Abstract
In the current study we investigate the mechanisms of action of short acting inhaled insulin Exubera®, on hepatic glucose production (HGP), plasma glucose and free fatty acid (FFA) concentrations. 11 T2D (Type 2 Diabetes) subjects (age = 53 ± 3 years) were studied at baseline (BAS) and after 16-weeks of Exubera® treatment. At BAS and after 16-weeks subjects received: measurement of HGP (3-3H-glucose); oral glucose tolerance test (OGTT); and a 24-h plasma glucose (24-h PG) profile. At end of study (EOS) we observed a significant decrease in fasting plasma glucose (FPG, 215 ± 15 to 137 ± 11 mg/dl), 2-hour plasma glucose (2-h PG, 309 ± 9 to 264 ± 11 mg/dl), glycated hemoglobin (HbA1c, 10.3 ± 0.5% to 7.5 ± 0.3%,), mean 24-h PG profile (212 ± 17 to 141 ± 8 mg/dl), FFA fasting (665 ± 106 to 479 ± 61 μM), post-OGTT (433 ± 83 to 239 ± 28 μM), and triglyceride (213 ± 39 to 120 ± 14 mg/dl), while high density cholesterol (HDL-C) increased (35 ± 3 to 47 ± 9 mg/dl). The basal HGP decreased significantly and the insulin secretion/insulin resistance (disposition) index increased significantly. There were no episodes of hypoglycemia and no change in pulmonary function at EOS. After 16-weeks of inhaled insulin Exubera® we observed a marked improvement in glycemic control by decreasing HGP and 24-h PG profile, and decreased FFA and triglyceride concentrations.
Highlights
Type 2 diabetic patients are characterized by fasting and postprandial hyperglycemia [1]
At end of study (EOS) we observed a significant decrease in fasting plasma glucose (FPG, 215 ± 15 to 137 ± 11 mg/dl), 2-hour plasma glucose (2-h PG, 309 ± 9 to 264 ± 11 mg/dl), glycated hemoglobin (HbA1c, 10.3 ± 0.5% to 7.5 ± 0.3%,), mean 24-h plasma glucose (24-h PG) profile (212 ± 17 to 141 ± 8 mg/dl), free fatty acid (FFA) fasting (665 ± 106 to 479 ± 61 μM), post-oral glucose tolerance test (OGTT) (433 ± 83 to 239 ± 28 μM), and triglyceride (213 ± 39 to 120 ± 14 mg/dl), while high density cholesterol (HDL-C) increased (35 ± 3 to 47 ± 9 mg/dl)
Postprandial hyperglycemia results from insulin resistance in muscle [7], impaired suppression of hepatic glucose production [3,8], and decreased insulin secretion [9,10]
Summary
Type 2 diabetic patients are characterized by fasting and postprandial hyperglycemia [1]. Because Exubera®is a short acting (4–6 hours) inhaled insulin, it is somewhat paradoxical that three daily administrations (7–8 a.m., 12–1 p.m., 6–7 p.m.) could influence the basal rate of HGP that prevails from 12 a.m. to 7–8 a.m. on the following day This has important clinical implications since it implies that a ‘short acting’ insulin preparation can normalize/cause near-normalization of the FPG concentration, obviating the need for a ‘long acting’ basal insulin. In the present study we have, for the first time, examined the effect of inhaled insulin on HGP in poorly controlled (defined as glycated hemoglobin HbA1c≥8 %) patients with T2D These results have important implications for the mechanisms of action of inhaled insulin on whole body glucose metabolism in patients with T2D
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