Development of a long-acting insulin analog using albumin fusion technology.
(1/19)
The primary therapeutic goal for the treatment of diabetes is maintenance of a long-term, near-normoglycemic condition and prevention of the onset or progression of the complications associated with the disease. Although several analogs of human insulin have been developed, the currently prescribed long-acting insulin analogs do not provide a stable basal glycemia for more than a few hours. Here, we report the development of Albulin, a long-acting insulin analog obtained by direct gene fusion of a single-chain human insulin to human serum albumin. Albulin showed an elimination t(1/2) of approximately 7 h in normoglycemic mice. In vitro pharmacodynamic profiles for Albulin characterized by receptor binding, inhibition of gluconeogenesis, induction of glucose uptake, and global regulation of gene expression in relevant cell types showed that Albulin produced similar activity profiles compared with that of recombinant human insulin. A single Albulin administration in vivo normalized blood glucose level in diabetic mice in a relatively peakless and sustained (24-h) fashion. A further reduction in glucose levels was achieved by administering a recombinant human insulin a few hours after Albulin injection in mice, indicating the potential for Albulin therapy in combination with available fast-acting insulin derivatives. In summary, Albulin displays characteristics of a potent long-acting insulin analog that can be evaluated for use as a novel insulin therapy for patients with insulin-dependent diabetes. (+info)
Newer insulin analogues and inhaled insulin.
(2/19)
Diabetes is a metabolic disease with high prevalence worldwide. Exogenous insulin is used in the management of this condition. The development of human insulin has provided tighter control of glycaemia in diabetic patients. Insulin analogues like insulin lispro and aspart were developed to closely match its profile with physiological secretion. The newer additions to this armamentarium are insulin glulisine, insulin detemir and albulin. Insulin glulisine is a short acting analogue with a rapid onset of action. The antiapoptotic property, mediated through insulin substrate receptor-2 has a favourable protective action on beta cells. Insulin detemir is a long acting analogue, soluble at neutral pH, which reversibly binds to albumin in plasma, prolonging its action. Its lower affinity for insulin receptors necessitates higher doses compared to human insulin. The reduction in body weight is an additional advantage of detemir. A major concern about all newer insulin analogues is their altered mitogenic properties and resultant risk of carcinogenicity on long term use. Albulin is a latest addition of insulin analogue which is under various in vitro and in vivo studies. Inhaled insulin in powder form (Exubera) is recently approved by FDA and appears promising. (+info)
Strain differences influence murine pulmonary responses to Stachybotrys chartarum.
(3/19)
When the fungus Stachybotrys chartarum is inhaled, its mycotoxins may cause lung injury and inflammation. The severity of human responses to S. chartarum in both occupational and home settings varies widely. To explore these differences, we intratracheally instilled C3H/HeJ, BALB/c, and C57BL/6J mice with S. chartarum spores suspended in saline. One day later, the mice were humanely killed, bronchoalveolar lavage (BAL) was performed, and biochemical and cellular indicators of lung injury and inflammation were measured. BALB/c mice showed the highest myeloperoxidase activity, albumin and hemoglobin levels, and neutrophil numbers in their BAL among the three strains. BALB/c was the only strain to show significant increases in keratinocyte-derived cytokine (KC), monocyte chemotactic protein (MCP)-1, MCP-3, macrophage inflammatory protein (MIP)-1alpha, MIP-1beta, MIP-1gamma, MIP-2, RANTES, IL-1alpha, IL-1beta, IL-3, IL-6, IL-18, leukemia inhibitory factor, macrophage colony-stimulating factor, and TNF-alpha. A model of allergen-induced airway inflammation was examined to assess whether underlying allergic inflammation might contribute to increased susceptibility to S. chartarum-induced pulmonary inflammation and injury. Surprisingly, in BALB/c mice, ovalbumin-induced airway inflammation produced a protective effect against some S. chartarum-induced pulmonary responses. This is the first report of mammalian strain differences affecting responses to S. chartarum. These responses differ from those reported for LPS and other fungi. Analogous underlying genetic differences may contribute to the wide range of sensitivity to Stachybotrys among humans. (+info)
The B2 receptor of bradykinin is not essential for the post-exercise increase in glucose uptake by insulin-stimulated mouse skeletal muscle.
(4/19)
Bradykinin can enhance skeletal muscle glucose uptake (GU), and exercise increases both bradykinin production and muscle insulin sensitivity, but bradykinin's relationship with post-exercise insulin action is uncertain. Our primary aim was to determine if the B2 receptor of bradykinin (B2R) is essential for the post-exercise increase in GU by insulin-stimulated mouse soleus muscles. Wildtype (WT) and B2R knockout (B2RKO) mice were sedentary or performed 60 minutes of treadmill exercise. Isolated soleus muscles were incubated with [(3)H]-2-deoxyglucose +/-insulin (60 or 100 microU/ml). GU tended to be greater for WT vs. B2RKO soleus with 60 microU/ml insulin (P=0.166) and was significantly greater for muscles with 100 microU/ml insulin (P<0.05). Both genotypes had significant exercise-induced reductions (P<0.05) in glycemia and insulinemia, and the decrements for glucose (approximately 14 %) and insulin (approximately 55 %) were similar between genotypes. GU tended to be greater for exercised vs. sedentary soleus with 60 microU/ml insulin (P=0.063) and was significantly greater for muscles with 100 microU/ml insulin (P<0.05). There were no significant interactions between genotype and exercise for blood glucose, plasma insulin or GU. These results indicate that the B2R is not essential for the exercise-induced decrements in blood glucose or plasma insulin or for the post-exercise increase in GU by insulin-stimulated mouse soleus muscle. (+info)
Short-term intensive therapy in newly diagnosed type 2 diabetes partially restores both insulin sensitivity and beta-cell function in subjects with long-term remission.
(5/19)
Strategy of insulin intensification after basal failure for type 2 diabetes in the outpatient setting.
(6/19)
Type 2 diabetes has become a worldwide pandemic and the problem continues to grow. As the disease progresses, the majority of patients will require insulin therapy within 6 years of diagnosis. During the therapy, evaluation and intensification of the current treatment is required in order to achieve the good glycaemic state. In patients who are taking basal insulin or premix OD but failing to achieve the recommended glycaemic targets of HbA1c <6.5%-7%, one option is to intensify to a modern premixed insulin BID or TID. Its formulations have both basal and short or rapid-acting insulin capabilities, enabling them to cover both fasting and postprandial blood glucose levels. Other strategy is known as basal-plus method, basal plus 1 and then basal plus 2. This strategy is used by adding OD short-acting or rapid-acting insulin (analog) before having largest portion meal or before meal when blood glucose before the next meal is high. It is very important for clinicians to have the capability of choosing the right regimen based on individual's need and applying the right strategy to intensify the insulin therapy for their patients. (+info)
Liposomes containing glycocholate as potential oral insulin delivery systems: preparation, in vitro characterization, and improved protection against enzymatic degradation.
(7/19)
Risk of cancer in patients on insulin glargine and other insulin analogues in comparison with those on human insulin: results from a large population-based follow-up study.
(8/19)