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)

Exposure to maternal gestational diabetes (GD) "programs" offspring for obesity in childhood and later life. Recent clinical data suggest that neonatal ingestion of breast milk from diabetic mothers might be crucially involved. Mediobasal hypothalamic nuclei such as the ventromedial nucleus (VMN), the paraventricular nucleus (PVN) and the arcuate nucleus (ARC) play a key role in the central nervous system regulation of food intake and body weight. In the ARC, orexigenic neuropeptides such as neuropeptide Y (NPY), galanin (GAL), and agouti-related peptide (AGRP) and anorexigenic neuropeptides such as proopiomelanocortin (POMC) and alpha-melanocyte-stimulating hormone (MSH) are expressed. We investigated the effects of neonatal exposure to milk from GD rat dams on the development of hypothalamic nuclei in weanling rats. Offspring of control (CO) rat dams cross-fostered to GD rat dams (CO-GD) developed early postnatal growth delay. On d 21 of life, CO-GD rats showed structural and functional hypothalamic "malprogramming." The ARC of CO-GD rats showed increased immunopositivity of both NPY and AGRP under basal conditions, despite normal levels of glucose, leptin, and insulin. Conversely, CO-GD rats showed decreased immunopositivity of both POMC and MSH and decreased density of immunopositive neurons, compared with offspring of control rat dams cross-fostered to control rat dams. No morphometric alterations were found in the VMN, whereas CO-GD rats showed an increased total number of neurons in the PVN. In summary, neonatal exposure to maternal diabetes through the intake of dam's milk in rats leads to a complex malprogramming of hypothalamic orexigenic and anorexigenic circuits that are critically involved in the lifelong regulation of food intake, body weight, and metabolism.
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PMID:Cross-fostering to diabetic rat dams affects early development of mediobasal hypothalamic nuclei regulating food intake, body weight, and metabolism. 1498 62

Glucokinase (GK) is hypothesized to be the critical glucosensor of pancreatic beta-cells and hypothalamic glucosensing neurons. To understand the role of GK in glucoprivic counterregulatory responses, we injected alloxan, a GK inhibitor and toxin, into the third ventricle (3v) to target nearby GK-expressing neurons. Four and 6 days after 3v, but not 4v, alloxan injection, alloxan-treated rats ate only 30% and their blood glucose area under the curve was only 28% of saline controls' after systemic 2-deoxy-D-glucose. In addition, their hyperglycemic response to hindbrain glucoprivation induced with 5-thio-glucose was impaired, whereas fasting blood glucose levels and food intake after an overnight fast were elevated. These impaired responses were associated with the destruction of 3v tanycytes, reduced glial fibrillary acidic protein-immunoreactivity surrounding the 3v, neuronal swelling, and decreased arcuate nucleus neuropeptide Y (NPY) mRNA. Nevertheless, hypothalamic GK mRNA was significantly elevated. Two weeks after alloxan injection, 3v tanycyte destruction was reversed along with restoration of feeding and hyperglycemic responses to both systemic and hindbrain glucoprivation. At this time there were significant decreases in GK, NPY, and proopiomelanocortin mRNA. Thus, neural substrates near and around the 3v affected by alloxan may be critically involved in the expression of these glucoprivic responses.
Diabetes 2004 May
PMID:Third ventricular alloxan reversibly impairs glucose counterregulatory responses. 1511 91

Peptide YY(3-36) (PYY(3-36)) is released by the gut in response to nutrient ingestion. It modulates the activities of orexigenic neuropeptide Y (NPY) neurons and anorexigenic proopiomelanocortin (POMC) neurons in the hypothalamus to inhibit food intake. Because both NPY and POMC have also been shown to impact insulin action, we wondered whether PYY(3-36) could improve insulin sensitivity. To address this question, we examined the acute effect of intravenous PYY(3-36) on glucose and free fatty acid (FFA) flux during a hyperinsulinemic-euglycemic clamp in mice maintained on a high-fat diet for 2 weeks before the experiment. We also evaluated the effects of PYY(3-36) infusion on glucose uptake in muscle and adipose tissue in this experimental context. Under basal conditions, none of the metabolic parameters were affected by PYY(3-36). Under hyperinsulinemic conditions, glucose disposal was significantly increased in PYY(3-36)-infused compared with vehicle-infused mice (103.8 +/- 10.9 vs. 76.1 +/- 11.4 micromol.min(-1).kg(-1), respectively; P = 0.001). Accordingly, glucose uptake in muscle and adipose tissue was greater in PYY(3-36)-treated animals, although the difference with controls did not reach statistical significance in adipose tissue (muscle: 2.1 +/- 0.5 vs. 1.5 +/- 0.5 micromol/g tissue, P = 0.049; adipose tissue: 0.8 +/- 0.4 vs. 0.4 +/- 0.3 micromol/g tissue, P = 0.08). In contrast, PYY(3-36) did not impact insulin action on endogenous glucose production or FFA metabolism. These data indicate that PYY(3-36) reinforces insulin action on glucose disposal in mice fed a high-fat diet, through a mechanism that is independent of food intake and body weight. In contrast, it leaves glucose production and lipid flux largely unaffected in this experimental context.
Diabetes 2004 Aug
PMID:PYY3-36 reinforces insulin action on glucose disposal in mice fed a high-fat diet. 1527 71

