15 research outputs found
Valine Pyrrolidide Preserves Intact Glucose-Dependent Insulinotropic Peptide and Improves Abnormal Glucose Tolerance in Minipigs With Reduced β-Cell Mass
The incretin hormones glucagon-like peptide-1 (GLP-1)
and glucose-dependent insulinotropic polypeptide (GIP)
are important in blood glucose regulation.However, both incretin
hormones are rapidly degraded by the enzyme dipeptidyl
peptidase IV (DPPIV). The concept of DPPIV inhibition
as a treatment for type 2 diabetes was evaluated in a new
large animal model of insulin-deficient diabetes and reduced
β-cell mass, the nicotinamide (NIA) (67 mg/kg) and streptozotocin
(STZ) (125 mg/kg)âtreated minipig, using the
DPPIV inhibitor, valine pyrrolidide (VP) (50 mg/kg).VP did
not significantly affect levels of intact GLP-1 but increased
levels of intact GIP (from 4543 Âą 1880 to 9208 Âą 3267 pM
Ă min; P<.01), thus improving glucose tolerance (area under
the curve [AUC] for glucose reduced from 1904 Âą 480 to
1582 Âą 353 mM Ă min;P = .05).VP did not increase insulin
levels during the oral glucose tolerance test (OGTT) but increased
the insulinogenic index in normal animals (from 83 Âą 42 to 192 Âą 108; P < .05), but not after NIA + STZ,
possibly because of less residual insulin secretory capacity
in these animals. GIP seems to contribute to the antihyperglycemic
effect of VP in this model; however, additional
mechanisms for the effect of DPPIV inhibition cannot be
excluded. The authors conclude that DPPIV inhibitors may
be useful to treat type 2 diabetes, even when this is due to
reduced β-cell mass
Sensory nerve desensitization by resiniferatoxin improves glucose tolerance and increases insulin secretion in Zucker Diabetic Fatty rats and is associated with reduced plasma activity of dipeptidyl peptidase IV.
Sensory nerve desensitization by capsaicin has been shown to improve the diabetic condition in Zucker Diabetic Fatty rats. However, administration of capsaicin to adult rats is associated with an increased mortality. Therefore, in this experiment, we examined the influence of resiniferatoxin, a tolerable analogue of capsaicin suitable for in vivo use, on the diabetic condition of Zucker Diabetic Fatty rats. A single subcutaneous injection of resiniferatoxin (0.01 mg/kg) to these rats was tolerable, with no mortality. When administered to early diabetic rats at 15 weeks of age, the further deterioration of glucose homeostasis was prevented by resiniferatoxin. Further, when administered to overtly diabetic rats at 19 weeks of age, resiniferatoxin markedly improved glucose tolerance at two weeks after administration and this was accompanied by an increased insulin response to oral glucose as well as a reduction in the plasma levels of dipeptidyl peptidase IV. Therefore, resiniferatoxin is a safe alternative to capsaicin for further investigations of the role of the sensory nerves in experimental diabetes
Insulin analog with additional disulfide bond has increased stability and preserved activity
Insulin is a key hormone controlling glucose homeostasis. All known vertebrate insulin analogs have a classical structure with three 100% conserved disulfide bonds that are essential for structural stability and thus the function of insulin. It might be hypothesized that an additional disulfide bond may enhance insulin structural stability which would be highly desirable in a pharmaceutical use. To address this hypothesis, we designed insulin with an additional interchain disulfide bond in positions A10/B4 based on Cι-Cι distances, solvent exposure, and side-chain orientation in human insulin (HI) structure. This insulin analog had increased affinity for the insulin receptor and apparently augmented glucodynamic potency in a normal rat model compared with HI. Addition of the disulfide bond also resulted in a 34.6°C increase in melting temperature and prevented insulin fibril formation under high physical stress even though the C-terminus of the B-chain thought to be directly involved in fibril formation was not modified. Importantly, this analog was capable of forming hexamer upon Zn addition as typical for wild-type insulin and its crystal structure showed only minor deviations from the classical insulin structure. Furthermore, the additional disulfide bond prevented this insulin analog from adopting the R-state conformation and thus showing that the R-state conformation is not a prerequisite for binding to insulin receptor as previously suggested. In summary, this is the first example of an insulin analog featuring a fourth disulfide bond with increased structural stability and retained function