Need for Better Diabetes Treatment: The Therapeutic Potential of NMDA Receptor Antagonists.

Diabetes mellitus is the most common metabolic disorder in children and adolescents. Optimal control of blood glucose concentration is essential to prevent acute and diabetic long-term complications. The options to treat diabetes have clearly improved over the last decades, however, to date neither type 1 diabetes nor type 2 diabetes mellitus can be cured. Therefore, diabetes research aims at developing ß-cell protective agents that prevent or even reverse diabetes onset. N-methyl-D-aspartate receptors (NMDARs) are glutamate-gated ion channels that are widely expressed in the central nervous system (CNS) where they hold central roles in CNS function. NMDAR dysfunction is associated with several neurological and psychiatric disorders and therefore NMDAR modulators have several potential therapeutic indications. Only little is known about the role of pancreatic NMDA receptors. Our data provide evidence that inhibition of pancreatic NMDARs, either genetically or pharmacologically with the over-the-counter drug dextromethorphan, increases glucose-stimulated insulin secretion from mouse and human pancreatic islets, improves glucose tolerance in mice and individuals with diabetes and promotes islet cell survival under diabetogenic conditions. Thus, our data indicate for the first time that NMDAR antagonists could serve as adjunct treatment for diabetes mellitus. The development of a safe, blood glucose lowering and particularly ß-cell protective medication would significantly enhance current diabetes treatment.

Effects of dextromethorphan as add-on to sitagliptin on blood glucose and serum insulin concentrations in individuals with type 2 diabetes mellitus: a randomized, placebo-controlled, double-blinded, multiple crossover, single-dose clinical trial.

In this clinical trial, we investigated the blood glucose (BG)-lowering effects of 30, 60 and 90 mg dextromethorphan (DXM) as well as 100 mg sitagliptin alone versus combinations of DXM and sitagliptin during an oral glucose tolerance test (OGTT) in 20 men with T2DM. The combination of 60 mg DXM plus 100 mg sitagliptin was observed to have the strongest effect in the OGTT. It lowered maximum BG concentrations and increased the baseline-adjusted area under the curve for serum insulin concentrations in the first 30 min of the OGTT (mean ± standard deviation 240 ± 47 mg/dl and 8.1 ± 6.1 mU/l/h, respectively) to a significantly larger extent than did 100 mg sitagliptin alone (254 ± 50 mg/dl and 5.8 ± 2.5 mU/l/h, respectively; p < 0.05) and placebo (272 ± 49 mg/dl and 3.9 ± 3.0 mU/l/h, respectively; p < 0.001). All study drugs were well tolerated, alone and in combination, without serious adverse events or hypoglycaemia. Long-term clinical trials are now warranted to investigate the potential of the combination of 30 or 60 mg DXM and dipeptidyl peptidase-4 inhibitors in the treatment of individuals with T2DM, in particular as preclinical studies have identified the ß-cell protective properties of DXM.

Association of exercise-induced hyperinsulinaemic hypoglycaemia with MCT1-expressing insulinoma.

AIMS/HYPOTHESIS: Exercise-induced hyperinsulinism (EIHI) is a hypoglycaemic disorder characterised by inappropriate insulin secretion following anaerobic exercise or pyruvate load. Activating promoter mutations in the MCT1 gene (also known as SCLA16A1), coding for monocarboxylate transporter 1 (MCT1), were shown to associate with EIHI. Recently, transgenic Mct1 expression in pancreatic beta cells was shown to introduce EIHI symptoms in mice. To date, MCT1 has not been demonstrated in insulin-producing cells from an EIHI patient. METHODS: In vivo insulin secretion was studied during an exercise test before and after the resection of an insulinoma. The presence of MCT1 was analysed using immunohistochemistry followed by laser scanning microscopy, western blot analysis and real-time RT-PCR of MCT1. The presence of MCT1 protein was analysed in four additional insulinoma patients. RESULTS: Clinical testing revealed massive insulin secretion induced by anaerobic exercise preoperatively, but not postoperatively. MCT1 protein was not detected in the patient's normal islets. In contrast, immunoreactivity was clearly observed in the insulinoma tissue. Western blot analysis and real-time RT-PCR showed a four- to fivefold increase in MCT1 in the insulinoma tissue of the EIHI patient compared with human pancreatic islets. MCT1 protein was detected in three of four additional insulinomas. CONCLUSIONS/INTERPRETATION: We show for the first time that an MCT1-expressing insulinoma was associated with EIHI and that MCT1 might be present in most insulinomas. Our data suggest that MCT1 expression in human insulin-producing cells can lead to EIHI and warrant further studies on the role of MCT1 in human insulinoma patients.

Influence of aprotinin on the thrombomodulin/protein C system in pediatric cardiac operations.

