Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: HUMANGGP:036187 (gut)
 73,132 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In normal man, glucose serves to regulate basal insulin secretion by its participation with insulin in a feedback loop. In addition, glucose stimulates insulin secretion directly and potentiates insulin responses to nonglucose stimuli such as amino acids, beta-adrenergic stimuli, and gut hormones. Maximal glycemic potentiation of the acute insulin response to IV arginine occurs at a glucose level of approx. 450 mg/dl. In patients with noninsulin dependent diabetes mellitus (NIDDM), basal insulin levels have usually been reported as normal, but if plasma glucose is lowered to normal levels, a deficiency of basal insulin becomes apparent. In addition, the first phase (0-10 min) insulin response to IV glucose is absent in virtually all patients with overt NIDDM. In contrast, the second-phase (greater than 10 min) response is often preserved in NIDDM due to its maintenance by ambient hyperglycemia. Similarly, insulin responses to nonglucose stimuli such as arginine often appear normal in NIDDM because of potentiation by hyperglycemia. However, insulin responses to arginine are lower than those of nondiabetic controls when compared at multiple matched glucose levels. Indeed, maximal potentiation by glucose of the insulin response to arginine is markedly subnormal in NIDDM, suggesting a loss of functional B cell secretory capacity. In patients with long-standing insulin-dependent diabetes mellitus (IDDM), basal insulin secretion and insulin responses to all stimuli are virtually absent. However, in a remission phase, or in IDDM of short duration, basal insulin secretion and insulin responses to nonglucose stimuli may be relatively preserved. Therefore, islet dysfunction in IDDM and NIDDM, while etiologically different, share some common pathophysiological features.
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PMID:Pathophysiology of insulin secretion in diabetes mellitus. 389 62

Gastric inhibitory polypeptide (GIP) is one of the strongest insulinotropic gut factors. Its secretion is induced by oral (but not intravenous) glucose and it has been implicated in the pathogenesis of hyperinsulinemic states (NIDDM, obesity). To determine its relevance to hypertension, 54 subjects were studied: 26 normotensives (12 with and 14 without family history of essential hypertension), and 28 essential hypertensive subjects. Plasma glucose, serum insulin (IRI), and GIP were evaluated after a mixed meal containing a total of 82 g of carbohydrates, and 2 g sodium chloride. Venous blood was collected at baseline and every 15 min during a 3-h period. Baseline levels of glucose, IRI, and GIP were comparable in the three groups. At 30 min, however, IRI and GIP were higher in normotensives with a family history of hypertension and in established hypertensive versus control subjects. Both in normotensive and in hypertensive groups, glucose, IRI, and GIP responses to the meal were significantly correlated. Our data suggest the contribution of altered GIP secretion in the pathogenesis of hyperinsulinemia in essential hypertension.
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PMID:Hyperinsulinemia and hypertension. Do intestinal hormones play a role? 775 55

Glucagon-like peptide-I(GLP-I), encoded by the glucagon gene and released from the gut in response to nutrients, is a potent stimulator of glucose-induced insulin secretion. In human subjects GLP-I exerts its physiological effect as an incretin. The incretin effect of GLP-I is preserved in patients with Type II diabetes mellitus (NIDDM), suggesting that GLP-I receptor agonist can be used therapeutically in this group of patients. In these studies we addressed the question of whether GLP-I has broader actions in human physiology. To investigate this issue we examined the tissue distribution of GLP-I receptor using RNAse protection assay in order to avoid the cross-reactivities with structurally related receptors and to increase the sensitivity of detection. The riboprobe was synthesized from the human pancreatic GLP-I receptor cDNA and used in hybridization experiments with total RNA isolated from different human tissues. In addition to the pancreas, we found expression of GLP-I receptor mRNA in lung, brain, kidney, stomach and heart. Peripheral tissues which are the major sites of glucose turnover, such as liver, skeletal muscle and adipose did not express the pancreatic form of the GLP-I receptor. We also cloned and sequenced GLP-I receptor cDNA from human brain and heart. The deduced amino acid sequences are the same as the sequence found in the pancreas. These results indicate that GLP-I might have effects beyond the pancreas, including the cardiovascular and central nervous systems where a receptor with the same ligand binding specificity is found.
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PMID:Tissue-specific expression of the human receptor for glucagon-like peptide-I: brain, heart and pancreatic forms have the same deduced amino acid sequences. 784 4

