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Muraglitazar, a Novel Dual (α/γ) Peroxisome Proliferator–Activated Receptor Activator, Improves Diabetes and Other Metabolic Abnormalities and Preserves β-Cell Function in db/db Mice Thomas Harrity 1 , Dennis Farrelly 1 , Aaron Tieman 1 , Cuixia Chu 1 , Lori Kunselman 1 , Liqun Gu 1 , Randolph Ponticiello 1 , Michael Cap 1 , Fucheng Qu 2 , Chunning Shao 2 , Wei Wang 2 , Hao Zhang 2 , William Fenderson 3 , Sean Chen 2 , Pratik Devasthale 2 , Yoon Jeon 2 , Ramakrishna Seethala 1 , Wen-Pin Yang 3 , Jimmy Ren 1 , Min Zhou 1 , Denis Ryono 2 , Scott Biller 2 , Kasim A. Mookhtiar 1 , John Wetterau 1 , Richard Gregg 1 , Peter T. Cheng 2 and Narayanan Hariharan 1 1 Department of Metabolic Diseases Biology, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey 2 Department of Metabolic Diseases Chemistry, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey 3 Department of Applied Genomics, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey Address correspondence and reprint requests to Narayanan Hariharan, PhD, Metabolic Diseases, HWP-21-2.02, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ 08543. E-mail: narayanan.hariharan{at}bms.com Abstract Muraglitazar, a novel dual (α/γ) peroxisome proliferator–activated receptor (PPAR) activator, was investigated for its antidiabetic properties and its effects on metabolic abnormalities in genetically obese diabetic db/db mice. In db/db mice and normal mice, muraglitazar treatment modulates the expression of PPAR target genes in white adipose tissue and liver. In young hyperglycemic db/db mice, muraglitazar treatment (0.03–50 mg · kg −1 · day −1 for 2 weeks) results in dose-dependent reductions of glucose, insulin, triglycerides, free fatty acids, and cholesterol. In older hyperglycemic db/db mice, longer-term muraglitazar treatment (30 mg · kg −1 · day −1 for 4 weeks) prevents time-dependent deterioration of glycemic control and development of insulin deficiency. In severely hyperglycemic db/db mice, muraglitazar treatment (10 mg · kg −1 · day −1 for 2 weeks) improves oral glucose tolerance and reduces plasma glucose and insulin levels. In addition, treatment increases insulin content in the pancreas. Finally, muraglitazar treatment increases abnormally low plasma adiponectin levels, increases high–molecular weight adiponectin complex levels, reduces elevated plasma corticosterone levels, and lowers elevated liver lipid content in db/db mice. The overall conclusions are that in db/db mice, the novel dual (α/γ) PPAR activator muraglitazar 1 ) exerts potent and efficacious antidiabetic effects, 2 ) preserves pancreatic insulin content, and 3 ) improves metabolic abnormalities such as hyperlipidemia, fatty liver, low adiponectin levels, and elevated corticosterone levels. ACO, acyl coenzyme-A oxidase FFA, free fatty acid HMW, high molecular weight LMW, low molecular weight MMW, medium molecular weight PPAR, peroxisome proliferator–activated receptor WAT, white adipose tissue Footnotes S.B. is currently affiliated with Novartis Institute Bio-Med Research, Cambridge, Massachusetts. K.A.M. is currently affiliated with Advinus Therapeutics, Pune, India. J.W. is currently affiliated with the Department of Cardiovascular Pharmaceuticals, Pfizer, Ann Arbor, Michigan. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Accepted September 26, 2005. Received May 23, 2005. DIABETES

