Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011860 (type 2 diabetes)
 57,723 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Glucagon-like peptide-1(7-36)amide (GLP-1) possesses several unique and beneficial effects for the potential treatment of type 2 diabetes. However, the rapid inactivation of GLP-1 by dipeptidyl peptidase IV (DPP IV) results in a short half-life in vivo (less than 2 min) hindering therapeutic development. In the present study, a novel His(7)-modified analogue of GLP-1, N-pyroglutamyl-GLP-1, as well as N-acetyl-GLP-1 were synthesised and tested for DPP IV stability and biological activity. Incubation of GLP-1 with either DPP IV or human plasma resulted in rapid degradation of native GLP-1 to GLP-1(9-36)amide, while N-acetyl-GLP-1 and N-pyroglutamyl-GLP-1 were completely resistant to degradation. N-acetyl-GLP-1 and N-pyroglutamyl-GLP-1 bound to the GLP-1 receptor but had reduced affinities (IC(50) values 32.9 and 6.7 nM, respectively) compared with native GLP-1 (IC(50) 0.37 nM). Similarly, both analogues stimulated cAMP production with EC(50) values of 16.3 and 27 nM respectively compared with GLP-1 (EC(50) 4.7 nM). However, N-acetyl-GLP-1 and N-pyroglutamyl-GLP-1 exhibited potent insulinotropic activity in vitro at 5.6 mM glucose (P<0.05 to P<0.001) similar to native GLP-1. Both analogues (25 nM/kg body weight) lowered plasma glucose and increased plasma insulin levels when administered in conjunction with glucose (18 nM/kg body weight) to adult obese diabetic (ob/ob) mice. N-pyroglutamyl-GLP-1 was substantially better at lowering plasma glucose compared with the native peptide, while N-acetyl-GLP-1 was significantly more potent at stimulating insulin secretion. These studies indicate that N-terminal modification of GLP-1 results in DPP IV-resistant and biologically potent forms of GLP-1. The particularly powerful antihyperglycaemic action of N-pyroglutamyl-GLP-1 shows potential for the treatment of type 2 diabetes.
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PMID:N-terminal His(7)-modification of glucagon-like peptide-1(7-36) amide generates dipeptidyl peptidase IV-stable analogues with potent antihyperglycaemic activity. 1501 92

Diabetic nephropathy is the common cause of end stage renal disease in diabetes mellitus. But other glomerular pathologies have been also described in diabetic patients. We described 3 cases with diabetes mellitus and other glomerular diseases. Case I: A 59-year-old male patient with type 2 diabetes mellitus for 4 years was evaluated for generalized edema. Physical examination showed pretibial edema and no diabetic retinopathy. The cause of nephrotic syndrome was membranoproliferative glomerulonephritis. Conservative therapy could not control the severe proteinuria and renal dysfunction. With corticosteroid and cyclophosphamide therapy partial remission was obtained. Case II: A 46-year-old diabetic woman was evaluated for severe proteinuria. Diabetic retinopathy was not found on her funduscopic examination. Mesangioproliferative glomerulonephritis was found on renal biopsy. Proteinuria did not regress with conservative therapy and corticosteroid and cyclophosphamide. Case III: A 48-year-old male patient with diabetes mellitus type 2 for 2 years was admitted to the hospital because of nephrotic syndrome and weakness. At another hospital his diagnosis with biopsy showed minimal change disease. He was treated with corticosteroid since 3 months. His renal biopsy was reevaluated and found amyloid deposition but not diabetic nephropathy or minimal change disease. In diabetic patients, nondiabetic nephropathy is not uncommon and it was reported as common as about 30%. In addition to therapy for diabetes mellitus these patients can need specific therapy.
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PMID:Other glomerular pathologies in three patients with diabetes mellitus. 1528 4