Despite similar glycemic profiles, higher insulin levels are achieved following oral versus intravenous administration of glucose. This discrepancy is due to the incretin effect and is believed to be mediated via stimulation of beta-cells by hormone(s) released from the gut. The leading gut hormone candidates are glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide (GLP-1). To determine the relative insulinotropic activity of these peptides, we infused GLP-1(7-37) and GIP into normal subjects and patients with non-insulin dependent diabetes mellitus (NIDDM). In normal subjects during euglycemia, GLP-1(7-37) stimulated insulin release, whereas GIP did not. Using the Andres clamp technique, we established stable hyperglycemia for 2 h (5.4 mmol/l above the basal level). During the second hour, either GIP, GLP-1(7-37), or both were infused in normal healthy volunteers and in patients with NIDDM. In normal subjects, at a glucose level of 10.4 mmol/l, the 90-120 min insulin response was 279 pmol/l. GIP at a dose of 1, 2 or 4 pmol/kg/min augmented the 90-120 min insulin response by 69, 841 and 920 pmol/l, while GLP-1(7-37), at a dose of 1.5 pmol/kg/min augmented the insulin response by 2106 pmol/l. When both hormones were administered simultaneously, the augmentation was additive--2813 pmol/l. In the diabetic subjects, GIP had no effect, while GLP-1(7-37) augmented the insulin response by 929 pmol/l. We conclude that in normal healthy subjects, GLP-1(7-37), on a molar basis, is several times more potent than GIP at equivalent glycemic conditions. The additive insulinotropic effect suggests that more than one incretin may be responsible for the greater insulin levels observed following oral administration of glucose compared to the intravenous route. In NIDDM, GIP had no insulinotropic effect, while GLP-1(7-37) had a marked effect. This suggests that GLP-1(7-37) may have therapeutic potential as a hypoglycemic agent in NIDDM patients.
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PMID:The insulinotropic actions of glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (7-37) in normal and diabetic subjects. 803 84

Non-insulin-dependent diabetes (NIDDM) is a common problem in the elderly. The discovery of several classes of oral antidiabetic agents has increased the prospects of achieving better control of hyperglycaemia with reduced risk of severe adverse events. Some of these agents, such as acarbose or miglitol, do not cause hypoglycaemia and act locally in the gut. As such they are safer agents. On the other hand, the low cost of some sulphonylurea agents and a once or twice daily administration schedule make them an attractive option. Metformin appears to be especially useful in obese insulin-resistant patients with NIDDM. However, obesity is not as much of a problem in the elderly as it is in middle-aged patients, and contraindications to the use of metformin are common in the elderly. The use of a combination of 2 or 3 oral antidiabetic agents to delay the need for insulin therapy is now possible. The long term effects of this approach are not known and the cost of polypharmacy is of concern.
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PMID:Drug therapy of non-insulin-dependent diabetes mellitus in the elderly. 873 15

Acarbose represents a new pharmacological approach to achieving the metabolic benefits of a slower carbohydrate absorption in diabetes, by acting as a potent, competitive inhibitor of intestinal alpha-glucosidases. Acarbose molecules attach to the carbohydrate binding sites of alpha-glucosidases, with an affinity constant that is much higher than that of the normal substrate. Because of the reversible nature of the inhibitor-enzyme interaction, the conversion of oligosaccharides to monosaccharides is only delayed rather than completely blocked. Acarbose has the structural features of a tetrasaccharide and does not cross the enterocytes after ingestion. Thus, its pharmacokinetic properties are well suited to the pharmacological action directed exclusively towards the intestinal glucosidases. The most important clinical consequence of the delayed carbohydrate digestion caused by acarbose is the attenuation of postprandial increases in blood glucose levels. Other effects have also been described: a decreased beta-pancreatic response to meals, and influences on gut hormone secretion and plasma lipid levels. Gastrointestinal discomfort is frequently reported as an adverse effect of acarbose administration, but incidence usually decreases with time. The suitability of acarbose for improving glucose homeostasis as an adjunct to dietary control or to administration of sulphonylureas or insulin has been extensively studied in patients both with type 1 (insulin-dependent) and type 2 (non-insulin-dependent) diabetes mellitus. Acarbose can be used as first-line therapy in patients with type 2 diabetes which is poorly controlled by diet alone. Moreover, the lack of bodyweight gain or hypoglycaemic effects reported during acarbose treatment may be advantageous for obese or elderly patients. Finally, the reduction in fluctuations of glucose levels throughout the day may help to control type 1 diabetes in patients with 'brittle diabetes'. Long term prospective studies are still needed to confirm these indications and the usefulness of acarbose in conditions other than diabetes, notably reactive hypoglycaemia and dumping syndrome.
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PMID:Pharmacokinetic-pharmacodynamic relationships of Acarbose. 890 94

