ISSN:0272-4391    

DOI:10.1002/ddr.430320202

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1994

数据来源: WILEY

摘要:

AbstractA third β‐adrenoceptor subtype has been cloned form the rat, mouse, and human genomes. The presence of these receptors primarily on adipose tissue has raised the possibility that β3‐adrenoceptor selective agonists may be useful antiobesity agents. CL 316,243 is a highly selective β3‐agonist; it has a<30,000 to 1 β3‐to‐β1‐adrenoceptor selectivity ratio and a 10,000 to 1 β3‐to‐β2‐adrenoceptor selectivity ratio in in vitro functional assays. In vivo, animals were treated with CL 314,698, a diester prodrug of CL 316,243, which is rapidly converted to CL 316,243. In obese (ob/ob) and diabetic (db/db) mice, treatment with CL 314,698 reduced their hyperglycemia to the euglycemia of their lean littermates, and decreased plasma insulin levels. In obese mice, the compound also caused decreased weight gain despite increased food consumption, and the decreased weight was due to loss of fat while lean body mass was spared. CL 314,698 treatment also improved both glucose and insulin tolerance in obese mice, suggesting that it decreased insulin resistance. CL 314,698 also prevented further weight gain, without affecting food consumption, in rats previously made obese by feeding a high fat diet. The compound reduced plasma insulin and triglyceride levels, and reduced fat pad weights, while having no effect on plasma glucose, cholesterol, thyroxine, or T3levels or on skeletal muscle weight. Decreased weight gain without decreased food consumption suggested that CL 316,243 stimulated thermogenesis. Treatment of obese mice for 3 weeks with CL 316,243 increased thermogenesis by 45% as measured by indirect calorimetry. Thus, CL 316,243 is a potent, β3‐adrenoceptor selective agonist with thermogenic, antidiabetic, and antiobesity properties in several models of non‐insulin d

ISSN:0272-4391    

DOI:10.1002/ddr.430320203

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1994

数据来源: WILEY

摘要:

AbstractReducing sugars such as glucose react non‐enzymatically with the amino groups of macromolecules to initiate a chemical modification process known as advanced glycosylation. This pathway proceeds from reversible Schiff base adducts to a heterogenous group of irreversibly‐bound, cross‐linking moieties called advanced glycosylation endproducts or AGEs. Recent progress in our understanding of this process in vivo has affirmed the hypothesis that AGEs play an intimate role in the evolution of both diabetic and non‐diabetic vascular disease. Utilizing newly developed AGE‐specific ELISA techniques, AGEs have been identified to be present on a variety of vascular wall, lipoprotein, and lipid constituents. Protein‐bound AGEs, for example, contribute to a variety of pathological effects in vivo by acting to increase vascular permeability, enhance subintimal protein and lipoprotein deposition, and exert direct toxic effects on endothelial cells. Lipid‐AGEs promote oxidative modification and may contribute to atherogenesis by initiating the formation of oxidized low density lipoprotein (ox‐LDL). Aminoguanidine, a recently developed pharmacological inhibitor of advanced glycosylation, is presently undergoing phase II clinical trials and may offer a specific therapeutic modality for the treatment of pathological conditions that result from excessive advance

ISSN:0272-4391    

DOI:10.1002/ddr.430320204

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1994

数据来源: WILEY

摘要:

AbstractA 37 amino‐acid peptide, amylin, is secreted from the pancreatic β‐cell in response to stimuli similar to those causing insulin secretion. Plasma amylin levels are generally elevated under circumstances where insulin is elevated, including in insulin resistance and in essential (obesity‐related) hypertension. Several of amylin's actions may contribute to key features of insulin resistance and the insulin resistance syndrome (Syndrome‐X). Actions on muscle glycogen metabolism, Cori cycle activity, and endogenous glucose production may contribute to glucose intolerance while amylin's effects to suppress β‐cell secretion could account for the secretory defect observed in early glucose intolerance. Amylin also potently increases plasma renin activity, and could contribute to the hypertension that is associated with obesity and insulin

ISSN:0272-4391    

DOI:10.1002/ddr.430320205

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1994

数据来源: WILEY

摘要:

