Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hypothalamic neuropeptide Y (NPY) is implicated in the regulation of a variety of physiological functions, notably energy homeostasis and reproduction. Chronically elevated NPY levels in the hypothalamus, as in genetically obese ob/ob mice, are associated with obesity, a syndrome of type 2 diabetes, and infertility. However, it is not known which of the five cloned Y receptors mediate these effects. Here, we show that crossing the Y2 receptor knockout mouse (Y2(-/-)) onto the ob/ob background attenuates the increased adiposity, hyperinsulinemia, hyperglycemia, and increased hypothalamo-pituitary-adrenal (HPA) axis activity of ob/ob mice. Compared with lean controls, ob/ob mice had elevated expression of NPY and agouti-related protein (AgRP) mRNA in the arcuate nucleus and decreased expression of proopiomelanocortin (POMC) and cocaine- and amphetamine-regulated transcript (CART) mRNA. Y2 deletion in ob/ob mice significantly increased the hypothalamic POMC mRNA expression, with no effect on NPY, AgRP, or CART expression. [Y2(-/-)ob/ob] mice were no different from ob/ob littermates with respect to food intake and body weight, and Y2 receptor deficiency had no beneficial effect on the infertility or the reduced hypothalamo-pituitary-gonadotropic function of ob/ob mice. These data demonstrate that Y2 receptors mediate the obese type 2 diabetes phenotype of ob/ob mice, possibly via alterations in melanocortin tonus in the arcuate nucleus and/or effects on the HPA axis.
Diabetes 2002 Dec
PMID:Y2 receptor deletion attenuates the type 2 diabetic syndrome of ob/ob mice. 1245 95

Energy balance is a highly regulated, complex process which is modulated by central and peripheral systems. Dysregulation of energy homeostasis can result in metabolic disorders, such as obesity and type II diabetes. Obesity and type II diabetes are two of the most prevalent and challenging clinical conditions in society today. A growing body of evidence has implicated the melanocortin system as an important component in the maintenance of energy balance. alpha-MSH, a 13 amino acid peptide secreted as a product of the pro-opiomelanocortin (POMC) gene in the pituitary is a potent agonist of 4 of the 5 cloned melanocortin receptors (MCR). MC receptors are members of a G-protein-coupled receptor (GPCR) family, which signal through cAMP. Agouti and agouti-related protein (AGRP) are natural antagonists of melanocortin receptors and participate in regulation of skin/fur pigmentation, body weight, and adiposity. Stimulation of MC receptors has pleiotropic effects, which impact the nervous system as well as endocrine and immune functions. One of the most prominent effects of MC receptor stimulation is a dramatic suppression of food intake and body weight, which has led to the hypothesis that the MC receptor system plays a primary role in the maintenance of energy balance. This idea is supported by a large body of pharmacological, molecular and human genetic evidence. The following review summarizes the role of melanocortin receptors in the regulation of food intake and energy homeostasis and highlights the opportunities for MC receptors as drug development targets in treating eating disorders and diabetes.
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PMID:The role of melanocortin peptides and receptors in regulation of energy balance. 1257 Jul 96

Dyslipidemia is now recognized as a significant potential adverse event in HIV-positive patients who are on ART. The tide of evidence continues to flow between the shore of HIV being the primary factor behind increased cardiovascular risk in HIV-positive patients, and the ocean of HAART being the primary cause. However, there clearly is an association between long-term infection with HIV and metabolic abnormalities. HIV-infected adults should undergo evaluation and treatment based on the NCEP ATP III guidelines. The NCEP recommends non-pharmacologic interventions be given a thorough trial prior to consideration of drug therapy. The recommendations also stipulate that intensive therapy with lipid-lowering medications should be used in individuals with metabolic syndrome. This includes aggressive treatment of hypertension, diabetes, and dyslipidemia. The NCEP also emphasizes the importance of smoking cessation, weight reduction, increased physical activity, and a salubrious diet. The fundamental message still is that physicians must treat HIV infection first. The choice of ART depends on many patient-specific factors, of which cardiovascular risk is only one.
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PMID:Cardiovascular risk among HIV-positive patients on antiretroviral therapy. 1456 35

