Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0028754 (obesity)
 124,988 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The tripeptide hormone, TRH, is metabolized by three enzymes, the most specific of which is pyroglutamyl peptide hydrolase-II (also termed thyroliberinase), a metalloenzyme present in serum and brain. Because pyroglutamyl peptidase-II activity in rat serum is regulated by thyroid hormone levels, we tested the hypothesis that this activity is similarly altered in humans. We studied serum pyroglutamyl peptidase-II activity in 6 patients with hyperthyroidism, 18 patients with hypothyroidism, and 31 euthyroid, normal weight volunteers. Because TRH [or its metabolite cyclo(His-Pro)] is believed to be an important hormone regulating appetite and metabolism, we also evaluated pyroglutamyl peptidase-II activity in 27 euthyroid patients with obesity. Serum pyroglutamyl peptidase-II activity was elevated in patients with hypothyroidism (mean +/- SEM, 33.9 +/- 3.7 nmol/mL.h) compared to that in euthyroid, normal weight volunteers (24.5 +/- 2.8 nmol/mL.h; P < 0.05), but not that in patients with hyperthyroidism (28.3 +/- 4.1 nmol/mL.h; P = NS). Euthyroid obese patients had the highest pyroglutamyl peptidase-II activity (43.6 +/- 2.8 nmol/mL.h; P < 0.0001 vs. normal weight volunteers). Pyroglutamyl peptidase-II activity was positively correlated with body mass index (r2 = 0.30; P < 0.0001). After correction for body mass index, there were no difference in pyroglutamyl peptidase-II activity in hypothyroid, hyperthyroid, and euthyroid individuals. We conclude that serum pyroglutamyl peptidase-II activity is regulated by, or regulates, body weight.
 ...
PMID:Pyroglutamyl peptidase-II ("thyroliberinase") activity in human serum: influence of weight and thyroid status. 771 73

GLP-1 lowers blood glucose in fasting type 2 diabetic patients. To clarify the relation of the effect of GLP-1 to obesity, blood glucose, beta-cell function, and insulin sensitivity, GLP-1 (1.2 pmol/kg.min) was infused iv for 4-6 h into 50 fasting type 2 diabetic patients with a wide range of age, body mass index, HbA1c, and fasting plasma glucose. The effectiveness of GLP-1 was evaluated by calculation of a glucose disappearance constant for each individual (Kg, linear slope of log-transformed plasma glucose), and by the lowest stable glucose level (Nadir plasma glucose) obtained during the infusion. Grouped according to fasting plasma glucose (<10, 10-15, >15 mmol/liter), Kg values were 0.45 +/- 0.03, 0.38 +/- 0.04, and 0.28 +/- 0.04%/min (P = 0.005), and Nadir plasma glucose values were 4.7 +/- 0.1 (3.9-5.9), 5.8 +/- 0.4 (4.3-8.4), and 8.7 +/- 1.4 (6.2-18.7) mmol/liter (P = 0.0003). Nonresponders were not identified. Multiple regression analysis with Kg or Nadir plasma glucose as the dependent parameter and body mass index, age, gender, diabetes duration, and significantly correlated parameters (in multiple regression for Kg: fasting plasma glucose, fasting nonesterified fatty acid, dipeptidyl peptidase activity, peak insulin, and the logarithm of beta-cell function; and for Nadir plasma glucose: fasting plasma glucose, fasting nonesterified fatty acid, dipeptidyl peptidase activity, delta glucagon decrement, F-GLP-1 total, logarithm of beta-cell function, and Kg) as independent parameters resulted in fasting plasma glucose as the only significant predictor of Kg, and fasting plasma glucose and Kg as predictors of Nadir plasma glucose. Kg and Nadir plasma glucose were neither influenced by treatment nor by neuropathy per se. In conclusion, GLP-1 lowers plasma glucose in type 2 diabetes regardless of severity, but glucose elimination is faster and obtained glycemic level lower in patients with the lower fasting plasma glucose. Not all patients can be expected to reach normoglycemia.
 ...
PMID:Determinants of the effectiveness of glucagon-like peptide-1 in type 2 diabetes. 1150 23

