FBP1

Researchers describe a key player in the defense mechanism that safeguards against excessive insulin in the body, which can be as harmful as too little. Just over a century has passed since the discovery of insulin, a time period during which the therapeutic powers of the hormone have broadened and refined. Insulin is an essential treatment for type 1 diabetes and often for type 2 diabetes, as well. Roughly 8.4 million Americans use insulin, according to the American Diabetes Association. One hundred years of research have greatly advanced medical and biochemical understanding of how insulin works and what happens when it is lacking, but the reverse, how potentially fatal insulin hyper-responsiveness is prevented, has remained a persistent mystery. In a new study, published in the April 20, 2023 online edition of Cell Metabolism, a team of scientists at the University of California San Diego School of Medicine, with colleagues elsewhere, describe a key player in the defense mechanism that safeguards us against excessive insulin in the body. "Although insulin is one of the most essential hormones, whose insufficiency can result in death, too much insulin can also be deadly," said senior study author Michael Karin, PhD, Distinguished Professor of Pharmacology and Pathology at UC San Diego School of Medicine. "While our body finely tunes insulin production, patients who are treated with insulin or drugs that stimulate insulin secretion often experience hypoglycemia, a condition that if gone unrecognized and untreated can result in seizures, coma and even death, which collectively define a condition called insulin shock." Hypoglycemia (low blood sugar) is a significant cause of death among persons with diabetes. In the new study, Karin, first author Li Gu, PhD, a postdoctoral scholar in Karin's lab, and colleagues describe "the body's natural defense or safety valve" that reduces the risk of insulin shock. That valve is a metabolic enzyme called fructose-1,6-bisphosphate phosphatase or FBP1, which acts to control gluconeogenesis, a process in which the liver synthesizes glucose (the primary source of energy used by cells and tissues) during sleep and secretes it to maintain steady supply of glucose in the bloodstream. Some antidiabetic drugs, such as metformin, inhibit gluconeogenesis but without apparent ill effect. Children born with a rare, genetic disorder in which they do not produce sufficient FBP1 can also remain healthy and live long lives. But in other cases, when the body is starved for glucose or carbohydrates, an FBP1 deficiency can result in severe hypoglycemia. Without a glucose infusion, convulsions, coma and possibly death can ensue. Compounding and confounding the problem, FPB1 deficiency combined with glucose starvation produces adverse effects unrelated to gluconeogenesis, such as an enlarged, fatty liver, mild liver damage and elevated blood lipids or fats. To better understand the roles of FBP1, researchers created a mouse model with liver specific FBP1 deficiency, accurately mimicking the human condition. Like FBP1-deficient children, the mice appeared normal and healthy until fasted, which quickly resulted in the severe hypoglycemia and the liver abnormalities and hyperlipidemia described above. Gu and her colleagues discovered that FBP1 had multiple roles. Beyond playing a part in the conversion of fructose to glucose, FBP1 had a second non-enzymatic but critical function: It inhibited the protein kinase AKT, which is the primary conduit of insulin activity. "Basically, FBP1 keeps AKT in check and guards against insulin hyper-responsiveness, hypoglycemic shock and acute fatty liver disease," said first author Gu. Working with Yahui Zhu, a vising scientist from Chongqing University in China and second author of the study, Gu developed a peptide (a string of amino acids) derived from FBP1 that disrupted the association of FBP1 with AKT and another protein that inactivates AKT. "This peptide works like an insulin mimetic, activating AKT," said Karin. "When injected into mice that have been rendered insulin resistant, a highly common pre-diabetic condition, due to prolonged consumption of high-fat diet, the peptide (nicknamed E7) can reverse insulin resistance and restore normal glycemic control." Karin said the researchers would like to further develop E7 as a clinically useful alternative to insulin "because we have every reason to believe that it is unlikely to cause insulin shock." Co-authors include: Kosuke Watari, Maiya Lee, Junlai Liu, Sofia Perez, Melinda Thai, Joshua E. Mayfield, Bichen Zhang, Karina Cunha e Rocha, Alexander C. Jones, Igor H. Wierzbicki, Xiao Liu, Alexandra C. Newton, Tatiana Kisseleva, Wei Ying, David J. Gonzalez and Alan R. Saltiel, all at UC San Diego; Fuming Li, University of Pennsylvania and Fudan University, China; Laura C. Kim and M. Celeste Simon, University of Pennsylvania; Jun Hee Lee, University of Michigan. Funding for this research came, in part, from the National Institutes of Health (grants R01DK120714, R01CA234128, R01DK133448, P01CA104838, R35CA197602, R01DK117551, R01DK125820, R01DK76906, P30DK063491, R21HD107516, R00DK115998, R01DK125560 AND R35GM122523), the UC San Diego Graduate Training Program in Cellular and Molecular Pharmacology (GM007752) and the National Science Foundation Graduate Research Fellowship (#DGE-1650112).

SAN DIEGO--(BUSINESS WIRE)--Metabasis Therapeutics, Inc. (Nasdaq: MBRX) announced today results from a clinical trial in which MB07803 was administered twice-daily for 14 days to patients with poorly controlled type 2 diabetes. In the trial, MB07803 treatment resulted in dose-related, clinically meaningful and statistically significant reductions in day long glycemia (24-hour weighted mean glucose levels) at all doses evaluated (50 mg, 200 mg and 400 mg, twice-daily). In addition, clinically and statistically significant reductions in fasting plasma glucose (FPG) were observed at the two highest doses. MB07803 was considered safe at all doses tested and well tolerated up to 200 mg twice-daily. MB07803 is Metabasis’ second-generation product candidate from a new class of drugs that the Company discovered internally for the treatment of type 2 diabetes. MB07803 reduces glucose production in the liver by inhibiting the enzyme fructose-1,6-bisphosphatase (FBPase). Excess glucose production is believed to be a major contributor to the elevated glucose levels found in patients with type 2 diabetes.

