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)

Diabetes mellitus (DM), as chronic stress activates the hypothalamo-pituitary-adrenocortical axis. We examined whether arginine vasopressin (AVP) and the hypothalamic paraventricular nucleus (PVN) participate in DM-induced chronic stress symptoms. AVP-deficient Brattleboro or PVN-lesioned Wistar rats were used with heterozygous or sham-operated controls. The rats were studied 2 wk after a single injection of streptozotocin. The appearance of DM (enhanced water consumption and blood glucose elevation) and the chronic stress-like somatic changes (body weight decrease, thymus involution, adrenal gland hypertrophy) were not influenced by the lack of AVP. By contrast, PVN lesion significantly attenuated DM-induced thymus involution and adrenal gland hypertrophy as well as the increase in water consumption. The corticotropin-releasing hormone mRNA in PVN was diminished by DM and elevated by the lack of AVP without interaction. DM elevated the proopiomelanocortin (POMC) mRNA in the anterior lobe of the pituitary. The lack of AVP had no effect, whereas lesioning the PVN significantly diminished the elevation. The elevated basal corticosterone plasma levels detectable in DM were influenced neither by the lack of AVP nor by lesioning the PVN. Thus the lack of AVP had no influence on DM-induced chronic stress symptoms, but lesioning the PVN attenuated part of them. However, the lack of elevation in POMC mRNA after PVN lesion, together with the maintained corticosterone elevation, suggests that direct adrenal gland activation occurs in untreated DM.
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PMID:Hypothalamic paraventricular nucleus, but not vasopressin, participates in chronic hyperactivity of the HPA axis in diabetic rats. 1614 20

Prevalence of uterine progesterone receptors over estrogen ones, high uterine cAMP level, and low uterine prostaglandin level are necessary conditions of normal pregnancy. In cases of spontaneous and antiprogestin RU486-induced abortions, estrogen receptors prevail over progesterone ones, cAMP level decreases, and prostaglandin concentration in decidual tissue increases. Porcine and bovine beta-lipotropines were the first proteins, whose correct amino acid sequence was first determined in Russia. Several research centers carried out collaborative studies of the nucleotide sequences of human and animal proopiomelanocortin (lipotropin precursor) and prolactin cDNA. Researchers constructed genetic engineering producers of human pre-proinsulin and somatostatin, identified structural genes expressed in pancreatic beta-cells, studied antigenic properties of glutamic acid decarboxylase (GAD), which determine insulin-dependent diabetes, and identified the cholesterase determinant. They revealed mutations in the genes of proopiomelanocortin and melanocortin receptors (MC4-P), which inhibit leptin regulation of appetite and are associated with human obesity.
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PMID:[Molecular and genetic study of the role of hormones, receptors, and enzymes in regulation of reproduction, lipid metabolism, and other human physiological functions]. 1625 Mar 24

We have generated mice that carry a neuron-specific leptin receptor (LEPR) transgene whose expression is driven by the rat synapsin I promoter synapsin-LEPR B (SYN-LEPR-B). We have also generated mice that are compound hemizygotes for the transgenes SYN-LEPR-B and neuron-specific enolase-LEPR B (NSE-LEPR-B). We observed a degree of correction in db/db mice that are hemizygous (Syn db/db) and homozygous (Syn/Syn db/db) for the SYN-LEPR-B transgene similar to that previously reported for the NSE-LEPR-B transgene. We also show complete correction of the obesity and related phenotypes of db/db mice that are hemizygous for both NSE-LEPR-B and SYN-LEPR-B transgenes (Nse+Syn db/db). Body composition, insulin sensitivity, and cold tolerance were completely normalized in Nse+Syn db/db mice at 12 weeks of age compared with lean controls. In situ hybridization for LEPR B isoform expression in Nse+Syn db/db mice showed robust expression in the energy homeostasis-relevant regions of the hypothalamus. Expression of 3 neuropeptide genes, agouti-related peptide (Agrp), neuropeptide Y (Npy), and proopiomelanocortin (Pomc), was fully normalized in dual transgenic db/db mice. The 2 transgenes in concert conferred normal fertility to male and female db/db mice. Male mice with partial peripheral deletion of Lepr, induced in the periweaning phase, did not show alterations in body composition or mass. In summary, we show that brain-specific leptin signaling is sufficient to reverse the obesity, diabetes, and infertility of db/db mice.
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PMID:Complete rescue of obesity, diabetes, and infertility in db/db mice by neuron-specific LEPR-B transgenes. 1628 52

