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)

Exenatide is the first incretin mimetic, introduced into type 2 diabetes mellitus therapy in 2005, with first approval in the US. It is a glucagon-like peptide-1 (GLP-1) receptor agonist that can be used for treatment by twice-daily injection. A long-acting release formulation for once-weekly injection is in clinical development. Clinical studies and postmarketing experience with exenatide have shown a significant and sustained reduction in glycosylated haemoglobin (HbA(1c)) by approximately 1% together with other gylcaemic parameters without an intrinsic risk for hypoglycaemias, and a reduction in bodyweight by 5.3 kg in 82 weeks. Blood pressure and lipids are also favourably affected, but hard cardiovascular endpoints are not yet available. Animal studies show an improvement of beta-cell function and an increase in beta-cell mass after exenatide treatment. The most frequent adverse events associated with exenatide therapy are nausea and antibody formation (both approximately 40%). Nausea, mostly mild and transient, was responsible for a 6% dropout rate in clinical studies. A recent review on the association of acute pancreatitis with exenatide treatment showed no increased risk (relative risk 1.0; 95% CI 0.6, 1.7). This review gives a benefit-risk assessment of exenatide.
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PMID:Benefit-risk assessment of exenatide in the therapy of type 2 diabetes mellitus. 2008 36

Recent case reports of acute pancreatitis in patients with type 2 diabetes (T2DM) treated with incretin-based therapies have triggered interest regarding the possibility of a mechanism-based association between pancreatitis and glucagon-like peptide-1 mimetics or dipeptidyl peptidase-4 (DPP-4) inhibitors. The objective of this review was to describe the controlled preclinical and clinical trial data regarding the incidence of pancreatitis with sitagliptin, the first DPP-4 inhibitor approved for use in patients with T2DM. Tissue samples from multiple animal species treated with sitagliptin for up to 2 years at plasma exposures substantially in excess of human exposure were evaluated to determine whether any potential gross or histomorphological changes suggestive of pancreatitis occurred. Sections were prepared by routine methods, stained with haematoxylin and eosin and examined microscopically. A pooled analysis of 19 controlled clinical trials, comprising 10,246 patients with T2DM treated for up to 2 years, was performed using patient-level data from each study for the evaluation of clinical and laboratory adverse events. Adverse events were encoded using the Medical Dictionary for Regulatory Activities (MedDRA) version 12.0 system. Incidences of adverse events were adjusted for patient exposure. Tissue samples from preclinical studies in multiple animal species did not reveal any evidence of treatment-related pancreatitis. The pooled analysis of controlled clinical trials revealed similar incidence rates of pancreatitis in patients treated with sitagliptin compared with those not treated with sitagliptin (0.08 events per 100 patient-years vs. 0.10 events per 100 patient-years, respectively). Preclinical and clinical trial data with sitagliptin to date do not indicate an increased risk of pancreatitis in patients with T2DM treated with sitagliptin.
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PMID:Sitagliptin: review of preclinical and clinical data regarding incidence of pancreatitis. 2041 32

In what corresponds to a life span, metallocarboxypeptidases (MCPs) have jumped from being mere contaminants in animal pancreas powders (in depression year 1929) to be key players in cellular and molecular processes (in yet-another-depression years 2009-2010). MCPs are unique zinc-dependent enzymes that catalyze the breakdown of the amide bond at the C-terminus of peptide and protein substrates and participate in the recovery of dietary amino acids, tissue organogenesis, neurohormone and cytokine maturation and other important physiological processes. More than 26 genes code for MCPs in the human genome, many of them still waiting to be fully understood in terms of physiological function. A variety of MCPs have been linked to diseases in man: acute pancreatitis and pancreas cancer, type 2 diabetes, Alzheimer's Disease, various types of cancer, and fibrinolysis and inflammation. Many of these discoveries have been made possible thanks to recent advances, as exemplified by plasma carboxypeptidases N and B, known for fifty and twenty years, respectively, which have had their structures released only very recently. Plasma carboxypeptidase B is a biological target for therapy because of its involvement in the coagulation/fibrinolysis processes. Besides, the widespread use of carboxypeptidase A as a benchmark metalloprotease since the early days of Biochemistry has allowed the identification and design of an increasingly vast repertory of small molecular weight inhibitors. With these two examples we wish to emphasize that MCPs have become part of the drug discovery portfolio of pharmaceutical companies and academic research laboratories. This paper will review key developments in the discovery and design of MCP small molecular weight inhibitors, with an emphasis on the discovery of chemically diverse entities. Although encouraging advances have been achieved in the last few years, the specificity and oral bioavailability of the new chemotherapeutic agents seem to pose a challenge to medicinal chemists.
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PMID:Progress in metallocarboxypeptidases and their small molecular weight inhibitors. 2046 32

