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)

The present status of knowledge about glucagon pathophysiology in diabetes is reviewed. 1) A-cells behave abnormally in all varieties of diabetes mellitus, spontaneous and experimental, except perhaps in case of pancreatectomized humans. These abnormalities are : hyperreactivity of A-cells to arginine, non suppressibility by glucose, and absence of stimulation following hypoglycemia. 2) These abnormalities appear as secondary in most instances : a) A-cells behave in a normal way in most studies with prediabetics ; b) plasma glucagon concentration is normalized by excellent control of diabetes or following prolonged insulin infusion. High doses of insulin are required most of the times to obtain a normalization of A-cell function : in insulin-dependent diabetics, the physiological portoperipheral insulin gradient no longer exists, and the high doses of insulin which are necessary may be the only mean to reconstitute the high insulin concentrations supposed to be present at the A-cell level. 3) Conflicting results have been collected about the role of this glucagon excess in aggravating the diabetic metabolic syndrome. Evanescent effects follow sustained glucagon infusions: but in diabetics, glucagon bursts rather than permanent hyperglucagonemia are observed and these appear deleterious to glucose tolerance. It seems clear however that insulin deprivation is required for the full expression of the consequences of glucagon excess.
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PMID:Glucagon and diabetes mellitus. 37 65

Noninsulin-dependent diabetes mellitus is a genetically determined form of diabetes, due to impaired insulin secretion by the B-cells as well as to insulin resistance of the peripheral tissues. According to the glucose toxicity theory hyperglycemia and hyperinsulinemia exist in a vicious circle. Therefore, it is a major therapeutical aim to put the B-cell to rest and improve insulin sensitivity by a strict control of fasting blood glucose and of postprandial hyperglycemia. Furthermore, associated abnormalities within the metabolic syndrome, such as hypertension, dyslipoproteinemia and hemostatic disorders should be corrected to avoid vessel complications. Therefore, it should be started with basic measures as body weight reduction, carbohydrate-rich and fat-poor diet and exercise. If these measures fail to achieve acceptable glycemic control, antihyperglycemic drugs (acarbose, metformin) are indicated, eventually in a combination with small doses of short-acting sulfonylureas. Further impairment of insulin secretion is the indication for sulfonylurea and/or insulin application. HbA1c of 7 to 7.5% should be the goal of antidiabetic therapy, also for patients in advanced age. The main criterion for the choice of antidiabetics is the present insulin secretion capacity. Simple indicators in this respect are changes of body weight, plasma triglycerides and C-Peptide after i.v. glucagon stimulation. Application of insulin in combination with other antidiabetics or in the form of intensified insulin therapy should not be too much postponed.
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PMID:[Rational therapy of Type II diabetes]. 903 69

Pancreastatin is a regulatory peptide known to inhibit insulin secretion and insulin action with a glycogenolytic effect in the liver. This peptide is present in and secreted by many endocrine and chromaffin cells. Abnormalities of glucose, insulin and lipoprotein metabolism are common in patients with hypertension, as well as their first-degree relatives. We have recently studied a group of non-obese hypertensive subjects in which pancreastatin-like levels were increased compared with controls, and correlated with norepinephrine levels. We hypothesized that pancreastatin alongside the sympathoadrenal system might have a part in the insulin resistance of these patients, and this metabolic syndrome could play a role in the pathogenesis and complications of hypertension. In this article, we studied the normotensive offspring of these nonobese hypertensive patients and looked for metabolic abnormalities as well as plasma pancreastatin, glucagon and catecholamine levels. The subjects were separated into two groups: (1) offspring from non-insulin-resistant patients and (2) offspring from insulin-resistant patients. We found that after an intravenous glucose load, offspring from insulin-resistant patients were already hyperinsulinemic, although glucose clearance was normal, suggesting an early alteration in insulin sensitivity, whereas pancreastatin and catecholamine levels were normal compared with matched controls. However, offspring from non-insulin-resistant patients had no differences with controls. These results suggest that pancreastatin and catecholamines may not play an important role in triggering insulin resistance, although they may be important once the syndrome is established.
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PMID:Normal pancreastatin-like and increased post-glucose insulin levels in young offspring of insulin-resistant non-obese essential hypertensive patients. 916 22

