Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P01275 (glucagon)
 26,492 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Diabetes is known to result in depression of myocardial function, whereas hearts from insulin-treated diabetic rats exhibit functional characteristics similar to controls. In the present study, we have studied the effect of insulin perfusion on cardiac performance of 3-day and 6-week streptozotocin (STZ) diabetic rats. Three days of diabetes did not result in depressed cardiac performance when the hearts were isolated and perfused in the working heart mode. Increasing the concentration of glucose from 5 to 10 mM in the perfusion fluid did not alter the function in either control or in diabetic rat hearts. However, when regular insulin or glucagon-free insulin (Humulin) (5 mU/mL) was included in the perfusion medium, the ventricular function of hearts from control rats was significantly enhanced, while diabetic myocardial function remained unaffected. When the study was repeated on hearts from 6-week diabetic animals, cardiac function of diabetic rats was significantly depressed as compared with controls. As in the 3-day study, contractility was not affected in either group by increasing glucose concentration in the perfusion medium. Again, inclusion of insulin in the medium enhanced cardiac contractility only in control hearts. These results suggest that diabetes results in a loss of myocardial sensitivity to insulin which seems to occur as early as 3 days after induction of diabetes with STZ. The study also demonstrates that the beneficial effects of in vivo insulin treatment on myocardial alterations induced by diabetes are not due to its direct myocardial effects.
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PMID:Effects of insulin perfusion and altered glucose concentrations on heart function in 3-day and 6-week diabetic rats. 351 48

In order to examine the effect of short-acting insulin analogue on the exercise-induced hypoglycaemia in insulin-dependent diabetes mellitus (IDDM) patients we compared the glycaemic response of 40 min cycle ergometer exercise performed either shortly (40 min) or later (180 min) after a breakfast meal and subcutaneous injection of either short-acting insulin analogue [Lys(B28) Pro(B29)] or soluble human insulin (Humulin Regular) in ten IDDM patients with long duration of the disease. Both preparations had been used 1 month before respective studies. Changes in blood glucose, insulin and counterregulatory hormones were assayed. As compared to human insulin, after the analogue injection the peak insulin concentration came earlier, was 56% higher (p < 0.05) and disappeared faster, and the postprandial blood glucose response was lower (p < 0.05). In the analogue-treated patients the exercise-induced hypoglycaemia was 2.2-fold greater (p < 0.01) during the early exercise, but 46% less (p < 0.05) during late exercise as compared to the treatment with human insulin. Serum insulin or analogue concentration at the beginning of the exercise correlated closely with the fall in blood glucose during exercise (r = 0.74, p < 0.01; r = 0.73, p < 0.02, respectively). In the analogue-treated patients, fasting serum glucagon and adrenalin concentrations were higher than during human insulin therapy (p < 0.05) and remained so throughout the study.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Exercise-induced hypoglycaemia in IDDM patients treated with a short-acting insulin analogue. 774 14

Antecedent hypoglycemia is a primary factor in hypoglycemia-associated autonomic failure, a pathophysiological condition characterized by impaired glucose counterregulatory function. Conventional therapeutic strategies involving administration of intermediate dosage-release formulations of insulin in the management of insulin-dependent diabetes mellitus result in frequent iatrogenic hypoglycemia. This study investigated the neuroanatomical location, direction, and magnitude of CNS neuronal genomic activation by singular versus repeated induction of hypoglycemic bouts of greater than 6 h duration achieved by administration of the intermediate-acting insulin, humulin neutral protamine Hagedorn (NPH). Adult male rats injected subcutaneously with Humulin NPH exhibited robust immunolabeling for the nuclear transcription factor, Fos, in discrete telencephalic, diencephalic, midbrain, and caudal hindbrain loci in a pattern that was not identical to that described for regular insulin. Administration of four doses of insulin on as many days significantly diminished or extinguished Fos immunostaining within the parvocellular hypothalamic paraventricular nucleus, lateral hypothalamic area, dorsomedial hypothalamic nucleus, thalamic paraventricular nucleus, nucleus tractus solitarius, and area postrema, but did not modify labeling of other metabolic loci. However, numbers of Fos-immunoreactivity-positive magnocellular neurons in the hypothalamic paraventricular and supraoptic nuclei were significantly increased after the second and fourth insulin doses, relative to the single-dose group. Concurrent observations of exacerbated hypoglycemia and modified patterns of glucoregulatory hormone secretion after serial injections of intermediate-acting insulin suggest that central mechanisms governing compensatory endocrine responses, specifically glucagon, become habituated to repetitive hypoglycemia of extended duration. Resultant alterations in CNS-islet and -adrenomedullary output and hypothalamic-pituitary-adrenal activity may reflect diminished neuronal activation within one or more of the brain loci characterized here by nonuniform transcriptional activation. The current studies provide a neuroanatomical foundation for further investigation of the neurochemical phenotypes and interconnectivity of functionally adaptive neurons, underlying cellular and molecular mechanisms of diminished or enhanced activation, as well as the impact of these modified cellular responses on glucose counterregulation during administration of intermediate-acting insulin.
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PMID:Recurrent insulin-induced hypoglycemia causes site-specific patterns of habituation or amplification of CNS neuronal genomic activation. 1565 93