Anorexia is one of the common symptoms caused by various psychiatric disorders. Increasing evidence indicates that neuroleptics can induce weight gain, obesity, and diabetes mellitus. However, the mechanisms underlying these conditions have not been fully elucidated. In this review, we describe molecular neuroanatomic aspects of current biology of energy homeostasis that would help to address the psychiatric issues noted above, focusing on the central leptin/melanocortin system. An adipocyte-derived hormone, leptin acts on the arcuate hypothalamic nucleus (Arc) to inhibit feeding behavior and simultaneously to promote energy expenditure. Leptin activates Arc neurons producing alpha-melanocyte-stimulating hormone (alpha-MSH) and inhibits those producing agouti-related protein (AgRP). alpha-MSH is an endogenous agonist for the melanocortin-4 receptor (MC4-R) that is expressed exclusively in the central nervous system (CNS), whereas AgRP acts as a MC4-R antagonist. It is also established that MC4-R blockade produces an over-eating/obesity syndrome in rodents and humans. Thus, MC4-R-expressing neurons are downstream targets of leptin. Of interest, MC4-R-positive neurons densely populate in CNS sites critical for energy homeostasis and associated with psychiatric disorders, including the paraventricular hypothalamic nucleus and central amygdaloid nucleus. In addition, Arc alpha-MSH neurons receive serotonergic inputs from raphe neurons. Finally, an AgRP gene polymorphism has been associated with anorexia nervosa. These findings suggest that the central melanocortin system is a target for psychiatry.
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PMID:[Psychiatric disorders and neural mechanisms underlying energy intake and expenditure: a review]. 1465 25

It is well known that peripherally administered growth hormone (GH) results in decreased body fat mass. However, GH-deficient patients increase their food intake when substituted with GH, suggesting that GH also has an appetite stimulating effect. Transgenic mice with an overexpression of bovine GH in the central nervous system (CNS) were created to investigate the role of GH in CNS. This study shows that overexpression of GH in the CNS differentiates the effect of GH on body fat mass from that on appetite. The transgenic mice were not GH-deficient but were obese and showed increased food intake as well as increased hypothalamic expression of agouti-related protein and neuropeptide Y. GH also had an acute effect on food intake following intracerebroventricular injection of C57BL/6 mice. The transgenic mice were severely hyperinsulinemic and showed a marked hyperplasia of the islets of Langerhans. In addition, the transgenic mice displayed alterations in serum lipid and lipoprotein levels and hepatic gene expression. In conclusion, GH overexpression in the CNS results in hyperphagia-induced obesity indicating a dual effect of GH with a central stimulation of appetite and a peripheral lipolytic effect.
Diabetes 2005 Jan
PMID:Growth hormone overexpression in the central nervous system results in hyperphagia-induced obesity associated with insulin resistance and dyslipidemia. 1561 10

Expression of the agouti signaling protein (ASIP) during hair growth produces the red/yellow pigment pheomelanin. ASIP, and its neuropeptide homolog the agouti-related protein (AgRP) involved in energy balance, are novel, paracrine signaling molecules that act as inverse agonists at distinct subsets of melanocortin receptors. Ubiquitous ASIP expression in mice gives rise to a pleiotropic phenotype characterized by a uniform yellow coat color, obesity, overgrowth, and metabolic derangements similar to type II diabetes in humans. Here we report the synthesis and NMR structure of ASIP's active, cysteine-rich, C-terminal domain. ASIP adopts the inhibitor cystine knot fold and, along with AgRP, are the only known mammalian proteins in this structure class. Moreover, ASIP populates two distinct conformers resulting from a cis peptide bond at Pro102-Pro103 and a coexistence of cis/trans isomers of Ala104-Pro105. Pharmacologic studies of Pro-->Ala mutants demonstrate that the minor conformation with two cis peptide bonds is responsible for activity at all MCRs. The loop containing the heterogeneous Ala-Pro peptide bond is conserved in mammals, and suggests that ASIP is either trapped by evolution in this unusual configuration or possesses function outside of strict MCR antagonism.
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PMID:Structures of the agouti signaling protein. 1570 17