Insulin resistance is associated with a plethora of chronic illnesses, including Type 2 diabetes, dyslipidemia, clotting dysfunction, and colon cancer. The relationship between obesity and insulin resistance is well established, and an increase in obesity in Western countries is implicated in increased incidence of diabetes and other diseases. Central, or visceral, adiposity has been particularly associated with insulin resistance; however, the mechanisms responsible for this association are unclear. Our laboratory has been studying the physiological mechanisms relating visceral adiposity and insulin resistance. Moderate fat feeding of the dog yields a model reminiscent of the metabolic syndrome, including visceral adiposity, hyperinsulinemia, and insulin resistance. We propose that insulin resistance of the liver derives from a relative increase in the delivery of free fatty acids (FFA) from the omental fat depot to the liver (via the portal vein). Increased delivery results from 1) more stored lipids in omental depot, 2) severe insulin resistance of the central fat depot, and 3) possible regulation of visceral lipolysis by the central nervous system. The significance of portal FFA delivery results from the importance of FFA in the control of liver glucose production. Insulin regulates liver glucose output primarily via control of adipocyte lipolysis. Thus, because FFA regulate the liver, it is expected that visceral adiposity will enhance delivery of FFA to the liver and make the liver relatively insulin resistant. It is of interest how the intact organism compensates for insulin resistance secondary to visceral fat deposition. While part of the compensation is enhanced B-cell sensitivity to glucose, an equally important component is reduced liver insulin clearance, which allows for a greater fraction of B-cell insulin secretion to bypass liver degradation, to enter the systemic circulation, and to result in hyperinsulinemic compensation. The signal(s) resulting in B-cell up-regulation and reduced liver insulin clearance with visceral adiposity is (are) unknown, but it appears that the glucagon-like peptide (GLP-1) hormone plays an important role. The integrated response of the organism to central adiposity is complex, involving several organs and tissue beds. An investigation into the integrated response may help to explain the features of the metabolic syndrome.
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PMID:Central role of the adipocyte in the metabolic syndrome. 1121 41

Android obesity is associated with increased cortisol secretion. Direct effects of cortisol on gluconeogenesis and other parameters of insulin resistance were determined in normal subjects. Gluconeogenesis was determined using the reciprocal pool model of Haymond and Sunehag (HS method), and by the Cori cycle/lactate dilution method of Tayek and Katz (TK method). Glucose production (GP) and gluconeogenesis were measured after a 3 h baseline infusion and after a 4-8 h pituitary-pancreatic infusion of somatostatin, replacement insulin, growth hormone (GH), glucagon and a high dose of cortisol (hydrocortisone). The pituitary-pancreatic infusion maintains insulin, GH and glucagon concentrations within the fasting range, while increasing the concentration of only one hormone, cortisol. Two groups of five subjects were each given high-dose cortisol administration, and results were compared with those from a group of six 'fasting alone' subjects (no infusion) at 16 and 20 h of fasting. Fasting GP (12 h fasting) was similar in all groups, averaging 12.5+/-0.2 micromol x min(-1) x kg(-1). Gluconeogenesis, as a percentage of GP, was 35+/-2% using the HS method and 40+/-2% using the TK method. After 16 h of fasting, GP had fallen (11.5+/-0.6 micromol x min(-1) x kg(-1)) and gluconeogenesis had increased (55+/-5% and 57+/-5% of GP by the HS and TK methods respectively; P<0.05). High-dose cortisol infusion for 4 h increased serum cortisol (660+/-30 nmol/l; P<0.05), blood glucose (7.9+/-0.5 mmol/l; P<0.05) and GP (14.8+/-0.8 micromol x min(-1) x kg(-1); P<0.05). The increase in GP was due entirely to an increase in gluconeogenesis, determined by either the HS or the TK method (66+/-6% and 65+/-5% of GP respectively; P<0.05). Thus cortisol administration in humans increases GP by stimulating gluconeogenesis. Smaller increases in serum cortisol may contribute to the abnormal glucose metabolism known to occur in the metabolic syndrome.
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PMID:Cortisol increases gluconeogenesis in humans: its role in the metabolic syndrome. 1172 64