Epinephrine, norepinephrine, and corticosterone responses to hypoglycemia are impaired in diabetic rats. Recurrent hypoglycemia further diminishes epinephrine responses. This study examined the sympathoadrenal system and hypothalamo-pituitary-adrenal axis for molecular adaptations underlying these defects. Groups were normal (N) and diabetic (D) rats and diabetic rats exposed to 4 days of 2 episodes/day of hyperinsulinemic hypoglycemia (D-hypo) or hyperinsulinemic hyperglycemia (D-hyper). D-hypo and D-hyper rats differentiated effects of hypoglycemia and hyperinsulinemia. Adrenal tyrosine hydroxylase (TH) mRNA was reduced (P < 0.05 vs. N) 25% in all diabetic groups. Remarkably, mRNA for phenylethanolamine N-methyltransferase (PNMT), which converts norepinephrine to epinephrine, was reduced (P < 0.05 vs. all) 40% only in D-hypo rats. Paradoxically, dopamine beta-hydroxylase mRNA was elevated (P < 0.05 vs. D, D-hyper) in D-hypo rats. Hippocampal mineralocorticoid receptor (MR) mRNA was increased (P < 0.05 vs. N) in all diabetic groups. Hippocampal glucocorticoid receptor (GR), hypothalamic paraventricular nucleus (PVN) GR and corticotropin-releasing hormone (CRH), and pituitary GR and proopiomelanocortin (POMC) mRNA levels did not differ. We conclude that blunted corticosterone responses to hypoglycemia in diabetic rats are not due to altered basal expression of GR, CRH, and POMC in the hippocampus, PVN, and pituitary. The corticosterone defect also does not appear to be due to increased hippocampal MR, since we have reported normalized corticosterone responses in D-hypo and D-hyper rats. Furthermore, impaired epinephrine counterregulation in diabetes is associated with reduced adrenal TH mRNA, whereas the additional epinephrine defect after recurrent hypoglycemia is associated with decreases in both TH and PNMT mRNA.
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PMID:Effects of diabetes and recurrent hypoglycemia on the regulation of the sympathoadrenal system and hypothalamo-pituitary-adrenal axis. 1549 9

AMP-activated protein kinase (AMPK) acts as a cellular energy sensor, being activated during states of low energy charge. Hypothalamic AMPK activity is altered by hormonal and metabolic signals and mediates the feeding response. To determine the effect of diabetes on hypothalamic AMPK activity, we assayed this activity in streptozotocin (STZ)-induced diabetic rats. Compared with control rats, STZ-induced diabetic rats had significant hyperphagia and weight loss. Hypothalamic AMPK phosphorylation and alpha2-AMPK activity were higher and acetyl-CoA carboxylase activity was lower in diabetic rats than in control rats. Chronic insulin treatment or suppression of hypothalamic AMPK activity completely prevented diabetes-induced changes in food intake as well as in hypothalamic AMPK activity and mRNA expression of neuropeptide Y and proopiomelanocortin. Plasma leptin and insulin levels were profoundly decreased in diabetic rats. Intracerebroventricular administration of leptin and insulin reduced hyperphagia and the enhanced hypothalamic AMPK activity in diabetic rats. These data suggest that leptin and insulin deficiencies in diabetes lead to increased hypothalamic AMPK activity, which contributes to the development of diabetic hyperphagia.
Diabetes 2005 Jan
PMID:Enhanced hypothalamic AMP-activated protein kinase activity contributes to hyperphagia in diabetic rats. 1561 11

Exposure to maternal diabetes in utero (GD) may 'program' for obesity. Orexigenic neuropeptides, like neuropeptide Y (NPY) and agouti-related peptide (AGRP), and anorexigenic neuropeptides, like proopiomelanocortin (POMC) and alpha-melanocyte-stimulating hormone (MSH), are decisively involved in body weight regulation. We investigated consequences of GD and its treatment by pancreatic islet transplantation in rats for development of neuropeptidergic neurons in the arcuate hypothalamic nucleus (ARC) in weanling offspring. In GD, islet transplantation on d15 of pregnancy led to normalized blood glucose. Sham-transplanted GD mothers (TSGD) remained hyperglycemic. Twenty-one-day-old TSGD offspring developed hypothalamic 'malorganization'. Despite of normal leptin and insulin levels in TSGD offspring, increased immunopositivity of NPY and AGRP appeared. TSGD offspring showed unchanged POMC, but decreased MSH-immunopositivity. In conclusion, untreated diabetes in pregnant rats leads to 'malprogramming' of hypothalamic neuropeptidergic neurons in offspring, probably contributing to later development of overweight. These acquired alterations are preventable by treatment of maternal GD.
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PMID:'Programming' of orexigenic and anorexigenic hypothalamic neurons in offspring of treated and untreated diabetic mother rats. 1564 53