It is well known that adrenalectomy (ADX) reverses the eating and energy balance disturbances in a variety of models of obesity associated with elevated food intake. We have previously demonstrated enhanced functional activity in the small intestine of neonatally monosodium glutamate-treated (MSG) obese rats despite the absence of overeating and we concluded that these changes might also contribute to the development of MSG obesity. The objective of the present experiments was to investigate whether ADX would affect the small intestinal functions and whether their changes would counteract attenuation or prevention of obesity development in MSG rats. Therefore the investigation was carried out in MSG-obese Wistar male rats and untreated intact rats adrenalectomized on day 40, as well as in lean littermates of MSG rats and intact rats subjected to Sham-ADX surgery. All animals had free access to a standard pellet diet after weaning. At the age of 80 days, body mass, body fat content and food consumption as well as changes of the brush-border-bound duodenal and jejunal alkaline phosphatase (AP), the dipeptidyl(amino)peptidase IV (DPP IV) and maltase activity were measured. During the postoperative period, ADX resulted in a significant decrease of mass gain in both MSG and control rats (P<0.05). ADX fully prevented the development of obesity in MSG rats (significantly decreased epididymal+retroperitoneal fat pad mass, P<0.05) and increased mean daily food intake (P<0.001). These effects were only minimal in the ADX controls suggesting that enhanced adrenal secretion is involved in the expression of MSG obesity and its complications. The AP activity in obese MSG rats was increased by about 21 % (P<0.01) in both intestinal segments when compared to the lean controls, whereas no parallel variations in the activities of DPP IV and maltase were observed in the intestinal parts mentioned. In MSG rats, ADX significantly reduced the AP activity in the duodenum and jejunum (P<0.01). A similar tendency was also seen in the DPP IV activity of adrenalectomized MSG rats as well as in lean control rats. Nevertheless, no significant effect of adrenal withdrawal on maltase activity was found. These results indicate that the decrease of enzyme activities in the small intestine and the different effectiveness of nutrient absorption might be a significant factor preventing the development of excess adiposity in glutamate-treated rats. This information contributes to a better understanding of the importance of small intestinal function for the development of obesity and its maintenance in later life.
 ...
PMID:Effect of adrenalectomy on the activity of small intestine enzymes in monosodium glutamate obese rats. 1531 1

The coexistence of type 2 diabetes and obesity presents a complex therapeutic challenge. Future combination tablets may include agents to address diabetes and any accompanying cardiovascular risk factors. Injectable agents that improve glycemic control and facilitate weight loss have recently become available: the soluble amylin analogue pramlintide provides an adjunct to insulin therapy in type 1 and type 2 diabetes, and the incretin mimetic exenatide can enhance prandial insulin release in type 2 diabetes. Orally active inhibitors of the incretin-degrading enzyme dipeptidyl peptidase-IV, agonists of peroxisome proliferator-activated receptor (PPAR)-a and PPAR-g ("dual PPARs"), and the CB1 cannabinoid receptor inhibitor rimonabant are advanced in clinical development. Many novel antidiabetic and antiobesity compounds are emerging in preclinical development.
 ...
PMID:Drugs on the horizon for diabesity. 1618 70

Metabolic effects of the glucagon-like peptide-1 analog liraglutide and the dipeptidyl peptidase-IV inhibitor vildagliptin were compared in rats made obese by supplementary candy feeding. Female Sprague-Dawley rats were randomized to 12-week diets of chow or chow plus candy. The latter were randomized for 12 further weeks to continue their diet while receiving 0.2 mg/kg liraglutide twice daily subcutaneously, 10 mg/kg vildagliptin twice daily orally, or vehicle or to revert to chow-only diet. Energy expenditure was measured, and oral glucose tolerance tests (OGTTs) were performed. Body composition was determined by dual-energy X-ray absorptiometry scanning, and pancreatic beta-cell mass was determined by histology. Candy feeding increased weight, fat mass, and feeding-associated energy expenditure. Liraglutide or reversal to chow diet fully reversed weight and fat gains. Liraglutide was associated with decreased calorie intake and shifted food preference (increased chow/decreased candy consumption). Despite weight loss, liraglutide-treated rats did not decrease energy expenditure compared with candy-fed controls. Vildagliptin affected neither weight, food intake, nor energy expenditure. OGTTs, histology, and blood analyses indirectly suggested that both drugs increased insulin sensitivity. Liraglutide and vildagliptin inhibited obesity-associated increases in beta-cell mass. This was associated with weight and fat mass normalization with liraglutide, but not vildagliptin, where the ratio of beta-cell to body mass was low.
 ...
PMID:Liraglutide, a long-acting glucagon-like peptide-1 analog, reduces body weight and food intake in obese candy-fed rats, whereas a dipeptidyl peptidase-IV inhibitor, vildagliptin, does not. 1719 59