Thirty consecutive children scheduled for pediatric cardiac operation with cardiopulmonary bypass were included in the study. Before the operation, the patients were randomly divided into two groups: with aprotinin (n = 15, 30,000 U/kg after induction of anesthesia, 30,000 U/kg added to the prime of the cardiopulmonary bypass or without aprotinin (n = 15). Thrombomodulin, (free) protein S, protein C, and thrombin/antithrombin III complex were measured from arterial blood samples taken after induction of anesthesia (at baseline, before aprotinin) and before, during, and after cardiopulmonary bypass until the first postoperative day. Standard coagulation parameters (antithrombin III, fibrinogen, platelet count, and partial thromboplastin time) were without differences between the groups. Thrombomodulin plasma concentrations were within normal range ( < 40 micrograms/L) and were similar in both groups at baseline. During cardiopulmonary bypass and until 5 hours after cardiopulmonary bypass, however, thrombomodulin plasma levels were significantly lower in the children treated with aprotinin. No further differences were observed on the first postoperative day. Protein C and protein S plasma levels did not differ between the two groups. Thrombin/antithrombin III-complex plasma concentrations increased significantly during cardiopulmonary bypass, however, without showing differences between children with (225 +/- 49 micrograms/L) and without (149 +/- 31 micrograms/L) aprotinin treatment. Blood loss and the need for homologous blood and blood products did not differ significantly between the two groups. We concluded that administration of aprotinin resulted in reduced thrombomodulin plasma levels in pediatric patients undergoing cardiac operation without altering protein C/protein S plasma concentration. The exact role of aprotinin in endothelium-derived coagulation should be further studied.

Thrombomodulin in intensive care patients.

OBJECTIVE: Changes of endothelial-related coagulation was studied in intensive care patients. DESIGN: Descriptive, prospective. SETTING: Clinical investigation, intensive care unit of an university hospital. PATIENTS: 40 consecutive critically ill patients with severe trauma (n = 20) or postoperative complications (n = 20) were studied. 14 patients suffered from sepsis, 12 patients suffered from acute renal failure. INTERVENTIONS: 12 patients with acute renal failure were continuously hemofiltrated. All patients were on continuous sedation (fentanyl and midazolam) and mechanical ventilation. MEASUREMENTS: In addition to standard coagulation variables, thrombomodulin (TM), protein C and protein S as well as thrombin/antithrombin III (TAT) plasma concentrations were measured from arterial blood samples using enzyme-linked immuno-sorbent assays (ELISA). Measurements were carried out on the day of admission (trauma patients) or on the day of diagnosis of sepsis and during the next 4 days. MAIN RESULTS: Throughout the entire investigation period, TM plasma concentrations in patients with sepsis (baseline: 90 +/- 25 micrograms/l, 4th day: 152 +/- 28 micrograms/l) were significantly higher than in non-septic patients (baseline: 60 +/- 29 micrograms/l, 4th day: 42 +/- 15 micrograms/l). 15 of the 40 patients died within or after the end of the investigation period. TM plasma concentrations of survivors were lower (maximum: 63 +/- 18 micrograms/l) than in the non-survivors (maximum: 159 +/- 22 micrograms/l) (p < 0.05). Hemofiltered patients showed higher TM plasma levels, which further increased during the hemofiltration procedure. Protein C and (free) protein S were without significant group differences. TAT plasma levels were elevated above normal in all patients (no group differences). CONCLUSIONS: Besides plasmatic and platelet-related coagulation, endothelium-associated coagulation appears to be also important for maintenance of hemostasis. TM plasma concentrations were elevated in all our critically ill patients, particularly when sepsis was evident. This appears to be most likely due to endothelial membrane damage with increased release of membrane-bound TM into the circulating blood in these patients. The importance of the elevated plasma levels of circulating soluble TM on hemostasis in these patients is an ongoing debate and warrants further studies.

Thrombomodulin in pediatric cardiac surgery.

In 30 consecutive children with congenital heart disease scheduled for pediatric cardiac operations, thrombomodulin, protein C, free protein S, and thrombin-antithrombin complex were measured by enzyme-linked immunosorbent assay after the induction of anesthesia (baseline value), and then before, during, and after cardiopulmonary bypass until the first postoperative day. The patients were divided prospectively into two groups: children weighing less than 10 kg (group 1; n = 15) and those weighing more than 10 kg (group 2; n = 15). At baseline, the plasma concentration of thrombomodulin was significantly higher in the children in group 1 than in those in group 2 (83.1 +/- 11.0 ng/mL versus 29.2 +/- 12.1 ng/mL). During cardiopulmonary bypass, the thrombomodulin level was reduced in both groups without showing any significant group differences. Five hours after cardiopulmonary bypass and on the first postoperative day, the thrombomodulin level exceeded normal values only in the children weighing less than 10 kg. In both groups, the protein C levels were already below normal at the beginning of the study. The baseline protein S concentration was higher in the smaller children (80% +/- 18%) than in the larger children (66% +/- 11%). It was reduced by cardiopulmonary bypass in both groups; however, postoperatively it did not return to normal in group 1 (45.1% +/- 10%). Plasma levels of the thrombin-antithrombin complex were similar in both groups, with a marked increase at the end of cardiopulmonary bypass, and returned to near-normal levels by 5 hours after bypass.(ABSTRACT TRUNCATED AT 250 WORDS)

[Color vision testing in patients with diabetes mellitus and arterial hypertension]. / Farbsehuntersuchung bei Patienten mit Diabetes mellitus und arterieller Hypertonie.

BACKGROUND: This study aimed to discover the influence of the chronic diseases diabetes mellitus and arterial hypertension on color vision. METHODS: The study included 96 voluntary participants age 19-65 years. They were divided into four groups. Group I consisted of patients with arterial hypertension; group II included those with both arterial hypertension and diabetes mellitus; those in group III had diabetes mellitus; and group IV consisted of healthy individuals. RESULTS: The duration of diabetes in group II correlated with the Rayleigh calculation. Those in group III showed significant differences when the maximum brightness setting (Moreland) and the minimum anomalous quotient (Raleigh) were used. The duration of diabetes had correlations at some parameters of the Rayleigh and Moreland calculation. CONCLUSION: In conclusion, we are able to say that the all-color anomaloscope is useful for determining alterations in color vision in patients with diabetes mellitus.