Gastric emptying (GE), major contributor for postprandial hyperglycemia in type 1 diabetes mellitus (T1DM)

Postprandial (PP) hyperglycemia has been identified as an important risk factor for cardiovascular disease. The pancreatic hormone amylin is postprandially released and inhibits gastric emptying. T1DM are amylin deficient. Accordingly, we hypothesised that 1) in contrast to current view T1DM without neuropathy should have increased GE, 2) that the latter may be an important regulator of PP glycemia, 3) Amylin substitution should normalize GE in T1DM and reduce PP glucose excursion.

Methods: We studied 12 healthy subjects (HS) and 12 otherwise healthy subjects with T1DM each on two occasions after ingestion of a mixed 472 kcal meal with placebo or with the amylin analogue pramlintide sc. T1DM were infused with IV insulin such as to guarantee fasting euglycemia of 90mg/dl and to prevent PP hyperglycemia >180mg/dl to avoid effects of hyperglycemia on gastric emptying. Insulin was infused in an identical manner on both days. GE was determined by high-resolution scintigraphy (20 fr/min) over 330 min.

Results: PP glucose excursions in T1DM exceeded those of HS during the first 150 min after meal ingestion (AUC 416±64 vs. 307±24), and remained greater throughout, even though PP plasma insulin levels were 3-fold greater in T1DM. During this time period, GE was accelerated in T1DM (55.7±4.7 vs. 41.7±4.6% emptied, p<0.05). GE was closely correlated to peak plasma glucose excursions (r=0.75, p<0.001). Pramlintide delayed gastric emptying in HS (50% emptying at 225±16 vs. 177±10 min) and T1DM (217±10 vs. 149±10 min, both p<0.001). It abolished the increase of glycemia during the first 150 min in T1DM (–12±56 vs. 416±64) and markedly reduced overall PP glucose excursions in both HS and T1DM (195±21 vs. 283±25 and 119±73 vs. 389±75, both p<0.01). Although there was greater GE during the second part of the pramlintide experiment in T1DM, peak glucose levels did not exceed 138±8mg/dl in T1DM compared to placebo (178±9mg/dl, p<0.01).

Discussion: Gastric emptying is increased in T1DM and may be an important contributor to PP hyperglycemia. The amylin analogue pramlintide retards gastric emptying and significantly reduces PP hyperglycemia in T1DM. Modulation of gastric emptying is a promising tool to regulate intestinal nutrient flow and to reduce PP glycemia.

Keywords: Amylin, Glukose, Magenentleerung, Pramlintide, Typ 1 Diabetes mellitus