This review presents recent concepts of how beta-agonists affect glucose homeostasis by modulating insulin secretion, liver metabolism, and uptake of glucose into muscle, with attention to the influence of hypoglycemia on beta-agonist sensitivity and the effects of beta(3)-adrenergic receptor (beta(3)AR) polymorphisms on adipocyte metabolism. Specific beta(2)-agonist effects on the pancreatic beta cell result in increased insulin secretion, yet other mechanisms, such as increased glucagon secretion and hepatic effects, cause an overall increase in serum glucose and an apparent decrease in insulin sensitivity. Human studies confirm the presence of beta(2)ARs on pancreatic beta cells. Intensive treatment of diabetes mellitus with insulin, especially in type 1 diabetes, has led to increased incidence of hypoglycemia. Repeated episodes of hypoglycemia lead to unawareness of neuroglycopenia, a major limitation to intensive treatment. Hypoglycemic unawareness is associated with reduced beta-agonist sensitivity. Scrupulous avoidance of hypoglycemia over many weeks to months can restore beta-agonist sensitivity and improve detection of hypoglycemia. beta-agonists have also been employed to prevent hypoglycemia. beta-agonists can increase thermogenesis and lipolysis, leading to increased energy expenditure and decreased fat stores. While beta(1)ARs and beta(2)ARs mediate many of these actions, it is likely that beta(3)ARs in the adipocyte membrane also play an important role. Specific beta(3)AR subtypes have been associated with obesity and the metabolic syndrome.
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PMID:beta-Agonists and metabolism. 1246 41

Stevioside, a glycoside present in the leaves of the plant, Stevia rebaudiana Bertoni (SrB), has acute insulinotropic effects in vitro. Its potential antihyperglycemic and blood pressure-lowering effects were examined in a long-term study in the type 2 diabetic Goto-Kakizaki (GK) rat. Rats were fed 0.025 g x kg(-1) x d(-1) of stevioside (purity > 99.6%) for 6 weeks. An intra-arterial catheter was inserted into the rats after 5 weeks, and conscious rats were subjected to arterial glucose tolerance test (2.0 g x kg(-1)) during week 6. Stevioside had an antihyperglycemic effect (incremental area under the glucose response curve [IAUC]): 985 +/- 20 (stevioside) versus 1,575 +/- 21 (control) mmol/L x 180 minutes, (P <.05), it enhanced the first-phase insulin response (IAUC: 343 +/- 33 [stevioside] v 136 +/- 24 [control] microU/mL insulin x 30 minutes, P <.05) and concomitantly suppressed the glucagon levels (total AUC: 2,026 +/- 234 [stevioside] v 3,535 +/- 282 [control] pg/mL x 180 minutes, P <.05). In addition, stevioside caused a pronounced suppression of both the systolic (135 +/- 2 v 153 +/- 5 mm Hg; P <.001) and the diastolic blood pressure (74 +/- 1 v 83 +/- 1 mm Hg; P <.001). Bolus injections of stevioside (0.025 g x kg(-1)) did not induce hypoglycemia. Stevioside augmented the insulin content in the beta-cell line, INS-1. Stevioside may increase the insulin secretion, in part, by induction of genes involved in glycolysis. It may also improve the nutrient-sensing mechanisms, increase cytosolic long-chain fatty acyl-coenzyme A (CoA), and downregulate phosphodiesterase 1 (PDE1) estimated by the microarray gene chip technology. In conclusion, stevioside enjoys a dual positive effect by acting as an antihyperglycemic and a blood pressure-lowering substance; effects that may have therapeutic potential in the treatment of type 2 diabetes and the metabolic syndrome.
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PMID:Antihyperglycemic and blood pressure-reducing effects of stevioside in the diabetic Goto-Kakizaki rat. 1264 78

Blood glucose concentrations are unaffected by exercise despite very high rates of glucose flux. The plasma ionised calcium levels are even more tightly controlled after meals and during lactation. This implies 'integral control'. However, pairs of integral counterregulatory controllers (e.g. insulin and glucagon, or calcitonin and parathyroid hormone) cannot operate on the same controlled variable, unless there is some form of mutual inhibition. Flip-flop functional coupling between pancreatic alpha- and beta-cells via gap junctions may provide such a mechanism. Secretion of a common inhibitory chromogranin by the parathyroids and the thyroidal C-cells provides another. Here we describe how the insulin:glucagon flip-flop controller can be complemented by growth hormone, despite both being integral controllers. Homeostatic conflict is prevented by somatostatin-28 secretion from both the hypothalamus and the pancreatic islets. Our synthesis of the information pertaining to the glucose homeostat that has accumulated in the literature predicts that disruption of the flip-flop mechanism by the accumulation of amyloid in the pancreatic islets in type 2 diabetes mellitus will lead to hyperglucagonaemia, hyperinsulinaemia, insulin resistance, glucose intolerance and impaired insulin responsiveness to elevated blood glucose levels. It explains syndrome X (or metabolic syndrome) as incipient type 2 diabetes in which the glucose control system, while impaired, can still maintain blood glucose at the desired level. It also explains why it is characterised by high plasma insulin levels and low plasma growth hormone levels, despite normoglycaemia, and how this leads to central obesity, dyslipidaemia and cardiovascular disease in both syndrome X and type 2 diabetes.
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PMID:A reappraisal of the blood glucose homeostat which comprehensively explains the type 2 diabetes mellitus-syndrome X complex. 1271 5