Neuropeptide Y receptors are critical regulators of energy homeostasis, but the functional interactions and relative contributions of Y receptors and the environment in this process are unknown. We measured the effects of an ad libitum diet of normal or high-fat food on energy balance in mice with single, double, or triple deficiencies of Y1, Y2, or Y4 receptors. Whereas wild-type mice developed diet-induced obesity, Y2Y4 double knockouts did not. In contrast, Y1 knockout or Y1Y2 or Y1Y4 receptor double knockout mice developed an exacerbated diet-induced obesity syndrome. Remarkably, the antiobesity effect of Y2Y4 deficiency was stronger than the obesogenic effect of Y1 deficiency, since Y1Y2Y4 triple knockouts did not develop obesity on the high-fat diet. Resistance to diet-induced obesity in Y2Y4 knockouts was associated with reduced food intake and improved glucose tolerance in the absence of changes in total physical activity. Fecal concentration of free fatty acids was significantly increased in Y2Y4 knockouts in association with a significantly reduced bile acid pool and marked alterations in intestinal morphology. In addition, hypothalamic proopiomelanocortin expression was decreased in diet-induced obesity (in both wild-type and Y1 receptor knockout mice) but not in obesity-resistant Y2Y4 receptor knockout mice fed a high-fat diet. Therefore, deletion of Y2 and Y4 receptors synergistically protects against diet-induced obesity, at least partially via changes in food intake and hypothalamic proopiomelanocortin expression.
Diabetes 2006 Jan
PMID:Y2Y4 receptor double knockout protects against obesity due to a high-fat diet or Y1 receptor deficiency in mice. 1638 Apr 72

Discrepancy of plasma ACTH levels measured by different immunoradiometric assays (IRMA) in a case with malignant gastric carcinoid causing ectopic ACTH syndrome was examined by gel chromatography and immunohistochemical analysis. A 49-year-old male was found to have a large gastric tumor, with muscle wasting, hypertension, diabetes and hypokalemia caused by hypercortisolemia. His plasma ACTH levels, although initially elevated, were found to be almost in normal ranges. The discrepancy of plasma ACTH levels was proven to be due to different IRMA kits used; the initial assay was performed by a kit that could recognize high-molecular weight (HMW) form as well as ACTH(1-39), but the later assay by another kit that could recognize only ACTH(1-39). Pathological examination of the gastric tumor was consistent with the diagnosis of malignant carcinoid. Immunohistochemical study revealed that immunoreactivity of proopiomelanocortin (POMC) was positive within the tumor cells, whereas those of ACTH and prohormone convertase 1/3 were negative. Molecular sieving analysis of patient's plasma by gel chromatography coupled with ACTH radioimmunoassay which could recognize HMW form and ACTH(1-39) and two different IRMAs revealed that the predominant form of ACTH was HMW form with a minor peak of ACTH(1-39). This is a rare case of ectopic ACTH syndrome caused by malignant gastric carcinoid with preferential production of HMW form of ACTH, possibly due to unprocessed POMC.
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PMID:Malignant gastric carcinoid causing ectopic ACTH syndrome: discrepancy of plasma ACTH levels measured by different immunoradiometric assays. 1641 Jun 67

Congenital deficiency of proopiomelanocortin (POMC) results in a syndrome of hypoadrenalism, severe obesity, and altered skin and hair pigmentation. The concept that subtle variation in POMC expression and/or function might contribute to common obesity is suggested by studies reporting linkage of obesity-related traits to a locus on chromosome 2p22 encompassing the POMC gene. We identified a novel homozygous frameshift (C6906del) mutation in POMC in a child of Turkish origin with severe obesity and hypoadrenalism. This mutation would be predicted to lead to the loss of all POMC-derived peptides. The availability of a large extended pedigree provided the opportunity to address whether loss of one copy of the POMC gene was sufficient to alter obesity risk. Twelve relatives were heterozygous for the mutation and 7 were wild type. Of the heterozygotes, 11 of 12 heterozygotes were obese or overweight compared with only 1 of 7 of the wild-type relatives. The mean BMI SD score was 1.7 +/- 0.5 in heterozygotes and 0.4 +/- 0.4 in the wild-type relatives. Parametric linkage analysis of the trait "overweight" provided statistically significant evidence of linkage with this locus, with a maximum "location score" (comparable with multipoint logarithm of odds scores) of 3.191. We conclude that loss of one copy of the POMC gene predisposes to obesity in humans. Thus, genetic variants having relatively subtle effects on POMC expression and function could influence susceptibility to obesity.
Diabetes 2006 Sep
PMID:Heterozygosity for a POMC-null mutation and increased obesity risk in humans. 1693 3

Because appetite, hypothalamic gene expression, reproductive function, and adrenal function are highly sensitive to acute changes in plasma glucose levels, it has been hypothesized hypothalamic neurons sensitive to glucose play a role in regulating these functions. To assess this hypothesis, we examined these neuronendocrine functions in mice in which the glucokinase gene, which plays an essential role in neuroendocrine glucose sensing, has been ablated. Haploinsufficiency in heterozygous glucokinase knockout mice produced effects similar to those produced by hypoglycemia: impaired reproductive function, elevated plasma corticosterone, increased food intake, and hypothalamic gene expression similar to that observed in fasted or leptin-deficient obese mice (increased hypothalamic neuropeptide Y mRNA and reduced hypothalamic proopiomelanocortin mRNA). Plasma glucose was elevated 2-fold in glucokinase knockout mice, consistent with a maturity-onset diabetes of the young phenotype, but plasma insulin and leptin levels were normal. These data support the hypothesis that glucokinase plays a key role in the neuroendocrine regulation of metabolic economy.
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PMID:Glucokinase regulates reproductive function, glucocorticoid secretion, food intake, and hypothalamic gene expression. 1721 12

