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Possible New Type 2 Diabetes Mellitus Therapy – A PPAR³ Sparing Thiazolidinedione

A TZD without the side-effects of increased fluid retention and edema, and changes in the vascular and circulating lipids; is that possible? Our current intern Amy Talmage, from the University of Florida College of Pharmacy has found some research that might separate out the players in this class.

Possible New Type 2 Diabetes Mellitus Therapy – A PPAR? Sparing Thiazolidinedione

Amy Talmage, University of Florida College of Pharmacy PharmD Candidate

A first in a new class of second-generation thiazolidinediones (TZDs), MSDC-0160 (Mitoglitazone®), is currently a participant in preliminary clinical trials with hopes to file an Investigational New Drug Application with the Food and Drug Administration (FDA) in late 2009.  The Metabolic Solutions Development Company (MSDC) is developing the new compound, a peroxisome proliferator-activated receptor-gamma (PPAR?) sparing TZD.  The scientists involved hope their new compound will exhibit the positive antidiabetic effects that traditional TZDs have without their negative cardiovascular effects.

Preliminary evidence from already performed clinical trials has shown that MSDC-0160 exhibits the beneficial effects of traditional TZDs without their negative side effects.  Results from the trials show that the new compound, when taken over a 28-day period, increases insulin sensitivity and lowers glucose without the risk factors for cardiovascular disease that traditional TZDs carry. 

Traditional TZDs are believed to exert their antidiabetic effects via activation of the nuclear receptor PPAR? which leads to improved insulin sensitivity and reduced metabolic inflammation.  Improved insulin sensitivity occurs when PPAR? are activated to regulate the gene transcription of insulin responsive genes that control carbohydrate and lipid metabolism.  Furthermore, reduced metabolic inflammation assists in reducing insulin resistance.  This is done by slowing the effects metabolic inflammation has on the pathology of diabetes mellitus.  Inappropriate oxidative metabolism at the cellular site of the energy-producing organelles, mitochondria, causes tissue inflammation.  Increased metabolic inflammation results in increased peripheral tissues’ resistance to insulin which in turn puts pressure on the pancreatic ?- cells to produce and secrete more insulin.  This overstimulation creates a “tiring” effect on the pancreatic ?- cells leading to a decline in function over time, which is part of the progressive pathology of Type 2 diabetes mellitus.  TZDs assist in slowing this progression.

TZDs also have the potential to assist in treating metabolic syndrome, which is a syndrome of multiple risk factors in which diabetes mellitus is one.  Metabolic syndrome is typically defined when a patient has three or more of the following: elevated glucose or insulin resistance, elevated triglycerides, elevated blood pressure, low HDL cholesterol levels, increased waist size or body weight, and factors that favor the formation of blood clots.  Metabolic syndrome, like diabetes mellitus, results from metabolic inflammation.  A reduced metabolic inflammation caused by TZDs creates a potential to assist in the treatment of metabolic syndrome along with diabetes mellitus. 

However, it has been discovered by the founders of Metabolic Solutions Development Company that activation of the PPAR? nuclear transcription factor is also cause for the unwanted side effects seen with traditional TZDs.  These limiting side effects include fat deposits, increased fluid retention and edema, and changes in the vascular and circulating lipids.  Thus this is the basis for the development of MSDC-0160 which is a PPAR? sparing insulin sensitizer. 

A sparing effect on the PPAR? will allow for a decreased activation of the nuclear transcription factor PPAR? creating a better alternative to the traditional TZDs.  In addition to its antidiabetic effects and its prevention of metabolic syndrome with such effects as increased antihypertensive activity, increased HDL/total cholesterol, increased cardiovascular outcomes, MSDC-0160 has potential for a reduced incidence of edema, reduced weight gain, and reduced bone loss. 

Larger and longer clinical trials need to be done to get a complete understanding of the actual effects this new compound has.  These trials will help determine if the reduced detrimental cardiovascular effects are significant enough to allow MSDC-0160 to reach the market.  If there is a significance it will be cause for a substantial change in the treatment of diabetes because many of the leading Type 2 diabetes therapies are complicated by these side effects of weight gain, edema, and bone loss.

 

References: 

American Heart Association. Metabolic Syndrome. Copyright 2009. Retrieved May 18, 2009 from
http://www.americanheart.org/presenter.jhtml?identifier=4756

Metabolic Solutions Development Company. Metabolic Solutions Development Company Announces Preliminary
Results from Phase IIa Clinical Trial. May 2009. Retrieved May 18, 2009 from http://www.msdrx.com/resources/2009%2005-14%20Phase%20IIa%20preliminary%20data%20nr.pdf

Metabolic Solutions Development Company. The Science. Copyright 2007. Retrieved May 18, 2009 from
http://www.msdrx.com/science.aspx

 

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