Pioglitazone & TirzepatideNormal-weight Diabetes: Adipocyte-directed Therapy With Pioglitazone or Tirzepatide

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.

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