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)

Growth retardation is a common feature in children with end-stage renal failure (ESRF). Medical management of renal insufficiency rarely normalizes growth and optimistic reports on the effect of rhGH treatment on growth velocity may presage more extensive use of rhGH in pediatric nephrology. Ample evidence has shown beneficial effects of GH replacement therapy in both childhood and adolescent hypopituitarism. However, the remarkably few side effects of treatment reported in these conditions cannot necessarily be extrapolated to children with ESRF. Uremia is associated with a wide range of metabolic and hormonal derangements including decreased glucose tolerance. This is mainly due to impaired insulin-stimulated glucose disposal in peripheral tissues and insufficient insulin-induced suppression of hepatic glucose production. Insulin-stimulated glucose uptake in skeletal muscle in ESRF is reduced by 30-50% as compared to that in healthy subjects, and a reduction may be detected even in subjects with a more moderate reduction in renal function (GFR around 25 ml/min). Dialysis therapy improves the disturbed insulin action significantly. The cause of the insulin resistance in ESRF is multifactorial. Impaired physical fitness, accumulation of uremic toxins, raised levels of GH and glucagon, metabolic acidosis, dyslipidemia and the medication applied may all contribute. If exogenous GH administration is added to the already marked uremic insulin resistance, insulin action may be severely disturbed and the secondary hyperinsulinism further magnified. However, frank diabetes mellitus does not develop unless the beta cells fail to meet the enhanced demands. This will probably occur only in patients with a beta-cell genotype pivotal for the phenotypic expression of non-insulin dependent diabetes mellitus.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Glucose metabolism in chronic renal failure with reference to GH treatment of uremic children. 837 90

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

New agents are being developed to address the underlying endocrinopathies and metabolic disturbances of type 2 diabetes. Stimulants of the nuclear peroxisome proliferator-activated receptor gamma (PPAR gamma) are being identified to selectively improve insulin actions, and dual agonists of PPAR gamma and PPAR alpha are being evaluated for enhanced control of hyperglycemia and dyslipidemia. Novel activators of insulin receptor phosphorylation and inhibitors of receptor dephosphorylation are offering encouraging leads for new agents. Analogues of glucagon-like peptide-1 that increase glucose-induced insulin secretion may additionally increase beta-cell neogenesis from progenitor duct cells. The amylin analogue pramlintide, which suppresses glucagon secretion and reduces weight, is advancing in clinical trial. Direct stimulants of glucose utilization and partial inhibitors of gluconeogenesis are providing useful new drug templates. Thus, new pharmacologic approaches are emerging to treat the multiple lesions of type 2 diabetes.
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PMID:New pharmacologic agents for diabetes. 1264 7

The world witnesses an explosive increase in diabetes, demanding intensified prevention and treatment not least for the low-income population. The plant, Stevia rebaudiana Bertoni, has been used for the treatment of diabetes in traditional medicine. We have previously demonstrated that stevioside, a diterpene glycoside isolated from the plant Stevia rebaudiana Bertoni, possesses insulinotropic, glucagonostatic, antihyperglycemic, and blood pressure-lowering effects in animal studies. We have also found that a dietary supplement, Abalon, of soy protein, isoflavones, and cotyledon fiber has beneficial effects on cardiovascular risk markers in type 2 diabetes. The aim of this study was to investigate if the combination of stevioside and a dietary supplement of soy protein possesses beneficial qualities in the treatment of type 2 diabetes and the metabolic syndrome. We randomized male Zucker diabetic fatty rats into 4 groups and fed them the different test diets for 10 weeks: (A) standard carbohydrate-rich laboratory diet (chow), (B) chow+stevioside (0.03 g/kg body weight [BW] per day), (C) 50% soy (Abalon)+50% chow (adjusted for vitamins and minerals), and (D) 50% soy (Abalon)+50% chow+stevioside 0.03 g/kg BW per day. We measured plasma glucose, blood pressure, weight, and food intake once weekly. The animals were equipped with an intra-arterial catheter, and at week 10, the conscious rats underwent an intra-arterial glucose tolerance test (2.0 g/kg BW). Stevioside exerts beneficial effects in type 2 diabetic Zucker diabetic fatty rats, that is, lowers blood glucose (area under the glucose curve [AUC(30min)]: group A vs B, a 19% reduction; and group C vs D, a 12% reduction; P<.001). We did not detect any effect on insulin or glucagon responses. After 2 weeks of treatment, a decrease in the systolic blood pressure was observed in the stevioside-treated groups (P<.01). Abalon had beneficial effects on cardiovascular risk markers, that is, (1) lowers total cholesterol (P<.01), (2) reduces triglycerides (P=.01), and (3) reduces free fatty acids (P<.001). The combination of stevioside and soy supplementation appears to possess the potential as effective treatment of a number of the characteristic features of the metabolic syndrome, that is, hyperglycemia, hypertension, and dyslipidemia. A long-term human study of the concept in type 2 diabetic subjects is needed to verify these promising results in animal diabetes.
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PMID:Preventive effects of a soy-based diet supplemented with stevioside on the development of the metabolic syndrome and type 2 diabetes in Zucker diabetic fatty rats. 1612 30

