Although abnormal insulin has been associated with milder cases of type 2 diabetes since the discovery of "insulin Chicago" in 1979, this is the first time that an insulin mutation has been connected to severe diabetes with onset early in life.
The researchers describe 10 mutations, found in 21 patients from 16 families. They suspect that the mutations alter the way insulin folds during its synthesis. They suggest that these improperly folded proteins interfere with other cellular processes in ways that eventually kill the cells that produce insulin.
"This is a novel and potentially treatable cause of diabetes in infants," said study author Louis Philipson, MD, PhD, professor of medicine at the University of Chicago. "It's exciting because each of these patients has one normal insulin gene as well as one mutated gene. If we could detect the disease early enough and somehow silence the abnormal gene, or just protect insulin-producing cells from the damage caused by misfolding, we might be able to preserve or restore the patient's own insulin production."
The effort to learn more about possible genetic causes of neonatal diabetes followed a flurry of publicity last September. Philipson and colleagues at the University of Chicago -- using a protocol developed by co-author Andrew Hattersley, MD, Professor of Molecular Medicine at Peninsula University -- were able to wean a young diabetes patient with a known, treatable mutation in an ion channel protein essential for insulin secretion, off of insulin. This was one of the first such cases in the United States.
Media coverage of that case and outreach by the Juvenile Diabetes Research Foundation stimulated parents of other children diagnosed as infants with type-1 diabetes to contact one of the two centers to request genetic testing. Testing at the University of Chicago uncovered more than a dozen patients with the same treatable mutation.
The publicity also brought calls from the families of more than 70 patients who had been diagnosed with diabetes at less than one year of age but who, as it turned out, did not have a known mutation.
In one family with four affected individuals, tests for known mutations were negative. A combination of linkage studies and candidate-gene testing, however, traced the problem to an abnormal insulin gene. Further tests identified a total of 10 different insulin-gene mutations in patients from 15 other families.
All ten are "missense" mutations; they code for a different amino acid than the one normally found at that position. Such mutations can prevent a protein from folding into its customary shape.
Dysfunctional proteins are usually dismantled by the endoplasmic reticulum, an organelle that can detect misfolded proteins and degrade them. Prolonged demands on this system, however, can cause chronic endoplasmic reticulum stress that can lead eventually to cell death.
The authors postulate that misfolded insulin and its precursors could induce prolonged ER stress, causing the insulin-producing pancreatic beta cells to die.
Treatments aimed at reducing ER stress "might result in better beta cell survival," they suggest. "This could partially ameliorate the diabetic state if secretion resulting from the normal insulin allele could be better preserved."
"Insulin mutations are an important cause of neonatal diabetes," say the authors, accounting for about 20 percent of cases of this rare disorder. Most cases tied to insulin mutation were diagnosed in the first six months of life, with an average age at diagnosis of only 13 weeks. Three of the cases were diagnosed between 6 months and one year after birth.
Neonatal diabetes is considered a genetic disorder by many, said Philipson. Mutations in known genes explain 50 to 60 percent of cases and research teams in the US and Europe are trying to identify a genetic cause of diabetes in the remaining patients.
Even though neonatal diabetes is a rare disease, identification of genes causing it has lead to important knowledge about pancreatic development and function, as well as to more precise diagnosis and improved management of patients.
In 2001, Graeme Bell, PhD, the Louis Block Distinguished Service Professor of Medicine and Human Genetics at the University of Chicago and a co-author of this paper, discovered one of the first gene defects associated with neonatal diabetes, mutation of the gene for glucokinase, an enzyme that helps regulate blood-sugar levels. Bell also discovered several genes that cause other forms of monogenic diabetes and the first gene associated with Type 2 diabetes.
In 1979, co-author Donald Steiner, MD, the A.N. Pritzker Professor in Biochemistry & Molecular Biology and a member of the Howard Hughes Medical Institute at the University of Chicago, was a member of the team that discovered the first mutant insulin, known as "insulin Chicago."
John Easton | EurekAlert!
Don't Give the Slightest Chance to Toxic Elements in Medicinal Products
23.03.2018 | Physikalisch-Technische Bundesanstalt (PTB)
North and South Cooperation to Combat Tuberculosis
22.03.2018 | Universität Zürich
Satellites in near-Earth orbit are at risk due to the steady increase in space debris. But their mission in the areas of telecommunications, navigation or weather forecasts is essential for society. Fraunhofer FHR therefore develops radar-based systems which allow the detection, tracking and cataloging of even the smallest particles of debris. Satellite operators who have access to our data are in a better position to plan evasive maneuvers and prevent destructive collisions. From April, 25-29 2018, Fraunhofer FHR and its partners will exhibit the complementary radar systems TIRA and GESTRA as well as the latest radar techniques for space observation across three stands at the ILA Berlin.
The "traffic situation" in space is very tense: the Earth is currently being orbited not only by countless satellites but also by a large volume of space...
An international team of researchers has discovered a new anti-cancer protein. The protein, called LHPP, prevents the uncontrolled proliferation of cancer cells in the liver. The researchers led by Prof. Michael N. Hall from the Biozentrum, University of Basel, report in “Nature” that LHPP can also serve as a biomarker for the diagnosis and prognosis of liver cancer.
The incidence of liver cancer, also known as hepatocellular carcinoma, is steadily increasing. In the last twenty years, the number of cases has almost doubled...
In just a few weeks from now, the Chinese space station Tiangong-1 will re-enter the Earth's atmosphere where it will to a large extent burn up. It is possible that some debris will reach the Earth's surface. Tiangong-1 is orbiting the Earth uncontrolled at a speed of approx. 29,000 km/h.Currently the prognosis relating to the time of impact currently lies within a window of several days. The scientists at Fraunhofer FHR have already been monitoring Tiangong-1 for a number of weeks with their TIRA system, one of the most powerful space observation radars in the world, with a view to supporting the German Space Situational Awareness Center and the ESA with their re-entry forecasts.
Following the loss of radio contact with Tiangong-1 in 2016 and due to the low orbital height, it is now inevitable that the Chinese space station will...
Fraunhofer Institute for Organic Electronics, Electron Beam and Plasma Technology FEP, provider of research and development services for OLED lighting solutions, announces the founding of the “OLED Licht Forum” and presents latest OLED design and lighting solutions during light+building, from March 18th – 23rd, 2018 in Frankfurt a.M./Germany, at booth no. F91 in Hall 4.0.
They are united in their passion for OLED (organic light emitting diodes) lighting with all of its unique facets and application possibilities. Thus experts in...
A new scenario seeking to explain how Mars' putative oceans came and went over the last 4 billion years implies that the oceans formed several hundred million...
23.03.2018 | Event News
19.03.2018 | Event News
16.03.2018 | Event News
23.03.2018 | Materials Sciences
23.03.2018 | Agricultural and Forestry Science
23.03.2018 | Physics and Astronomy