We examined the extent to which priming the liver with a pulse of Humulin or the insulin analog hexyl-insulin monoconjugate 2 (HIM2) reduces postprandial hyperglycemia. Somatostatin (0.5 microg.kg(-1).min(-1)) was given with basal intraportal insulin and glucagon for 4.5 h into three groups of 42-h-fasted conscious dogs. From 0-5 min, group 1 (BI, n = 6) received saline, group 2 (HI, n = 6) received a Humulin pulse (10 mU.kg(-1).min(-1)), and group 3 (HIM2, n = 6) received a HIM2 pulse (10 mU.kg(-1).min(-1)). Duodenal glucose was infused (5.0 mg.kg(-1).min(-1)) from 15 to 270 min. Arterial insulin in BI remained basal (6 +/- 1 microU/ml) and peaked at 52 +/- 15 (HI) and 164 +/- 44 microU/ml (HIM2) and returned to baseline by 30 and 60 min, respectively. Arterial plasma glucose plateaued at 265 +/- 20, 214 +/- 15, and 193 +/- 14 mg/dl in BI, HI, and HIM2. Glucose absorption was similar in all groups. Significant net hepatic glucose uptake occurred at 85, 55, and 25 min in BI, HI, and HIM2, respectively. Nonhepatic glucose clearance at 270 min differed among groups (BI, HI, HIM2): 0.62 +/- 0.11, 0.76 +/- 0.26, and 1.61 +/- 0.29 ml.kg(-1).min(-1) (P < 0.05). A brief (5-min) insulin pulse improved postprandial glycemia, stimulating hepatic glucose uptake and prolonging enhancement of nonhepatic glucose clearance. HIM2 was more effective than Humulin, perhaps because its lowered clearance caused higher levels at the liver and periphery and its biological activity was not reduced proportionally to its decreased clearance.
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PMID:Simulated first-phase insulin release using Humulin or insulin analog HIM2 is associated with prolonged improvement in postprandial glycemia. 1571 85

Hypoglycemia elicits an integrated array of CNS-mediated counterregulatory responses, including activation of the hypothalamic-pituitary-adrenal axis. The role of antecedent adrenocortical hypersecretion in impaired glucose counterregulation remains controversial. The present studies utilized the selective, nonsteroidal glucocorticoid receptor antagonist, CP-472555, as a pharmacological tool to investigate the hypothesis that hypoglycemic hypercorticosteronemia modulates CNS efferent autonomic and neuroendocrine motor responses to recurring insulin-induced hypoglycemia via glucocorticoid receptor-dependent mechanisms. Groups of adult male rats were injected s.c. with either one or four doses of the intermediate-acting insulin, Humulin neutral protamine Hagedorn (NPH), on as many days, while controls were injected with diluent alone. Animals injected with four doses of insulin were pretreated by i.c.v. administration of graded doses of the glucocorticoid receptor antagonist or vehicle alone prior to the first three doses of insulin. Repeated daily injection of NPH exacerbated hypoglycemia, attenuated patterns of glucagon and epinephrine secretion, and diminished neuronal transcriptional activation in discrete CNS metabolic loci, including the lateral hypothalamic area, dorsomedial hypothalamic nucleus, paraventricular hypothalamic nucleus, and nucleus of the solitary tract. While i.c.v. delivery of 25 or 100 ng doses of CP-472555 did not alter any of these parameters, animals treated with 500 ng exhibited circulating glucose, glucagon, and epinephrine levels that were similar to those in rats injected with one dose of insulin, as well as a reversal of recurring insulin-induced hypoglycemia-associated reductions in Fos immunolabeling in the lateral hypothalamic area, dorsomedial hypothalamic nucleus, and paraventricular hypothalamic nucleus. These results provide unique pharmacological evidence that antecedent activation of central glucocorticoid receptor is required for exacerbation of hypoglycemia during recurring insulin-induced hypoglycemia, and that these receptors mediate modulatory effects of hypoglycemic hypercorticosteronemia on autonomic efferent responses to recurring insulin-induced hypoglycemia. The data also suggest that neurons in central loci characterized here by antagonist-mediated overturn of recurring insulin-induced hypoglycemia-induced decreases in neuronal transcriptional activation may be direct or indirect substrates for this hormonal modulation action.
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PMID:I.c.v. administration of the nonsteroidal glucocorticoid receptor antagonist, CP-472555, prevents exacerbated hypoglycemia during repeated insulin administration. 1662 67