Congenital lack of proopiomelanocortin (POMC) causes obesity and glucocorticoid deficiency. The responses of Pomc-/- and wild-type mice to the administration of corticosterone were compared. In study 1, mice were given corticosterone-supplemented water (CORT) for 10 days, resulting in plasma CORT levels within the physiological range, with partial suppression of hypothalamic corticotropin-releasing hormone expression to a similar degree between genotypes. Body weight, fat mass, and food intake increased in CORT-treated Pomc-/- but not wild-type mice. CORT increased plasma insulin levels 50-fold in Pomc-/- versus 14-fold in wild-type mice (P < 0.01) and increased hypothalamic agouti-related protein (AgRP) expression by more than 200% in Pomc-/- versus 40% in wild type (P < 0.05). In study 2, mice were given CORT from weaning, and Pomc-/- but not wild-type mice developed hyperglycemia, ketonuria, and hepatic steatosis by 8-12 weeks. Thus, Pomc-/- mice are hypersensitive to the adverse metabolic effects of glucocorticoids. Additionally, as the levels of plasma CORT achieved, especially in study 1, were not grossly supraphysiological, we conclude that glucocorticoid deficiency may afford Pomc-/- mice some protection from the full adverse consequences of melanocortin deficiency. This may occur through a mechanism involving the suppression of AgRP by the hypoadrenal state.
Diabetes 2005 Aug
PMID:Proopiomelanocortin-deficient mice are hypersensitive to the adverse metabolic effects of glucocorticoids. 1604 91

In this restrospetive study, data on 272 coronary artery disease patients with concomitant diabetes mellitus treated between 12/1997 and 12/2002 were analyzed. Eighty patients inderwent complete arterial revascularization (DM-ART), whereas 192 patients underwent coronary revascularization using arterial-venous grafts (DN-NEART). The following preoperative data and risk factors were analyzed: arterial hypertension, hyperlipoproteinemia, number of vessels involved, left coronary artery stenosis, unstable angina, previous myocardial infarction (MI), previous cardiac surgery, EuroScore. During a 30-day postoperative period, the following complications were analyzed: bleeding, perioperative MI, wound infection, sternal dehiscence, neurologic dysfunction, mortality. DM-ART patients had a higher rate of hyperlipoproteinemia (p=0.004). Difference was only found for the occurrence of perioperative MI in DM-NEART group (p<0.001). Total arterial revascularization without cardiopulmonary bypass is a reliable and safe choice in patients with concomitant diabetes mellitus irrespective of its type. Definitive conclusions can only be made after five- or ten-year evaluation of postoperative mirbidity and mortality.
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PMID:[Advanced myocardial ischemia in patients with diabetes mellitus--early results of surgical treatment]. 1628 70

Stem cell research shows an immense diagnostic and therapeutic potential. The procedures based on human stem cells seem to allow new medical treatments for serious diseases like Parkinson's or Alzheimer's disease, leukaemia or diabetes. However, as no company or inventor would take the risk of immense investments without an adequate legal protection of the possible benefits arising out of their work, intellectual property law plays a pivotal role for the further development of stem cell techniques. Although international patent law knows protection of inventions using biological substances and living matter for about 160 years, patents on stem cells, DNA and other parts of the human body raise specific objections. Nevertheless, from a strictly legal angle, there are no barriers to patents on stem cell procedures. In particular, Art. 6 of the "Directive 98/44/EC of the European Parliament and of the Council of the European Union of July 6, 1998 on the legal protection of biotechnological inventions" - which qualifies inventions as unpatentable where their commercial exploitation would be contrary to ordre public or morality - does not hinder patent protection for stem cell research.
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PMID:Patent protection for stem cell procedures under the law of the European Union. 1629 39

Alpha melanocyte-stimulating hormone (alpha-MSH) is an agonist at the melanocortin 3 (MC3-R) and melanocortin 4 (MC4-R) receptors. Alpha-MSH stimulates corticosterone release from rat and human adrenal cells. Patients with Cushing's syndrome have elevated levels of serum alpha-MSH. Agouti related protein (AgRP) is an endogenous antagonist at the MC3-R and MC4-R and is expressed in the rat adrenal cortex. AgRP antagonises alpha-MSH-induced corticosterone release from rat and bovine adrenal cells. This suggests that AgRP may have an inhibitory paracrine role in the adrenal gland. We measured adrenal AgRP mRNA expression and circulating AgRP in 2 patients with Cushing's syndrome and controls. Adrenal AgRP mRNA expression and plasma AgRP were higher in the patients with Cushing's syndrome compared to controls. Plasma AgRP in the patients with Cushing's syndrome following bilateral adrenalectomy and hydrocortisone replacement were similar to the levels seen in controls. Our results suggest that AgRP may have a novel inhibitory paracrine role in the human adrenal gland.
Exp Clin Endocrinol Diabetes 2005 Dec
PMID:Agouti related protein (AgRP) is upregulated in Cushing's syndrome. 1632 Jan 60


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