Insulin receptor substrate 2 (Irs2) plays complex roles in energy homeostasis. We generated mice lacking Irs2 in beta cells and a population of hypothalamic neurons (RIPCreIrs2KO), in all neurons (NesCreIrs2KO), and in proopiomelanocortin neurons (POMCCreIrs2KO) to determine the role of Irs2 in the CNS and beta cell. RIPCreIrs2KO mice displayed impaired glucose tolerance and reduced beta cell mass. Overt diabetes did not ensue, because beta cells escaping Cre-mediated recombination progressively populated islets. RIPCreIrs2KO and NesCreIrs2KO mice displayed hyperphagia, obesity, and increased body length, which suggests altered melanocortin action. POMCCreIrs2KO mice did not display this phenotype. RIPCreIrs2KO and NesCreIrs2KO mice retained leptin sensitivity, which suggests that CNS Irs2 pathways are not required for leptin action. NesCreIrs2KO and POMCCreIrs2KO mice did not display reduced beta cell mass, but NesCreIrs2KO mice displayed mild abnormalities of glucose homeostasis. RIPCre neurons did not express POMC or neuropeptide Y. Insulin and a melanocortin agonist depolarized RIPCre neurons, whereas leptin was ineffective. Insulin hyperpolarized and leptin depolarized POMC neurons. Our findings demonstrate a critical role for IRS2 in beta cell and hypothalamic function and provide insights into the role of RIPCre neurons, a distinct hypothalamic neuronal population, in growth and energy homeostasis.
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PMID:The role of insulin receptor substrate 2 in hypothalamic and beta cell function. 1584 Nov 80

Hypothalamic anorexigenic [corticotropin-releasing factor (CRF) and proopiomelanocortin] peptides decrease and the orexigen, neuropeptide Y, increases with diabetic hyperphagia. However, when diabetic rats are allowed to eat lard (saturated fat) as well as chow, both caloric intake and hypothalamic peptides normalize. These neuropeptide responses to lard require an intact hepatic vagus [la Fleur et al. (2003) Diabetes, 52, 2321-2330]. Here, we delineate temporal interactions after lard consumption +/- hepatic vagotomy (HV) between feeding and brain neuropeptide expression in insulin-dependent diabetic rats. CRF-mRNA was reduced in the paraventricular nuclei (PVN) by 6 h after presentation of lard, before caloric intake increased in HV-diabetic rats, and did not increase at 30 or 36 h, as it did in shamHV-diabetic rats eating lard. CRF-mRNA was increased in the bed nuclei of the stria terminalis of HV-diabetic rats compared with shamHV-diabetic rats only when caloric intake was high at 30 or 36 h. At 36 h, shamHV-diabetic rats eating chow had increased CRF-mRNA in the central amygdala but diabetic rats eating lard had decreased CRF-mRNA, whereas HV-diabetic rats eating chow or lard had normal CRF-mRNA in the central amygdala. We conclude that eating lard restores peptide expression to normal in the hypothalamus of diabetic rats, and because decreased CRF-mRNA in the PVN precedes the increase in caloric intake in HV-diabetic rats eating lard, that the loss of a hepatic vagal signal to PVN may be responsible for increased intake; moreover, CRF-mRNA in limbic structures is also sensitive to both HV and lard ingestion in diabetic rats.
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PMID:Hepatic vagotomy alters limbic and hypothalamic neuropeptide responses to insulin-dependent diabetes and voluntary lard ingestion. 1592 21

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

Rare mutations in the proopiomelanocortin (POMC) gene cause severe early-onset childhood obesity. However, it is unknown whether common variants in POMC are responsible for variation in body weight or fat distribution within the commonly observed range in the population. We tested for association between three polymorphisms spanning the POMC gene and obesity phenotypes in 1,428 members of 248 families. There was significant association between genotypes at the C8246T (P < 0.0001) and C1032G (P = 0.003) polymorphisms and waist-to-hip ratio (WHR) corrected for age, sex, smoking, exercise, and alcohol consumption. Each T allele at C8246T (or G allele at C1032G) was associated with a 0.2-SD-higher WHR in a codominant fashion. When WHR was additionally corrected for BMI, thus providing a measure of body fat distribution throughout the range of BMI, there remained significant evidence for association with both markers that was of similar magnitude and statistical significance. There was no association between genotype at any polymorphism and BMI or plasma leptin level. These data show that genetic variants at the POMC locus influence body fat distribution within the normal range, suggesting a novel role for POMC in metabolic regulation.
Diabetes 2005 Aug
PMID:Association between common polymorphisms of the proopiomelanocortin gene and body fat distribution: a family study. 1604 20


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