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)

Postprandial reactive hypoglycemia (PRH) can be diagnosed if sympathetic and neuroglucopenic symptoms develop concurrently with low blood sugar (<3.3 mmol). Neither the oral glucose tolerance test (OGTT) nor mixed meals are suitable for this diagnosis, due to respectively false positive and false negative results. They should be replaced by ambulatory glycemic control or, as recently proposed, an hyperglucidic breakfast test. PRH patients often suffer from an associated adrenergic hormone postprandial syndrome, with potential pathologic consequences such as cardiac arrhythmia. PRH could result from (a) an exaggerated insulin response, either related to insulin resistance or to increased glucagon-like-peptide 1; (b) renal glycosuria; (c) defects in glucagon response; (d) high insulin sensitivity, probably the most frequent cause (50-70%), which is not adequately compensated by hypoinsulinemia and thus cannot be measured by indices of insulin sensitivity such as the homeostatic model assessment. Such situations are frequent in very lean people, or after massive weight reduction, or in women with moderate lower body overweight. PRH is influenced by patient's alimentary habits (high carbohydrate-low fat diet, alcohol intake). Thus, diet remains the main treatment, although alpha-glucosidase inhibitors and some other drugs may be helpful.
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PMID:Postprandial reactive hypoglycemia. 1111 13

Currently available oral agents for the treatment of type 2 diabetes mellitus include a variety of compounds from 5 different pharmacologic classes with differing mechanisms of action, adverse effect profiles, and toxicities. The oral antidiabetic drugs can be classified as either hypoglycemic agents (sulfonylureas and benzoic acid derivatives) or antihyperglycemic agents (biguanides, alpha-glucosidase inhibitors, and thiazolidinediones). In this review, a brief discussion of the pharmacology of these agents is followed by an examination of the adverse effects, drug-drug interactions, and toxicities. Finally, treatment of sulfonylurea-induced hypoglycemia is described, including general supportive care and the management of pediatric sulfonylurea ingestions. The adjunctive roles of glucagon, diazoxide, and octreotide for refractory hypoglycemia are also discussed.
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PMID:Oral agents for the treatment of type 2 diabetes mellitus: pharmacology, toxicity, and treatment. 1142 16

We investigated the effect of acarbose, an alpha-glucosidase and pancreatic alpha-amylase inhibitor, on gastric emptying of solid meals of varying nutrient composition and plasma responses of gut hormones. Gastric emptying was determined with scintigraphy in healthy subjects, and all studies were performed with and without 100 mg of acarbose, in random order, at least 1 wk apart. Acarbose did not alter the emptying of a carbohydrate-free meal, but it delayed emptying of a mixed meal and a carbohydrate-free meal given 2 h after sucrose ingestion. In meal groups with carbohydrates, acarbose attenuated responses of plasma insulin and glucose-dependent insulinotropic polypeptide (GIP) while augmenting responses of CCK, glucagon-like peptide-1 (GLP-1), and peptide YY (PYY). With mixed meal + acarbose, area under the curve (AUC) of gastric emptying was positively correlated with integrated plasma response of GLP-1 (r = 0.68, P < 0.02). With the carbohydrate-free meal after sucrose and acarbose ingestion, AUC of gastric emptying was negatively correlated with integrated plasma response of GIP, implying that prior alteration of carbohydrate absorption modifies gastric emptying of a meal. The results demonstrate that acarbose delays gastric emptying of solid meals and augments release of CCK, GLP-1, and PYY mainly by retarding/inhibiting carbohydrate absorption. Augmented GLP-1 release by acarbose appears to play a major role in the inhibition of gastric emptying of a mixed meal, whereas CCK and PYY may have contributory roles.
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PMID:Inhibition of gastric emptying by acarbose is correlated with GLP-1 response and accompanied by CCK release. 1151 88

Glucagon-like peptide-2 (GLP-2) is a potent intestinotropic factor in neonatal and adult animals. However, the GLP-2 responsiveness of the fetal intestine has not been established. To determine how stage of development affects the responsiveness to GLP-2, we examined GLP-2 receptor (GLP-2R) expression, gut morphology, and brush-border enzyme mRNA and activities in late-gestation fetal (n = 7) and parenterally fed neonatal (n = 7) piglets given GLP-2 (12.5 nmol/kg) twice daily for 6 days. The GLP-2R was expressed in the fetal and neonatal gastrointestinal tract. The biologically active GLP-2-(1-33) was undetectable (<5 pmol/l) in plasma of 98-day-gestation fetuses but increased significantly toward full term (115 days, 11 +/- 1 pmol/l) and in neonates fed by total parenteral nutrition (23 +/- 5 pmol/l). Exogenous GLP-2 had no effect on gut growth in fetuses but increased intestinal weight and villus height in neonates (P < 0.05). Crypt cell proliferation and the enzymes sucrase-isomaltase, lactase-phloridzin hydrolase, aminopeptidase A, and dipeptidyl peptidase IV were unchanged by GLP-2 in both groups. Aminopeptidase N mRNA and activity were increased in fetuses, while maltase mRNA and activity were increased in neonates. In conclusion, exogenous GLP-2 had different effects on small intestine growth and function in fetuses and neonates. This may be related to the normal developmental changes in intestine growth and function and to a maturation of the GLP-2R signaling pathways around the time of birth.
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PMID:GLP-2 has differential effects on small intestine growth and function in fetal and neonatal pigs. 1170 85

