Additive Effects of GLP-1 and Pioglitazone
Additive Effects of GLP-1 and Pioglitazone
Objective: To evaluate the effect of combination therapy with pioglitazone and glucagon-like peptide (GLP)-1 in patients with type 2 diabetes.
Research Design and Methods: Eight patients with type 2 diabetes (BMI 32.7 ± 1.3 kg/m and fasting plasma glucose 13.5 ± 1.2 mmol/l) underwent four different treatment regimens in random order: saline therapy, monotherapy with continuous subcutaneous infusion of GLP-1 (4.8 pmol · kg · min), monotherapy with pioglitazone (30-mg tablet of Actos), and combination therapy with GLP-1 and pioglitazone. The observation period was 48 h. End points were plasma levels of glucose, insulin, glucagon, free fatty acids (FFAs), and sensation of appetite.
Results: Fasting plasma glucose decreased from 13.5 ± 1.2 mmol/l (saline) to 11.7 ± 1.2 (GLP-1) and 11.5 ± 1.2 (pioglitazone) and further decreased to 9.9 ± 1.0 (combination) (P < 0.001). Eight-hour mean plasma glucose levels were reduced from 13.7 ± 1.1 mmol/l (saline) to 10.6 ± 1.0 (GLP-1) and 12.0 ± 1.2 (pioglitazone) and were further reduced to 9.5 ± 0.8 (combination) (P < 0.0001). Insulin levels increased during monotherapy with GLP-1 compared with monotherapy with pioglitazone (P < 0.01). Glucagon levels were reduced in GLP-1 and combination therapy compared with saline and monotherapy with pioglitazone (P < 0.01). FFAs during breakfast (area under the curve, 03 h) were reduced in combination therapy compared with saline (P = 0.03). Sensation of appetite was reduced during monotherapy with GLP-1 and combination therapy (P < 0.05).
Conclusions: GLP-1 and pioglitazone show an additive glucose-lowering effect. A combination of the two agents may, therefore, be a valuable therapeutic approach for the treatment of type 2 diabetes.
Glucagon-like peptide (GLP)-1 is an intestinally produced peptide hormone that stimulates insulin secretion, inhibits glucagon secretion, reduces plasma glucose levels in patients with type 2 diabetes, and has, therefore, been proposed as a new antidiabetic agent. In short-term studies, continuous subcutaneous infusion of GLP-1 reduces plasma glucose levels by 23 mmol/l, whereas in longer-term studies (6 weeks), fasting plasma glucose levels are reduced by 45 mmol/l and HbA1c by 1.3%. Furthermore, GLP-1 stimulates proinsulin gene expression and proinsulin biosynthesis, and in animal studies GLP-1 receptor agonists stimulate ß-cell neogenesis and proliferation. Thus, theoretically, long-term treatment with GLP-1 may protect against the deterioration of ß-cell function, which inevitably occurs as a part of the natural history of the disease. Several studies have shown that GLP-1 inhibits appetite and reduces food intake in humans; therefore, treatment with GLP-1 may inhibit weight gain or even result in weight loss. The peroxisome proliferator- activated receptor-γ agonists, the thiazolidinediones, have been shown to reduce fasting plasma glucose levels by 34 mmol/l and HbA1c by 12% when administered to patients with type 2 diabetes. Thiazolidinediones enhance insulin sensitivity in skeletal muscles and in peripheral adipocytes.
Since type 2 diabetes is a progressive disease, a combination of therapies may be required to bring about acceptable glycemic control. Thus, to judge the clinical value of a new agent, it is important to examine the possibility of combining it with other agents.
GLP-1 and the thiazolidinediones have differential mechanisms of action, and combination treatment with both of them might, therefore, result in additive glucose-lowering effects. The purpose of the present study was to assess the effect of GLP-1, administered in combination with the thiazolidinedione, pioglitazone, on glucose, insulin, glucagon, free fatty acids (FFAs), and appetite regulation in patients with type 2 diabetes.
