The effect of single doses of pramlintide on gastric emptying of two meals in men with IDDM

Abstract

Gastric emptying is a significant determinant of the blood glucose response after an oral carbohydrate load [1] due to the key role this process plays in regulating the rate of nutrient delivery to the small intestine. Gastric emptying may therefore be a previously under-recognized contributor to variations in glycaemic control in diabetes mellitus. Faster rates of gastric emptying have been reported not only in rat models of insulin-dependent diabetes mellitus (IDDM) [2,3] but also in patients with IDDM [4,5] and recent studies suggest that modulation of gastric emptying could be used to improve glycaemic control in patients with diabetes [6].Amylin is a 37 amino acid polypeptide co-secreted with insulin by pancreatic beta cells, in response to nutrient stimuli. It circulates at concentrations of 5±30 pmol/l in normal subjects. IDDM patients are not only insulin deficient but also amylin deficient [7,8]. Amylin concentrations in IDDM patients range from the lower end of the normal range to undetectable and do not increase in response to a glucose load. The peptide pramlintide is a stable trisub- Diabetologia (1998) Summary In a previous study we have shown that an intravenous infusion of pramlintide (an analogue of human amylin) delayed gastric emptying, but the dose of pramlintide was supraphysiological in relation to the amylin response to food in non-diabetic subjects. The purpose of this study was to examine the dose response relationship of subcutaneous injections of pramlintide on gastric emptying and to determine whether administration of the drug before one meal has an impact on the subsequent meal. Eleven men with insulin-dependent diabetes mellitus were studied in a double-blind, randomised, four-way crossover design. None had autonomic neuropathy. Euglycaemia was maintained overnight before the study day. At 30 min the patients self-injected their usual morning insulin and at 15 min they injected the study drug (either placebo or 30, 60 or 90 mg pramlintide) subcutaneously. At 0 min they ate a standard meal consisting of a pancake, labelled with 99m Tc, and a milkshake containing 3-ortho-methylglucose (3-OMG). Gastric emptying images were obtained for the next 8 h. At 240 min the subjects ate a similar meal, but on this occasion the pancake was labelled with 111 In. All three doses of pramlintide delayed emptying of the solid component of the first meal (p < 0.004) with no significant difference between the drug doses. There were no differences between placebo and pramlintide after the second meal. All three doses of pramlintide resulted in a prolongation in the time to peak plasma 3-OMG level (p < 0.0001) after the first meal but there was no difference after the second meal. [Diabetologia (1998) 41: 577±583]

A Randomized Study and Open-Label Extension Evaluating the Long-Term Efficacy of Pramlintide as an Adjunct to Insulin Therapy in Type 1 Diabetes

“…Consistent with preclinical findings of the physiologic role of amylin in postprandial glucose homeostasis (9,10), previous clinical trials in patients with type 1 diabetes have shown that mealtime amylin replacement with pramlintide slows the rate of nutrient delivery from the stomach to the small intestine (15,16) and prevents an abnormal increase in glucagonemia after meals (17,18). Collectively, these effects result in a marked improvement in postprandial glycemic excursions compared with prandial injections of insulin alone (17,19).…”

“…First, a slowing of the rate of nutrient delivery from the stomach to the small intestine was demonstrated (15,16). Second, prevention of an abnormal postprandial increase in plasma glucagon was demonstrated (17,18).…”

Impaired Hyperglycemia-Induced Delay in Gastric Emptying in Patients With Type 1 Diabetes Deficient for Islet Amyloid Polypeptide

“…Healthy subjects were studied on two occasions (euglycemia and hyperglycemia), and type 1 diabetic subjects were studied on three occasions (euglycemia and hyperglycemia with and without 30 g pramlintide [Amylin Pharmaceuticals, San Diego, CA], injected subcutaneously in the lower abdominal wall with the meal, which was designed to replace absent IAPP secretion as indicated by its effects on gastric emptying compared with hyperglycemia in healthy subjects estimated from previous studies [13,14]). Healthy subjects received only placebo injections.…”

Effects of a Patient Education Support Program on Pramlintide Adherence

“…Pramlintide has multiple mechanisms of action [16][17][18] that decrease postprandial glycemia, resulting in improved glycemic control with less insulin and the potential for weight loss.…”