The anti-hyperglycemic effect of alpha-glucosidase inhibitors (AGI) is partly attributed to their ability to stimulate the secretion of glucagon-like peptide-1 (GLP-1), a gut hormone with insulin stimulating capability. To determine if this mechanism of action contributes significantly to the therapeutic efficacy of AGI in the elderly, 10 type 2 diabetic subjects over the age of 65 years were given a standardized test meal with or without 25, 50, or 100 mg acarbose. The serum glucose, insulin, triglycerides and GLP-1 levels were measured at baseline and at 1 and 2 h postprandially. The anti-hyperglycemic effect of acarbose was maximal at 25-mg dose under these experimental conditions. Serum postprandial insulin and triglycerides levels were not significantly altered with acarbose treatment. The postprandial serum GLP-1 levels rose significantly only in two subjects and only during treatment with 100-mg acarbose. There were no significant correlations between serum GLP-1 and serum glucose or insulin levels. It is concluded that in most elderly type 2 diabetic subjects, maximal anti-hyperglycemic effects can be achieved with relatively small doses of acarbose and that GLP-1 is unlikely to contribute to the clinical efficacy of this agent in this subgroup of subjects.
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PMID:Glucagon-like peptide-1 response to acarbose in elderly type 2 diabetic subjects. 1189 Oct 17

Besides dietary approaches, various pharmacological means have been recently developed in order to better control postprandial hyperglycaemia. This objective may be obtained: 1) by slowing down the intestinal absorption of carbohydrates; 2) by insuring a better insulin priming soon after the meal; and 3) by inhibiting post-prandial glucagon secretion or action. Some hormones (amylin, glucagon-like peptide-1) can slow gastric emptying while alpha-glucosidase inhibitors (acarbose, miglitol) retard intestinal digestion and resorption of complex carbohydrates. A more physiological post-meal profile of insulin may be obtained in type 2 diabetes by using new insulin secretagogues of the glinide family (repaglinide, nateglinide) with an earlier and shorter insulinotropic action or, mainly in type 1 diabetes but also in type 2 diabetes, by using short-acting insulin analogues (lispro. Asp B28) or inhated insulin the action of which is faster than that of subcutaneous insulin. Post-prandial glucagon secretion can be inhibited by amylin. GLP-1 or insulin while other glucagon antagonists are currently in development.
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PMID:[Postprandial hyperglycemia. II. Pharmacological approaches]. 1207 90

Exogenous glucagon-like peptide 2 (GLP-2) mimics the stimulatory effect of enteral nutrition on intestinal mucosal growth in preterm neonatal pigs. Little is known about its effects on small intestinal function. In this study, we investigated whether the trophic actions of GLP-2 and enteral nutrition are paralleled by effects on small intestinal function. Cesarean-delivered piglets (92% of gestation) were given either a parenteral nutrient infusion [total parenteral nutrition (TPN), n = 7], TPN + human GLP-2 (25 nmol/kg/d, n = 8), or enteral nutrition (ENT, n = 6) for 6 d. Gene expression (mRNA) and activities of lactase phlorizin hydrolase (LPH), maltase-glucoamylase (MGA), sucrase-isomaltase (SI), aminopeptidase N (ApN), and A (ApA) and dipeptidyl peptidase IV (DPP IV) were measured. Both GLP-2 and enteral nutrition increased mucosal weight (+30-40%, p < 0.05) relative to TPN. GLP-2 stimulated jejunal MGA and SI mRNA abundance and activity levels but did not change LPH in parenterally fed pigs (p < 0.05). Enteral nutrition decreased jejunal LPH and MGA mRNA abundance and activity and increased ileal ApN, ApA, and DPP IV activities relative to TPN (p < 0.05). We conclude that GLP-2 and enteral nutrition exert different effects on intestinal enzyme function despite similar effects on intestinal growth. In addition, the effects of GLP-2 on intestinal function in these parenterally fed, premature neonatal pigs differed from those previously reported for similarly fed term neonates.
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PMID:Glucagon-like peptide 2 enhances maltase-glucoamylase and sucrase-isomaltase gene expression and activity in parenterally fed premature neonatal piglets. 1235 42