Severe and resistant hypoglycemia occurred in two patients with diabetes mellitus who were receiving concomitant gatifloxacin and glyburide. An 84-year-old woman treated with glyburide for type 2 diabetes mellitus experienced, for the first time, a severe episode of hypoglycemia after 2 days of gatifloxacin 400 mg/day for nonproductive cough. Her blood glucose level on hospital admission was 28 mg/dl. Gatifloxacin and glyburide were discontinued, and the patient was treated with intravenous dextrose infused over 36 hours. Glyburide was restarted before her discharge, with no recurrence of hypoglycemia. A 79-year-old man with type 2 diabetes mellitus treated with glyburide was prescribed gatifloxacin 400 mg/day for pneumonia. After 1 day of therapy, the patient was admitted to the emergency department in a coma. His blood glucose level was 18 mg/dl. Despite discontinuation of gatifloxacin and oral hypoglycemic therapy, hypoglycemia was reversed only after administration of multiple boluses of intravenous dextrose, followed by intravenous dextrose infused over 48 hours. On hospital day 7, gliclazide and levofloxacin were started; the patient experienced no recurrence of hypoglycemia and was discharged on day 10. Several cases of severe and resistant hypoglycemia associated with gatifloxacin therapy have been reported in the recent literature. Although the exact mechanism is not fully understood, it may be linked to a gatifloxacin-induced closing of the adenosine 5'-triphosphate-sensitive potassium channels in the pancreatic beta cells, leading to insulin secretion. The onset of hypoglycemia in relation to the start of gatifloxacin suggests that the drug precipitated this adverse event. Patients receiving oral hypoglycemic agents are at greater risk of experiencing gatifloxacin-induced hypoglycemia than patients not receiving these agents. Clinicians should be aware of this potentially life-threatening adverse event and monitor blood glucose levels in all patients receiving concomitant oral hypoglycemic agents and gatifloxacin.
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PMID:Severe and resistant hypoglycemia associated with concomitant gatifloxacin and glyburide therapy. 1530 56

Dominant hand dysfunction due to cerebrovascular accident or fracture makes it more difficult to self-inject insulin. This would likely lead to diminishing a patient's quality of life. We made a new device to introduce self-injection of insulin by a patient's non-dominant hand and tested it. This device was built into a 600-g block of wood 11.5 cm x 8 cm x 8 cm, to be used with the InnoLet insulin kit system (Novo Nordisk Pharmaceuticals Inc., Bagsvaerd, Denmark). It had an insulin injector clamp on the front and a needle holder on the top. The bottom and the back were covered with silicon rubber, which allows the device's own weight to affix it on a table. The insulin injector is placed upright in a holder and fastened with a bar. A needle is installed on the insulin injector with a needle cap. After this cap was removed, the patient could remove any air bubbles by pushing 2 units of insulin through the needle. After the insulin injector was unfastened from the device, the patient injected the insulin subcutaneously into his abdomen or thigh. Then, the insulin injector was removed from the device. We introduced this device in a 59-year-old man with type 2 diabetes mellitus who had suffered from ischemic cerebral infarction in the left middle cerebral artery distribution, resulting in complete right hemiparesis. Our patient mastered this procedure within a few days. At the time of discharge, he could self-inject regular human insulin in a dose of 16 units in the morning, 6 units at noon, and 8 units in the evening. Two weeks after he was admitted to our hospital, he continued independent insulin self-injection three times per day without any help. His hemoglobin A(1c) level gradually decreased until it reached 5.7%. The self-injection of insulin may be introduced with a new device by the non-dominant hand in a patient with diabetes having a disabled dominant hand.
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PMID:A new device to introduce self-injection of insulin by his non-dominant hand in a patient with hemiplegia. 1532 Oct 7

We investigated amino acid metabolism in the Zucker diabetic fatty (ZDF Gmi fa/fa) rat during the prediabetic insulin-resistant stage and the frank type 2 diabetic stage. Amino acids were measured in plasma, liver, and skeletal muscle, and the ratios of plasma/liver and plasma/skeletal muscle were calculated. At the insulin-resistant stage, the plasma concentrations of the gluconeogenic amino acids aspartate, serine, glutamine, glycine, and histidine were decreased in the ZDF Gmi fa/fa rats, whereas taurine, alpha-aminoadipic acid, methionine, phenylalanine, tryptophan, and the 3 branched-chain amino acids were significantly increased. At the diabetic stage, a larger number of gluconeogenic amino acids had decreased plasma concentrations. The 3 branched-chain amino acids had elevated plasma concentrations. In the liver and the skeletal muscles, concentrations of many of the gluconeogenic amino acids were lower at both stages, whereas the levels of 1 or all of the branched-chain amino acids were elevated. These changes in amino acid concentrations are similar to changes seen in type 1 diabetes. It is evident that insulin resistance alone is capable of bringing about many of the changes in amino acid metabolism observed in type 2 diabetes.
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PMID:Amino acid metabolism in the Zucker diabetic fatty rat: effects of insulin resistance and of type 2 diabetes. 1538 98

