New oral antidiabetic drugs. Synthesis and structure-activity relationships.
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Two members of the group, thiazolidinediones, have been approved for the treatment of type 2 diabetes mellitus. These novel oral antihyperglycaemic agents reduce insulin resistance through binding to and activation of the nuclear receptor, PPAR gamma, with subsequent effects on the glucose and lipid homoeostasis. The compounds will probably exhibit beneficial effects on other facets of the metabolic syndrome. Their effectiveness on glycaemic control appears comparable, as assessed by the literature available. HbA1c is lowered by 1.0 to 1.5%. Both drugs are approved for combination therapy with either metformin or sulphonylureas, not as monotherapy or in combination with insulin. Disturbed heart function (NYHA I-IV) is a contra-indication. In contrast to troglitazone, there is so far no evidence of liver toxicity. In spite of the limited literature, it is anticipated that the present class of oral hypoglycaemic agents will turn out to be an important contribution to improving the metabolic control of patients with type 2 diabetes, if the safety profile remains unchanged in long-term studies.
Phenformin and metformin have a stimulating effect on lipolysis as determined by the action of mouse pancreas lipase on the dilauric (dido-decanoic) acid ester of fluorescein. Tolbutamide and chlorpropamide have an inhibitory effect.
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Calcium chloride increased the liver insulinase activity (LIA) in normal rabbits. No significant changes were noted in the plasma insulinlike activity (PILA), serum zinc level (SZ), and pancreatic zinc content (PZ). Insulin elevated PILA, SZ and PZ but did not affect LIA. Calcium chloride enhanced the effect of insulin on PILA, SZ and PZ. However, insulin did not affect the action of calcium chloride on LIA. Tolbutamide raised PILA, inhibited both LIA and SZ but did not affect PZ. Calcium chloride produced no change in the action of tolbutamide on PILA. On the other hand, tolbutamide prevented the rise of PILA obtained by calcium chloride. PZ was unaltered with calcium chloride and tolbutamide combination. Phenformin increased PILA, LIA, SZ and PZ. When it was given with calcium chloride no further changes in PILA and PZ were observed. The elevation of SZ was abolished but the rise of LIA was synergized. In alloxanized rabbits, LIA was decreased by calcium chloride. No changes were found in PILA, SZ and PZ. Insulin elevated PILA, LIA and SZ although it reduced PZ. Calcium chloride stimulated insulin effect on PILA, did not affect its action on SZ or PZ, and antagonized its effect on LIA. Tolbutamide increased LIA and SZ but did not affect PILA or PZ. Calcium chloride could not change the effect of tolbutamide on SZ or PILA although it could abolish the action of this drug on LIA and PZ. Phenformin significantly lowered PILA, LIA and PZ but raised SZ. Calcium chloride combination with phenformin produced a further decrease in LIA but no other changes in PIAL, SZ or PZ were recorded.
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Type 2 diabetes is a metabolic disorder that, if untreated, can result in macrovascular and microvascular complications. Lowering blood glucose levels primarily reduces microvascular risk; other treatment strategies are necessary to lower the risk for macrovascular disease. Because most patients with diabetes die of macrovascular disease, it is vitally important that patients with diabetes receive aggressive therapies to lessen this risk. It has been found that the risk for macrovascular complications begins even earlier than the risk for microvascular complications. Therefore, patients with insulin resistance (now called prediabetes) should be identified and treated to lower their risk of cardiovascular disease and reduce their risk for progression to diabetes. Two cases are reviewed--a patient with prediabetes and the metabolic syndrome, and a second patient with type 2 diabetes and advanced cardiovascular disease. A review of potential cardiovascular therapies is included.
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The main pitfalls regarding the use of sulphonylureas and metformin in type 2 diabetic patients are described and illustrated by a clinical case. Advices are given in order to avoid the occurrence of severe hypoglycaemic episodes with sulphonylureas and to minimise the risk of lactic acidosis with metformin. These drugs, when used appropriately with respect of contra-indications, have an excellent safety profile and remain the basis of the treatment of type 2 diabetes.