A CNS component of glucose counterregulatory collapse is supported by evidence for nonuniform genomic responsiveness of neurons in characterized central autonomic loci during recurring insulin-induced hypoglycemia (IIH). We have reported that exacerbated hypoglycemia and attenuated patterns of glucagon and epinephrine secretion in rats treated by daily sc injection of the intermediate-acting insulin formulation, Humulin NPH (NPH), are correlated with diminished immunodemonstrability of the AP-1 transcription factor, Fos, in several components of the central metabolic regulatory circuitry, including the lateral hypothalamic area (LHA). Neurons that synthesize the potent orexigenic peptide neurotransmitter, orexin-A, are restricted to the LHA and adjacent hypothalamic loci, and project throughout the central neuroaxis to structures that govern autonomic and behavioral motor output. Dual-label immunocytochemical and real-time RT-PCR techniques were utilized here to evaluate the functional status of this LHA phenotype during a single versus repetitive exposure to prolonged IIH. Tissue sections were collected at predetermined rostrocaudal levels of the LHA after acute or repeated NPH administration, and processed for nuclear Fos- and cytoplasmic orexin-A-immunoreactivity (-ir). Mean numbers of orexin-A-ir neurons were not different between treatment groups. Colabeling of these cells for Fos was increased relative to controls following a single injection of insulin, but numbers of Fos-ir-positive orexin-A neurons were significantly reduced after treatment with four versus one dose of insulin. Prepro-orexin mRNA levels in microdissected LHA tissue were upregulated during acute hypoglycemia, but were returned to control levels by repeated IIH. These data corroborate previous evidence that IIH is an activational stimulus for orexin-A-synthesizing neurons in the LHA, and further demonstrate that induction of cfos and prepro-orexin gene expression by acute hypoglycemia is attenuated by precedent exposure to hypoglycemia. The current results thus provide unique evidence for neurotransmitter-specific habituation of LHA neuronal sensitivity to IIH.
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PMID:Habituation of insulin-induced hypoglycemic transcription activation of lateral hypothalamic orexin-A-containing neurons to recurring exposure. 1667 83

The metabolic stressor, hypoglycemia, elicits integrated counterregulatory responses, including activation of the hypothalamic-pituitary-adrenal axis. Type II glucocorticoid receptors (GR) occur in multiple components of the central autonomic circuitry that regulates glucostasis, and antecedent GR stimulation is implicated in impaired glucagon and counterregulatory dysfunction during recurrent insulin-induced hypoglycemia (RIIH). To examine the hypothesis that this chronic stress may alter basal and/or hypoglycemic patterns of GR gene expression in a site-specific manner, real-time RT-PCR techniques were utilized to evaluate tissue GR mRNA levels in the microdissected lateral hypothalamic area (LHA) and paraventricular (PVH), dorsomedial (DMH), ventromedial (VMH), and arcuate (ARH) hypothalamic nuclei, before and after one or four injections, on as many days, of the intermediate-acting insulin formulation, Humulin NPH (NPH), while controls were treated with diluent alone. Rats injected with four doses of NPH were pretreated by intracerebroventricular (icv) administration of the selective nonsteroidal GR antagonist, CP-472555, or vehicle alone prior to insulin injections on days 1-3. The results show that acute hypoglycemia had no impact on GR mRNA levels in each structure evaluated. Basal GR gene expression was not altered by antecedent hypoglycemia, but tissue transcript levels were elevated in the DMH, PVH, VMH, and ARH during RIIH. Icv CP-472555 administration prior to antecedent hypoglycemia prevented RIIH-associated increases in GR mRNA in each of these sites. These data show that GR gene transcripts are increased in discrete CNS metabolic loci during RIIH, and that these local responses are attenuated by pharmacological blockade of central GR activation. The present studies demonstrate that hypoglycemic hypercorticosteronemia causes upregulated GR gene expression during RIIH, and implicate GR in mechanisms underlying this action.
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PMID:Effects of acute and chronic insulin-induced hypoglycemia on type II glucocorticoid receptor (GR) gene expression in characterized CNS metabolic loci. 1686 Nov 9

