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The Use of Farnesoid X Receptor (FXR) Agonists and 11 Beta-Hydroxysteroid Dehydrogenase Type 1 Inhibitors in Diabetes Management

Oct 29, 2010
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By Iriny Nashed, PharmD Candidate

Just when we thought we had it all figured out when it comes to diabetes management, we find there are not only new drugs on the horizon but new classes of medications that might just change the entire outlook on diabetes treatments.

We’ve all seen how a drug such as Welchol®, a bile acid sequestrant, has been successful in treating diabetes. But a new class called Farnesoid X receptor (FXR) agonist, a nuclear hormone receptor that is found in the liver, intestines, adrenal glands and kidneys, could be superior because studies have shown that an important role for nuclear receptors is regulating lipid and carbohydrate metabolism, and fibrosis as well as inflammation. FXR has an important role in bile acid and triglyceride homeostasis. The receptor negatively regulates bile acid synthesis by decreasing the expression of cholesterol-7α-hydroxylase (Cyp7a1), the rate-limiting enzyme of bile acid synthesis. The effect on glucose control is less clear, but it is believed that by reducing triglyceride concentration in the liver insulin resistance may improve³.

Since FXR controls triglyceride metabolism and because hypertriglyceridemia is associated with Type 2 diabetes, bile composition is altered in diabetic patients. Researchers noted this change and began to look at a potential link between FXR and glucose metabolism². The first indication that FXR had a role to play in diabetes came from the observation that hepatic FXR expression is reduced in animal models of diabetes. Once the FXR was activated in FXR deficient mice there was an improvement in both impaired glucose tolerance and decreased insulin sensitivity⁴.

FXR agonists not only have demonstrated effectiveness in treating diabetes, but some studies have also shown that they may help prevent diabetic nephropathy. In diabetic kidney disease, altered lipid metabolism through sterol regulatory element binding proteins (SREBPs) is a factor and some studies have shown that FXR modulates renal SREBP-1 expression⁸. In trial results published in August, this theory was tested by inducing insulin deficiency and hyperglycemia in mice with streptozotocin, a chemical that is toxic to the insulin-producing beta cells of the pancreas. The mice with streptozotocin-induced hyperglycemia were treated with the FXR agonist INT-747 for 12 weeks. The study demonstrated that treatment with the FXR agonist INT-747 improves renal injury by decreasing proteinuria, glomerulosclerosis and tubulointerstitial fibrosis and modulating renal lipid metabolism, macrophage infiltration and renal expression of SREBPs, profibrotic growth factors and oxidative stress enzymes in diabetic strain⁸. Overall these findings indicate that there is a critical role for FXR agonists in the development of diabetic nephropathy and that FXR activation prevents nephropathy especially in Type 1 diabetes⁸.

The next class in line is called, 11 Beta-hydroxysteroid dehydrogenase Type 1 (11-βHSD1) inhibitor. 11-βHSD1 is an enzyme used to convert cortisone to cortisol. Cortisol is a steroid hormone produced by the adrenal gland and is usually released in response to stress and/or to low levels of blood glucocorticoids. When the blood sugars are low, its main function is to increase blood glucose through gluconeogenesis and aid in fat, protein and carbohydrate metabolism. This enzyme is mainly expressed in both liver cells as well as fat cells¹. There is data that suggests that the inhibition of 11-βHSD1 (INCB-13739) may provide a key treatment in reducing hyperglycemia and macrovascular disease risk in Type 2 diabetes. In trials where mice were engineered with increased 11-βHSD1 activity in the adipose tissue they exhibited increased weight and visceral fat mass, insulin resistance, hyperlipidemia, hyperphagia, and hypertension⁵. But when glucocorticoid levels were reduced through 11-βHSD1 gene deletion or inhibition, that was enough to push resistance towards weight gain on a high-fat diet, improve glucose tolerance and insulin sensitivity^1,5 and reduce the risk of dyslipidemia in rodents⁵. In a trial using human subjects, patients who were not controlled on metformin therapy with A1c between 7-11% were put on different doses of 11- βHSD-1 inhibitor and after the 12 week trial, the group taking 200 mg of 11-βHSD-1 inhibitor saw a 0.6% decrease in A1c when compared to placebo but with an increased level of nausea compared to other groups⁵. INCB-13739 is currently being developed by Incyte Corp⁶.

Since 11-βHSD-1 has an effect on cortisol levels, a study done in 2008 tested whether circadian rhythms had an effect on the efficacy of when the 11- βHSD-1 inhibitor was administered. Interestingly, the dose given in the afternoon was the most efficacious due to the higher plasma corticosterone level in the body at that time⁷.

Currently, there is a new trial recruiting patients in Switzerland to test the effects of FXR activation on hepatic lipid and glucose metabolism in patients with metabolic syndrome and hypertriglyceridemia. A similar trial is also recruiting in Germany but is testing for the 11-βHSD1 change in activity in metabolic syndrome.

It will be interesting to see what the future may hold for these new classes. However, at the pace the FDA is approving new medications it might be a while before we see these drugs on the market despite the various trials that have been done to prove their success in treating diabetes.

Bibliography:

Balasubramanyam, Ashok MD. “Disentangling the Threads of the Metabolic Syndrome.” Medscape Pharmacists (2004).
Claudel, Thierry; Staels, Bart; Kuipers, Folkert. “The Farnesoid X Receptor: A Molecular Link Between Bile Acid and Lipid and Glucose Metabolism.” ATVB: American Heart Association (2005): 2020-2030.
Duran-Sandoval, Daniel; Mautino, Gisèle. “Glucose Regulates the Expression of the Farnesoid X Receptor in Liver.” Diabetes Care 53 (2004): 890-898.
Lefebvre, P; Cariou, B Et al. “Role of bile acids and bile acid receptors in metabolic regulation.” Physiological Reviews 89 (2009) :147-91.
Rosenstock, J; Banarer, S Et al. “The 11-beta-hydroxysteroid dehydrogenase type 1 inhibitor INCB13739 improves hyperglycemia in patients with type 2 diabetes inadequately controlled by metformin monotherapy.” Diabetes Care (2010).
Tiwari, A. “INCB-13739, an 11beta-hydroxysteroid dehydrogenase type 1 inhibitor for the treatment of type 2 diabetes.” IDrugs (2010): 266-75.
Veniant, MM; Hale, C Et al. “Time of the day for 11beta-HSD1 inhibition plays a role in improving glucose homeostasis in DIO mice.” Diabetes, Obesity and Metabolism (2009): 109-17.
Wang XX, Jiang T, Shen Y, Et al. “Diabetic Nephropathy is Accelerated by Farnesoid X Receptor Deficiency and Inhibited by Farnesoid X Receptor Activation in a Type 1 Diabetes Model .” Diabetes Care (2010).