nn-414 and Diabetes-Mellitus--Type-2

Novo Nordisk is developing NN-414, an orally active beta-cell-selective regulator of insulin release, for the potential treatment of type 1 and type 2 diabetes. Phase 1 efficacy trials were underway by November 2000; these trials were ongoing in February 2002 and had been concluded by February 2003.

Topics: Animals; Bridged Bicyclo Compounds, Heterocyclic; Clinical Trials, Phase I as Topic; Contraindications; Cyclic S-Oxides; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Structure-Activity Relationship

Reducing the workload of the beta cell by inhibiting insulin secretion may provide beneficial effects for patients with type 2 diabetes. The aim of this study was to investigate the effect of NN414, a beta cell selective potassium channel opener in patients with type 2 diabetes. 24 patients were treated for seven days (placebo, 1.5, 4.5, and 10 mg/kg). In accordance with the pharmacological profile a significant and selective inhibition of insulin secretion was observed (1 h post dose). There were no statistically significant effects on overall glycaemic control. Based on OGTT derived parameters a borderline significant improvement in beta-cell function (1st and 2nd phase insulin secretion) was observed from Day 1 to Day 7.

Topics: Aged; ATP-Binding Cassette Transporters; Bridged Bicyclo Compounds, Heterocyclic; Cyclic S-Oxides; Diabetes Mellitus, Type 2; Double-Blind Method; Female; Humans; Insulin; Insulin Secretion; Insulin-Secreting Cells; Male; Middle Aged; Potassium Channels; Potassium Channels, Inwardly Rectifying; Receptors, Drug; Sulfonylurea Receptors; Time Factors

In type 2 diabetes mellitus (T2DM) chronic beta-cell stimulation and oligomers of aggregating human islet amyloid polypeptide (h-IAPP) cause beta-cell dysfunction and induce beta-cell apoptosis. Therefore we asked whether beta-cell rest prevents h-IAPP induced beta-cell apoptosis.. We induced beta-cell rest with a beta-cell selective K(ATP)-channel opener (K(ATP)CO) in RIN cells and human islets exposed to h-IAPP versus r-IAPP. Apoptosis was quantified by time-lapse video microscopy (TLVM) in RIN cells and TUNEL staining in human islets. Whole islets were also studied with TLVM over 48h to examine islet architecture.. In RIN cells and human islets h-IAPP induced apoptosis (p<0.001 h-IAPP versus r-IAPP). Concomitant incubation with K(ATP)CO inhibited apoptosis (p<0.001). K(ATP)CO also reduced h-IAPP induced expansion of whole islets (disintegration of islet architecture) by ~70% (p<0.05). Thioflavin-binding assays show that K(ATP)CO does not directly inhibit amyloid formation.. Opening of K(ATP)-channels reduces beta-cell vulnerability to apoptosis induced by h-IAPP oligomers. This effect is not due to a direct interaction of K(ATP)CO with h-IAPP, but might be mediated through hyperpolarization of the beta-cell membrane induced by opening of K(ATP)-channels. Induction of beta-cell rest with beta-cell selective K(ATP)-channel openers may provide a strategy to protect beta-cells from h-IAPP induced apoptosis and to prevent beta-cell deficiency in T2DM.

Topics: Bridged Bicyclo Compounds, Heterocyclic; Cyclic S-Oxides; Diabetes Mellitus, Type 2; Humans; In Vitro Techniques; Insulin-Secreting Cells; Islet Amyloid Polypeptide; Islets of Langerhans; KATP Channels

A novel potassium channel opener compound, NN414, selective for the SUR1/Kir6.2 subtype of the ATP-sensitive potassium channel, was used to examine the effect of reducing beta-cell workload in the male Vancouver diabetic fatty (VDF) Zucker rat model of mild type 2 diabetes. Two chronic dosing protocols of NN414 of 3 weeks' duration were compared with appropriate vehicle-treated controls. In the first group, rats received NN414 (continued group; 1.5 mg/kg p.o. twice daily), during which an oral glucose tolerance test (OGTT) (on day 19 of dosing) was performed and insulin secretion from an in situ perfused pancreas preparation (on day 21) was measured. The second group received NN414 (discontinued group; same dose), but active treatment was replaced by vehicle treatment 2 days before the OGTT and for a further 2 days before the perfused pancreas study. Basal glucose was significantly reduced by NN414, with the fall averaging 0.64 mmol/l after 3 weeks of treatment (P < 0.0001). The glucose excursion and hyperinsulinemia during the OGTT were significantly different between the continued, discontinued, and vehicle groups (glucose area under the curve [AUC]: 640 +/- 29, 740 +/- 27, and 954 +/- 82 mmol. l(-1). min(-1), respectively, P < 0.0001; insulin AUC: 38.9 +/- 4.2, 44.2 +/- 4.2, and 55.1 +/- 2.6 nmol.l(-1).min(-1), respectively, P < 0.0001). Hyperinsulinemia during the pancreas perfusion with 4.4 mmol/l glucose was significantly reduced in both treatment groups versus vehicle (P < 0.0005). Insulin secretory responsiveness to a step increase in glucose from 4.4 to 16.6 mmol/l, calculated relative to basal, was significantly improved in the continued group versus vehicle (P < 0.01). In conclusion, administration of NN414 for 3 weeks in VDF rats reduces basal hyperglycemia, improves glucose tolerance, and reduces hyperinsulinemia during an OGTT and improves insulin secretory responsiveness ex vivo. NN414 may therefore represent a novel approach to the prevention and treatment of impaired glucose tolerance and type 2 diabetes.

Topics: Animals; Blood Glucose; Body Weight; Bridged Bicyclo Compounds, Heterocyclic; Cyclic S-Oxides; Diabetes Mellitus, Type 2; Drug Administration Schedule; Fasting; Glucose; Glucose Tolerance Test; In Vitro Techniques; Insulin; Insulin Secretion; Islets of Langerhans; Male; Pancreas; Perfusion; Potassium Channels, Inwardly Rectifying; Rats; Rats, Zucker