The hypothesis of the study is that those obese patients with type 2 diabetes mellitus who do not respond to the FDA approved dose of 120 mcg of pramlintide (Symlin®) 3 times daily with expected glucose control require higher than FDA approved dosage.

The primary objective of the study is to determine whether higher doses of pramlintide (Symlin®) in patients with type 2 diabetes mellitus control glucose better than the FDA approved dose of 120 mcg three times daily.

The secondary objectives include proving whether higher dose pramlintide (Symlin®) is more efficacious in causing weight loss and reduction in waist circumference than standard dose pramlintide (Symlin®),to determine whether blood levels of certain hormones correlate with need for higher dose therapy,and to determine whether or not the rate of common adverse effects exceeds the maximum FDA approved pramlintide (Symlin®) dose of 120 mcg three times daily.

Inclusion Criteria:

1. Age 18-80 years.
2. Type 2 diabetes mellitus.
3. Obese (BMI > 30 kg/m2), waist circ. >35" women, >40" men.
4. Basal insulin plus at least 2 injections of mealtime insulin daily or pre-mixed insulin.
5. On stable insulin dose for at least 3 mos (baseline + 20%, no minimum).
6. If pramlintide treated, on stable full dose for at least 3 months.
7. A1c > 7.0% and < 9.0%.
8. Women of childbearing age if using a reliable form of birth control.
9. Women of childbearing age if post tubal ligation or surgical menopause.
10. Able to consent.
11. Willing to perform self-monitoring of glucose.
12. Willing to attend study visits.
13. Written informed consent to participate in the study.
14. Agreement to maintain prior diet and exercise throughout the full course of the study.

Exclusion Criteria:

1. Age <18 or >80 years.

2. Confirmed gastroparesis or taking medications affecting gastric motility.

3. A1c <7.0% or >9.0%.

4. Recurrent severe hypoglycemia or hypoglycemic unawareness.

5. CHF.

6. Creatinine clearance <30 ml/min.

7. History of MI <6 mos prior to enrollment.

8. History of ventricular arrhythmia.

9. History of cancer or chemotherapy <6 mos prior to enrollment.

10. Laboratory abnormalities as follows:

    1. Liver enzymes >3X ULN.
    2. Hematocrit less than 30.
    3. Serum creatinine >2.5 mg/dl.
    4. Fasting triglycerides >500 mg/dl.

11. Cirrhosis.

12. Pregnancy or nursing.

13. Inability to provide consent.

14. Unwilling to attend study visits.

15. Unwilling to perform self-monitoring of glucose.

16. Chronic oral or parenteral glucocorticoid therapy (over one week of treatment) within 3 months prior to screening.

17. Investigational drug treatment within 3 months prior to screening.

18. Donation of blood, significant blood loss or transfusion within 3 months of screening.

19. History of acromegaly or Cushing's syndrome.

20. Use of prohibited concomitant medications.

21. Type 1 diabetes mellitus.

22. Acute metabolic complication (hyperosmolar state) <6 months prior to screening.