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

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.     

Impaired β-cell regeneration after partial pancreatectomy in the adult Goto-Kakizaki rat, a spontaneous model of type II diabetes

In the Goto-Kakizaki (GK) rat, a genetic model of type II diabetes, there is a restriction of the beta-cell mass as early as fetal age, which is maintained reduced in the adult animal. In order to investigate the beta-cell growth potential in the adult hyperglycemic GK rat, and to determine whether it differs from non-diabetic Wistar (W) rats, we have performed 90% pancreatectomy (Px) in 8- to 10-week-old male animals. Spontaneous beta-cell regeneration and involvement of beta-cell replication, beta-cell neodifferentiation from ductal precursor, and beta-cell apoptosis were evaluated by immunocytochemistry and morphometry at different time points: day 0 (D0), D2, D7, and D14 after Px. In GK rats, deterioration of the diabetic state with severe and chronic hyperglycemia was evident as soon as D2, while in W/Px, normoglycemia to moderate hyperglycemia was observed. In W/Px rats, the total beta-cell mass gradually increased on D2, D7, and D14, as compared to non-Px W rats. By contrast, in GK/Px rats, there was only a non-significant tendency to increased total beta-cell mass, as compared to related non-Px group. Adult GK rats displayed lower beta-cell proliferation rates compared to W. In response to Px, early increase of beta-cell proliferation was present in both W/Px and GK/Px rats on D2, but it returned to non-Px values in GK rats on D7 and D14, while in W/Px rats beta-cell proliferation was maintained increased as compared to non-Px W rats. The very low apoptotic beta-cell frequency on D0, D2, D7, and D14, in both W and GK, either non-Px or Px, did not allow us to conclude that any significant differences exist between the different groups. beta-cell neoformation from ducts, and more specifically from foci of regeneration, was found to be less activated in GK/Px rats as compared to W/Px. Together, these results suggest that in the adult hyperglycemic GK rat undergoing Px, beta-cells still have the capacity to regenerate, but with a lower efficiency as compared to non-diabetic W rats. This defect in the GK rat is the result of both genetic predisposition contributing to an altered beta-cell neogenesis potential already present in the neonatal period, and environmental factors (chronic hyperglycemia) leading to a reduced beta-cell proliferative capacity specific to the adult animals.     

Progressive histopathological changes and β-cell loss in the pancreas of a new spontaneous rat model of type 2 diabetes

The eSMT rat is a new spontaneous model of type 2 diabetes that develops a progressive diabetic syndrome with a stronger incidence in males than in females. We decide to investigate the progression of the pancreatic histopathological changes during the lifespan of the eSMT rat, especially those associated with islet cell populations. Besides that, some plasmatic parameters were evaluated in order to correlate them with the morphological findings. Male eSMT and Sprague-Dawley control rats were used.The results showed a dramatic decrease of the volume density (VD) of endocrine tissue in the eSMT rats without evidence of insulitis. Islets became fragmented structures with strong presence of interstitial fibrosis. Consequently, plasma insulin levels showed a significant decrease, while plasma glucose, cholesterol and triglyceride levels were increased. Normal rats showed no significant changes in the VD of endocrine tissue, except for the older animals, where the VD of β-cell population was increased.Early derangements observed in islets, together with the progressive decrease of endocrine tissue and the metabolic disorders described, would be responsible for an irreversible pathologic condition which avoids the animal survival beyond about 18 months of age.However, there is still a need to investigate the causes of endocrine tissue decrease and its possible association with an inflammatory process that it could be associated with the development and progression of fibrosis.     

Docking studies on a refined human β2 adrenoceptor model yield theoretical affinity values in function with experimental values for R-ligands, but not for S-antagonists

G-protein coupled receptors (GPCR) belong to the largest group of membrane proteins involved in signal transduction. These receptors are implicated in diverse physiological and pathological events. The human β₂ adrenergic receptor (hβ₂AR) is one of the few GPCRs whose 3-D structures are available on the Protein Data Bank. Because there is great interest by drug developers for hβ₂AR as a target, it is necessary to study its ligand-recognition process at the atomic level. The hβ₂AR can recognize both R/S enantiomeric ligands, R-agonists result in a greater activation than do S-agonists (eutomers and distomers for activation, respectively), according to experimental results. In this work is reported the ligand recognition on a refined hβ₂AR-structure of a set of well-known R/S-ligands by means of docking studies. Data obtained in silico were analyzed and compared with those reported in vitro. The theoretical affinity values were reproduced for agonists, but not for antagonist (or inverse agonists). However, theoretical data for R-antagonists are in function to experimental data. The theoretical results confirm the role of amino acids previously reported by mutagenesis studies due to their important roles in drug affinity and stereoselectivity.