No abstract

Adiponectin has been shown to stimulate fatty acid oxidation and enhance insulin sensitivity through the activation of AMP-activated protein kinase (AMPK) in the peripheral tissues. The effects of adiponectin in the central nervous system, however, are still poorly understood. Here, we show that adiponectin enhances AMPK activity in the arcuate hypothalamus (ARH) via its receptor AdipoR1 to stimulate food intake; this stimulation of food intake by adiponectin was attenuated by dominant-negative AMPK expression in the ARH. Moreover, adiponectin also decreased energy expenditure. Adiponectin-deficient mice showed decreased AMPK phosphorylation in the ARH, decreased food intake, and increased energy expenditure, exhibiting resistance to high-fat-diet-induced obesity. Serum and cerebrospinal fluid levels of adiponectin and expression of AdipoR1 in the ARH were increased during fasting and decreased after refeeding. We conclude that adiponectin stimulates food intake and decreases energy expenditure during fasting through its effects in the central nervous system.

Excessive nitric oxide (NO) production in cytokine-activated ␤ cells has been implicated in ␤ cell disruption in type 1 diabetes. ␤ cells are very vulnerable to NO-induced apoptosis. However, the mechanism underlying this phenomenon is unclear. Low concentrations of NO that lead to apoptosis apparently do not cause severe DNA damage in mouse MIN6 ␤ cells. CHOP, a C͞EBP homologous protein that is induced by endoplasmic reticulum (ER) stress and plays a role in growth arrest and cell death, was induced by a NO donor, S-nitroso-N-acetyl-D,L-penicillamine (SNAP). SNAP increased cytosolic Ca 2؉ , and only agents depleting ER Ca 2؉ induced CHOP expression and led to apoptosis, suggesting that NO depletes ER Ca 2؉ . Overexpression of calreticulin increased the Ca 2؉ content of ER and afforded protection to cells against NO-mediated apoptosis. Furthermore, pancreatic islets from CHOP knockout mice showed resistance to NO. We conclude that NO depletes ER Ca 2؉ , causes ER stress, and leads to apoptosis. Thus, ER Ca 2؉ stores are a new target of NO, and the ER stress pathway is a major mechanism of NO-mediated ␤ cell apoptosis.

AMPK is a serine/threonine protein kinase, which serves as an energy sensor in all eukaryotic cell types. Published studies indicate that AMPK activation strongly suppresses cell proliferation in non-malignant cells as well as in tumour cells. These actions of AMPK appear to be mediated through multiple mechanisms including regulation of the cell cycle and inhibition of protein synthesis, de novo fatty acid synthesis, specifically the generation of mevalonate as well as other products downstream of mevalonate in the cholesterol synthesis pathway. Cell cycle regulation by AMPK is mediated by up-regulation of the p53-p21 axis as well as regulation of TSC2-mTOR (mammalian target of rapamycin) pathway. The AMPK signalling network contains a number of tumour suppressor genes including LKB1, p53, TSC1 and TSC2, and overcomes growth factor signalling from a variety of stimuli (via growth factors and by abnormal regulation of cellular proto-oncogenes including PI3K, Akt and ERK). These observations suggest that AMPK activation is a logical therapeutic target for diseases rooted in cellular proliferation, including atherosclerosis and cancer. In this review, we discuss about exciting recent advances indicating that AMPK functions as a suppressor of cell proliferation by controlling a variety of cellular events in normal cells as well as in tumour cells.

No abstract

Cyclooxygenase-2 (COX-2), a prostanoid-synthesizing enzyme that contributes to the toxicity associated with inflammation, has recently emerged as a promising therapeutic target for several illnesses, ranging from osteoarthritis to Alzheimer's disease. Although COX-2 has also been linked to ischemic stroke, its role in the mechanisms of ischemic brain injury remains controversial. We demonstrate that COX-2-deficient mice have a significant reduction in the brain injury produced by occlusion of the middle cerebral artery. The protection can be attributed to attenuation of glutamate neurotoxicity, a critical factor in the initiation of ischemic brain injury, and to abrogation of the deleterious effects of postischemic inflammation, a process contributing to the secondary progression of the damage. Thus, COX-2 is involved in pathogenic events occurring in both the early and late stages of cerebral ischemia and may be a valuable therapeutic target for treatment of human stroke.middle cerebral artery occlusion ͉ prostanoids ͉ cerebral blood flow ͉ NS398 ͉ stroke