Adaptation of the residual small bowel following resection is dependent on luminal and humoral factors. We aimed to establish if circulating levels of glucagon-like peptide (GLP-2) change under different dietary regimens following resection and to determine if there is a relationship between plasma GLP-2 levels and markers of intestinal adaptation. Four-week-old piglets underwent a 75% proximal small bowel resection (n = 31) or transection (n = 14). Postoperatively they received either pig chow (n = 14), nonpolymeric (elemental) infant formula (n = 7), or polymeric infant formula alone (n = 8) or supplemented either with fiber (n = 6) or with bovine colostrum protein concentrate (CPC; n = 10) for 8 weeks until sacrifice. Plasma GLP-2 levels were measured at weeks 0, 2, 4, and 8 postoperatively. In addition, end-stage parameters were studied at week 8 including weight gain, ileal villus height, crypt depth, and disaccharidase levels. Plasma GLP-2 levels were higher in resected animals compared to transected animals fed the same diet. Plasma GLP-2 levels were significantly increased in the colostrum protein isolate-supplemented animals following resection compared to all other diet groups. The increase in plasma GLP-2 (pM) was greatest in the first 2 weeks postresection (week 0, 15.5; week 2, 30.9), followed by a plateau at weeks 2 to 4 and a decrease in GLP-2 levels from week 4 to week 8. At week 8, no relationships were found between the plasma GLP-2 levels and the measurements of weight gain, villus height, lactase, sucrase, maltase, crypt depth, or villus/crypt ratio. Plasma GLP-2 levels increase in the first weeks following massive small intestinal resection. The increase in plasma GLP-2 levels was enhanced by supplementation of the diet with CPC. The changes in GLP-2 levels observed in this study may suggest that GLP-2 plays a role in the adaptive response in the intestine following resection in this preclinical model.
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PMID:Plasma GLP-2 levels and intestinal markers in the juvenile pig during intestinal adaptation: effects of different diet regimens. 1557 29

Two landmark intervention studies, the Diabetes Control and Complications Trial (DCCT) in patients with type 1 diabetes mellitus and the United Kingdom Prospective Diabetes Study (UKPDS) in patients with type 2 diabetes mellitus, have unequivocally demonstrated that intensive diabetes therapy reduces the risk of long-term diabetic complications. As a result, the commonly accepted treatment goal for most patients with diabetes is the achievement and maintenance of glycemic control that is as close to the normal range as safely possible. Important adverse effects of intensive diabetes therapy, particularly when the treatment includes insulin or several of the oral antihyperglycemic agents, are an increased risk of hypoglycemia and undesired weight gain. Improvement of glycemic control with insulin, insulin secretagogues (sulfonylureas, meglitinides), and insulin sensitizers (thiazolidinediones) is often accompanied by weight gain. The etiology of this weight gain is likely multifaceted, including a reduction of glucosuria, increased caloric intake to prevent hypoglycemia, and anabolic effects on adipose tissue. Biguanides and alpha-glucosidase inhibitors have a neutral or even positive effect (decrease) on weight, which may partly be attributable to their non-insulinotropic mechanism of action, a modest effect on satiety, and to their gastrointestinal adverse effect profile. Several antihyperglycemic agents that are currently in clinical development may improve glycemic control in conjunction with weight reduction. These include an analog of the pancreatic beta-cell hormone amylin (pramlintide), as well as glucagon-like peptide-1 (GLP-1) and exendin, and their analogs. Pharmacological agents with antihyperglycemic and positive weight effects have the potential to become important additions to our therapeutic armamentarium, in that they may help to achieve glycemic targets while addressing the long-standing clinical problem of weight gain as an adverse effect of intensive diabetes therapy.
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PMID:Weight effect of current and experimental drugs for diabetes mellitus: from promotion to alleviation of obesity. 1587 53

Type 2 diabetes mellitus affects 9.6% of the adults in the United States and more than 200 million people worldwide. Diabetes can be a devastating disease, but it can now be treated with nine classes of approved drugs (insulins, sulfonylureas, glinides, biguanides, alpha-glucosidase inhibitors, thiazolidinediones, glucagon-like peptide 1 mimetics, amylin mimetics, and dipeptidyl peptidase 4 inhibitors), in addition to diet and exercise regimens. Choosing which drug to give a patient is based on efficacy and also availability, cost, safety, tolerability, and convenience. Personalized medicine promises a path for individually optimized treatment choices, but realizing this promise will require a more comprehensive characterization of disease and drug response. In this issue of the JCI, Shu et al. make significant progress by integrating diverse data supporting the hypothesis that genetic variation in organic cation transporter 1 (OCT1) affects the response to the widely used biguanide metformin (see the related article beginning on page 1422). We discuss metformin, OCT1, pharmacogenetics, and how the integrative genomics revolution is likely to change our understanding and treatment of diabetes.
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PMID:Pharmacogenetics of metformin response: a step in the path toward personalized medicine. 1747 61


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