PROGRESSIVE IMPAIRMENT OF GASTRODUODENAL MYOELECTRICAL AND MOTOR ACTIVITIES AND AUTONOMIC FUNCTION DURING THE DEVELOPMENT OF TYPE 2 DIABETES IN RATS

Background & Aim: Gastrointestinal (GI) dysmotility is common in diabetes. However, little is known on the longitudinal alternations of GI motility during the development of type 2 diabetes mellitus (T2DM). This study aimed to explore the progressive impairment of gastric and duodenal slow waves in the progression of T2DM in rats and the mechanisms involving hyperglycemia and autonomic function. Methods: Twenty-four adult rats were fed with regular chows for 2 weeks (RC-2) and then high-fat diet (HFD) for 4 weeks, followed with streptozotocin (STZ, 35 mg/kg, diabetic stage). Gastric and duodenal slow waves were recorded via chronically implanted serosal electrodes longitudinally at different time points, including n-weeks after RC, HFD and STZ (RC-n, HFD-n and STZ-n), together with blood samples. The oral glucose tolerance test (OGTT) was also performed at various time points. Six weeks after STZ injection, gastric emptying (GE) and whole gut transit time (WGTT) were assessed in the T2DM rats and 8 normal rats. Results: 1) The percentage of normal slow waves (%NSW) in both stomach and duodenum was progressively decreased in the fasting state, starting from one week (duodenum, Fig.1B) or 4 weeks (stomach, Fig.1A) after HFD (pre-diabetes), whereas the decrease in the postprandial state appeared after STZ (diabetes). 2) A significant postprandial increase in the power of slow waves was noted in both stomach and duodenum after RC and one-week of HFD; this increase was, however, blunted starting from 2 weeks after HFD and persisted after STZ. 3) %NSW in the fasting state was negatively correlated with fasting blood glucose (BG) during the entire study period (stomach: r=-0.323, P<0.01; duodenum: r=-0.534, P<0.0001). 4) During the OGTT, the regularity of duodenal slow waves was positively correlated with BG in rats with HbA1c <5.0 (Fig.2A, C) but negatively correlated with BG in rats with HbA1c ≥ 5.0 (Fig.2B, D). 5) Six weeks after STZ, gastric emptying was delayed (P<0.05) and the WGTT was prolonged (P<0.05) in comparison with normal rats. 6) In comparison with baseline (RC-2), plasma pancreatic polypeptide (reflecting vagal activity) was progressively decreased (P<0.05, at HFD-4, STZ-2, STZ-6), whereas plasma norepinephrine (reflecting sympathetic activity) was progressively increased (P<0.05, at HFD-4, STZ-2, STZ-6). Conclusions: Both gastric and duodenal slow waves are progressively impaired during the development of diabetes in rats, reflected as a decrease in their regularities and blunted postprandial responses. The negative correlation between the regularity of slow waves and BG in both fasting and postprandial states suggests the role of hyperglycemia in slow wave dysrhythmia in diabetic rats. Autonomic function is also progressively impaired during the development of diabetes (Partially supported by an NIH grant (R01DK131524)).