Hemin may be key to improved gastroparesis therapies

Gastroparesis is a syndrome marked by slow gastric emptying and symptoms such as nausea, vomiting, bloating, early satiety and abdominal pain. Long associated with type 1 diabetes, the syndrome is now increasingly associated with type 2, and affects between 5 and 12 percent of diabetes patients.

Gastroenterologist Gianrico Farrugia, M.D., of Mayo Clinic in Rochester, Minn., explains, "In patients with diabetes, gastric motor dysfunction may result from autonomic neuropathy, enteric neuropathy involving excitatory and inhibitory nerves, abnormalities of the pacemaker cells, abnormalities of the interstitial cells of Cajal (ICC), acute fluctuations in blood glucose levels, incretin-based medications used to normalize postprandial blood glucose concentration, and psychosomatic factors."

Much of the current research focuses on the interstitial cells of Cajal, which act as intestinal pacemakers for smooth muscle function. They also amplify neuronal signals, act as mechanosensors and set the smooth muscle membrane potential gradient. Both human and animal models demonstrate loss of these cells in diabetic and idiopathic gastroparesis.

Normal gut function requires a balance between processes that injure ICC and processes that generate and maintain them. In people with diabetic gastroparesis, the balance shifts toward factors that damage ICC, including relative insulinopenia and deficiency of insulin-like growth factor-1 (IGF-1), both of which can cause smooth muscle atrophy.

A critical factor is oxidative stress resulting from low levels of heme oxygenase-1 (HO-1), an important protector against oxidative injury.

Dr. Farrugia explains, "When the mechanisms that normally counteract oxidative stress are impaired, especially upregulation of heme oxygenase-1, ICC are lost and gastric emptying is delayed. In mouse models, restoring HO-1 prevents and even reverses these cellular changes and restores normal gastric function."

Macrophage switching

In the stomach wall, HO-1 expression occurs in a particular subset of macrophages — CD206-positive M2 macrophages — whose cytoprotective effect on ICC appears related to the production of small amounts of carbon monoxide.

When the upregulation of HO-1 is lost, M2 macrophages are replaced by proinflammatory M1 macrophages. These cells, which do not produce carbon monoxide, are associated with ICC damage and the development of delayed stomach emptying. Thus, the upregulation of HO-1 in M2 macrophages seems critical to the prevention of diabetes-related gastroparesis.

Clinical trials

In mouse studies, hemin, a biological product of red blood cells, has been shown to boost the production of HO-1, thereby reducing oxidative stress, allowing repair of the ICC network and normalizing gastric function. Motivated by the results in mice, Dr. Farrugia and colleagues showed that HO-1 also can be pharmacologically upregulated in humans.

"In our experience, intravenous hemin, which is approved for treating acute porphyria, increased plasma HO-1 protein concentrations four- to five-fold and HO-1 activity about 15-fold relative to baseline at 24 and 48 hours in healthy subjects," he says.

Based on these findings, Dr. Farrugia and colleague Adil E. Bharucha, MBBS, M.D., are recruiting patients with diabetic gastroparesis for a study comparing the effects of intravenous hemin and placebo. Patients who have moderately severe symptoms and delayed gastric emptying with no structural cause for symptoms within the past 12 months are eligible to participate.

The hope is that the clinical trial may lead to an effective medication for gastroparesis — one that doesn't just manage symptoms but actually targets the cause of the disease.

The need for better treatments is especially critical now, Dr. Farrugia says, because the incidence of gastroparesis is increasing. The number of hospitalizations for the disorder grew by nearly 158 percent from 1995 to 2004. He notes, "The vast majority of patients are young women of childbearing age. This disease causes tremendous disruption in patients' lives and in the lives of their families, and none of the treatments we have are ideal."

To enter a patient in this study, contact Shannon L. Thieke, study coordinator, at thieke.shannon@mayo.edu or 507-538-3883.

For more information

A Pilot Study of Hemin Therapy for Gastroparesis (Diabetes Mellitus) ClinicalTrials.gov