TIGAR, a p53-Inducible Regulator of Glycolysis and Apoptosis

Metabolic syndrome is defined by a constellation of interconnected physiological, biochemical, clinical, and metabolic factors that directly increases the risk of cardiovascular disease, type 2 diabetes mellitus, and all cause mortality. Insulin resistance, visceral adiposity, atherogenic dyslipidemia, endothelial dysfunction, genetic susceptibility, elevated blood pressure, hypercoagulable state, and chronic stress are the several factors which constitute the syndrome. Chronic inflammation is known to be associated with visceral obesity and insulin resistance which is characterized by production of abnormal adipocytokines such as tumor necrosis factor α , interleukin-1 (IL-1), IL-6, leptin, and adiponectin. The interaction between components of the clinical phenotype of the syndrome with its biological phenotype (insulin resistance, dyslipidemia, etc.) contributes to the development of a proinflammatory state and further a chronic, subclinical vascular inflammation which modulates and results in atherosclerotic processes. Lifestyle modification remains the initial intervention of choice for such population. Modern lifestyle modification therapy combines specific recommendations on diet and exercise with behavioural strategies. Pharmacological treatment should be considered for those whose risk factors are not adequately reduced with lifestyle changes. This review provides summary of literature related to the syndrome's definition, epidemiology, underlying pathogenesis, and treatment approaches of each of the risk factors comprising metabolic syndrome.

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A Comprehensive Review on Metabolic Syndrome

Protein phosphorylation and regulation of adaptive responses in bacteria.

Pathogenesis of type 2 diabetes mellitus

Dual roles for glucokinase in glucose homeostasis as determined by liver and pancreatic beta cell-specific gene knock-outs using Cre recombinase.

MODULATION OF THE PHOSPHORYLATION STATE OF KEY REGULATORY HEPATIC ENZyMES. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 759 Pyruvate Kinase . . . . . .. . . . . . . . . . .. . . . . . . . . . . . .. . . . . ..... . . .. . . . . . . . . . . .... . .. . . .. . . . . . . . .. . . . . . . ... 759 6-Phosphofructo-l-Kinase and Fructose-l ,6-Bisphosphatase . . . . . . . ... . . . .. . . . .. . . . . . . . . . 761 6-Phosphofructo-2-KinaselFructose-2 ,6-Bisphosphatase . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 762 POSSIBLE MlITOCHONDRIAL SITES OF HORMONE ACTION ....... . . 769 LONG-TERM HORMONAL CONTROL OF GLYCOLYTIC AND GLUCONEOGENIC ENZyMES . . . . . . . .. . . . . . . . . . . . .. . . . . . . . . .. . . . . . . . . . . ". . . . . . . . . 770 Pyruvate Kinase... . . . . . . ..... . . . . . . . . . . .... . . . .... . . . ..... . . . . . . . . ..... . . .... . . . . . . . . . . .. . . .. . . . . . 770 Glucokinase. " . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . , . . . . . . . . . 770 6-Phosphofructo-l-Kinase and Fructose 1 ,6-Bisphosphatase. . . . . . .. . . . . . . . . . . .. . . .. . . . . . 771 6-Phospho}'ructo-2-KinaselFructose-2 ,6-Bisphosphatase . . . . . . . . . . . . .. . . . . ... . . . . .. .. . . . . . . 77 1 Phosphoenolpyruvate Carboxykinase.. . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . .. . . . . . . ....... . . . . . . . . 772 INTEGRATED REGULATION OF HEPATIC GLYCOLYSIS, GLUCONEOGENESIS, AND GLYCOGEN METABOLISM . . . . . . . . . . . . . . . . . . 773

Hormonal Regulation of Hepatic Gluconeogenesis and Glycolysis

Mutations in glucokinase are associated with defects in insulin secretion and hepatic glycogen synthesis resulting in mild chronic hyperglycaemia, impaired glucose tolerance or diabetes mellitus. We screened members of 35 families with features of maturity-onset diabetes of the young for mutations in the glucokinase gene and found 16 different mutations. They included 14 new mutations in the glucokinase gene: 9 missense mutations (A53S, G80A, H137R, T168P, M210T, C213R, V226M, S336L and V367M); 2 nonsense mutations (E248X and S360X); a deletion of one nucleotide resulting in a frameshift (V401del1); a substitution of a conserved nucleotide at a splice acceptor site (L122-1G-->T); and a 10 base pair deletion that removed the GT of the splice donor site and the following eight nucleotides (K161 + 2del10). In addition, we found two previously identified mutations: R186X and G261R. Study of 260 subjects with glucokinase-deficient hyperglycaemia from 42 families with 36 different GCK mutations made it possible to define the clinical profile of this subtype of non-insulin-dependent diabetes mellitus (NIDDM). Hyperglycaemia due to glucokinase deficiency is often mild (fewer than 50% of subjects have overt diabetes) and is evident during the early years of life. Despite the long duration of hyperglycaemia, glucokinase-deficient subjects have a low prevalence of micro- and macro-vascular complications of diabetes. Obesity, arterial hypertension and dyslipidaemia are also uncommon in this form of NIDDM.

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Simon J. Pilkis

Papers

Hormonal Regulation of Hepatic Gluconeogenesis and Glycolysis

Identification of 14 new glucokinase mutations and description of the clinical profile of 42 MODY-2 families.

6-Phosphofructo-2-Kinase/Fructose-2,6-Bisphosphatase: A Metabolic Signaling Enzyme

Inhibition of fructose-1,6-bisphosphatase by fructose 2,6-bisphosphate.

Fructose 2,6-bisphosphate. A new activator of phosphofructokinase.