1. Diabetes Update Division of Endocrinology Department of Medicine Wayne State University Medical School Detroit, Michigan Part 3 of 3

2. 2 Insulin Analogs u Analogs are more predictable and more reliable and consistent in action. Less chance of hypoglycemia. u Rapid Acting: -Humalog (Lispro) -Humalog (Lispro) -Novolog (Aspart) -Novolog (Aspart) -Apidra (Glulisine) -Apidra (Glulisine) u Long Acting (Basal): - Lantus (Glargine) - Lantus (Glargine) - Levemir (Detemir) - Levemir (Detemir)  Mixes: Novolog 70/30 and Humalog 75/25 & 50/50

3. 3 Insulin analogs Regular insulin Peak Time = 80 – 120 min Peak Time = 40 – 50 min Capillary membrane Subcutaneous tissue Dissociation and Absorption of Analogs

4. 4 0 2468 10 12141618202224 Plasma Insulin Levels Hours NPH ( 12–16 hr ) Regular ( 6–8 hr ) Glargine/Detemir ( ~24 hr ) Aspart, Lispro, Glulisine ( 4–5 hr ) Profiles Human Insulin and Analogs Based on Rosenstock J, Wyne K. In: Goldstein BJ, Muller-Wieland D, eds. Textbook of Type 2 Diabetes. 2003: 131-154.

5. 5 Principles of Insulin Therapy

6. 6 Newer Directions The role of Dopamine in type 2 Diabetes The use of constant glucose monitors (CGMS).

7. Proposed mechanism of action of Bromocriptine in relation to type 2 DM Diabetes patients may have low morning levels of hypothalamic dopamine, which is thought to lead to hyperglycemia and dyslipidemia Diabetes patients may have low morning levels of hypothalamic dopamine, which is thought to lead to hyperglycemia and dyslipidemia CYCLOSET (special form of bromocriptine) is thought to reset aberrant low morning hypothalamic dopaminergic activity, which may reset neuroendocrine metabolic control CYCLOSET (special form of bromocriptine) is thought to reset aberrant low morning hypothalamic dopaminergic activity, which may reset neuroendocrine metabolic control Decreased lipolysis in adipose tissue Decreased postprandial hepatic glucose output Decreased insulin resistance

8. 8 Glucose Fluctuations Are Not Adequately Measured by A1C Type 1 diabetes, N = 9 24-h CGMS glucose sensor data Data on file, Amylin Pharmaceuticals, Inc. 100 200 300 400 12 AM4 AM8 AM12 PM4 PM8 PM12 AM Glucose Concentration (mg/dL) 0 Mean A1C = 6.7%

10. Constant Glucose Monitoring Devices (CGMS)

11. 6.8% A1C

12. Indications for I Pro Insulin –requiring Diabetic Patient who is: Insulin –requiring Diabetic Patient who is: 1. Unacceptable HbA1c (not at goal) 1. Unacceptable HbA1c (not at goal) 2. Unexplained hypoglycemic episodes 2. Unexplained hypoglycemic episodes 3.Unexplained postprandial hyperglycemia. 3.Unexplained postprandial hyperglycemia. 4.Recurrent DKA 4.Recurrent DKA 5. Pregnancy. 5. Pregnancy. 6. Prior to pump therapy. 6. Prior to pump therapy.

13. Newer Therapies Newer DDP IV inhibitors. Newer Insulin: Insulin Degludec which a new long acting insulin given only 3 times a week. Newer GLP 1 agonists: given once a week. Newer agents such as inhibitors of renal tubular glucose re absorption. Newer smart pumps which communicate with CGMS monitors to deliver insulin more physiologically.

14. Summary Newer emphasis on post prandial sugars and therapies ot address those. Newer emphasis on replacing the defective incretin pathway in type 2 DM and hence achieving better glycemic control without hypoglycemia and without weight gain or even some weight loss. Newer understanding of the role of dopamine in type 2 DM and how to replace that with bromocriptine (centrally acting). Expanding the use of ambulatory constant glucose monitors The future is bright and promising!