By itself, glucagon-like peptide-1(GLP-1) appears to be an excellent drug for appetite control and the treatment of obesity. Unfortunately, few enzymes, such as IV dipeptidyl peptidase and renal excretin, degrade and render GLP-1 inactive within minutes. A receptor agonist, exendin-4, with a longer biological half-life than GLP-1, has been tried. Subcutaneous injection of exendin-4 or continuous IV injection of GLP-1 warrants further research and investigation.
 ...
PMID:The multiple faces of glucagon-like peptide-1--obesity, appetite, and stress: what is next? A review. 1726 38

The majority of patients with type 2 diabetes mellitus are overweight or obese at the time of diagnosis, and obesity is a recognised risk factor for type 2 diabetes and coronary heart disease (CHD). Conversely, weight loss has been shown to improve glycaemic control in patients with type 2 diabetes, as well as to lower the risk of CHD. The traditional pharmacotherapies for type 2 diabetes can further increase weight and this may undermine the benefits of improved glycaemic control. Furthermore, patients' desire to avoid weight gain may jeopardise compliance with treatment, thereby limiting treatment success and indirectly increasing the risk of long-term complications. This review evaluates the influences of established and emerging therapies on bodyweight in type 2 diabetes. Improvement in glycaemic control with insulin secretagogues has been associated with weight gain. On the other hand, biguanides such as metformin have been consistently shown to have a beneficial effect on weight; metformin appears to modestly reduce weight when used as a monotherapy. alpha-Glucosidase inhibitors are considered weight neutral; in fact, the results of some studies show that they cause reductions in weight. Thiazolidinediones (TZDs) are typically associated with weight gain and increased risk of oedema, while the impact of some TZDs, such as pioglitazone, on lipid homeostasis could be beneficial. Insulin, the most effective therapy when oral agents are ineffective, has always been linked to significant weight gain. Newly developed insulin analogues can lower the risk of hypoglycaemia compared with human insulin, but most have no advantage in terms of weight gain. The basal analogue insulin detemir, however, has been demonstrated to cause weight gain to a lesser extent than human insulin. The emerging treatments, such as glucagon-like peptide-1 agonists and the amylin analogue, pramlintide, seem able to decrease weight in patients with type 2 diabetes, whereas dipeptidyl peptidase-4 inhibitors seem to be weight neutral. In summary, while reduction of hyperglycaemia remains the foremost goal in the treatment of patients with type 2 diabetes, the avoidance of weight gain may be a clinically important secondary goal. This is already possible with careful selection of available therapies, while several emerging therapies promise to further extend the options available.
 ...
PMID:Bodyweight changes associated with antihyperglycaemic agents in type 2 diabetes mellitus. 1803 65

We measured gene expression of paracrine regulators involved in adipocyte differentiation within the stromovascular fraction of abdominal subcutaneous adipose tissue from obese individuals with (n=30) and without (n=18) type 2 diabetes mellitus (T2DM). Despite similar adiposity by design, subjects with T2DM had larger adipocytes (0.92+/-0.28 vs. 0.75+/-0.17 microl, p<0.05) than controls. Gene expression of the adipogenic marker aP2 was lower (0.35+/-0.16 vs. 0.58+/-0.27 arbitrary units, p<0.05) whereas the expression of matricellular peptidase, MMP2 was higher (1.65+/-0.17 vs. 1.27+/-0.21, p=0.02) in T2DM vs. controls. The gene expression levels between the aP2 and MMP2 were inversely correlated (r=-0.32, p=0.03). We conclude that early steps of adipogenesis may be impaired in T2DM independently of obesity due, in part, to an upregulation of the MMP2 transcription.
 ...
PMID:Potential role of increased matrix metalloproteinase-2 (MMP2) transcription in impaired adipogenesis in type 2 diabetes mellitus. 1818 54

