Glycemia and Gastric Emptying Disturbances in Diabetes

Abstract and Introduction

Abstract

Background & Aims: Hyperglycemia is implicated as a major risk factor for delayed gastric emptying in diabetes mellitus and vice versa. However, the extent to which hyperglycemia can affect gastric emptying and vice versa and the implications for clinical practice are unclear. We systematically reviewed the evidence for this bidirectional relationship and the effects of pharmacotherapy for diabetes on gastric emptying.

Methods: Full-length articles investigating the relationship between diabetes mellitus and gastroparesis were reviewed primarily to quantify the relationship between blood glucose concentrations and gastrointestinal sensorimotor functions, particularly gastric emptying, and gastrointestinal symptoms. The effects of drugs and hormones that affect glycemia on gastrointestinal sensorimotor functions were also evaluated.

Results: Acute severe hyperglycemia delayed gastric emptying relative to euglycemia in type 1 diabetes; the corresponding effects in type 2 diabetes are unknown. Limited evidence suggests that even mild hyperglycemia (8 mmol/L) can delay gastric emptying in type 1 diabetes. Long-term hyperglycemia is an independent risk factor for delayed gastric emptying in type 1 diabetes. There is little evidence that delayed gastric emptying causes hypoglycemia in diabetes and no evidence that improved control of glycemia improves gastric emptying or vice versa. Glucagon-like peptide-1 agonists but not dipeptidylpeptidase-4 inhibitors given acutely delay gastric emptying, but tachyphylaxis may occur.

Conclusions: Although acute severe and chronic hyperglycemia can delay gastric emptying, there is limited evidence that delayed gastric emptying is an independent risk factor for impaired glycemic control or hypoglycemia in diabetes. The impact of improved glycemic control on gastric emptying and vice versa in diabetes is unknown.

Introduction

Diabetes mellitus has been associated with delayed and, to a lesser extent, rapid gastric emptying (GE).^[1,2] Delayed GE is associated with upper gastrointestinal (GI) symptoms, impaired quality of life, poor nutrition, and increased morbidity and mortality. It has also been suggested that GE disturbances may impair glycemic control in diabetes.^[3] Several abnormalities, including autonomic neuropathy, enteric neuropathy involving excitatory and inhibitory nerves, abnormalities of interstitial cells of Cajal (ICC), acute fluctuations in blood glucose, and other considerations, such as incretin-based medications used to normalize postprandial blood glucose and psychosomatic factors, may be responsible for gastric motor dysfunction in diabetes.^[2] Studies in animal models of diabetes mellitus suggest that hyperglycemia affects the enteric nervous system and GE. For example, compared with normoglycemia (5 mmol/L glucose), hyperglycemia (20 mmol/L glucose) increased apoptosis of rodent enteric neurons in culture.^[4] Spontaneously diabetic non-obese diabetic (NOD) mice and streptozocin-diabetic mice developed reduced neuronal nitric oxide synthase expression and delayed GE of liquids.^[5] In NOD mice, hyperglycemia for approximately 2 months was also associated with depletion of the ICC.^[6]

However, these effects of hyperglycemia on enteric neurons^[4] or GE in NOD mice and streptozocin-diabetic mice^[5] were not reversed by restoring normoglycemia, albeit for a brief duration. In contrast, treatment with insulin or sildenafil^[5] or hemin^[7] restored GE in NOD mice. Together, these data indicate that hyperglycemia is but one factor that affects the enteric nervous system in diabetes. Restoring normoglycemia may not be sufficient to interrupt or reverse the signaling cascades that are altered in diabetes.

Much attention has focused on the impact of hyperglycemia on GE in humans. Fewer studies have evaluated the contribution of delayed GE to poor glycemic control.^[3] Prompted in part by recent studies,^[8,9] this review, which is geared toward gastroenterologists, focuses on the bidirectional relationship between hyperglycemia and gastric functions, the effects of pharmacologic therapy for diabetes on GE, and the implications of these findings to clinical practice.

Table 1. Summary of the Evidence of the Relationship Between Delayed GE and Hyperglycemia in Diabetes
Concept	Evidence
Acute hyperglycemia delays GE in diabetes	Type 1 diabetes: Marked hyperglycemia (blood glucose of 16–20 mmol/L) delayed gastric emptying in diabetes.^13,14 The magnitude of delay varied between studies. Modest hyperglycemia (8 mmol/L) also delayed GE¹⁵; however, the effects were small and not greater than the intraindividual day-to-day coefficient of variation for GE in type 1 diabetes.¹⁶ Type 2 diabetes: Not assessed.
If blood glucose is greater than 275 mg/dL on the morning of the GE study, the glucose should be lowered with insulin to 275 mg/dL before commencing the test.¹⁸	Type 1 diabetes: This recommendation is based on the finding that acute hyperglycemia delayed GE.^13,14 However, there is no evidence that reducing blood glucose improves GE in patients with severe hyperglycemia. Type 2 diabetes: An inverse correlation between fasting glucose concentration and GE was observed.⁸ Among 9 of 90 GE studies preceded by a blood glucose concentration >275 mg/dL, 2 had normal, 2 had delayed, and 5 had rapid GE.
Improved long-term control of glycemia may improve GE in diabetes	Type 1 diabetes: Not assessed. Type 2 diabetes: Acute and long-term (6 months) improvement in glycemia did not affect GE in one study⁸ but markedly reduced GE in another study of patients with poorly controlled type 2 diabetes and delayed GE.³⁶
Delayed GE predisposes to hypoglycemia in diabetes	Although delayed GE was a risk factor for hypoglycemia in 1 study, patients with delayed GE also had other complications of diabetes.⁷² There is no evidence that delayed GE is an independent risk factor for unexplained hypoglycemia. The effect of accelerating GE on glycemic control has not been evaluated.