The importance of glucokinase (GK; EC 2.7.1.12) in glucose homeostasis has been demonstrated by the association of GK mutations with diabetes mellitus in humans and by alterations in glucose metabolism in transgenic and gene knockout mice. Liver GK activity in humans and rodents is allosterically inhibited by GK regulatory protein (GKRP). To further understand the role of GKRP in GK regulation, the mouse GKRP gene was inactivated. With the knockout of the GKRP gene, there was a parallel loss of GK protein and activity in mutant mouse liver. The loss was primarily because of posttranscriptional regulation of GK, indicating a positive regulatory role for GKRP in maintaining GK levels and activity. As in rat hepatocytes, both GK and GKRP were localized in the nuclei of mouse hepatocytes cultured in low-glucose-containing medium. In the presence of fructose or high concentrations of glucose, conditions known to relieve GK inhibition by GKRP in vitro, only GK was translocated into the cytoplasm. In the GKRP-mutant hepatocytes, GK was not found in the nucleus under any tested conditions. We propose that GKRP functions as an anchor to sequester and inhibit GK in the hepatocyte nucleus, where it is protected from degradation. This ensures that glucose phosphorylation is minimal when the liver is in the fasting, glucose-producing phase. This also enables the hepatocytes to rapidly mobilize GK into the cytoplasm to phosphorylate and store or metabolize glucose after the ingestion of dietary glucose. In GKRP-mutant mice, the disruption of this regulation and the subsequent decrease in GK activity leads to altered glucose metabolism and impaired glycemic control.

Muraglitazar, a novel dual (alpha/gamma) peroxisome proliferator-activated receptor (PPAR) activator, was investigated for its antidiabetic properties and its effects on metabolic abnormalities in genetically obese diabetic db/db mice. In db/db mice and normal mice, muraglitazar treatment modulates the expression of PPAR target genes in white adipose tissue and liver. In young hyperglycemic db/db mice, muraglitazar treatment (0.03-50 mg . kg(-1) . day(-1) for 2 weeks) results in dose-dependent reductions of glucose, insulin, triglycerides, free fatty acids, and cholesterol. In older hyperglycemic db/db mice, longer-term muraglitazar treatment (30 mg . kg(-1) . day(-1) for 4 weeks) prevents time-dependent deterioration of glycemic control and development of insulin deficiency. In severely hyperglycemic db/db mice, muraglitazar treatment (10 mg . kg(-1) . day(-1) for 2 weeks) improves oral glucose tolerance and reduces plasma glucose and insulin levels. In addition, treatment increases insulin content in the pancreas. Finally, muraglitazar treatment increases abnormally low plasma adiponectin levels, increases high-molecular weight adiponectin complex levels, reduces elevated plasma corticosterone levels, and lowers elevated liver lipid content in db/db mice. The overall conclusions are that in db/db mice, the novel dual (alpha/gamma) PPAR activator muraglitazar 1) exerts potent and efficacious antidiabetic effects, 2) preserves pancreatic insulin content, and 3) improves metabolic abnormalities such as hyperlipidemia, fatty liver, low adiponectin levels, and elevated corticosterone levels.

This monograph reviews literature pertaining to children without permanent parents. Chapters review (1) the development of children while institutional residents; (2) the development of postinstitutionalized children transitioned to family environments (i.e., adoption); the effects of institutionalization on (3) attachment behaviors, (4) physical growth, and (5) neurobiological development; (6) the possibility of a sensitive period in early development during which institutionalization may be most damaging; (7) best practices in low-resource countries in moving toward family alternatives to institutions; (8) challenges faced by these countries in formulating and implementing such policies; and (9) more speculative interpretations of major research, practice, and policy issues in this field. It is clear that: (1) Infants and young children being reared in most institutions are substantially delayed in their physical, neurobiological, cognitive, and social-emotional development; (2) If such children are transitioned to family environments (e.g., adoptive, foster families), immediate and substantial catch-up growth is observed in all domains; (3) However, deficiencies and problems in all developmental domains can persist at higher than expected rates even after transitioning to families, especially in children leaving the institution after 6-24 months depending on the severity of the depriving institutional conditions, the particular developmental outcome and measure, and other factors; (4) Family alternatives generally provide better rearing environments for young children than institutions and usually at less cost; (5) Many children in institutions have one or both parents, who with financial and social support could retain their children. Ideally, others should be transitioned to family alternatives as early in life as possible. Institutions could be improved to enhance the development of children who must remain in their care because of lack of alternative arrangements, special needs, and health status (e.g., HIV); and (6) Child welfare systems that operate within a children's rights framework are preferred, but there are a variety of historical, cultural, political, administrative, and financial challenges to implementing such systems. This volume is a synthesis of empirical research on the development of children without permanent parents that contributes to scholarship on the effects of early experience on development. In addition, it provides a basis of evidence that supports changes in practice and policy that promote better rearing environments worldwide for these children consistent with international agreements concerning the rights of all children. (Contains 8 tables, 1 figure, and 4 notes.)