Elevated anxiety symptoms have been reported to be present in many patients with diabetes mellitus. The underlying mechanisms by which diabetes mellitus influences behavior remain to be determined. We assessed feeding and anxiety behaviors in spontaneously diabetic Ins2Akita mice. We measured blood glucose, body weight, and food and water intakes in C57BL/6 heterozygote Ins2Akita mice. The behavioral properties of Ins2Akita mice were assessed in an open-field test and an elevated plus-maze. The gene expression of hypothalamic neuropeptides was examined in non-food-deprived Ins2Akita mice. Body weights of the Ins2Akita mice were less than those of the age-matched C57BL/6 mice, as controls. Food and water intakes were increased in the Ins2Akita mice. In the open-field test, the Ins2Akita mice had decreased locomotor activity and increased immobilization time. The Ins2Akita mice exhibited anxiety behavior in the elevated plus-maze. RT-PCR analysis showed decreased proopiomelanocortin (POMC) mRNA expression and increased agouti-related protein (AGRP) mRNA expression in Ins2Akita mice. There were no significant differences in hypothalamic ghrelin mRNA expression. These observations indicate that Ins2Akita mice, which are characterized by hypoinsulinemia and hyperglycemia, exhibited hyperphagia and anxiety behavior; the mechanism of action involved the activation of hypothalamic AGRP and the inactivation of hypothalamic POMC. In addition, Ins2Akita mice are a useful model for understanding the mechanisms involved in the psychological complications of diabetes mellitus. Further, melanocortin systems may be therapeutic targets not only for diabetes but also for its associated complications.
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PMID:Ins2Akita mice exhibit hyperphagia and anxiety behavior via the melanocortin system. 1733 40

In the present review, we discuss the sorting mechanism of peptide hormones and the biogenesis mechanism of secretory granules in view of the significance of the high cholesterol composition of secretory granule membranes. Peptide hormones and granin-family proteins are sorted to immature budding granules at the trans-Golgi network in neuroendocrine cells. Two models have been proposed for granule protein sorting: "aggregation-mediated sorting" and "receptor-mediated sorting". In the aggregation-mediated sorting model, granin-family proteins such as chromogranin A and B form aggregates with peptide hormones in weakly acidic, high calcium milieu of the budding granules. Chromogranins have a disulfide loop at their N-terminal at which they bind to the budding granular membrane, and bring hormones to the granules. In the receptor-mediated sorting model, carboxypeptidase E and/or secretogranin III function as a sorting receptor for peptide hormones. They bind peptide hormones, such as proopiomelanocortin, and have a high-cholesterol-binding domain. Since secretory granule membranes contain high levels of cholesterol, peptide hormones are brought to the secretory granules by these receptors. Although the two models have been conflicting, we suggest that both are cooperative and compensating each other for the sorting of peptide hormones and the biogenesis of secretory granules.
Curr Diabetes Rev 2008 Feb
PMID:Sorting mechanism of peptide hormones and biogenesis mechanism of secretory granules by secretogranin III, a cholesterol-binding protein, in endocrine cells. 1822 Jun 93

Exercise is a mechanism for maintenance of body weight in humans. Morbidly obese human patients have been shown to possess single nucleotide polymorphisms in the melanocortin-4 receptor (MC4R). MC4R knockout mice have been well characterized as a genetic model that possesses phenotypic metabolic disorders, including obesity, hyperphagia, hyperinsulinemia, and hyperleptinemia, similar to those observed in humans possessing dysfunctional hMC4Rs. Using this model, we examined the effect of voluntary exercise of MC4R knockout mice that were allowed access to a running wheel for a duration of 8 wk. Physiological parameters that were measured included body weight, body composition of fat and lean mass, food consumption, body length, and blood levels of cholesterol and nonfasted glucose, insulin, and leptin. At the termination of the experiment, hypothalamic mRNA expression levels of neuropeptide Y (NPY), agouti-related protein (AGRP), proopiomelanocortin (POMC), cocaine- and amphetamine-regulated transcript (CART), orexin, brain-derived neurotropic factor (BDNF), phosphatase with tensin homology (Pten), melanocortin-3 receptor (MC3R), and NPY-Y1R were determined. In addition, islet cell distribution and function in the pancreas were examined. In the exercising MC4R knockout mice, the pancreatic islet cell morphology and other physiological parameters resembled those observed in the wild-type littermate controls. Gene expression profiles identified exercise as having a significant effect on hypothalamic POMC, orexin, and MC3R levels. Genotype had a significant effect on AGRP, POMC, CART, and NPY-Y1R, with an exercise and genotype interaction effect on NPY gene expression. These data support the hypothesis that voluntary exercise can prevent the genetic predisposition of melanocortin-4 receptor-associated obesity and diabetes.
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PMID:Voluntary exercise prevents the obese and diabetic metabolic syndrome of the melanocortin-4 receptor knockout mouse. 1897 Dec 58


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