We have previously demonstrated abnormalities in insulin secretion in adolescents with type 2 diabetes mellitus (DM2) in response to the mixed meal test and to glucagon. In order to further assess beta-cell function in DM2, we measured insulin and C-peptide responses to oral glucose in adolescents with DM2 in comparison to non-diabetic obese and lean adolescents. We studied 20 patients with DM2, 25 obese adolescents with matching body mass index (BMI) (33.8 +/- 1.4 vs 34.3 +/- 1.0 kg/m2), and 12 non-obese control adolescents (BMI 22.6 +/- 0.6 kg/m2). Mean age, sex and sexual maturation did not differ between the three groups. All adolescents with DM2 had negative islet cell antibodies (ICA); five patients were on diet and 15 on insulin treatment. Fasting lipid profiles were determined in all participants. Plasma glucose and serum C-peptide and insulin levels were measured at 0, 30, 60, 90, and 120 min after an oral glucose load. The C-peptide increment (deltaCP) was calculated as peak minus fasting C-peptide. Area under the curve (AUC) was estimated using the trapezoid method. Insulin resistance was estimated using the HOMA model (HOMA-IR). The first phase of insulin secretion (PH1) was computed using a previously published formula. Serum triglyceride levels were significantly higher in the patients with DM2 compared to the non-obese controls (1.4 +/- 0.1 vs 0.9 +/- 0.1 mmol/l; p = 0.02). Plasma glucose AUC was greater in the patients with DM2 compared to the obese and non-obese control groups (1,660 +/- 130 vs 717 +/- 17 vs 647 +/- 14 mmol/l x min; p < 0.0001). ACP was lower in adolescents with DM2 than in obese and non-obese adolescents (761 +/- 132 vs 1,721 +/- 165 vs 1,225 +/- 165 pmol/l; p < 0.001). Insulin AUC was lower in the patients with DM2 compared to obese controls (888 +/- 206 vs 1,606 +/- 166 pmol/l x h; p = 0.009), but comparable to that of the non-obese controls (888 +/- 206 vs 852 +/- 222 pmol/l x h; p = 0.9). Insulin AUC was also higher in the obese than in the non-obese group (p = 0.05). PH1 was significantly higher in the obese group compared to the patients with DM2 as well as to the non-obese controls (2,614 +/- 2,47.9 vs 929.6 +/- 403.5 vs 1,946 +/- 300.6 pmol/l, respectively; p = 0.001). PH1 was also higher in the non-obese controls than in the patients with DM2 (p = 0.05). HOMA-IR was three-fold higher in the patients with DM2 than in the BMI-matched obese group, and five-fold higher than in the lean controls (14.3 +/- 1.2 vs 5.4 +/- 0.8 vs 2.9 +/- 0.4; p = 0.0002). Adolescents with DM2 have dyslipidemia, a significant cardiovascular risk factor. Decreased beta-cell function is characteristic of adolescents with DM2 in the presence of severe insulin resistance.
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PMID:Type 2 diabetes mellitus in African-American adolescents: impaired beta-cell function in the face of severe insulin resistance. 1656 86