Glucagon receptor antagonists have been actively pursued as potential therapeutics for the treatment of type 2 diabetes. Peptidyl and non-peptidyl glucagon receptor antagonists have been shown to block glucagon-induced blood glucose elevation in both animals and humans. How the antagonists and the glucagon receptor interact in vivo has not been reported and is the subject of the current study. Using (125)I-labeled glucagon as a radiotracer, we developed an in vivo glucagon receptor occupancy assay in mice expressing a human glucagon receptor in place of the endogenous mouse glucagon receptor (hGCGR mice). Using this assay, we first showed that the glucagon receptor is expressed predominantly in liver, to a much lesser extent in kidney, and is below detection in several other tissues/organs in the mice. We subsequently showed that, at 2 mg/kg body weight (mg/pk) dosed intraperitoneally (i.p.), peptidyl glucagon receptor antagonist des-His-glucagon binds to approximately 78% of the hepatic glucagon receptor and blocks an exogenous glucagon-induced blood glucose elevation in the mice. Finally, we also showed that, at 10 and 30 mg/kg dosed orally (p.o.), compound A, a non-peptidyl small molecule glucagon receptor antagonist, occupied 65-70% of the hepatic glucagon receptor, and significantly diminished exogenous glucagon-induced blood glucose elevation in the mice. At 3 mg/kg, however, compound A occupied only approximately 39% of the hepatic glucagon receptor and did not affect exogenous glucagon-induced blood glucose elevation in the mice. Taken together, the results confirmed previous reports that glucagon receptors are present predominantly in the liver, and provide the first direct evidence that peptidyl and non-peptidyl glucagon receptor antagonists bind to the hepatic glucagon receptor in vivo, and that at least 60% receptor occupancy correlates with the glucose lowering efficacy by the antagonists in vivo.
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PMID:Hepatic glucagon receptor binding and glucose-lowering in vivo by peptidyl and non-peptidyl glucagon receptor antagonists. 1546 82

Here we demonstrate 2 patients who showed marked hyperglycemia after androgen-deprivation therapy for prostate cancer and the efficacy of the thiazolidinedione pioglitazone on their glycemic control. Case 1 was a 61-year-old man diagnosed with prostate cancer who had type 2 diabetes mellitus for 7 years. His glycemic control had been good for the previous 5 years because of diet therapy and acarbose administration. He was given the gonadotropin-releasing hormone agonist leuprolide acetate and the androgen receptor antagonist flutamide for the treatment of prostate cancer. After the second injection of leuprolide acetate, fasting glucose and hemoglobin A1c (HbA1c) levels were found to be markedly elevated (22.8 mmol/L and 10.5%, respectively). Case 2 was an 81-year-old man whose fasting glucose and HbA1c had been normal 10 months ago. He was injected with leuprolide acetate for the treatment of prostate cancer. Six months after starting the leuprolide treatment, the patient complained of thirst and weight loss and was diagnosed with diabetes mellitus with a fasting glucose of 19.4 mmol/L and HbA1c of 9.9%. The correct homeostasis model assessment evaluation indexes for pancreatic beta-cell function (HOMA-%beta )A and for insulin sensitivity (HOMA-%S) were reduced in these 2 patients compared with control men. Their serum testosterone and 17beta -estradiol concentrations were depressed. After improvement of hyperglycemia by insulin treatment, their glycemic control remained good after treatment with pioglitazone without use of insulin. The values of HOMA-%beta and HOMA-%S increased to control ranges. Insulin resistance after the androgen-deprivation therapy might lead to marked hyperglycemia in these patients.
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PMID:Marked hyperglycemia after androgen-deprivation therapy for prostate cancer and usefulness of pioglitazone for its treatment. 1556 80

The authors conducted a prospective, open-label, pilot trial of the effects of the antidiabetic thiazolidinedione (TZD) rosiglitazone in two patients with moderate to severe plaque psoriasis. Case 1: A lean, euglycemic 43-year-old nondiabetic man with a 2-year history of plaque psoriasis presented with lesions involving 10% of his body surface (Figures 1A, 1B, 1C). He had no other chronic or acute medical problems. He had previously been managed sporadically with topical triamcinolone acetonide, an intermediate-strength glucocorticoid, and was off antipsoriatic medication for 5 months. He was started on rosiglitazone p.o., 8 mg q.d. After 10 weeks on rosiglitazone, the lesions developed increased erythema, spreading, and shedding of scale (Figures 2A, 2B, 2C). After an additional 26 weeks, the lesions had largely disappeared (Figures 3A, 3B, 3C). The patient remained euglycemic throughout the study. His liver function enzymes (alanine transferase [ALT] and aspartate transferase [AST]) remained normal throughout the study: ALT, 23 IU/L; AST, 47 IU/L before treatment; ALT, 25 IU/L; AST, 33 IU/L after treatment. There were no adverse events. Case 2: An overweight 68-year-old woman (body mass index, 29 kg/m2; with a 12-year history of type 2 diabetes and 5-year history of psoriasis presented with generalized plaque psoriasis over 20% of her body, including two large, thick, silvery plaques with the texture of leather over the lower part of the back (Figure 4A). She was given rosiglitazone p.o., 4 mg b.i.d. for 24 weeks, which resulted in significant improvement in psoriasis (Figure 4B). After an additional 26 weeks on rosiglitazone, the plaques had cleared on her back (Figure 4C) and over her entire body, including scalp, ears, and posterior forearms (not shown). Her glycemic control improved (hemoglobin A1c decreased from 7.7% to 7.2%) and liver function remained normal throughout the study (ALT, 24 IU/L; AST, 14 IU/L before treatment; and ALT, 26 IU/L; AST, 15 IU/L after treatment). There were no adverse events.
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PMID:Improvement in psoriasis with rosiglitazone in a diabetic and a nondiabetic patient. 1627 61