Failure of secretion of the incretin hormone glucagon-like peptide-1 (GLP-1) plays a prominent role in type 2 diabetes, and restoration of GLP-1 action is an important therapeutic objective. Although the short duration of action of GLP-1 renders it unsuited to therapeutic use, 2 long-acting GLP-1 receptor agonists, exenatide and liraglutide, represent a significant advance in treatment. In controlled trials, both produce short-term glucose-lowering effects, with the reduction in hemoglobin A(1c) of up to 1.3%. These responses are often superior to those observed with additional oral agents. However, unlike sulfonylureas, thiazolidinediones, or insulin, all of which lead to significant weight gain, GLP-1 receptor agonists uniquely result in long-term weight loss of around 5 kg, and higher doses may enhance this further. Reduction in blood pressure of 2-7 mm Hg also has been observed. Both drugs produce transient mild gastrointestinal side effects; although mild hypoglycemia can occur, this is usually in combination with other hypoglycemic therapies. However, serious hypoglycemia and acute pancreatitis are rare. The once-daily dosage of liraglutide makes it more convenient than twice-daily dosage of prandial exenatide, and a superior glucose-lowering effect was observed in the only head-to-head comparison reported so far. Besides cost, these considerations currently favor liraglutide over exenatide. Further studies are needed to confirm long-term safety, and most importantly, that short-term benefits translate into long-term reductions of diabetes-related cardiovascular events and other complications.
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PMID:Selecting GLP-1 agonists in the management of type 2 diabetes: differential pharmacology and therapeutic benefits of liraglutide and exenatide. 2085 86

More research is now focused on pancreatic steatosis. Multiple definitions, clinical associations and synonyms for pancreatic steatosis are described in the literature and can be confusing. The integration and comparison of several studies concerning this topic is therefore challenging. In the past, pancreatic steatosis was considered an innocuous condition, a bystander of many underlying diseases (such as congenital syndromes, hemochromatosis and viral infection). However, evidence that pancreatic steatosis (strongly associated with obesity and the metabolic syndrome) has a role in type 2 diabetes mellitus, pancreatic exocrine dysfunction, acute pancreatitis, pancreatic cancer and the formation of pancreatic fistula after pancreatic surgery is emerging. This Review focuses on the different etiological factors and the clinical consequences of pancreatic steatosis.
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PMID:The clinical significance of pancreatic steatosis. 2130 75

The increased number of subjects with type 2 diabetes and putting into clinical practice further new hypoglycemic agents and also aspiring to achieve the bettest glycemic control using a few medications may cause that undesirable actions of these agents may be observed more frequently. One undesirable effect of hypoglycemic drugs is acute pancreatitis; therefore the aim of the present paper is to review data concerning the development of this complication during type 2 diabetes pharmacotherapy.
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PMID:[Can drugs used in type 2 diabetes therapy induce acute pancreatitis?]. 2210 Aug 1

