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)

The metabolic syndrome (MS), a cluster of risk factors, such as obesity, hyperglycemia, hypertension and dyslipidemia, contributes to the development of cardio-vascular diseases and type 2 diabetes mellitus (DM2). Insulin resistance (IR) plays a key role in MS being strongly linked to abdominal visceral fat. Treatment for obese patients with MS should aim at improving IR, delaying the onset of DM2 and at reducing cardio-vascular risk. Weight loss, first therapeutic target, may be obtained through life-style modifications and anti-obesity drugs or bariatric surgery, at need. In these patients drug therapy is necessary if therapeutic life-style changes are not sufficient. Some drugs have adverse metabolic effects, therefore the therapeutic choices must be specific and rational. Metformin, Thiazolidinediones and Acarbose are anti-hyperglycemic drugs of choice: they reduce the incidence of DM2 and IR (or improve insulin sensitivity) and they decrease or stabilize the visceral adipose tissue mass (Thiazolidinediones increases subcutaneous fat only). Also Angiotensin II receptor blockers and Angiotensin-converting enzyme inhibitors reduce the incidence of DM2 and insulin resistance and they are first-line antihypertensive drugs in MS. Calcium channel blockers, Alpha-1 antagonists and Alpha-2 agonists drugs are metabolically neutral and slight weight gains are related to the hydro-sodium retention. Beta-blockers and Diuretics, except for Indapamide and Anti-aldosterone drugs, can reduce insulin sensitivity, impair lipid profile and increase DM2 incidence; they are not first-line therapy yet they are necessary in selected cases only. Statins, Fibrates and omega-3 Fatty acids are indicated to normalize dyslipidemia. Low doses of acetylsalicylic acid are also recommended.
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PMID:[Therapeutic options for metabolic syndrome in obese patients]. 1806 54

4-Chloro-N-(2-methyl-1-indolinyl)-3-sulfamoylbenzamide (indapamide), an indoline-containing diuretic drug, has recently been evaluated in a large Phase III clinical trial (ADVANCE) with a fixed-dose combination of an angiotensin-converting enzyme inhibitor, perindopril, and shown to significantly reduce the risks of major vascular toxicities in people with type 2 diabetes. The original metabolic studies of indapamide reported that the indoline functional group was aromatized to indole through a dehydrogenation pathway by cytochromes P450. However, the enzymatic efficiency of indapamide dehydrogenation was not elucidated. A consequence of indoline aromatization is that the product indoles might have dramatically different therapeutic potencies. Thus, studies that characterize dehydrogenation of the functional indoline of indapamide were needed. Here we identified several indapamide metabolic pathways in vitro with human liver microsomes and recombinant CYP3A4 that include the dehydrogenation of indapamide to its corresponding indole form, and also hydroxylation and epoxidation metabolites, as characterized by liquid chromatography/mass spectrometry. Indapamide dehydrogenation efficiency (V(max)/K(m)=204 min/mM) by CYP3A4 was approximately 10-fold greater than that of indoline dehydrogenation. In silico molecular docking of indapamide into two CYP3A4 crystal structures, to evaluate the active site parameters that control dehydrogenation, produced conflicting results about the interactions of Arg212 with indapamide in the active site. These conflicting theories were addressed by functional studies with a CYP3A4R212A mutant enzyme, which showed that Arg212 does not seem to facilitate positioning of indapamide for dehydrogenation. However, the metabolites of indapamide were precisely consistent with in silico predictions of binding orientations using three diverse computer methods to predict drug metabolism pathways.
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PMID:Dehydrogenation of the indoline-containing drug 4-chloro-N-(2-methyl-1-indolinyl)-3-sulfamoylbenzamide (indapamide) by CYP3A4: correlation with in silico predictions. 1907 30

The year 2008 was rich in teachings and suspense in diabetology. Past studies, i.e. United Kingdom Prospective Diabetes Study (UKPDS) in type 2 diabetic patients and Diabetes Control and Complications Trial (DCCT) in type 1 diabetic patients, have shown that in the short term, intensive treatment reduces the incidence of microvascular complications linked to diabetes and in the long term that of both microvascular and macrovascular ones. The in-the-raw conclusions of the recent Action to Control Cardiovascular risk in Diabetes (ACCORD) study note an increase in mortality in type 2 diabetic patients treated intensively, while the Action in Diabetes and Vascular disease, Perindopril and Indapamide Controlled Evaluation (ADVANCE) study evidences a reduction in microvascular complications and the Veterans Affairs Diabetes Trial (VADT) study shows that intensive treatment has no significant effect. A well thought-out analysis of the studies published in 2008 (ACCORD, STENO 2 post-trial, ADVANCE, VADT, UKPDS post-trial, Epidemiology of Diabetes Interventions and Complications [EDIC]) is particularly instructive and highlights the existence of glycaemic memory, the non-existence of blood pressure memory, the need to control all cardiovascular risk factors and to treat diabetes early while avoiding hypoglycaemic incidents. The glycaemic target based on HbA1c must take into account the patient's age and the duration of his diabetes, as well as his cardiovascular risk factors and previous glycaemic control. All in all, the intensive treatment of type 2 diabetes must begin early; it must not be too rapid and must avoid hypoglycaemic incidents and be combined with a strict control of other cardiovascular risk factors.
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PMID:Glycaemic control and cardiovascular morbi-mortality: the contribution of the 2008 studies. 1919 63

The aim of this work was to investigate influence of indapamide and perindopril on blood pressure and metabolism at patients with type 2 diabetes and new diagnosed arterial hypertension. It was shown that monotherapy with indapamide lowered systolic and diastolic arterial pressure and allowed to achieve full normalization of arterial pressure in 36,4+/-6,55% of cases. Monotherapy with perindopril also lowered systolic and diastolic arterial pressure and allowed to achieve full normalization of arterial pressure in 37,5+/-6,53% of cases (>0,05). Indapamide and perindopril had no negative effect on glycemia (HbA1c) and have shown a metabolic neutrality concerning lipids.
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PMID:[Hypotensive and metabolic effect of indapamide and perindopril in patients with type 2 diabetes and arterial hypertensia]. 1943 43