In humans, mice, and other mammals, the melanocortin system consists of four peptide hormones with a core amino acid sequence of histidine-phenylalanine-arginine-tryptophan and five melanocortin receptors. Both the melanocortin hormones and their receptors are produced in diverse tissues throughout the body. The ligand of primary interest for treatment of insulin resistance is alpha-melanocyte-stimulating hormone (alpha-MSH), which is derived, as are all melanocortins, from tissue-specific post-translational proteolytic processing of the pro-opiomelanocortin (POMC) precursor protein. Recent results have shown that alpha-MSH is the complement of leptin in the endocrine circuit, regulating bodyweight, food intake, and metabolic rate. alpha-MSH can decrease bodyweight, weight gain, and food intake in mice with diet-induced and genetic obesity. As obesity is a major risk factor for type 2 diabetes mellitus, it was reasonable to investigate the endocrine agents involved in obesity for their involvement in diabetes. alpha-MSH analogs have also been shown to affect blood glucose levels in some mouse models of obesity. For instance, the POMC null mouse is extremely sensitive to insulin in an insulin tolerance test, while being otherwise euglycemic. The results from rodent studies with alpha-MSH suggest reciprocal effects: alpha-MSH appears to increase sensitivity to insulin when present in the CNS, while alpha-MSH in the periphery is necessary for insulin resistance. Should these trends be validated in humans, alpha-MSH-based therapeutics specifically active in the CNS or peripheral circulation may be promising for the treatment of type 2 diabetes.
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PMID:The role of melanocyte-stimulating hormone in insulin resistance and type 2 diabetes mellitus. 1639 14

We report on a patient whose type 2 diabetes mellitus resolved during IFN-alpha therapy for hepatitis C virus (HCV). A 40-year-old man was diagnosed with type II diabetes in year 2000. His body mass index (BMI) was 30.8 kg/m and glycosylated haemoglobin (HbA1c) was 10.7%. He was treated with metformin. Later, his glycaemic control deteriorated despite additional dietary and lifestyle advice and the addition of glibenclamide. He was started on subcutaneous insulin in 2002 with the continuation of metformin. In 2003 he was diagnosed with chronic hepatitis caused by HCV. In September 2003 he was started on IFN-alpha and ribavirin. After 24 weeks of treatment his HCV polymerase chain reaction remained positive and treatment was stopped as per guidelines. At the commencement of antiviral therapy, HbA1c was 7.7%. In April 2004 his BMI of 29.38 kg/m had reduced and he then stopped insulin therapy because of repeated hypoglycaemia. After stopping insulin his HbA1c was 4.7%. Fasting plasma glucose of 6.2 mmol/l and anti-glutamic acid decarboxylase antibodies were negative. Urea and creatinine levels were normal. Most of the earlier literature describes diabetes developing in the course of IFN-alpha therapy for a variety of diseases. More recent research has described a relationship between hepatitis C infection and the development of diabetes and insulin resistance. Responders to IFN-alpha treatment manifest an improvement in insulin sensitivity compared with non-responders after the completion of IFN-alpha therapy. Our case shows the resolution of pre-existing diabetes in a patient with chronic HCV infection, which did not respond to IFN-alpha therapy. Whether this occurred as a direct result of IFN-alpha on insulin sensitivity or indirectly as a result of weight loss because the therapy for HCV precipitated additional lifestyle changes in the patient is as yet unclear.
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PMID:Resolution of diabetes in type 2 diabetic patient treated with IFN-alpha and ribavirin for hepatitis C. 1646 44


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