[MUSIC] Hello, my name is Signe Torekov, and I am cost director of diabetes at Global Challenge, as well as assistant professor and group leader at University of Copenhagen. Furthermore, I'm Deputy Director of Education at the Novo Nordisk Foundation Center for Basic Metabolic Research. In this module, I'll present you case stories of translational metabolism, which means that we go from genotype to phenotype, and translate our knowledge form genetics into clinically relevant patient stories. Translational science is a multidisciplinary form of science that bridges the gap between basic science and applied science. Translational science is often used in health sciences and refers to the translation of bench science conducted in a lab to bedside clinical practice. In this module, we translate the knowledge from genetics and see how it affects real patients. We have demonstrated another link between heart disease that is congenital arrhythmia and the body's ability to handle sugar. The results can be of vital importance for patients with the disease and for future treatment of diabetes. In summary, patients with congenital arrhythmia produce twice the amount of insulin after consuming sugar, compared to healthy subjects. At the same time the patient's blood sugar decreases drastically a few hours after consuming sugar or food compared to the healthy subjects who had a normal blood sugar levels. Since patients with a particular kind of congenital arrhythmia become hypoglycemic after meals, this further increases their risk of heart failure. For that reasons, the patients have to pay attention, for example by changing diet and lowering the meal size to avoid low blood sugar levels. In general, hypoglycemia is rare and when it occurs the cause is often unknown, here we have found a new cause. On a long term basis, the results can also be of importance to the treatment of diabetes, since the quality of the treatment increases as we uncover more aspects of sugar metabolism. Healthy persons without diabetes usually have a blood sugar value between four and seven. Low blood glucose can cause for example anger, irritability, fatigue and dizziness. Very low blood sugar that is less than one causes black outs, cramps and ultimately, cardiac arrest. The period of time ranging from the heart's chambers pull together until they are relaxed again is called the QT Interval. Long QT Syndrome is a congenital heart disease that affects 1 in 2000 people. The disease causes arrhythmia that in worst case scenario can cause heart arrest. We already knew that a certain ion channel, kind of an on off switch within the cell is significant to genetically determine arrhythmia. The same ion channel is also present in the insulin producing cells. Cell studies have shown, that when you turn off the ion channel, the cells of the pancreas produce more insulin. Therefore, we wanted to look into these heart patient's blood sugar as they are born with this ion channel turned off. Until now, doctors have thought that symptoms like fatigue and malaise in these heart patients were only caused by the arrhythmia. But the feelings of discomfort were also caused by the blood sugar levels being too low with our discovery, we can connect a specific potassium ion channel to block sugar levels. And this could benefit the diabetes patients of the future because we'll be able to gather more knowledge on the body's sugar metabolism. So what are the potential mechanisms behind the observations? The blood glucose level increases after meal intake leading to formation of ATP in the beta cell. Closure of the ATP dependent potassium channel and there by a reduction of the ATP sensitive potassium current. Depolarization of the beta cell and increased insulin secretion. KV7 is another potassium channel causing a voltage gated repolarization current. KV7 is encoded by the KCNQ1 gene, and expressed both in beta cells and in cardiomyocytes. Functional mutations in KCNQ1 lead to KCNQ1 Long QT Syndrome. A patient's characterized by a delayed cardiac repolarization. Prolonged QT interval on the ECG, fainting, malignant arrhythmias, and sudden death. But the clinical and physiological significance of functional KCNQ1 mutations in beta cells was unknown. Interestingly, carriers of frequent intronic single nucleotide polymorphisms, also known as SNPs in KCNQ1 have increased susceptibility for type 2 diabetes and impaired beta cell function. Recent studies show that inhibition of KV7 in beta cells increases insulin secretion due to