Adiponectin is a novel adipocytokine negatively correlated with parameters of the metabolic syndrome, such as body mass index (BMI), body fat mass (BFM), and circulating insulin levels. Furthermore, metabolic actions directly on the liver have been described. The aim of the present study was to characterize circulating adiponectin levels, hepatic turnover, and the association of adiponectin with key parameters of hepatic as well as systemic metabolism in cirrhosis, a catabolic disease. Circulating adiponectin levels and hepatic turnover were investigated in 20 patients with advanced cirrhosis. Hepatic hemodynamics [portal pressure, liver blood flow, hepatic vascular resistance, indocyanine green (ICG) half-life], body composition, resting energy expenditure, hepatic free fatty acids (FFA) and glucose turnover, and circulating levels of hormones (catecholamines, insulin, glucagon) and proinflammatory cytokines (IL-1beta, TNF-alpha, IL-6) were also assessed. Circulating adiponectin increased dependently on the clinical stage in cirrhosis compared with controls (15.2 +/- 1.7 vs. 8.2 +/- 1.1 microg/ml, respectively, P < 0.01), whereas hepatic extraction decreased. Adiponectin was negatively correlated with parameters of hepatic protein synthesis (prothrombin time: r = -0.62, P = 0.003; albumin: r = -0.72, P < 0.001) but not with transaminases or parameters of lipid metabolism. In addition, circulating adiponectin increased with portal pressure (r = 0.67, P = 0.003), hepatic vascular resistance (r = 0.60, P = 0.008), and effective hepatic blood flow (ICG half-life: r = 0.69, P = 0.001). Adiponectin in cirrhosis was not correlated with BMI, BFM, parameters of energy metabolism, insulin levels, hepatic FFA and glucose turnover, and circulating proinflammatory cytokines. These results demonstrate that 1) adiponectin plasma levels in cirrhosis are significantly elevated, 2) the liver is a major source of adiponectin extraction, and 3) adiponectin levels in cirrhosis do not correlate with parameters of body composition or metabolism but exclusively with reduced liver function and altered hepatic hemodynamics.
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PMID:Elevated circulating adiponectin levels in liver cirrhosis are associated with reduced liver function and altered hepatic hemodynamics. 1501 Mar 38

Prevention and treatment of type 2 diabetes mellitus (T2DM) and the metabolic syndrome represent a major clinical challenge, because effective strategies such as fat restriction and exercise are difficult to implement into diabetes treatment. Based on the increasing knowledge on the pathogenesis of T2DM, new therapeutic approaches are currently under investigation. Potential targets of new therapeutic approaches include: (i) Inhibition of hepatic glucose production, (ii) stimulation of glucose-dependent insulin secretion, (iii) enhancement of insulin signal transduction, and (iv) reduction of body fat mass. Agonists of glucagon-like-peptide 1 (GLP-1) and antagonists of dipeptidylpeptidase IV, which inactivates GLP-1, stimulate glucose-dependent insulin secretion, improve hyperglycemia and are already tested in clinical trials. In humans, glucagon antagonists and an amylin analogue reduce glucagon-dependent glucose production. The glucose-lowering effect of current modulators of lipid oxidation is not pronounced and their use could be limited by side effects. In addition to clinically approved thiazolidendiones, new agonists of the peroxisome proliferator activator receptor gamma (PPAR gamma) as well as combined PPAR alpha/gamma agonists are developed at present. The direct modulation of insulin signal transduction is still limited to experimental studies.
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PMID:[Future targets in the treatment of type 2 diabetes]. 1514 60


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