Summary Concept of diabetes mellitusDiabetes mellitus is a group of diseases associated with various metabolic disorders, the main feature of which is chronic hyperglycemia due to insufficient insulin action. Its pathogenesis involves both genetic and environmental factors. The long-term persistence of metabolic disorders can cause susceptibility to specific complications and also foster arteriosclerosis. Diabetes mellitus is associated with a broad range of clinical presentations, from being asymptomatic to ketoacidosis or coma, depending on the degree of metabolic disorder.Classification (Tables 1, 2; Fig. 1) The classification of glucose metabolism disorders is principally derived from etiology, and includes staging of pathophysiology based on the degree of deficiency of insulin action. These disorders are classified into four groups: (i) type 1 diabetes mellitus; (ii) type 2 diabetes mellitus; (iii) diabetes mellitus those due to other specific mechanisms or diseases; and (iv) gestational diabetes mellitus. Type 1 diabetes is characterized by destruction of pancreatic b-cells. Type 2 diabetes is characterized by combinations of decreased insulin secretion and decreased insulin sensitivity (insulin resistance). Glucose metabolism disorders in category (iii) are divided into two subgroups; subgroup A is diabetes in which a genetic abnormality has been identified, and subgroup B is diabetes associated with other pathologic disorders or clinical conditions.

Concept of Diabetes Mellitus:Diabetes mellitus is a group of diseases associated with various metabolic disorders, the main feature of which is chronic hyperglycemia due to insufficient insulin action. Its pathogenesis involves both genetic and environmental factors. The long‐term persistence of metabolic disorders can cause susceptibility to specific complications and also foster arteriosclerosis. Diabetes mellitus is associated with a broad range of clinical presentations, from being asymptomatic to ketoacidosis or coma, depending on the degree of metabolic disorder.Classification (Tables 1 and 2, and Figure 1):Table 1 Etiological classification of diabetes mellitus and glucose metabolism disordersI. Type 1 (destruction of pancreatic β‐cells, usually leading to absolute insulin deficiency) A. Autoimmune B. IdiopathicII. Type 2 (ranging from predominantly insulin secretory defect, to predominantly insulin resistance with varying degrees of insulin secretory defect)III. Due to other specific mechanisms or diseases (see Table 2 for details) A. Those in which specific mutations have been identified as a cause  of genetic susceptibility  (1) Genetic abnormalities of pancreatic β‐cell function  (2) Genetic abnormalities of insulin action B. Those associated with other diseases or conditions  (1) Diseases of exocrine pancreas  (2) Endocrine diseases  (3) Liver disease  (4) Drug‐ or chemical‐induced  (5) Infections  (6) Rare forms of immune‐mediated diabetes  (7) Various genetic syndromes often associated with diabetesIV. Gestational diabetes mellitusNote: Those that cannot at present be classified as any of the above are called unclassifiable.The occurrence of diabetes‐specific complications has not been confirmed in some of these conditions.Table 2 Diabetes mellitus and glucose metabolism disorders due to other specific mechanisms and diseasesA. Those in which specific mutations have been identified as a cause of genetic susceptibilityB. Those associated with other diseases or conditions(1) Genetic abnormalities of pancreatic β‐cell function
Insulin gene (abnormal insulinemia, abnormal proinsulinemia, neonatal diabetes mellitus) 
HNF 4α gene (MODY1) 
Glucokinase gene (MODY2) 
HNF 1α gene (MODY3) 
IPF‐1 gene (MODY4) 
HNF 1β gene (MODY5) 
Mitochondria DNA (MIDD) 
NeuroD1 gene (MODY6) 
Kir6.2 gene (neonatal diabetes mellitus) 
SUR1 gene (neonatal diabetes mellitus) 
Amylin
Others
(2) Genetic abnormalities of insulin action
Insulin receptor gene (type A insulin resistance, leprechaunism, Rabson–Mendenhall syndrome etc.) 
Others(1) Diseases of exocrine pancreas
Pancreatitis
Trauma/pancreatectomy
Neoplasm
Hemochromatosis
Others
(2) Endocrine diseases
Cushing’s syndrome
Acromegaly
Pheochromocytoma
Glucagonoma
Aldosteronism
Hyperthyroidism
Somatostatinoma
Others
(3) Liver disease
Chronic hepatitis
Liver cirrhosis 
Others
(4) Drug‐ or chemical‐induced
Glucocorticoids
Interferon
Others
(5) Infections
Congenital rubella
Cytomegalovirus
Others
(6) Rare forms of immune‐mediated diabetes
Anti‐insulin receptor antibodies
St...