The prevalence of obesity has been increasing dramatically in the last decades; the major metabolic complication of obesity is insulin resistance and type-2 diabetes because there are pathogenetic mechanisms linking obesity and type-2 diabetes. Diabetes is also rapidly increasing worldwide; such a description of the key stages in the evolution of type-2 diabetes may be of great interest for implementing antidiabetes treatment. In recent times, type-2 diabetes therapy has been based on drugs, which improve insulin sensibility or stimulate insulin secretion or slow down glucose absorption. Recently, an ADA and EASD consensus has been released to develop a common approach for the management of hyperglycaemia in adults. The development of new classes of blood-glucose-lowering medications to supplement the older therapies, such as lifestyle-directed interventions, insulin, sulfonylureas, and metformin, has increased the different possible options for the treatment of type-2 diabetes. Therapeutic approaches aiming to potentiate the biological effects of incretins include degradation-resistant GLP-1 receptor agonists (incretin mimetics), and inhibitors of dipeptidyl peptidase-IV (DPP-IV) activity (incretin enhancers) will be very useful to slow down type-2 diabetes progression. Weight-loss interventions, such as a hypocaloric diet and physical exercise, in addition to agents such as orlistat, sibutramine and cannabinoid receptor antagonists, may have favourable effects upon fat storage, nutrient metabolism and ultimately glucose tolerance or type-2 diabetes. When the therapeutic target is not achieved, insulin with metformin could be suggested, but is this approach the ideal one for all patients? Perhaps it is possible to delay the initiation of insulin therapy, therefore, the actual and future therapeutical options are considered in the present review.
 ...
PMID:Time to insulin in type-2 diabetes: high hurdles or Santiago way? 1840 82

Type 2 diabetes mellitus and obesity share a pathogenic relationship, and both have rapidly increased in prevalence over the past decade. This review evaluates the effects of antidiabetes therapies on weight and glycemic control in the type 2 diabetes mellitus population. A PubMed search was conducted to identify randomized controlled trials that reported the weight effects of antidiabetes treatments. The search focused on the newer incretin-based therapies, including dipeptidyl peptidase-4 (DPP-4) inhibitors and glucagon-like peptide-1 (GLP-1) agonists. Antiobesity drugs and treatment options potentially available to patients with type 2 diabetes mellitus, including bariatric surgery, were also examined. Most of the established antidiabetes therapies (eg, sulfonylureas, thiazolidinediones) promote weight gain, thereby exacerbating insulin resistance and glucose intolerance. Dipeptidyl peptidase-4 inhibitors exhibit a weight-neutral profile, however, and GLP-1 receptor agonists (eg, exenatide, liraglutide) have achieved significant body weight reductions in spite of improved glycemic control, which is often accompanied by weight gain. Antiobesity drugs, such as orlistat and sibutramine, are effective weight-lowering agents in patients with type 2 diabetes mellitus, but safety and tolerability concerns may limit their use. Bariatric surgery in obese patients is associated with improved glycemic values and decreased mortality. Clinical evidence substantiating the weight-neutral effects of DPP-4 inhibitors and the weight-loss effects of GLP-1 agonists is promising, offering an expansion of therapeutic options for overweight and obese patients with type 2 diabetes mellitus. Evidence on the clinical utility of antiobesity drugs is more equivocal, and more data are needed to evaluate the safety and tolerability of these agents.
 ...
PMID:The effects of pharmacologic agents for type 2 diabetes mellitus on body weight. 1865 64


1 2 3 4 5 6 7 8 9 10 Next >>