Of the physiological subsystems involved in glucose metabolism, all have now been modelled with continuous-time compartmental models except the gut. To address this omission, three progressively more complex models of the conversion of food by the gut into the rate of appearance of glucose in plasma were identified, using two different sample input foods which were tested on a type 1 diabetic patient. The minimal model that achieved a reasonable match with measured values had one compartment. Two model parameters specific to the food modelled were glycaemic value (grams of glucose per gram of food), and the fractional turnover rate, corresponding to a combination of the gastric emptying time constant and other rate limiting metabolic processes. Parameters specific to the individual were compartmental volumes, specifically for the glucose distribution space. It was only possible to achieve an adequate model prediction with a one compartmental model by explicitly incorporating transport delay into the model. By combining this model with models of insulin production and glucose disposal, the glycaemic response of an identified food may also be predicted for patients with type 2 diabetes mellitus. This predicted responses, along with the predicted response for bread or glucose, enables calculation of the Glycaemic Index for the food from its glycaemic value, time constant, and transport delay, along with the insulin production and glucose disposal model parameters for the individual patient. These three minimal model parameters therefore embody all the information of the Glycaemic Index, and more, allowing a continuous prediction of the effect of eating a given food over time. Together with a means of combining the parameters of individual foods into a combination set for a composite meal, this minimal model could enable diabetic patients to predict the time course of glycaemic action for a meal and to adjust treatment accordingly.
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PMID:Minimal model of food absorption in the gut. 918 79

Glucagon-like peptide 1 (GLP-1) is a peptide hormone that is released from the gut after luminal stimulation. The hormone is a potent insulin secretagogue and is a potential novel pharmaceutical adjuvant in the treatment of NIDDM. Insulin is secreted as a series of punctuated secretory bursts superimposed on a basal insulin release. Recently, the contribution of these secretory bursts to overall insulin secretion has been evaluated, and studies using catheterization across the pancreas in a canine model and studies using deconvolution in humans have revealed that the majority of insulin is released during these secretory bursts. Moreover, the main regulation of insulin secretion is through perturbation of mass and frequency of these secretory bursts. The mode of delivery of insulin into the circulation seems important for insulin action, and it is therefore important to know the impact of a potential therapeutic insulin secretagogue on the mode of insulin secretion. To assess the effects of GLP-1 on the mass, frequency, amplitude, and overall contribution of pulsatile insulin secretion, we used a recently validated deconvolution model to examine these variables before and during infusion of GLP-1 in eight healthy men (age 28 +/- 2 years; BMI 24 +/- 2 kg/m2). At a constant glucose infusion (2.5 mg x kg-1 x min-1), near-steady state was reached at 75 min, and sampling was performed every minute at t = 75-115 and 145-185 min. At t = 115 min, an infusion of saline or GLP-1 (50 pmol x kg-1 x min-1) was given. The regularity of insulin secretion was measured by approximate entropy, a recently developed mathematical statistic, applied herein to assess the regularity in a hormone concentration time series. After GLP-1 infusion, there was an abrupt increase in the peripheral concentrations of serum C-peptide (696 +/- 65 vs. 1,538 +/- 165 pmol/l) and insulin (49 +/- 8 vs. 138 +/- 21 pmol/l) concentrations. This increase was mainly due to an increase in the pulsatile component of insulin secretion that was achieved by a fourfold increase in secretory burst mass (28.2 +/- 4.4 vs. 100.1 +/- 15.8 pmol x l-1 x pulse-1; P < 0.001), and amplitude (12.7 +/- 2.2 vs. 4.3 +/- 7.7 pmol x l-1 x min-1; P < 0.002), whereas the secretory burst frequency was not affected by GLP-1 (11.5 +/- 0.7 vs. 12.6 +/- 0.6 pulses/h; P = 0.4). As a consequence, the detected contribution of pulsatile to overall insulin secretion was increased from 56 +/- 4 to 77 +/- 4% (P < 0.005). The orderliness of the insulin release process was not deteriorated by short-term GLP-1 infusion as assessed by approximate entropy (1.19 +/- 0.04 vs. 1.18 +/- 0.04; P = 0.7).
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PMID:Glucagon-like peptide 1 increases mass but not frequency or orderliness of pulsatile insulin secretion. 942 73

