The proper insulin rhythm is crucial
HZI and BRICS researchers use mathematical modelling to discover a possible cause of the development of early diabetes
The regulation of the sugar and lipid balance in the body is a vital function of the liver: In times without food intake, the liver produces glucose, a sugar, but quits producing glucose right after a meal, since glucose can now be obtained from the food in the bowels. The signal that makes the liver quit the release of glucose originates in the pancreas, i.e. the insulin hormone. Upon the manifestation of a diabetic disease, this signal is too late and reduced in intensity, which may result in a high blood sugar level after a meal. Scientists from the Helmholtz Centre for Infection Research (HZI) and the Braunschweig Integrated Centre of Systems Biology (BRICS) investigated these relationships with a mathematical model of liver cells and found that not only the overall quantity of the insulin signal, but the fact that insulin is released to the liver in a pulsatile manner is crucial. Infections or systemic inflammations afflicting the pancreas may change this and thereby cause the first symptoms of diabetes. The scientists published their results in Nature Communications.
Like cardiovascular diseases and cancer, diabetes is one of the most widespread diseases of modern societies. The current German Health Report Diabetes presumes the number of afflicted individuals in Germany alone to be 6.7 million people, of which two million have not been diagnosed with the disease yet. In an early type 2 diabetes disease, the regulation of the glucose balance by the liver is impaired: Usually, the liver produces glucose only if no food intake takes place, in order to keep the glucose level constant. Right after eating, the body obtains its glucose from the food. To make sure that the glucose levels do not get too high in this case, the pancreas releases the insulin hormone, which then inhibits the production of glucose in the liver. This is coupled to an increased production of lipids, i.e. to the regulation of the lipid balance.
However, the exact interplay of these regulatory mechanisms is not fully understood. Researchers from the HZI and the BRICS in Braunschweig developed a mathematical model of liver cells and used it to investigate the cellular impact of changes in the temporal pattern of insulin doses.
The model is based on values that were measured in mice. Our calculations were based on a healthy liver and we only varied the insulin signal.
In a healthy body, the so-called beta cells of the pancreas produce insulin in a five minute cycle. After a meal, the amplitude of these insulin pulses is increased within 30 minutes. "Infections or inflammations afflicting the pancreas can impair this increase in the amplitude of insulin pulses. In order to study the significance of this effect we changed the shape of the insulin pulses in our model, but kept the overall amount of the hormone unchanged," says Zhao. They found: If the liver received, within 30 minutes after a meal, insulin pulses of the same shape that is typical of diabetes patients, this resulted in a disturbed sequence of signaling events, which finally leads to more glucose and more lipid production– just as in early diabetes.
The focus of the researchers was on two signal molecules in liver cells, called Akt and aPKC, by means of which insulin regulates the glucose and lipid balance. The molecule called aPKC – short for "atypical protein kinase C" – inhibits the production of glucose and enhances the production of lipids. The model calculations have shown that aPKC – unlike Akt – responds to changes in the shape of the insulin signal. "The insulin pulse must possess the correct shape to up-regulate aPKC initially and then to switch it off again at the proper time. If aPKC is switched off too late or not at all, the body produces too much glucose and also increased amounts of fat tissue," says Michael Meyer-Hermann. "Accordingly, our model contributes to the understanding of the phenomenon called selective insulin resistance in diabetes patients, in which the liver produces both high blood sugar levels and high lipid levels after a meal."
The model calculations have shown how the dynamic shape of a signal – i.e. the insulin signal – can be crucial for its function, i.e. the regulation of the glucose and lipid balance in the liver. "If the shape of the five-minute pulses of insulin release in the pancreas is disturbed, even a healthy liver can develop insulin resistance – which is an early step of a diabetic disease," says Michael Meyer-Hermann. Moreover, the signal molecule aPKC promotes chronic inflammations if its activity is too high, which may be another corollary of the disturbed insulin rhythm. "We are confident that the dynamic rhythm of signals is crucial for the function of the signal and that this applies to many other signaling pathways as well," says Meyer-Hermann. The model calculations were done in close cooperation with the HZI research groups "Model Systems for Infection and Immunity" of Prof Dagmar Wirth and "Systems-Oriented Immunology and Inflammation Research" of Prof Ingo Schmitz, in the scope of the "Metabolic Dysfunction and Human Disease" project funded by the Helmholtz Association.
Gang Zhao, Dagmar Wirth, Ingo Schmitz, Michael Meyer-Hermann: A mathematical model of the impact of insulin secretion dynamics on selective hepatic insulin resistance. Nature Communications, 2017, DOI: 10.1038/s41467-017-01627-9
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