Type 2 diabetes mellitus in children and adolescents is becoming an increasingly important public health concern throughout the world. This epidemic is closely associated with the increased prevalence of obesity among youth of all ethnic backgrounds, as increased visceral adipose tissue produces adipokines that increase insulin resistance. Type 2 diabetes represents one arm of the metabolic syndrome, which includes abdominal obesity, disturbed glucose regulation and insulin resistance, dyslipidemia, and hypertension. The treatment of type 2 diabetes and the metabolic syndrome poses a challenge for pediatric endocrinologists. This review provides information regarding diagnosis of type 2 diabetes in children, as well as prevention strategies, such as lifestyle modification and pharmacologic options for weight loss, including metformin, orlistat, and sibutramine. Pharmacologic treatment options, their modes of action, and clinical indications for use are also reviewed. Treatment regimens for youth-onset type 2 diabetes that are discussed include metformin, sulfonylureas, glucosidase inhibitors, thiazolidinediones, glucagon-like peptide-1, and insulin.
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PMID:The treatment of type 2 diabetes mellitus in youth : which therapies? 1687 99

Cardiovascular disease (CVD) is the leading cause of death in the United States and many parts of the world. Potentially modifiable risk factors for CVD include tobacco use, physical inactivity, hypertension, elevated low-density lipoprotein cholesterol, and a cluster of interrelated metabolic risk factors. Over the last several decades, efforts to prevent or treat CVD risk factors have resulted in significantly lower rates of CVD-related mortality. However, many patients never achieve adequate control of CVD risk factors even when these factors have been identified. In addition, the growing prevalence of obesity and type 2 diabetes mellitus (DM) threatens to undermine the improvements in CVD that have been achieved. In the United States, approximately two thirds of adults are overweight or obese, and even modest excess body weight is associated with a significantly increased risk of CVD-related mortality. Lifestyle interventions to promote weight loss reduce the risk of CVD-related illness but are difficult for patients to sustain over long periods of time. The increased incidence of obesity has also contributed to significant increases in the prevalence of other important CVD risk factors, including hypertension, dyslipidemia, insulin resistance, and type 2 DM. Pharmacologic therapies are currently available to address individual CVD risk factors, and others are being evaluated, including endocannabinoid receptor antagonists, inhibitors of peroxisome proliferator-activated receptor subtypes alpha and gamma, and several agents that modulate the activity of glucagon-like peptide-1. The new agents have the potential to significantly improve several CVD risk factors with a single medication and may provide clinicians with several new strategies to reduce the long-term risk of CVD.
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PMID:Cardiovascular disease and modifiable cardiometabolic risk factors. 1845 39

There has been a dramatic increase in the prevalence of the most common form of diabetes, with approximately 14.6 million diagnosed and 6.2 million undiagnosed cases of type 2 (non-insulin-dependent) diabetes in the United States since 2005. If diabetes is not diagnosed early and managed properly, patients are at greater risk for microvascular and macrovascular complications, such as nerve damage, heart disease, blindness, and kidney damage. The pathogenesis of type 2 diabetes includes impaired insulin secretion, increased hepatic and muscle/fat insulin resistance, and increased glucagon secretion. Problems commonly associated with type 2 diabetes and consequent hyperglycemia are weight gain, hypertension, and dyslipidemia. The natural progression of type 2 diabetes involves increased insulin deficiency as a result of decreased beta cell function over time, which can raise glycosylated hemoglobin to dangerous levels and consequently increase the risk of death. Lifestyle modifications (eg, diet changes and increased physical activity) remain the cornerstone of early treatment, but glycemic control may worsen despite behavior changes and treatment with oral hypoglycemic agents. Historically, upon failure to maintain glucose levels with exercise and oral medication, insulin was the second-line treatment option. Current treatment algorithms include a new class of agents, incretin mimetics, such as the glucagon-like peptide-1 (GLP-1) receptor agonist exenatide. Exenatide mimics the actions of the hormone GLP-1 that occurs naturally in the gastrointestinal tract and has emerged as an efficacious therapy adjunct to 1 or more oral hypoglycemic agent(s).
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PMID:Exploring the pharmacotherapeutic options for treating type 2 diabetes. 1852 66

