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)

We previously reported that adiposity and serum leptin levels increase with age in male F-344xBN rats and that when physiological levels of serum leptin are manipulated by fasting, there is a corresponding reciprocal change in hypothalamic neuropeptide Y (NPY) mRNA in young rats, but there are no changes in older rats. These findings suggest that the regulation of hypothalamic NPY mRNA by leptin may be impaired with age. To test this hypothesis, we infused saline or leptin for 7 days into ad libitum-fed rats and compared these with saline-infused rats that were pair-fed the amount of food consumed by the leptin-treated rats. We examined daily food consumption, body weight, whole-body oxygen consumption, serum leptin, and NPY mRNA in the hypothalamus. Food consumption decreased by 50% in the leptin-infused compared with the saline-infused young rats but only decreased by 20% in the aged rats. In the leptin-treated young rats, there was a 24% increase in oxygen consumption compared with the pair-fed rats, but there were no changes in oxygen consumption in the aged rats. Leptin infusion diminished hypothalamic NPY levels by nearly 50% compared with pair-fed young rats, whereas there were no changes in the hypothalamic NPY mRNA levels in senescent rats. In summary, aged rats demonstrate a reduced responsiveness to leptin, including a diminished decrease in food intake and no increase in energy expenditure. These diminished responses to leptin were associated with and may be the result of an impaired suppression of hypothalamic NPY mRNA levels. This leptin resistance may be due to either the elevated obesity and serum leptin with age or due to age itself, or both.
Diabetes 2000 Mar
PMID:Impaired leptin responsiveness in aged rats. 1086 65

The brain contains a subpopulation of glucosensing neurons that alter their firing rate in response to elevated glucose concentrations. In pancreatic beta-cells, glucokinase (GK), the rate-limiting enzyme in glycolysis, mediates glucose-induced insulin release by regulating intracellular ATP production. A similar role for GK is proposed to underlie neuronal glucosensing. Via in situ hybridization, GK mRNA was localized to hypothalamic areas that are thought to contain relatively large populations of glucosensing neurons (the arcuate, ventromedial, dorsomedial, and paraventricular nuclei and the lateral area). GK also was found in brain areas without known glucosensing neurons (the lateral habenula, the bed nucleus stria terminalis, the inferior olive, the retrochiasmatic and medial preoptic areas, and the thalamic posterior paraventricular, interpeduncular, oculomotor, and anterior olfactory nuclei). Conversely, GK message was not found in the nucleus tractus solitarius, which contains glucosensing neurons, or in ependymal cells lining the third ventricle, where others have described its presence. In the arcuate nucleus, >75% of neuropeptide Y-positive neurons also expressed GK, and most GK+ neurons also expressed KIR6.2 (the pore-forming subunit of the ATP-sensitive K+ channel). The anatomic distribution of GK mRNA was confirmed in micropunch samples of hypothalamus via reverse transcription-polymerase chain reaction (RT-PCR). Nucleotide sequencing of the recovered PCR product indicated identity with nucleotides 1092-1411 (within exon 9 and 10) of hepatic and beta-cell GK. The specific anatomic localization of GK mRNA in hypothalamic areas known to contain glucosensing neurons and the coexpression of KIR6.2 and NPY in GK+ neurons support a role for GK as a primary determinant of glucosensing in neuropeptide neurons that integrate multiple signals relating to peripheral energy metabolism.
Diabetes 2000 May
PMID:Localization of glucokinase gene expression in the rat brain. 1090 75