SAN DIEGO, Feb. 1 /PRNewswire-FirstCall/ -- Metabasis Therapeutics today announced that enrollment was recently completed in the ongoing Phase 2b clinical trial for CS-917, a compound being developed for the treatment of type 2 diabetes by Daiichi Sankyo pursuant to a licensing agreement between the two companies. This proof-of-concept study is designed to evaluate safety and tolerability after three months of dosing of CS-917, as well as its effect on blood levels of the molecule HbA1c, an important measure of glucose control in patients with type 2 diabetes. A total of 392 patients have been enrolled at over 100 sites in this randomized, double-blind, placebo controlled trial. Patients are evenly distributed among four groups consisting of two active dose groups of CS-917, an active comparator and placebo. If successful, the trial could support selection of a dose for a pivotal Phase 3 clinical trial. In two successfully completed Phase 2a clinical trials (14-day and 28-day) in patients with type 2 diabetes, CS-917 was well tolerated and significantly reduced the elevated blood glucose levels that characterize the disease. The results from the 14-day Phase 2a clinical trial involving 39 patients were presented at the 2006 American Diabetes Association meeting and showed that oral administration of CS-917 in the morning resulted in significant lowering of post-dose fasting plasma glucose (FPG) compared to placebo. This study was followed by a 28-day study in 146 type 2 diabetic patients which indicated that CS-917 was most likely to be administered twice daily. "The completion of patient enrollment in this trial is another step forward in the development of this novel compound, designed to inhibit gluconeogenesis, for patients suffering from type 2 diabetes," stated Dr. Paul Laikind, president and chief executive officer of Metabasis. "With an estimated 180 million people worldwide with type 2 diabetes and with the incidence continuing to grow, new treatment options are urgently needed as current therapies often only achieve modest reduction in the production of glucose. We believe that CS-917 is the first of a new therapeutic class that has the potential to be an important distinctive approach for treating patients who suffer from type 2 diabetes." Dr. Mark Erion, executive vice president of research and development and chief scientific officer at Metabasis, commented. "CS-917 acts as a direct inhibitor of the pathway in the liver responsible for the production of glucose, the gluconeogenesis pathway. CS-917 is being evaluated to determine whether it may be used alone or in combination with certain other drugs designed to enhance removal of glucose from the bloodstream, and for the large number of patients who are unable to take metformin, a treatment currently used as first line therapy in patients with type 2 diabetes." About CS-917: CS-917 is a compound for the treatment of type 2 diabetes that was discovered by using Metabasis' proprietary NuMimetic(TM) technology, and is being developed by Daiichi Sankyo pursuant to a licensing agreement between Metabasis and Daiichi Sankyo. Metabasis retains co-promotion rights in North America. CS-917 is a prodrug of an orally active, potent and selective inhibitor of fructose-1, 6-bisphosphatase (FBPase), a regulatory enzyme in the pathway responsible for the production of glucose in the liver, known as the gluconeogenesis pathway. By specifically inhibiting this pathway, liver glucose production should be reduced and blood sugar levels decreased in patients with diabetes, independent of insulin levels, body weight and disease stage. Metabasis believes that CS-917 is the first product candidate to be studied in human clinical trials that is designed to directly block this pathway. Forward-Looking Statements: Statements in this press release that are not strictly historical in nature constitute "forward-looking statements." Such statements include, but are not limited to, references to the potential success of the Phase 2b clinical trial for CS-917 as well as the potential use and efficacy of CS-917. Such forward-looking statements involve known and unknown risks, uncertainties and other factors which may cause Metabasis' actual results to be materially different from historical results or from any results expressed or implied by such forward-looking statements. These factors include, but are not limited to, the progress and timing of clinical trials for Metabasis' product candidates; the fact that positive results from clinical trials does not necessarily mean later clinical trials will succeed; difficulties or delays in development, testing, obtaining regulatory approval, producing and marketing Metabasis' product candidates; the potential and progress of preclinical compounds and programs; and risks and uncertainties discussed in the "Risk Factors" section of Metabasis' Quarterly Report on Form 10-Q for the quarter ended September 30, 2006 and in Metabasis' other filings with the Securities and Exchange Commission. All forward-looking statements are qualified in their entirety by this cautionary statement. Metabasis is providing this information as of this date of this release and does not undertake any obligation to update any forward-looking statements contained in this release as a result of new information, future events or otherwise. About Metabasis ( ): Metabasis Therapeutics is a biopharmaceutical company focused on the discovery, development and commercialization of novel drugs to address some of the world's most widespread and costly chronic diseases. The Company has established a pipeline that includes clinical stage and preclinical product candidates targeting major diseases with significant unmet medical needs. Targeted diseases include major metabolic diseases such as diabetes, hyperlipidemia and obesity as well as liver diseases such as hepatitis and primary liver cancer. Metabasis has developed several proprietary technologies for use in discovering and optimizing drugs, including the NuMimetic(TM) and HepDirect(R) technologies. Metabasis is continuing to identify and develop new product candidates using its proprietary technologies and expertise. Metabasis Therapeutics, Inc. 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