test; Other Names: SSPG; Procedure: OGTT; Will collect 5 blood draws during the test to measure insulin secretion; Other Names: Oral glucose tolerance test; Procedure: Fat biopsy; Needle biopsy to gather a sample of abdominal subcutaneous fat; Radiation: DXA scan; Whole body DXA scan; Procedure: MRI; Abdominal MRI; Procedure: 1H-MRS; Spectroscopy of the abdominal region; Other Names: proton magnetic resonance spectroscopy; Drug: Tirzepatide; 16 weeks started at 2.5mg/week and increased to 5mg/week dose; Other Names: Mounjaro; Drug: Pioglitazone; 16 weeks at a 45mg/day dose; Other Names: Actos

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
Effect of adipose-directed therapy pioglitazone on HbA1c in both men and women with normal weight diabetes	Hemoglobin A1C measures will be compared baseline to end of 16 weeks of intervention with pioglitazone.	16 weeks
Effect of pioglitazone in insulin resistance in both men and women.	SSPG test results will be compared from baseline to end of pioglitazone intervention. Results will be measured by glucose levels at steady state in mg/dL.	16 weeks
Fat storage in men with normal weight diabetes (NWD) compared to those without diabetes (NWC).	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
Adipocyte function in men with normal weight diabetes as compared with those without diabetes	Adipocyte function as measured by percent small adipocytes and peak diameter adipocytes from the fat biopsies.	Baseline comparisons
Insulin resistance in normal weight men 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
Insulin secretion in men and women with normal weight diabetes compared to those without diabetes	A five-point, three-hour OGTT will be done after overnight fast for calculation of insulin secretion using c-peptide deconvolution, and disposition index calculated by dividing this value by SSPG.	Baseline measured compared between the groups

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Effect of adipose-directed therapy with tirzepatide on insulin resistance in men and women with normal weight diabetes (NWD).	SSPG test results will be compared from baseline to end of tirzepatide intervention. Results will be measured by glucose levels at steady state in mg/dL.	16 weeks

Collaborators and Investigators

• Sponsor: Stanford University

Study record dates

Study Major Dates

• Study Start (Actual): January 13, 2025
• Primary Completion (Estimated): December 15, 2027
• Study Completion (Estimated): December 15, 2027

Study Registration Dates

• First Submitted: October 18, 2024
• First Submitted That Met QC Criteria: October 22, 2024
• First Posted (Actual): October 24, 2024

Study Record Updates

• Last Update Posted (Actual): April 20, 2026
• Last Update Submitted That Met QC Criteria: April 15, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Keywords: diabetes; insulin sensitivity; insulin resistance; metabolism; pre-diabetes; adipocyte; insulin resistant; insulin sensitive
• Additional Relevant MeSH Terms: Endocrine System Diseases; Metabolic Diseases; Glucose Metabolism Disorders; Hyperinsulinism; Hyperglycemia; Nutritional and Metabolic Diseases; Diabetes Mellitus, Type 2; Diabetes Mellitus; Insulin Resistance; Glucose Intolerance; Amino Acids, Peptides, and Proteins; Proteins; Sulfur Compounds; Organic Chemicals; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Investigative Techniques; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Thiazoles; Azoles; Diagnostic Imaging; Chemistry Techniques, Analytical; Spectrum Analysis; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptide Receptors; Receptors, G-Protein-Coupled; Receptors, Cell Surface; Membrane Proteins; Receptors, Gastrointestinal Hormone; Receptors, Peptide; Thiazolidinediones; Radiography; Densitometry; Photometry; Blood Chemical Analysis; Clinical Chemistry Tests; Diagnostic Techniques, Endocrine; Magnetic Resonance Spectroscopy; Pioglitazone; Tirzepatide; Absorptiometry, Photon; Glucose Tolerance Test; Proton Magnetic Resonance Spectroscopy
• Other Study ID Numbers: 77199

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: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes