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)

Glucagon-like peptide-2 (GLP-2) is an enteroendocrine hormone which is uniquely trophic for the intestine; a physiological role in regulating nutrient absorptive capacity is becoming apparent. GLP-2, independent of enteral feeding, stimulates a classical pattern of intestinal adaptation in terminal ileum following resection. Herein we investigate the effects of GLP-2 on the jejunal remant using a rat model of short bowel syndrome (SBS). Juvenile 250- to 275-g SD rats underwent 80% distal small bowel resection, leaving 20 cm of proximal jejunum and venous catheterization. Animals were maintained with total parenteral nutrition (TPN) or TPN+10 microg/kg/hr GLP-2 (n=8 per group). After 7 days, intestinal permeability was assessed by urinary recovery of gavaged carbohydrate probes. Animals were euthanized, and the intestines taken for analysis of morphology, crypt cell proliferation, apoptosis, and expression of SGLT-1 and GLUT-5 transport proteins. GLP-2 treatment reduced intestinal permeability and increased in vivo glucose absorption, small intestinal weight, surface area, villus height, crypt depth, and microvillus height. Intestinal mucosal DNA and protein content per unit length of the small bowel were increased (P < 0.05 for all comparisons). However, in contrast to previous studies examining GLP-2's effects on remnant ileum, the jejunal crypt apoptotic index was increased in GLP-2-treated animals, with no increase in SGLT-1 or GLUT 5 expression. These results show that exogenous GLP-2 treatment of animals with jejunal remnant reduces intestinal permeability, increases glucose absorption, and stimulates morphological features of intestinal adaptation including increased micovillus height and surface area. However, the pattern of changes seen is different from that in remnant ileum. This suggests that GLP-2's effects are specific to different regions of the bowel. Nonetheless, remnant jejunum is responsive to GLP-2 in the absence of enteral nutrition. Further studies are warranted to establish the mechanisms of action and therapeutic potential of GLP-2 in modulating nutrient absorptive capacity.
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PMID:Glucagon-like peptide-2 induces a specific pattern of adaptation in remnant jejunum. 1692 40

The actions of the structurally related proglucagon-derived peptides (PGDPs)-glucagon, glucagon-like peptide (GLP)-1 and GLP-2-are focused on complementary aspects of energy homeostasis. Glucagon opposes insulin action, regulates hepatic glucose production, and is a primary hormonal defense against hypoglycemia. Conversely, attenuation of glucagon action markedly improves experimental diabetes, hence glucagon antagonists may prove useful for the treatment of type 2 diabetes. GLP-1 controls blood glucose through regulation of glucose-dependent insulin secretion, inhibition of glucagon secretion and gastric emptying, and reduction of food intake. GLP-1-receptor activation also augments insulin biosynthesis, restores beta-cell sensitivity to glucose, increases beta-cell proliferation, and reduces apoptosis, leading to expansion of the beta-cell mass. Administration of GLP-1 is highly effective in reducing blood glucose in subjects with type 2 diabetes but native GLP-1 is rapidly degraded by dipeptidyl peptidase IV. A GLP-1-receptor agonist, exendin 4, has recently been approved for the treatment of type 2 diabetes in the US. Dipeptidyl-peptidase-IV inhibitors, currently in phase III clinical trials, stabilize the postprandial levels of GLP-1 and gastric inhibitory polypeptide and lower blood glucose in diabetic patients via inhibition of glucagon secretion and enhancement of glucose-stimulated insulin secretion. GLP-2 acts proximally to control energy intake by enhancing nutrient absorption and attenuating mucosal injury and is currently in phase III clinical trials for the treatment of short bowel syndrome. Thus the modulation of proglucagon-derived peptides has therapeutic potential for the treatment of diabetes and intestinal disease.
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PMID:Biologic actions and therapeutic potential of the proglucagon-derived peptides. 1692 63

Intestinal failure (IF) occurs when the body is unable to sustain its energy and fluid requirements without support, due to loss of functional small bowel. Prolonged IF is seen after large intestinal resection and described as short bowel syndrome (SBS). The hallmark of the management is parental nutrition (PN), which is costly and may be associated with the well-recognized problems of parental nutrition associated liver disease (PNALD) and line related sepsis. Cessation of PN at the earliest possible stage is desirable but for this enteral autonomy has to be achieved first. Intestinal adaptation occurs when the remaining gut goes through morphological changes increasing its absorptive capacity. Factors such as intraluminal nutrients, gastrointestinal secretions and hormones facilitate adaptation. Enteral feeds are a potent stimulant to adaptation and should be started as soon as the clinical situation permits. Some drugs are thought to increase intestinal adaptation. These include glutamine, growth hormone and glucagon like peptide- 2, but there is a paucity of pediatric data to guide their use. In some cases surgical bowel lengthening procedures can be performed to increase the absorptive surface area. An isolated liver transplantation may be required if the liver has sustained irreversible damage but intestinal autonomy seems achievable. When prolonged PN is either unsustainable or associated with unacceptable side effects, small bowel transplantation should be considered as a treatment option.
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PMID:Management of intestinal failure. 1709 Sep 4