This study assessed the site of increased glucose uptake resulting from insulin inhalation, quantified its effect under steady-state glucose concentrations, and identified the time to onset of effect. Human insulin was administered to 13 beagles via inhalation (Exubera [insulin human (rDNA origin)] Inhalation Powder; n = 7) or infusion into the inferior vena cava (Humulin R; n = 6) using an algorithm to match plasma insulin levels and kinetics for both groups. Somatostatin and glucagon were infused. Glucose was delivered into the portal vein (4 mg x kg(-1) x min(-1)) and a peripheral vein, as needed, to maintain arterial plasma glucose levels at 180 mg/dl. Hepatic exposure to insulin and glucose and liver glucose uptake were similar in both groups. Despite comparable arterial insulin and glucose levels, hind-limb glucose uptake increased 2.4-fold after inhalation compared with infusion due to increased muscle glucose uptake. Glucose infusion rate, nonhepatic glucose uptake, and tracer-determined glucose disposal were about twice as great compared with intravenous insulin. The effect appeared after 1 h, persisting at least as long as arterial insulin levels remained above basal. Pulmonary administration of insulin increases nonhepatic glucose uptake compared with infusion, and skeletal muscle is the likely site of that effect.
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PMID:Inhalation of human insulin (exubera) augments the efficiency of muscle glucose uptake in vivo. 1713 May 10

The potent orexigenic neuropeptide, orexin-A (ORX-A), acts at multiple sites within the central neuroaxis to control autonomic responses to energy imbalance, including the dorsal vagal motor nucleus (DMV), where it regulates pancreatic efferent nerve firing. Recent evidence that recurrent insulin-induced hypoglycemia (RIIH) attenuates lateral hypothalamic ORX-A-ergic neuronal transcriptional activation and prepro-orexin gene expression suggests that this phenotype undergoes functional adaptation to repeated glucoprivation. We examined the hypothesis that RIIH-associated patterns of ORX-A neurotransmission and/or orexin-receptor-1 (OR-1) expression within the DMV may be correlated with exacerbated hypoglycemic and impaired pancreatic counterregulatory responses to repeated insulin administration. Male rats were pretreated by bilateral intra-DMV infusion of the OR-1 antagonist, SB-334867, or vehicle prior to s.c. injection of Humulin NPH (NPH), or diluent alone. Other animals were injected with one or four doses of NPH, on as many days, or diluent alone, and pretreated by bilateral intra-DMV administration of graded doses of ORX-A or vehicle on the final day of the study. Effects of acute versus repeated insulin administration on ORX-A and OR-1 protein levels in the microdissected dorsal vagal complex (DVC) were evaluated by radioimmunoassay and Western blot analyses, respectively. SB-334867 treatment prior to acute NPH administration decreased plasma glucose and suppressed peak glucagon secretion, whereas exogenous ORX-A administration prior to RIIH did not reverse amplified patterns of hypoglycemia. RIIH did not alter intra-DVC ORX-A tissue concentrations, but diminished OR-1 levels in that site. These results show that DMV OR-1 function is critical for optimal glucagon secretory responsiveness to acute hypoglycemia, and that RIIH-associated downregulation of receptor expression in that brain site may contribute to impaired restoration of euglycemia. The current data provide unique evidence that ORX-A acts via OR-1-dependent mechanisms within DMV to regulate glucagon counterregulatory function during hypoglycemia, and that decreased receptor-mediated signaling during RIIH may underlie characteristic intensification of hypoglycemia.
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PMID:Role of dorsal vagal motor nucleus orexin-receptor-1 in glycemic responses to acute versus repeated insulin administration. 1727 8

Diabetic patients treated with inhaled insulin exhibit reduced fasting plasma glucose levels. In dogs, insulin action in muscle is enhanced for as long as 3 h after insulin inhalation. This study was designed to determine whether this effect lasts for a prolonged duration such that it could explain the effect observed in diabetic patients. Human insulin was administered via inhalation (Exubera; n = 9) or infusion (Humulin R; n = 9) in dogs using an infusion algorithm that yielded matched plasma insulin kinetics between the two groups. Somatostatin was infused to prevent insulin secretion, and glucagon was infused to replace basal plasma levels of the hormone. Glucose was infused into the portal vein at 4 mg/kg/min and into a peripheral vein to maintain the arterial plasma glucose level at 160 mg/dl. Arterial and hepatic sinusoidal insulin and glucose levels were virtually identical in the two groups. Notwithstanding, glucose utilization was greater when insulin was administered by inhalation. At its peak, the peripheral glucose infusion rate was 4 mg/kg/min greater in the inhalation group, and a 50% difference between groups persisted over 8 h. Inhalation of insulin caused a greater increase in nonhepatic glucose uptake in the first 3 h after inhalation; thereafter, net hepatic glucose uptake was greater. Inhalation of insulin was associated with greater than expected (based on insulin levels) glucose disposal. This may explain the reduced fasting glucose concentrations observed in humans after administration of certain inhaled insulin formulations compared with subcutaneous insulin.
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PMID:Inhaled insulin is associated with prolonged enhancement of glucose disposal in muscle and liver in the canine. 1909 61


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