The Effects of Liraglutide on Sudomotor Function and Inflammation in Type 2 Diabetes

Inclusion Criteria:

1. established type 2 diabetes (diabetes duration of >6 months and <10 years).

2. Age 18-80 years

3. HbA1c at screening ≤ 10%

4. Subjects on stable (≥3 months prior to Screening) Standard of Care background diabetictherapy. Diabetic treatment regimens include diet and exercise alone or in associationwith oral anti-diabetic drugs (monotherapy or combinations) and/or long-actinginsulin.

Exclusion Criteria:

1. Presence of type 1 diabetes mellitus (defined as C-peptide <1 ng /ml, <35y and proneto ketoacidosis)

2. Treatment with rapid-acting or short-acting insulin within the last 3 months

3. Proliferative retinopathy or maculopathy requiring acute treatment

4. Impaired renal function , defined as serum creatinine ≥ 125 µmol/L (≥1.4 mg/dL) formales and ≥ 110 µmol/L (≥1.24 mg/dL) for females

5. Impaired liver function, defined as aspartate transaminase (AST) or alaninetransaminase (ALT), ≥ 2.5 times the upper limit of normal

6. Presence of clinically significant peripheral or autonomic neuropathy that is clearlyof non-diabetic origin

7. Uncontrolled treated/untreated hypertension (systolic blood pressure (BP) ≥180 ordiastolic blood pressure (BP) ≥100 at screening)

8. Clinically significant active macrovascular disease including myocardial infarction orcerebrovascular event within the past 6 months. Other exclusions include coronaryartery bypass graft or coronary angioplasty in the previous 3 months, unstable anginapectoris (chest pain at rest, worsening chest pain, or admission to the emergency room (ER) or hospital for chest pain) within the previous 3 months, and/or congestive heartfailure (NYHA Class III-IV)

9. Subjects known to be Hepatitis B surface antigen or Hepatitis C antibody positive withactive hepatitis.

10. Active infection (e.g., human immunodeficiency virus (HIV), hepatitis), or a historyof severe infection during the 30 days prior to screening

11. Evidence of immunocompromised status, including but not limited to individuals whohave undergone organ transplantation, who are known to be HIV positive, or who aretaking immunosuppressive drugs or chronic systemic corticosteroid treatment.

12. Major surgical procedure during the 30 days prior to screening

13. Diagnosis and/or treatment of malignancy (except for basal cell or squamous cell skincancer, in-situ carcinoma of the cervix, or in-situ prostate cancer) within the past 5years

14. Known clinically significant gastric emptying abnormality (e.g. severe gastroparesis),or history of gastric bypass (bariatric) surgery

15. Thyroid stimulating hormone (TSH) outside of normal limits at screening, or presenceof a thyroid nodule detected on physical examination that has not been fully evaluated

16. Thyroid hormone therapy that has not been stable for ≥6 weeks prior to Screening

17. Personal or family history of medullary thyroid carcinoma or multiple endocrineneoplasia type 2 (MEN-2)

18. History of acute or chronic pancreatitis

19. Subjects taking medications that are known to affect autonomic function need to be ata stable dose of those medications ≥ 3 months prior to inclusion in the study

20. Other clinically significant, active (over the past 12 months) disease of thegastrointestinal, pulmonary, neurological, genitourinary or hematological system that,in the opinion of the investigator, would compromise the subject's participation inthe study, might confound the results of the study or pose additional risk inadministering the study drug

21. Recurrent severe hypoglycemia and/or hypoglycemia unawareness.

22. Concurrent participation in another clinical trial with use of an experimental drug ordevice within 30 days of study entry.

23. Known or suspected history of alcohol or substance abuse

24. Mental incapacity, unwillingness or language barrier precluding adequate understandingof or cooperation with the study.

25. Women of childbearing potential (WOCBP*) who are pregnant, breast-feeding or intend tobecome pregnant

26. WOCBP* must have a negative pregnancy test at Screening and must agree to use adequatecontraceptive methods** during the study and for one additional menstrual cyclefollowing the end-of-treatment visit

27. Known or suspected hypersensitivity to study product(s) or related products

28. Patients with low vitamin B12 levels will be excluded

29. Current use or use 6 months prior to study participation of dipeptidyl peptidase-4 (DPP-4) inhibitors or glucagon like peptide-1 (GLP-1) agonists will be excluded

30. Liraglutide has not been studied in combination with prandial insulin. Patients whouse prandial insulin may be excluded