New-onset diabetes mellitus after transplant is a well-recognized complication of tacrolimus immunosuppression and commonly occurs as a form of type 2 diabetes mellitus. However, tacrolimus-associated acute pancreatitis causing diabetic ketoacidosis has not been reported in heart transplant patients. We report a 22-year-old women hospitalized owing to diabetic ketoacidosis associated with acute pancreatitis 7 months after a heart transplant. Her immunosuppression included tacrolimus. She was admitted with complaints of polydipsia, anorexia, and abdominal pain of 3 days' duration. Her initial laboratory test revealed a toxic level of tacrolimus (> 30 ng/mL), severe hyperglycemia (39 mmol/L), severe metabolic acidosis (pH 6.9), and ketonuria, although diabetes mellitus had never been diagnosed. Serum amylase and lipase levels and abdominal computed tomography suggested the presence of acute pancreatitis. After correcting the diabetic ketoacidosis and getting the tacrolimus level to the normal range, she was discharged home. Three months later, insulin was replaced with oral hypoglycemic agents. Pancreatitis can present with diabetic ketoacidosis in the recipient of a heart transplant treated with tacrolimus. Clinicians should pay more attention to tacrolimus levels and the risk of pancreatitis.
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PMID:Diabetic ketoacidosis associated with acute pancreatitis in a heart transplant recipient treated with tacrolimus. 2307 84

Hypertriglyceridaemia is an established cause of acute pancreatitis and responds to insulin therapy in addition to lipid lowering medication. We report a case of severe hypertriglycaeridemia of 149 mmol/L in a 36-year-old man with type 2 diabetes who presented to the surgical ward with abdominal pain due to pancreatitis and developed acute cholestasis, jaundice and eruptive xanthomata. His triglycerides improved to 3.8 mmol/L with sliding scale insulin within two weeks of in-hospital stay. However, his total cholesterol remained raised at 23.7 mmol/L. The lipoprotein electrophoresis confirmed the presence of lipoprotein X associated with bile obstruction, which contributed to an increase in total cholesterol. The total cholesterol normalized on improvement of his cholestasis.
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PMID:Lipoprotein X in a patient with cholestasis and hypertriglyceridaemia. 2343 81

A 55-year-old Japanese man with a 3-year history of type 2 diabetes mellitus was admitted to our hospital for upper abdominal pain. Control of diabetes mellitus was good with voglibose and metformin, with sitagliptin added to this regimen 8 months prior. His pancreatic enzyme levels were elevated, and abdominal computed tomography (CT) showed diffuse pancreatic swelling with fluid accumulation and ascites of CT grade 3. The patient was diagnosed with severe acute pancreatitis. There were no obvious causes for pancreatitis except the recently administered sitagliptin. Since incretin-related drugs entered the market, the number of incretin-related drugs prescriptions rapidly increased and so did the incidence of pancreatitis. There are several reports suggesting the correlation between incretin-related drugs and pancreatitis, such as a report based on data obtained from the United States Food and Drug Administration (FDA) which revealed a significant correlation between the administration of exenatide or sitagliptin and pancreatitis. However, there also is a report that denied the evidence for such in a large cohort study. The relation between incretin based drugs and pancreatitis is still controversial.
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PMID:A case of severe acute necrotizing pancreatitis after administration of sitagliptin. 2346 28

A 23-year-old woman with a history of type 2 diabetes and non-compliance presented to the emergency department with abdominal epigastric pain and nausea. Laboratory examination revealed a mild ketoacidosis while an abdominal CT scan performed the following day demonstrated a severe acute pancreatitis of the body and tail (Balthazar grade E) despite normal amylase serum levels on admission. The presence of a lactescent serum was the clue to an extremely high triglyceride level (>10 000 mg/dl) causing the pancreatitis. The hypertriglyceridaemia itself was attributed mainly to the diabetic ketoacidosis. There was no family history of hypertriglyceridaemia. The triad consisting of diabetic ketoacidosis, hypertriglyceridaemia and acute pancreatitis is an unusual presentation of poorly controlled diabetes which can occur in type 1 as well as type 2 diabetic adults and children. Treatment with intravenous insulin and hydration successfully resolved the ketoacidosis and hypertriglyceridaemia and reversed the episode of acute pancreatitis.
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PMID:Poorly controlled type 2 diabetes complicated by an episode of severe hypertriglyceridaemia-induced pancreatitis. 2363 73


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