Hypoglycemia reduces sympathoadrenal responses to subsequent hypoglycemic bouts by an unknown mechanism. To assess whether such hypoglycemia-associated autonomic failure is due to actual brain damage, male Sprague-Dawley rats underwent 1-h bouts of insulin-induced (5 U/kg i.v.) hypoglycemia (1.6-2.8 mmol/l) 1 or 3 times on alternate days. Rats remained alert and were rescued with intravenous glucose at 60-80 min. Plasma epinephrine and corticosterone responses were significantly reduced during the second and third bouts. Brains from these rats were processed by the terminal transferase-mediated deoxyuridine triphosphate-biotin nick end-labeling (TUNEL) procedure as an index of apoptotic cell death at 24, 48, or 96 h after their first bout. At 48 h, but not 24 h, TUNEL+ cells were consistently seen only in the arcuate nucleus (arcuate hypothalamic nucleus [ARC]). Hypoglycemic rats had 188% more apoptotic ARC cells (1 bout 39+/-5; 3 bouts 37+/-4) than euglycemic controls (13+/-3;P = 0.001). In situ hybridization for neuropeptide Y (NPY) and proopiomelanocortin (POMC) mRNA was performed in sections of ARC containing maximal numbers of apoptotic cells as well as in other fresh frozen brains. After 1 bout, NPY (0.041+/-0.003) and POMC (0.119+/-0.022) mRNA were decreased, respectively, by 52 and 55% vs. controls (NPY 0.076+/-0.007; POMC 0.222+/-0.020; P = 0.01). NPY (0.029+/-0.002) but not POMC (0.093+/-0.013) fell 29% further after a third bout. NPY (r = -0.721; P = 0.001) and POMC (r = -0.756; P = 0.001) mRNA levels correlated negatively with the number of apoptotic ARC cells in the same sections. Thus, non-coma hypoglycemia produces apparent apoptotic cell death with reduced NPY and POMC expression selectively in the ARC. This may contribute to the reduced counterregulatory response following repeated bouts of hypoglycemia.
Diabetes 2000 May
PMID:Presumed apoptosis and reduced arcuate nucleus neuropeptide Y and pro-opiomelanocortin mRNA in non-coma hypoglycemia. 1090 92

Obesity is a common problem in Western society and is associated with significant morbidity and mortality. Energy homeostasis is regulated by a complex system involving both peripheral signals such as leptin and a number of orexigenic and anorectic neuropeptides. Obesity can result from dysregulation of the peripheral and/or central signals. Melanin-concentrating hormone (MCH) is a hypothalamic peptide that is important in the regulation of feeding behavior, primarily via uncharacterized signaling pathways in the central nervous system. Leptin, expressed in adipose tissue, mediates some of its actions through several hypothalamic neuropeptides, notably agouti-related peptide, proopiomelanocortin, and neuropeptide Y. Expression of leptin is regulated by dietary status, insulin, and glucocorticoids. Furthermore, certain neuropeptides may act on adipocytes. However, the potential effect of MCH has not been investigated. We report that MCH stimulates leptin mRNA expression and leptin secretion. MCH stimulated a 2-fold increase in leptin secretion by isolated rat adipocytes after 4 h of treatment. This increase in secreted leptin was preceded by a rapid and transient increase in ob mRNA levels; MCH stimulated a 2.5-fold increase in ob mRNA within 1 h of treatment, followed by a decline to basal levels within 4 h. In addition, we demonstrate that the MCH receptor SLC-1 is expressed in adipocytes, suggesting that fat cells may be targets of MCH or an MCH-like peptide under physiological conditions. Finally, using a radioimmunoassay, MCH/MCH-like peptide was detected in rat plasma. This study establishes a novel in vitro mammalian system for examining MCH signaling pathways.
Diabetes 2000 Jul
PMID:Melanin-concentrating hormone regulates leptin synthesis and secretion in rat adipocytes. 1090 60

In this study we tested the hypothesis that the Leu7Pro7 polymorphism in prepro neuropeptide Y (NPY) gene could be a risk marker for the development of diabetic retinopathy and analyzed a well characterized cohort of patients with Type 2 diabetes followed-up for 10 years from the time of diagnosis. The frequency of Leu7/Pro7-polymorphism was 9.3% (8 out of 86). At baseline, the frequency of retinopathy in patients with the Leu7/Pro7-polymorphism was 25% (2 out of 8) and in those without it 6.4% (5 out of 78) (p=0.126). At 10-year the respective figures were 88% and 50% (p=-0.040). The odds ratio for Leu7/Pro7-polymorphism in logistic regression analysis adjusted for age, gender and HbA1c was 8.97 (95% confidence intervals 1.09-98.0; p=0.049). Our finding based on elderly Finnish Type 2 diabetic subjects suggests that the Leu7Pro7-genotype in preproNPY gene is associated with the development of diabetic retinopathy.
Exp Clin Endocrinol Diabetes 2000
PMID:Leucine 7 to proline 7 polymorphism in the neuropeptide y gene is associated with retinopathy in type 2 diabetes. 1092 22

