Investigators propose to examine the effect of 12 weeks of Linagliptin, a diabetes drug, treatment on inflammation as well as vascular and mitochondrial function in diabetic patients. Investigators hypothesize that Linagliptin will reduce the proinflammatory state, improve endothelial function, increase the blood flow at the muscle microcirculation level and improve mitochondrial function. In this study, investigators will perform tests that evaluate the function of small and large blood vessels by employing ultrasound and laser doppler techniques. In addition MRI scans that evaluate the mitochondrial function of the lower extremity muscles at rest and during exercise will also be employed. Forty subjects with Type 2 diabetes will be studied for twelve weeks and half of them will be randomly assigned to receive linagliptin while the other half will receive placebo. All tests will be performed at the beginning and the end of the study.

Inclusion Criteria:

• Patients with T2DM whose medical or lifestyle treatment regimen is stable and not expected to be changed during the study period. Patients will be considered stable on their treatment regimen if there have not been any changes in the type of their antidiabetic medications over the past 3 months and/or there have not been any changes in their blood glucose levels that have caused them to see their health care provider more often than usual over the preceding three months. The diagnosis of T2DM will be according to the American Diabetes Association criteria. Subjects previously diagnosed with T2DM will not require confirmatory testing.
• Age 30-70 years
• Patients on insulin should be on a stable insulin regimen for at least 4 months prior to enrollment.
• Patients on antidiabetic treatment will be eligible if they are stable and no change in their treatment is planned for the next three months while they are in the study.
• HBA1c ≤ 10.0

Exclusion Criteria:

• Patient with unstable diabetes that has resulted in hyperosmolar coma, DKA, and/or documented increase or decrease in HbA1c of more than 2.0% within the previous 6 months

• Treatment with DPP4 Inhibitors or GLP-1 agonists. Patients who discontinued such treatment should be at least free for a 3-month period.

• Severe proliferative retinopathy that renders the subject legally blinded

• Previously intermittent claudication or diagnosed severe peripheral arterial disease requiring intervention.

• History of Deep Vein Thrombosis (DVT) within the past 3 months.

• Significant limb swelling due to lymphedema

• Previous diagnosis of severe gastroparesis diabeticorum due to autonomic neuropathy that has necessitated hospital admission

• Presence of non-healing foot ulceration due to severe peripheral diabetic neuropathy

• History of pancreatitis

• Documented diabetic nephropathy manifested as macro-albuminuria before enrollment in the study, (2 of 3 urine specimens collected within a 3-6 month period with urine albumin> 300 ug/mg creatinine - according to the ADA position statement)

• Smokers. Smokers will be defined as any subject who reports tobacco use during the three months before to study enrollment.

• Active or uncontrolled cardiovascular disease as follows:

  1. Myocardial infarction, or angina within 12 months of study participation
  2. Arrhythmia (uncontrolled, highly symptomatic, requires treatment or life-threatening).
  3. Patients with congestive heart failure requiring pharmacologic management, particularly when accompanied by hypoperfusion and hypoxemia due to unstable or acute failure, are at increased risk of lactic acidosis.
  4. Stroke or transient ischemic attack within 12 months of study participation
  5. Uncontrolled hypertension: SBP> 180 mmHg or DBP> 105 mmHg (2 abnormal readings during visit)

• Liver disease (AST, ALT Alk Phos levels >2x upper normal limit) at the time of enrollment

• Renal disease (creatinine > 2 mg/dL and/or estimated GFR <30 mL/min, history of dialysis, nephrotic syndrome) at the time of enrollment.

• Severe dyslipidemia (triglycerides>600 mg/dL or cholesterol >350 mg/dL) Subjects with hypertriglyceridemia may be retested in 2-3 weeks as the values can fluctuate tremendously within a few days. In the event that the retested value allows the patient to be enrolled, a planned deviation will be submitted to the CCI.

• Any other serious chronic disease requiring active treatment.

• Pregnancy or Lactation

• Females of childbearing potential not using an effective form of birth control as determined by the investigators.

• Subjects on any of the following medications:

  1. Systemic (not inhaled) Glucocorticoids
  2. Antineoplastic agents
  3. Rifampin

• Patient is known to have a history of immunodeficiency diseases, including a positive HIV (ELISA and Western blot) and/or positive Hepatitis B surface antigen (HBsAg) or Hepatitis C test result in the past.

• History of drug or alcohol abuse within the 12 months prior to dosing or evidence of such abuse as indicated by the laboratory assays conducted during the screening or baseline evaluations.

• Acute or chronic metabolic acidosis, including diabetic ketoacidosis.

• History of hypersensitivity reaction to linagliptin (such as urticaria, angioedema, or bronchial hyperreactivity) or metformin.

• Contraindications to MRI: Medically unstable or hematologic, renal, or hepatic dysfunction, cardiac pacemaker, Intracranial clips, metal implants, or external clips within 10 mm of the head,

• Metal in eyes.

• Pregnant or nursing women -

• Claustrophobia.

12 weeks

whole study period