AbstractBoth in the human and in several experimental models, hypertension is associated with insulin resistance. Thiazolidinedione derivatives are a novel group of oral hypoglycemic agents that increase insulin sensitivity without stimulating endogenous insulin secretion. These agents have been shown to attenuate the development of hypertension in the following experimental rat models: the Dahl salt‐sensitive rat, the one‐kidney, one‐clip hypertensive rat, the obese Zucker rat, and blood pressure increases in rats fed high carbohydrate or high fat diets. Clofibrate, a lipid lowering agent that also increases insulin sensitivity, also prevents the development of hypertension in Dahl salt sensitive rats. Additional studies will be required to determine if attenuation of hypertension by these agents is specifically related to their capacity to increase insulin sensit

ISSN:0272-4391    

DOI:10.1002/ddr.430320206

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1994

数据来源: WILEY

摘要:

AbstractDiabetic kidney disease or diabetic nephropathy is the leading cause of renal failure in the United States today. This review presents a brief overview of diabetic nephropathy—its current statistics, histopathology, natural history, and main risk factors, including hyperglycemia, hyperfiltration, and hypertension. Pathogenic mechanisms by which hyperglycemia, severe hyperfiltration, and capillary hypertension might cause renal injury are discussed. Evidence is reviewed indicating a potentially useful role for aldose reducatase inhibitors (ARIs) to normalize or reduce the impact of two possible risk factors for diabetic nephropathy, namely, elevated polyol pathway metabolism and severe hyperfiltration. Measurements in experimental models of whole kidney blood flow (57Co‐microspheres, clearance methods), superficial cortical blood flow (laser Doppler flowmetry), and single nephron hemodynamic parameters (renal micropuncture) concordantly indicate that the beneficial effect of ARIs on hyperfiltration is based on protection or restoration of normal renal microvascular resistance. Since ARIs affect neither blood sugar levels nor mean arterial pressure, ARIs have no increased risk attributable to hypoglycemia or hypotension. It is concluded that ARIs warrant further experimental and clinical research in early diabetic nephropa

ISSN:0272-4391    

DOI:10.1002/ddr.430320207

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1994

数据来源: WILEY

摘要:

AbstractAdipose tissue possesses considerable growth potential, and excess adipose tissue mass is associated with noninsulin dependent diabetes mellitus (NIDDM). Adipose tissue is a significant source of angiotensinogen, the precursor of angiotensin II (All), a vasoactive peptide with in vitro mitogenic effects. The renin‐angiotensin system remains only partially identified in adipose tissue, however, and knowledge of whether All has a physiologic role in this tissue is dependent in part upon other components of the system being characterized. We have chosen to further investigate aspects of the renin‐angiotensin system in separate adipose tissue depots of rats during growth and development of the tissue. Either epididymal or retroperitoneal adipose tissue was examined in young lean, or adult obese male Sprague‐Dawley rats. Adipose tissue was subjected to collagenase digestion, yielding separate vascular and fat cell fractions. Each fraction was analyzed for angiotensin converting enzyme (ACE) activity and All receptor binding capacity. ACE activity was significantly greater when expressed per gram of adipose tissue in the young lean rats. Vascular and fat cell fractions exhibited All receptors of high affinity, with a greater density of receptors observed in the epididymal adipose tissue fractions. Incubation of adipocytes with exogenous All was associated with the release of prostaglandin into the medium, and analyses of adipocyte cytosol indicated the presence of angiotensinogen. Growing rats given oral losartan, an All receptor antagonist, once daily (15 mg/kg) for 2 weeks exhibited reductions in body weight gain, fat mass, fat cell volume, and All receptor number. These data further document the presence of a peripheral renin‐angiotensin system in anatomically distinct adipose tissue depots at different stages of growth. While the characterization of the effects of All upon adipose tissue development remains incomplete, future investigations with agents affecting the adipocyte renin‐angiotensin system could provide additional information on the role of this system in adipose tiss

ISSN:0272-4391    

DOI:10.1002/ddr.430320208

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1994

数据来源: WILEY

ISSN:0272-4391    

DOI:10.1002/ddr.430320209

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1994

数据来源: WILEY

ISSN:0272-4391    

DOI:10.1002/ddr.430320201

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1994

数据来源: WILEY