Gastrointestinal symptoms in diabetic patients are commonplace, and are believed to be due, at least partly, to neuropathy of the gut. In the present study, therefore, some important neurotransmitters in the myenteric plexus were investigated in non-obese diabetic mice, an animal model of human type 1 diabetes. For this purpose, immunocytochemistry was applied on sections from antrum, duodenum and colon, subsequently quantified by computerized image analysis. Whereas the number of vasoactive intestinal peptide (VIP)-positive neurons was increased in antral myenteric ganglia of diabetic mice, there was a decreased density of nerve fibres in muscularis propria. No difference was seen in the VIP of duodenum and colon. Acetylcholine-containing nerve fibres showed an increased volume density in muscularis propria of antrum and duodenum, but a decreased density in colon of diabetic mice, as compared with controls. There was a decreased number of neurons containing nitric oxide synthase (NOS) in myenteric ganglia of antrum and duodenum. No difference was seen in density of NOS-containing nerve fibres in muscularis propria. There was no difference regarding neuropeptide Y (NPY) and galanin between diabetic and control mice; nor was there any difference between pre-diabetic NOD mice and controls regarding all bioactive substances investigated. It is concluded that the diabetic state affects the innervation of gut in this animal model. The present findings may be of some relevance to the gastrointestinal symptoms seen in patients with diabetes.
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PMID:Diabetic state affects the innervation of gut in an animal model of human type 1 diabetes. 1096 18

The hypothalamus plays a major role in the control of energy balance via the coordination of several neuropeptides and their receptors. We used a unique polygenic animal model of obesity, Psammomys obesus, and performed differential display polymerase chain reaction on hypothalamic mRNA samples to identify novel genes involved in obesity. In this study, we describe a novel gene that encodes a small protein we have termed "beacon." Beacon mRNA gene expression in the hypothalamus was positively correlated with percentage of body fat. Intracerebroventricular infusion of beacon resulted in a dose-dependent increase in food intake and body weight and an increase in hypothalamic expression of neuropeptide Y (NPY). Simultaneous infusion of beacon and NPY significantly potentiated the orexigenic response and resulted in rapid body weight gain. These data suggest a role for beacon in the regulation of energy balance and body weight homeostasis that may be mediated, at least in part, through the NPY pathway.
Diabetes 2000 Nov
PMID:Beacon: a novel gene involved in the regulation of energy balance. 1107 42

Leptin mediates neuroendocrine responses to fasting and restores the starvation-induced changes of several hypothalamic neuropeptides. Ciliary neurotrophic factor (CNTF), a cytokine closely related to leptin, reduces food intake and reverses obesity, but its role in restoring the starvation-induced changes of hormones or hypothalamic neuropeptides remains largely unknown. To comparatively assess the roles of CNTF and leptin in reversing the starvation-induced changes of hypothalamic neuropeptides and endocrine function and in inducing expression of hypothalamic inhibitors of leptin and CNTF signaling (suppressor of cytokine signaling 3 [SOCS-3]) and mediators of energy expenditure (cyclo-oxygenase 2 [COX-2]), we studied the effect of CNTF and leptin administered by intraperitoneal injections (1 microg/g twice daily) in C57Bl/6J mice fasted for 48 h. Serum corticosterone levels increased with fasting, and leptin administration partially normalized them, whereas CNTF administration had no effect. Hypothalamic neuropeptide Y (NPY) and agouti-related protein (AgRP) mRNA expression increased and pro-opiomelanocortin (POMC) decreased in response to fasting. Leptin administration decreased NPY and AgRP and increased POMC mRNA levels toward baseline, but CNTF administration in fasted mice had no effect of comparable significance. Both leptin and CNTF administration in fasted mice resulted in an induction of SOCS-3 mRNA expression. CNTF also induced hypothalamic SOCS-2 mRNA expression. Finally, neither leptin nor CNTF administration in mice fasted for 48 h alters hypothalamic COX-2 expression. Our data suggest that only falling leptin levels mediate the starvation-induced alterations in corticosterone levels and expression of hypothalamic neuropeptides, but inhibitors of leptin signaling are induced by both leptin and CNTF. This may be of clinical importance because both agents are now being evaluated for the treatment of obesity in humans.
Diabetes 2000 Nov
PMID:Unlike leptin, ciliary neurotrophic factor does not reverse the starvation-induced changes of serum corticosterone and hypothalamic neuropeptide levels but induces expression of hypothalamic inhibitors of leptin signaling. 1107 56

