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Title: The role of prandial pramlintide in the treatment of adolescents with type 1 diabetes

Author
item RODRIGUEZ, LUISA - BAYLOR COLLEGE OF MEDICIN
item MASON, KIMBERLY - BAYLOR COLLEGE OF MEDICIN
item Haymond, Morey
item HEPTULLA, RUBINA - BAYLOR COLLEGE OF MEDICIN

Submitted to: Pediatric Research
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 7/24/2007
Publication Date: 12/1/2007
Citation: Rodriguez, L.M., Mason, K., Haymond, M.W., Heptulla, R.A. 2007. The role of prandial pramlintide in the treatment of adolescents with type 1 diabetes. Pediatric Research. 62(6):746-749.

Interpretive Summary: In healthy people, an "after meal" blood sugar level is very carefully controlled with insulin (the hormone that lowers blood sugar) and glucagon (hormone that raises blood sugar) playing a key role in maintaining this careful balance. In persons with Type 1 diabetes (T1DM), there is a lack of insulin and failure of glucagon suppression, which leads to high blood sugars right after a meal. This makes it very difficult to have normal blood sugars when someone has T1DM. This imbalance may be due to another hormone called amylin, which may be too low in people with T1DM. Amylin is a newly discovered hormone that is made and released from the same cells in the pancreas which make and release insulin. It is thought to have its effects by blocking glucagon and by slowing digestion in the stomach (delaying the absorption of sugar and other nutrients). Pramlintide is man-made amylin and has been shown to improve blood sugars levels in people with diabetes after they eat a meal. The Diabetes Control and Complications Trial (DCCT) showed that improving blood sugar control for individuals with Type 1 diabetes (T1DM) stopped or delayed the onset of long-term complications. We compared a shot of pramlintide with a short infusion (2 hours) of pramlintide in teenagers with type 1 diabetes (T1DM). Eight subjects completed the study. Insulin doses were kept the same in both studies. Several other important hormones levels were also collected during the studies. We found that that the short infusion did not cause blood sugar levels to go too low. However, a shot of the drug caused low blood sugars in two subjects. The injection of pramlintide seemed to lower glucagon levels in the blood and cause the stomach to digest food more slowly. These two effects were not seen with the short infusion. We conclude that an injection of pramlintide may result in an increase in risk of low blood sugar levels immediately after a meal. Further changes in pramlintide delivery are indicated before it can be safely used in children.

Technical Abstract: Pramlintide, a synthetic analog of amylin, improves postprandial hyperglycemia. We compared subcutaneous (s.c.) pramlintide injection with square wave pramlintide infusion in adolescents with type 1 diabetes (T1DM). Eight subjects with T1DM underwent two randomized studies. Subcutaneous pramlintide (dose = 5 mug/unit of insulin) bolus was given one time, and another time the same dose was given as a 120-min s.c. infusion. Insulin dose was constant between studies. Gastric emptying was assessed with oral acetaminophen and [l-C]glucose in meal. Plasma glucagon, pramlintide, and insulin concentrations were measured. Insulin concentrations (p < 0.99) between pramlintide injection versus infusion were similar; however, glucose concentrations were different (p < 0.0001), with the absence of hypoglycemia during pramlintide infusion [AUC (0-120 min) -0.07 +/- 0.2 versus 1.05 +/- 0.24 mg * h/dL (p < 0.0088)]. Insulin-only administration resulted in postprandial hyperglycemia and late postprandial hypoglycemia (p < 0.0001). Two subjects experienced hypoglycemia with pramlintide injection. Pramlintide bolus caused pronounced glucagon suppression (p < 0.0003) and delayed gastric emptying as ([13CO2] p < 0.0003 and acetaminophen p < 0.01) compared with infusion. We conclude that pramlintide bolus may result in an increase in risk of immediate postprandial hypoglycemia. Further modifications in pramlintide delivery are indicated before it can be safely used in children.