The Science

Origins of Insulin Sensitizers

Insulin sensitizers were discovered more than 25 years ago by scientists at Takeda Pharmaceutical Company. At the time these compounds were discovered, researchers did not understand their potential mechanism of action. Today, it is generally believed that these compounds are activators of the nuclear receptor PPARγ.

The founders of Metabolic Solutions have recognized that PPARγ activation is the cause of the side effects associated with insulin sensitizers, while the useful pharmacology is secondary to the prevention of metabolic inflammation in the energy-producing cellular organelles called mitochondria.

Scientists’ failure to understand the mechanism of action of insulin sensitizers also explains why, in spite of considerable effort, no new insulin-sensitizing drugs have been developed since the first insulin sensitizers were first produced almost 20 years ago.

Insulin Resistance

The basis of insulin resistance is a mitochondrial dysfunction that ensues from inappropriate oxidative metabolism in the energy-producing mitochondria. This mitochondrial dysfunction, characterized as an insulin resistance, is at the heart of metabolic disease. The peripheral tissues’ resistance to insulin puts pressure on the β-cells of the pancreatic islets, causing them to produce and secrete more and more insulin.

In individuals who are genetically predisposed to type 2 diabetes, the function of the pancreatic β-cells progressively declines, eventually leading to a rise in circulating glucose (sugar) levels. The changes in pancreatic islet function are manifest first as a loss in the regulation of circulating glucose levels after meals and eventually as a rise in fasting glucose levels. Once circulating glucose levels are elevated above established standards, an individual is classified as having type 2 diabetes.

Although circulating glucose is elevated only after pancreatic β-cell function has declined, there is an entire pathology fueled by the metabolic inflammation that affects key risk factors for cardiovascular disease. This pathology occurs both in individuals who are susceptible to and in those who are resistant to developing type 2 diabetes. This pathology is called metabolic syndrome, or cardiometabolic syndrome.

Metabolic Syndrome and PPARγ Activation

Metabolic syndrome consists of a clustering of factors that are known to predispose individuals to the main causes of cardiovascular death, namely heart attacks and strokes. These well-known risk factors include:

  • Elevated glucose or insulin resistance
  • Elevated triglycerides
  • Elevated blood pressure
  • Low levels of HDL (good) cholesterol
  • Increased waist size or body weight

Pre-clinical (animal) and clinical (human) studies have shown that insulin sensitizers can partially correct all of these risk factors. These compounds are so broadly effective because they attack the metabolic inflammation that is the molecular cause of the syndrome. However, in addition to reducing the metabolic inflammation and improving insulin sensitivity, the first-generation insulin sensitizers also activate the expression of other factors that have a negative impact.

Insulin Sensitizers can directly activate the nuclear transcription factor PPARγ, which can generate unwanted side effects, including:

  • Fat deposits
  • Increased fluid retention (and edema) leading to a significant risk of congestive heart failure

All of these side effects limit the drugs’ effectiveness.

PPARγ-Sparing Solutions

MSDC is developing insulin sensitizers for the treatment of type 2 diabetes based on the hypothesis that PPARγ causes the negative side effects associated with those currently on the market. In a recently completed Phase IIa study, MSDC’s lead candidate, MSDC-0160, successfully achieved effective glucose control without the side effects that are associated with current insulin sensitizers. Based on MSDC’s novel strategy, MSDC-0160 successfully decouples insulin sensitizing activity from the side effects associated with other insulin sensitizers. Since insulin sensitizers remain among the most effective agents for controlling blood glucose and also improve key factors related to insulin sensitivity, such as circulating lipids and blood pressure, this candidate offers significant advantages over most type 2 diabetes treatments.

Phase IIa data has shown the potential for MSDC-0160 to have a significant impact on elevated blood glucose and insulin resistance but, importantly, without the increase in fluid retention and body weight gain seen with Actos®. Insulin resistance plays a key role in metabolic syndrome and the development of diabetes, dyslipidemia and hypertension, the major risk factors for cardiovascular disease. As such, these results also suggest this new class of insulin sensitizers may treat metabolic syndrome. Results from the Phase IIa trial also showed that MSDC-0160 lowered blood pressure and significantly increased HDL (so-called “good cholesterol”).

MSDC has identified a currently undisclosed second pharmacological target of the highly successful insulin sensitizers used to treat type 2 diabetes. MSDC believes that this novel target drives much of the positive effect of insulin sensitizers on blood glucose, serum lipids, and blood pressure. Importantly, by not directly activating nuclear receptors, compounds selective for this target avoid the adverse side effects of first generation insulin sensitizers, such as edema, weight gain, and danger of congestive heart failure.

We are also evaluating optimal combinations with other agents to control the key cardiovascular risk factors, including lipids and blood pressure. Our powerful partnerships will enable us to thoroughly evaluate these healthcare outcomes and pursue expansions of indications for the prevention of both diabetes and the cardiovascular deaths associated with metabolic inflammation (i.e., metabolic syndrome).

Insulin Sensitizers

References

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