Objective: To evaluate the effect of combination therapy with pioglitazone and glucagon-like peptide (GLP)-1 in patients with type 2 diabetes.
Research Design and Methods: Eight patients with type 2 diabetes (BMI 32.7 ± 1.3 kg/m and fasting plasma glucose 13.5 ± 1.2 mmol/l) underwent four different treatment regimens in random order: saline therapy, monotherapy with continuous subcutaneous infusion of GLP-1 (4.8 pmol · kg · min), monotherapy with pioglitazone (30-mg tablet of Actos), and combination therapy with GLP-1 and pioglitazone. The observation period was 48 h. End points were plasma levels of glucose, insulin, glucagon, free fatty acids (FFAs), and sensation of appetite.
Results: Fasting plasma glucose decreased from 13.5 ± 1.2 mmol/l (saline) to 11.7 ± 1.2 (GLP-1) and 11.5 ± 1.2 (pioglitazone) and further decreased to 9.9 ± 1.0 (combination) (P < 0.001). Eight-hour mean plasma glucose levels were reduced from 13.7 ± 1.1 mmol/l (saline) to 10.6 ± 1.0 (GLP-1) and 12.0 ± 1.2 (pioglitazone) and were further reduced to 9.5 ± 0.8 (combination) (P < 0.0001). Insulin levels increased during monotherapy with GLP-1 compared with monotherapy with pioglitazone (P < 0.01). Glucagon levels were reduced in GLP-1 and combination therapy compared with saline and monotherapy with pioglitazone (P < 0.01). FFAs during breakfast (area under the curve, 03 h) were reduced in combination therapy compared with saline (P = 0.03). Sensation of appetite was reduced during monotherapy with GLP-1 and combination therapy (P < 0.05).
Conclusions: GLP-1 and pioglitazone show an additive glucose-lowering effect. A combination of the two agents may, therefore, be a valuable therapeutic approach for the treatment of type 2 diabetes.
Glucagon-like peptide (GLP)-1 is an intestinally produced peptide hormone that stimulates insulin secretion, inhibits glucagon secretion, reduces plasma glucose levels in patients with type 2 diabetes, and has, therefore, been proposed as a new antidiabetic agent. In short-term studies, continuous subcutaneous infusion of GLP-1 reduces plasma glucose levels by 23 mmol/l, whereas in longer-term studies (6 weeks), fasting plasma glucose levels are reduced by 45 mmol/l and HbA1c by 1.3%. Furthermore, GLP-1 stimulates proinsulin gene expression and proinsulin biosynthesis, and in animal studies GLP-1 receptor agonists stimulate ß-cell neogenesis and proliferation. Thus, theoretically, long-term treatment with GLP-1 may protect against the deterioration of ß-cell function, which inevitably occurs as a part of the natural history of the disease. Several studies have shown that GLP-1 inhibits appetite and reduces food intake in humans; therefore, treatment with GLP-1 may inhibit weight gain or even result in weight loss. The peroxisome proliferator- activated receptor-γ agonists, the thiazolidinediones, have been shown to reduce fasting plasma glucose levels by 34 mmol/l and HbA1c by 12% when administered to patients with type 2 diabetes. Thiazolidinediones enhance insulin sensitivity in skeletal muscles and in peripheral adipocytes.
Since type 2 diabetes is a progressive disease, a combination of therapies may be required to bring about acceptable glycemic control. Thus, to judge the clinical value of a new agent, it is important to examine the possibility of combining it with other agents.
GLP-1 and the thiazolidinediones have differential mechanisms of action, and combination treatment with both of them might, therefore, result in additive glucose-lowering effects. The purpose of the present study was to assess the effect of GLP-1, administered in combination with the thiazolidinedione, pioglitazone, on glucose, insulin, glucagon, free fatty acids (FFAs), and appetite regulation in patients with type 2 diabetes.
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