the late repolarization. Whereas, overexpression of KCNQ1 in beta cells decreases insulin secretion. And since this SNPs' risk scale of KCNQ1 decreases insulin secretion, this suggests that the risk alleles of the intronic KCNQ1 SNPs again a function polymorphisms and increased susceptibility of type 2 diabetes due to increased KCNQ1 expression and thereby decreased insulin secretion. Consequently, we hypothesized that Long QT Syndrome patients with loss of function mutations of KCNQ1 may exhibit increased insulin secretion due to delayed repolarization of the beta cell causing increased exocytosis. We therefore, investigated 14 patients with KCNQ1 Long QT Syndrome and compared them to 28 maxed control participants. Interestingly, we found that the KCNQ1 Long QT Syndrome patients had post preminial hyperinsulinemia reactive hyperglycemia and experienced symptoms of hypoglycemia. Until now, although KCNQ1 is widely expressed the only extra cardial symptom reported in Long QT Syndrome patients is deafness in patients homozygous for KCNQ1 loss of function mutations. We observe that the patients became markedly hyperglycemic three and a half hours after glucose ingestion in contrast to the max control participants. Consistent with this observation, 24 hour glucose profiles show that the KCNQ1 Long QT Syndrome patients had symptomatic hypoglycemic episodes in their own living environment three to five hours after meal intake. Furthermore, the low circulating glucose levels observed in KCNQ1 Long QT Syndrome patient occurs hours after all glucose loads and agreement with observation of the low glucose levels in KCNQ1 knock out miles. The patients also had lower serum potassium levels. This is presumably due to insulin activating the sodium potassium ATPase to move potassium from the extracellular to the intercellular compartment. Other mechanisms leading to low potassium levels might include fecal loss of potassium as reported for the KCNQ1 knockout mouse. Patients with KCNQ1 Long QT Syndrome are characterized by rare episodes of syncope, ventricular tachyarrhythmia, and cardiac arrest which until now, have been ascribed to their Long QT interval. However, we now know that these patients, besides Long QT interval, also suffer from hyperinsulinemic reactive hypoglycemia along with low potassium levels and symptoms of hypoglycemia. Hypoglycemia may cause sympathetic activation which is associated with increased risk of arrhythmia and sudden cardiac arrest. Furthermore, in a population based study 2,570 elderly people without diabetes, it was demonstrated that hyperinsulinemia was associated with significantly increased QT interval and increased risks of sudden death. In addition, a recent study revealed that QT prolongation and hypokalemia were common in diabetes patients with severe hypoglycemia, which increased the risk of fatal arrhythmia and death. The combination of hyperinsulinemia, symptomatic postprandial hypoglycemia and low serum potassium levels might therefore, further increase the risk for cardiac events in KCNQ1 Long QT Syndrome patients. Our findings confirm that blocking KCNQ1 increases insulin release presumably due to prolonged depolarization of the beta cell causing calcium influx and insulin exocytocis. This observation also correlate with the genome wide association of study observations that SNPs and KCNQ1 are associated with type 2 diabetes. And reduce serum insulin levels, which could be secondary to increase expression of the channel and there by decrease insulin exocytocis taken together, these findings underline that the voltage gated potassium channel encoded by KCNQ1 is a key player in insulin secretion. Our findings suggest that functional KCNQ1 mutations underlie some cases of essential postprandial hypoglycemia. This syndrome is characterized by appearance of reactive hypoglycemia occurring up to four hours after food intake without known cause. Just ECG monitoring and genetic testing should be considered when other courses of reactive hypoglycemia have been excluded. In conclusion, besides prolonged QT interval, patients with KCNQ1 Long QT Syndrome were characterized by hyperinsulinemia upon oral glucose load, postprandial hypoglycemia, symptoms of clinical hypoglycemia and lower potassium levels, all of which increased risk of cardiac events. We confirm that the voltage gated protection channel encoded by KCNQ1 is engulfed by insulin secretion, and suggests that KCNQ1 mutations may explain some cases of essential reactive hypoglycemia. [MUSIC]