Treatment of short bowel syndrome (SBS) is often a difficult endeavor due to the high variability among patients with SBS in regard to remaining anatomical structure and functional capacity. Research efforts to substantiate the use of existing therapies in the treatment of SBS are ongoing, with newer developments yet to be fully explored. Current therapy for SBS begins with the implementation of a modified diet based on the presence or absence of the colon. Patients with difficulty ingesting enough nutrients and fluids for weight maintenance and fluid balance may benefit from nocturnal enteral nutrition and hydration. Those with inadequate absorptive capacity despite maximization of oral and enteral intake will need parenteral nutrition (PN) or hydration. Medications, including antisecretory agents, antidiarrheals, pancreatic enzymes, bile acid sequestrants, and antibiotics, often are useful in abating symptoms commonly associated with SBS. Growth factors, including recombinant human growth hormone and glucagon-like peptide 2, may be trialed to stimulate intestinal adaptation and enhance absorption in PN-dependent SBS patients. The gradual refinement of surgical procedures for SBS, including small bowel transplantation, has led to improved outcomes, and early referral of SBS patients to centers of excellence will optimize care.
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PMID:Short bowel syndrome. 1729 60

The short bowel syndrome (SBS) is a complex entity due to anatomical or functional loss of part of the small bowel originating a clinical picture with severe metabolic and nutritional impairments due to reduction of the effective absorptive surface area of the gut. SBS is one of the causes of a larger entity known as "intestinal failu-Currently, mesenteric vascular accidents are the main cause in adults, followed by inflammatory bowel disease, and radiation enteritis, whereas in children, the main causes are congenital and perinatal diseases. The clinical picture associated with SBS varies according to the length and location of affected small bowel, the presence of underlying disease, the presence or absence of the large bowel and ileocecal valve, and the nature of the underlying disease. Intestinal adaptation is the process by which, throughout 1-2 years, intestinal absorption is reestablished to the situation prior to intestinal resection, and is a key factor determining whether a patient with SBS will progress to intestinal failure and depend on DPN. Intestinal adaptation may take place if the patient does oral intake higher than the usual one (hyperphagia); besides, the bowel may also adapt to secure a more effective absorption per surface area unit, either by increasing the absorptive surface area (structural adaptation) and/or slowing intestinal transit (functional adaptation). These changes are not still clearly established in humans, but there are so in animal models. The presence of nutrients within the intestinal lumen and certain gastrointestinal hormones, particularly GLP-2, have an influence on a successful adaptation process. Patients with SBS are prone to the occurrence of bacterial overgrowth that makes adaptation difficult and worsens the symptoms, besides being a factor for dependence on parenteral nutrition.
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PMID:[Short bowel syndrome: definition, causes, intestinal adaptation and bacterial overgrowth]. 1767 96

There are various hormones and growth factors which may modify the intestinal absorption of nutrients, and which might thereby be useful in a therapeutic setting, such as in persons with short bowel syndrome. In part I, we focus first on insulin-like growth factors, epidermal and transferring growth factors, thyroid hormones and glucocorticosteroids. Part II will detail the effects of glucagon-like peptide (GLP)-2 on intestinal absorption and adaptation, and the potential for an additive effect of GLP2 plus steroids.
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PMID:Intestinal hormones and growth factors: effects on the small intestine. 1915 42

Inflammatory bowel disease (IBD) is a chronic, debilitating disease associated with severe damage to the intestinal mucosa. Glucagon-like peptide-2 (GLP-2) is a potent and specific gastrointestinal growth factor that is demonstrating therapeutic potential for the prevention or treatment of an expanding number of intestinal diseases, including short bowel syndrome (SBS), small bowel enteritis and IBD. The biological activity of GLP-2 is limited due to proteolytic inactivation by the protease dipeptidyl peptidase (DP)IV. Inhibitors of DPIV activity may represent a novel strategy to prolong the growth promoting actions of GLP-2. This review outlines evidence for the clinical application of GLP-2, its degradation resistant analogue, Teduglutide, and novel DPIV inhibitors in efficacy studies utilizing pre-clinical models of intestinal damage, in particular IBD.
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PMID:Growth factor based therapies and intestinal disease: is glucagon-like peptide-2 the new way forward? 1932 85