In genetically obese leptin-deficient ob/ob mice, adrenalectomy reverses or attenuates the obese phenotype. Relative to lean controls, ob/ob mice also exhibit decreased hypothalamic proopiomelanocortin (POMC) mRNA and increased hypothalamic agouti-related peptide (AGRP) mRNA and neuropeptide Y (NPY) mRNA. It has been hypothesized that this profile of hypothalamic gene expression contributes to the obese phenotype caused by leptin deficiency. To assess if reversal of obese phenotype by adrenalectomy entails normalization of hypothalamic gene expression, male wild-type and ob/ob mice were adrenalectomized (with saline supplementation) or sham adrenalectomized at 2 months of age. Mice were sacrificed 2 weeks after adrenalectomy, during which time food intake and body weight were monitored daily. After sacrifice, hypothalamic gene expression was assessed by Northern blot analysis as well as in situ hybridization. In wild-type mice, adrenalectomy significantly decreased AGRP mRNA but did not significantly influence POMC or NPY mRNA. In ob/ob mice, adrenalectomy reduced the levels of plasma glucose, serum insulin and corticosterone, and food intake toward or below wild-type levels, and it restored hypothalamic POMC and AGRP mRNA but not NPY mRNA to wild-type levels. These studies suggest that adrenalectomy reverses or attenuates the obese phenotype in ob/ob mice, in part by restoring hypothalamic melanocortin tone toward wild-type levels. These studies also demonstrate that factors other than leptin may play a major role in regulating hypothalamic melanocortin function.
Diabetes 2000 Nov
PMID:Adrenalectomy reverses obese phenotype and restores hypothalamic melanocortin tone in leptin-deficient ob/ob mice. 1107 60

Energy dissipating mechanisms and their regulatory components represent key elements of metabolism and may offer novel targets in the treatment of metabolic disorders, such as obesity and diabetes. Recent studies have shown that a mitochondrial uncoupling protein (UCP2), which uncouples mitochondrial oxidation from phosphorylation, is expressed in the rodent brain by neurons that are known to regulate autonomic, metabolic, and endocrine processes. To help establish the relevance of these rodent data to primate physiology, we now examined UCP2 messenger RNA and peptide expressions in the brain and pituitary gland of nonhuman primates. In situ hybridization histochemistry showed that UCP2 messenger RNA is expressed in the paraventricular, supraoptic, suprachiasmatic, and arcuate nuclei of the primate hypothalamus and also in the anterior lobe of the pituitary gland. Immunocytochemistry revealed abundant UCP2 expression in cell bodies and axonal processes in the aforementioned nuclei as well as in other hypothalamic and brain stem regions and all parts of the pituitary gland. In the hypothalamus, UCP2 was coexpressed with neuropeptide Y, CRH, oxytocin, and vasopressin. In the pituitary, vasopressin and oxytocin-producing axonal processes in the posterior lobe and POMC cells in the intermediate and anterior lobes expressed UCP2. On the other hand, none of the GH-producing cells of the anterior pituitary was found to produce UCP2. The abundance and distribution pattern of UCP2 in the primate brain and pituitary suggest that this protein is evolutionary conserved and may relate to central autonomic, endocrine and metabolic regulation.
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PMID:Mitochondrial uncoupling protein 2 (UCP2) in the nonhuman primate brain and pituitary. 1108 57


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