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

Prior treatment

• Prior Use of Pioglitazone: Participants who have previously used pioglitazone are excluded to avoid confounding effects of prior drug exposure.
• 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.

Other illness

• 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.
• Congestive Heart Failure or Fluid Overload History: These conditions are exclusionary due to the risk of fluid retention with pioglitazone.
• 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.
• 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.
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Lab values

• 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.

Other

• Pregnancy or Lactation: Women who are pregnant, planning to become pregnant, or breastfeeding are excluded due to potential risks to the fetus or infant.

• 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. -