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

Phase 4

Not yet recruiting

• Conditions: Diabetes Mellitus, Type 2
• Interventions: Procedure: Insulin resistance testing; Procedure: OGTT; Procedure: Fat biopsy; Radiation: DXA scan; Procedure: MRI; Procedure: 1H-MRS; Drug: Tirzepatide; Drug: Pioglitazone

• Registration Number: NCT06657209
• Lead Sponsor: Stanford University

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) 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.

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 Timeline

• Status Verified: 2024-10
• Study First Submitted: 2024-10-18
• Study First Submitted QC: 2024-10-22
• Last Update Submitted: 2024-10-22
• Study First Posted: 2024-10-24
• Last Update Posted: 2024-10-24
• Study Start: 2024-12-15
• Primary Completion: 2027-12-15
• Study Completion: 2027-12-15

Recruitment & Eligibility

• Status: NOT_YET_RECRUITING
• Sex: All
• Target Recruitment: 104

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 & Design

• Study Type: INTERVENTIONAL
• Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Normal weight with diabetes pioglitazone first, tirzepatide second	OGTT	Baseline testing Intervention with pioglitazone for 16 weeks Retesting Washout for 5 weeks Intervention with tirzepatide for 16 weeks Retesting
Normal weight with diabetes pioglitazone first, tirzepatide second	Fat biopsy	Baseline testing Intervention with pioglitazone for 16 weeks Retesting Washout for 5 weeks Intervention with tirzepatide for 16 weeks Retesting
Normal weight with diabetes pioglitazone first, tirzepatide second	DXA scan	Baseline testing Intervention with pioglitazone for 16 weeks Retesting Washout for 5 weeks Intervention with tirzepatide for 16 weeks Retesting
Normal weight with diabetes pioglitazone first, tirzepatide second	MRI	Baseline testing Intervention with pioglitazone for 16 weeks Retesting Washout for 5 weeks Intervention with tirzepatide for 16 weeks Retesting
Normal weight with diabetes pioglitazone first, tirzepatide second	1H-MRS	Baseline testing Intervention with pioglitazone for 16 weeks Retesting Washout for 5 weeks Intervention with tirzepatide for 16 weeks Retesting
Normal weight with diabetes tirzepatide first pioglitazone second	Tirzepatide	Baseline testing Intervention with tirzepatide for 16 weeks Retesting Washout for 5 weeks Intervention with pioglitazone for 16 weeks Retesting
Normal weight with diabetes tirzepatide first pioglitazone second	Pioglitazone	Baseline testing Intervention with tirzepatide for 16 weeks Retesting Washout for 5 weeks Intervention with pioglitazone for 16 weeks Retesting
Normal weight with diabetes pioglitazone first, tirzepatide second	Insulin resistance testing	Baseline testing Intervention with pioglitazone for 16 weeks Retesting Washout for 5 weeks Intervention with tirzepatide for 16 weeks Retesting
Normal weight controls	Insulin resistance testing	Control
Normal weight controls	OGTT	Control
Normal weight controls	Fat biopsy	Control
Normal weight controls	DXA scan	Control
Normal weight controls	MRI	Control
Normal weight controls	1H-MRS	Control
Normal weight with diabetes tirzepatide first pioglitazone second	Insulin resistance testing	Baseline testing Intervention with tirzepatide for 16 weeks Retesting Washout for 5 weeks Intervention with pioglitazone for 16 weeks Retesting
Normal weight with diabetes tirzepatide first pioglitazone second	OGTT	Baseline testing Intervention with tirzepatide for 16 weeks Retesting Washout for 5 weeks Intervention with pioglitazone for 16 weeks Retesting
Normal weight with diabetes tirzepatide first pioglitazone second	Fat biopsy	Baseline testing Intervention with tirzepatide for 16 weeks Retesting Washout for 5 weeks Intervention with pioglitazone for 16 weeks Retesting
Normal weight with diabetes tirzepatide first pioglitazone second	DXA scan	Baseline testing Intervention with tirzepatide for 16 weeks Retesting Washout for 5 weeks Intervention with pioglitazone for 16 weeks Retesting
Normal weight with diabetes tirzepatide first pioglitazone second	MRI	Baseline testing Intervention with tirzepatide for 16 weeks Retesting Washout for 5 weeks Intervention with pioglitazone for 16 weeks Retesting
Normal weight with diabetes tirzepatide first pioglitazone second	1H-MRS	Baseline testing Intervention with tirzepatide for 16 weeks Retesting Washout for 5 weeks Intervention with pioglitazone for 16 weeks Retesting
Normal weight with diabetes pioglitazone first, tirzepatide second	Tirzepatide	Baseline testing Intervention with pioglitazone for 16 weeks Retesting Washout for 5 weeks Intervention with tirzepatide for 16 weeks Retesting
Normal weight with diabetes pioglitazone first, tirzepatide second	Pioglitazone	Baseline testing Intervention with pioglitazone for 16 weeks Retesting Washout for 5 weeks Intervention with tirzepatide for 16 weeks Retesting

Primary Outcome Measures

Name	Time	Method
Insulin resistance in normal weight women with diabetes compared to those with no diabetes	Baseline measures comparison between the groups	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.
Adipocyte function in women with normal weight diabetes as compared with those without diabetes	Baseline comparisons	Adipocyte function will be measured as percent small adipocytes and peak diameter adipocytes from the fat biopsies.
Fat storage in women with normal weight diabetes compared to those without diabetes	Baseline comparisons between the groups	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.

Secondary Outcome Measures

Name	Time	Method
Effect of adipose-directed therapy pioglitazone on HbA1c in both men and women with normal weight diabetes	16 weeks	Hemoglobin A1C measures will be compared baseline to end of 16 weeks of intervention with pioglitazone.
Effect of pioglitazone in insulin resistance in both men and women.	16 weeks	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.
Fat storage in men with normal weight diabetes (NWD) compared to those without diabetes (NWC).	Baseline comparisons between the groups	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.
Adipocyte function in men with normal weight diabetes as compared with those without diabetes	Baseline comparisons	Adipocyte function as measured by percent small adipocytes and peak diameter adipocytes from the fat biopsies.
Insulin resistance in normal weight men with diabetes compared to those with no diabetes	Baseline measures comparison between the groups	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.
Insulin secretion in men and women with normal weight diabetes compared to those without diabetes	Baseline measured compared between the groups	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.

Trial Locations

Locations (1)

Stanford University, Clinical and Translational Research Unit (CTRU); 🇺🇸 Stanford, California, United States