Glucagon-like peptide-2 (GLP-2) is a nutrient-dependent intestinotropic hormone that promotes intestinal growth, via increased intestinal proliferation and decreased apoptosis, as well as increases in nutrient absorption and barrier function. The long-acting analog h(Gly(2))GLP-2[1-33] is currently being tested for treatment of short bowel syndrome and Crohn's disease. However, the role of GLP-2 in colon carcinogenesis is controversial. To assess the intestinotropic effects of exogenous and endogenous GLP-2, C57BL6/J mice were injected with 1 microg h(Gly(2))GLP-2[1-33]; 30 or 60 ng hGLP-2[3-33], a GLP-2 receptor antagonist; or PBS (4 wk, twice a day, sc). Chronic h(Gly(2))GLP-2[1-33] increased small intestinal weight/body weight (P < 0.001), villus height (P < 0.001), crypt depth (P < 0.001), and crypt cell proliferation, as measured by expression of the proliferative marker Ki67 (P < 0.05-0.01). In contrast, chronic hGLP-2[3-33] decreased small intestinal weight/body weight (P < 0.05) and colon weight/body weight (P < 0.05). To assess the carcinogenic effects of endogenous and exogenous GLP-2, separate mice were injected with azoxymethane (10 mg/kg, 4 wk, every 7 d, ip), followed by 1.5 microg h(Gly(2))GLP-2[1-33], 30 ng hGLP-2[3-33], or PBS (4 wk, twice a day, sc) 2 or 12 wk thereafter. At 10 or 46 wk after azoxymethane treatment, the numbers of aberrant crypt foci increased with h(Gly(2))GLP-2[1-33] (P < 0.001) and decreased with hGLP-2[3-33] (P < 0.01-0.05) treatment. Furthermore, mucin-depleted aberrant foci, consistent with progressive dysplasia, were almost exclusively present in h(Gly(2))GLP-2[1-33]-treated mice (P < 0.01-0.001). Additionally, adenocarcinomas developed in h(Gly(2))GLP-2[1-33]-treated mice but not in those receiving hGLP-2[3-33] or PBS. Taken together, these studies indicate that chronic treatment with GLP-2 enhances colon carcinogenesis, whereas antagonism of the GLP-2 receptor decreases dysplasia, with possible implications for human therapy.
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PMID:Carcinogenic effects of exogenous and endogenous glucagon-like peptide-2 in azoxymethane-treated mice. 1949 74

Undernutrition as well as specific nutrient deficiencies has been described in patients with Crohn's disease (CD), ulcerative colitis (UC) and short bowel syndrome. In the latter, water and electrolytes disturbances may be a major problem. The present guidelines provide evidence-based recommendations for the indications, application and type of parenteral formula to be used in acute and chronic phases of illness. Parenteral nutrition is not recommended as a primary treatment in CD and UC. The use of parenteral nutrition is however reliable when oral/enteral feeding is not possible. There is a lack of data supporting specific nutrients in these conditions. Parenteral nutrition is mandatory in case of intestinal failure, at least in the acute period. In patients with short bowel, specific attention should be paid to water and electrolyte supplementation. Currently, the use of growth hormone, glutamine and GLP-2 cannot be recommended in patients with short bowel.
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PMID:ESPEN Guidelines on Parenteral Nutrition: gastroenterology. 1951 65

Optimised Home Parenteral Nutrition is still, after 35 years of progress, the << gold standard >> of benign but chronic Intestinal Failure. A better recognition of chronic Intestinal Failure, in its multiple facets, is warranted for a better approach of associated treatment to Home Parenteral Nutrition, i.e., intestinal trophic factors (growth hormone, Glucagon Like Peptide-2), rehabilitative surgery (reestablishment of colonic continuity, reverse jejunal segment in severe short gut type II) and/or reconstructive surgery (intestinal transplantation for end stage intestinal failure patients). Boundaries of permanent, judged irreversible, intestinal failure will be certainly modified in the following years by combining the various and effective therapies which optimise management by ameliorating absorption of the remnant short gut. The work done on short bowel syndrome in the past 20 years should be done in the next years for chronic-intestinal - pseudo-obstruction patients presenting with intestinal failure on a large European scale because chronic-intestinal - pseudo-obstruction is a group of heterogeneous but rare intestinal diseases. Intestinal transplantation is now a mature therapy with formal indication especially in case of Home Parenteral Nutrition failure (mainly Home Parenteral Nutrition-associated severe liver disease) where combined Liver-intestine transplantation is indicated before end-stage liver failure occurs. For high-risk patients, "preemptive" indication for intestinal transplantation alone will be discussed before home parenteral nutrition complications occur. No doubt that, for improving overall outcome in intestinal failure patients, reference centres should have in expert hands the whole spectrum of medicosurgical therapies for intestinal failure.
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PMID:[Intestinal failure: from adaptation to transplantation]. 1969 89


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