Chronic β2 adrenergic agonist, but not exercise, improves glucose handling in older type 2 diabetic mice

Abstract

Insulin resistant type 2 diabetes mellitus in the obese elderly has become a worldwide epidemic. While exercise can prevent the onset of diabetes in young subjects its role in older diabetic people is less clear. Exercise stimulates the release of the β(2)-agonist epinephrine more in the young. Although epinephrine and β(2)-agonist drugs cause acute insulin resistance, their chronic effect on insulin sensitivity is unclear. We fed C57BL/6 mice a high fat diet to induce diabetes. These overweight animals became very insulin resistant. Exhaustive treadmill exercise 5 days a week for 8 weeks had no effect on their diabetes, nor did the β(2)-blocking drug ICI 118551. In contrast, exercise combined with the β(2)-agonist salbutamol (albuterol) had a beneficial effect on both glucose tolerance and insulin sensitivity after 4 and 8 weeks of exercise. The effect was durable and persisted 5 weeks after exercise and β(2)-agonist had stopped. To test whether β(2)-agonist alone was effective, the animals that had received β(2)-blockade were then given β(2)-agonist. Their response to a glucose challenge improved but their response to insulin was not significantly altered. The β(2)-agonists are commonly used to treat asthma and asthmatics have an increased incidence of obesity and type 2 diabetes. Although β(2)-agonists cause acute hyperglycemia, chronic treatment improves insulin sensitivity, probably by improving muscle glucose uptake.

Treatment with a β-2-adrenoceptor agonist stimulates glucose uptake in skeletal muscle and improves glucose homeostasis, insulin resistance and hepatic steatosis in mice with diet-induced obesity

“…Besides the beneficial effects on glucose tolerance, chronic treatment with clenbuterol or other β-AR agonists improves insulin resistance [13][14][15][16][17][18][19]. The underlying mechanism by which β-adrenergic agonists beneficially affect insulin sensitivity remains to be elucidated.…”

Improving Type 2 Diabetes Through a Distinct Adrenergic Signaling Pathway Involving mTORC2 That Mediates Glucose Uptake in Skeletal Muscle

“…In vivo, sympathetic effects on glucose homeostasis are complex, being influenced by glucose outflow from the liver, insulin release from the pancreas, as well as glucose uptake into peripheral tissues such as white fat, brown fat, and muscle. Long-term activation of b 2 -adrenoceptors in rats causes skeletal muscle hypertrophy (11), leading to decreased plasma insulin levels, increased insulin sensitivity, and improved glucose tolerance (12,13); in humans, there are beneficial metabolic changes (14,15), although some b-blockers exacerbate diabetes (16). Despite this circumstantial evidence (2)(3)(4)(5)(6)(7)(8)(9)(10), the mechanisms involved in adrenergic facilitation of glucose uptake in peripheral tissues and their potential therapeutic role are poorly understood.…”

The Effect of Salbutamol on Pgc-1 α and Glut4 Mrna Expression in the Liver and Muscle of Elderly Diabetic Mice

“…The diet mixture that achieved a weight gain in a pilot study was the one used throughout the whole experiment. It contained 60% animal fat (sheep) mixed with 40% crushed feed (Hammoudeh Food Industries Co., Amman, Jordan) (19).…”

“…Toward the end of 13 weeks of high fat feeding, 6 mice out of 24 died. The remaining 18 mice were divided into two groups, 9 mice received 5% of the selective β2-adrenoceptor agonist salbutamol (Asmadil 2, the Arab Pharmaceutical Manufacturing Co., Ltd., Jordan) dissolved in their drinking water for 4 weeks (HFD+Salbutamol group), and the other 9 mice (HFD group) continued to drink tap water (19). Both groups continued the high fat feeding till the end of the experiment.…”

“…This age matches the middle age in man, which is the age that type 2 DM develops. They suggested that the lack of response to exercise is consistent with a lack of endogenous β2 stimulation in older diabetic animals, but the response to a β2-agonist in older diabetic animals suggests that this can be overcome pharmacologically (19). EP release is diminished in the elderly (20) especially during exercise (21).…”