Type 2 diabetes mellitus (formerly named non-insulin-dependent diabetes mellitus or NIDDM) is a heterogeneous disease resulting from a dynamic interaction between defects in insulin secretion and insulin action. Various pharmacological approaches can be used to improve glucose homeostasis via different modes of action: sulphonylureas essentially stimulate insulin secretion, biguanides (metformin) act by promoting glucose utilisation and reducing hepatic-glucose production, alpha-glucosidase inhibitors (acarbose) slow down carbohydrate absorption from the gut and thiazolidinediones (troglitazone) enhance cellular insulin action on glucose and lipid metabolism. These pharmacological treatments may be used individually for certain types of patients, or may be combined in a stepwise fashion to provide more ideal glycaemic control for most patients. Selection of oral antihyperglycaemic agents as first-line drug or combined therapy should be based on both the pharmacological properties of the compounds (efficacy and safety, profile) and the clinical characteristics of the patient (stage of disease, bodyweight, etc.). Mildly hyperglycaemic patients should preferably be treated with metformin, acarbose or thiazolidinediones (which are not associated with any hypoglycaemic risk), while more severely hyperglycaemic individuals should receive a sulphonylurea. In moderately hyperglycaemic patients, sulphonylureas should be preferred in nonobese patients while metformin, and probably also thiazolidinediones, should have priority in obese insulin-resistant type 2 diabetic patients. Acarbose is mainly indicated to reduce post-prandial glucose fluctuations and improve glycaemic stability. Each antihyperglycaemic agent may also be combined with insulin therapy to improve glycaemic control and/or reduce the insulin requirement of diabetic patients after secondary failure to oral treatment. Finally, safety should be taken into account in elderly patients and/or those with renal impairment, especially as far as the use of sulphonylureas (higher risk of hypoglycaemia) and metformin (higher risk of lactic acidosis) is concerned.
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PMID:Oral antidiabetic agents. A guide to selection. 950 42

The incretins glucose-dependent insulinotropic polypeptide (GIP1-42) and truncated forms of glucagon-like peptide-1 (GLP-1) are hormones released from the gut in response to ingested nutrients, which act on the pancreas to potentiate glucose-induced insulin secretion. These hormones are rapidly inactivated by the circulating enzyme dipeptidyl peptidase IV ([DPIV] CD26). This study describes the effect on glucose tolerance and insulin secretion of inhibiting endogenous DPIV in the rat using Ile-thiazolidide, a specific DPIV inhibitor. High-performance liquid chromatography (HPLC) analysis of plasma following in vivo administration of 125I-labeled peptides showed that inhibition of DPIV by about 70% prevented the degradation of 90.0% of injected 125I-GLP-17-36 after 5 minutes, while only 13.4% remained unhydrolyzed in rats not treated with the DPIV-inhibiting agent after only 2 minutes. Ile-thiazolidide treatment also increased the circulating half-life of intact GLP-17-36 released in response to intraduodenal (ID) glucose (as measured by N-terminal specific radioimmunoassay [RIA]). In addition, inhibition of DPIV in vivo resulted in an earlier increase and peak of plasma insulin and a more rapid clearance of blood glucose in response to ID glucose challenge. When considered with the HPLC data, these results suggest that the altered insulin profile is an incretin-mediated response. DPIV inhibition resulting in improved glucose tolerance may have therapeutic potential for the management of type 2 diabetes mellitus.
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PMID:Improved glucose tolerance in rats treated with the dipeptidyl peptidase IV (CD26) inhibitor Ile-thiazolidide. 1009 18


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