The goal of antidiabetes therapy is to reduce glycosylated hemoglobin (HbA(1c)) levels to prevent or minimize the microvascular complications associated with this disease, such as retinopathy, nephropathy, and neuropathy. Glycemic control, defined by the American Diabetes Association (ADA) as HbA(1c) <7.0%, is often difficult to achieve despite current treatments, including oral antidiabetes agents, such as biguanides (metformin), sulfonylureas, thiazolidinediones, dipeptidyl peptidase-IV (DPP-IV) inhibitors, meglitinides, and alpha-glucosidase inhibitors, as well as injectable agents, such as glucagon-like peptide-1 (GLP-1) analogues and insulin. In addition, antidiabetes treatments often become less effective over time as insulin resistance increases and pancreatic beta-cell function deteriorates. The latest ADA guidelines also recommend a range of interventions to control the multiple coexisting conditions associated with this chronic, progressive disease, including dyslipidemia and hypertension. This review highlights the new antidiabetes drug classes, which include incretin mimetics, cannabinoid receptor type 1 antagonists, and bile acid sequestrants, and compares these agents to established treatments with regard to efficacy and tolerability. The more recently developed antidiabetes drugs have been shown in clinical trials to produce glucose-lowering effects similar to those of established antidiabetes agents. Many of the new antidiabetes agents can be safely combined with established therapies to further improve glycemic control. In addition, the new agents may provide additional significant cardiometabolic benefits, including improving the lipid profile, lowering blood pressure, and reducing body weight. These new treatments may have the potential to greatly improve the management of type 2 diabetes.
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PMID:More choices than ever before: emerging therapies for type 2 diabetes. 1853 25

Insulin resistance is strongly associated with metabolic dyslipidemia, which is largely a postprandial phenomenon. Though previously regarded as a consequence of delayed triglyceride-rich lipoprotein clearance, emerging evidence present intestinal overproduction of apoB-48-containing lipoproteins as a major contributor to postprandial dyslipidemia. The majority of mechanistic information is however derived from animal models, namely the fructose-fed Syrian Golden hamster, and extension to human studies to date has been limited. Work in our laboratory has established that aberrant insulin signalling exists in the enterocyte, and that inflammation appears to induce intestinal insulin resistance. The intestine is a major site of lipid synthesis in the body, and upregulated intestinal de novo lipogenesis and cholesterogenesis have been noted in insulin resistant and diabetic states. There is also enhanced dietary lipid absorption attributable to changes in ABCG5/8, NPC1L1, CD36/FAT, and FATP4. Proteins that are involved in chylomicron assembly and secretion, including MTP, MGAT, DGAT, apoAI-V, and Sar1 GTPase, show evidence of increased expression and activity levels. Increased circulating free fatty acids, typically observed in insulin resistant states, may serve to deliver lipid substrates to the intestine for enhanced chylomicron assembly and secretion. To compound the dysregulation of intestinal lipid metabolism, there are changes in the secretion of gut-derived peptides, which include GLP-1, GLP-2, and GIP. Thus, accumulating evidence presents intestinal lipoprotein secretion as a highly regulated process that is sensitive to perturbations in whole body energy homeostasis, and is severely perturbed in insulin resistant states.
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PMID:Postprandial dyslipidemia in insulin resistance: mechanisms and role of intestinal insulin sensitivity. 1865 87


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