Type 2 diabetes mellitus is a complex multifactorial disease of epidemic proportions. It involves genetic and lifestyle factors that lead to dysregulations in hormone secretion and metabolic homeostasis. Accumulating evidence indicates that altered mitochondrial structure, function, and particularly bioenergetics of cells in different tissues have a central role in the pathogenesis of type 2 diabetes mellitus. In the present study, we explore how mitochondrial dysfunction impairs the coupling between metabolism and exocytosis in the pancreatic alpha and beta cells. We demonstrate that reduced mitochondrial ATP production is linked with the observed defects in insulin and glucagon secretion by utilizing computational modeling approach. Specifically, a 30–40% reduction in alpha cells’ mitochondrial function leads to a pathological shift of glucagon secretion, characterized by oversecretion at high glucose concentrations and insufficient secretion in hypoglycemia. In beta cells, the impaired mitochondrial energy metabolism is accompanied by reduced insulin secretion at all glucose levels, but the differences, compared to a normal beta cell, are the most pronounced in hyperglycemia. These findings improve our understanding of metabolic pathways and mitochondrial bioenergetics in the pathology of type 2 diabetes mellitus and might help drive the development of innovative therapies to treat various metabolic diseases.

Pancreatic beta cells regulate insulin secretion in response to glucose by generating ATP, which modulates ATP-sensitive potassium channels (K_ATP) channel activity and Ca²⁺ dynamics. We present a model of ATP production in pancreatic beta cells, focusing on ATP dynamics within the bulk cytosol, submembrane region, and microdomains near K_ATP channels. ATP is generated through glycolysis, mitochondrial oxidative phosphorylation (OxPhos), and glycolytic pyruvate kinase-mediated phosphoenolpyruvate (PEP) production, supported by PEP cycling between mitochondria and the cytosol. The model examines ATP production in relation to Ca²⁺ oscillations, elucidating their interdependent dynamics. Our findings demonstrate that both mitochondrial OxPhos and PEP-mediated ATP production contribute substantially to cellular ATP levels. Specifically, glycolysis and mitochondrial OxPhos are crucial for the initial (first-phase) increase in bulk and subplasmalemmal ATP, effectively “filling up” the ATP pool in beta cells. In the second phase, coordinated cycling between OxPhos and PEP pathways enables cost-effective fine-tuning of ATP levels, with localized effects in the K_ATP channel microdomains. This model addresses and clarifies the recent debate regarding the mechanisms by which sufficient ATP concentrations are achieved to close K_ATP channels in glucose-stimulated beta cells, offering novel insights into the regulation of energy production and K_ATP channel activity.

Background: The pathogenesis of type 2 diabetes mellitus is complex and still unclear in some details. The main feature of diabetes mellitus is high serum glucose, and the question arises of whether there are other statistically observable dysregulations in laboratory measurements before the state of hyperglycemia becomes severe. In the present study, we aim to examine glucose and lipid profiles in the context of age, sex, medication use, and mortality. Methods: We conducted an observational study by analyzing laboratory data from 506,083 anonymized laboratory tests from 63,606 different patients performed by a regional laboratory in Slovenia between 2008 and 2019. Laboratory data-based results were evaluated in the context of medication use and mortality. The medication use database contains anonymized records of 1,632,441 patients from 2013 to 2018, and mortality data were obtained for the entire Slovenian population. Results: We show that the highest percentage of the population with elevated glucose levels occurs approximately 20 years later than the highest percentage with lipid dysregulation. Remarkably, two distinct inflection points were observed in these laboratory results. The first inflection point occurs at ages 55 to 59 years, corresponding to the greatest increase in medication use, and the second coincides with the sharp increase in mortality at ages 75 to 79 years. Conclusions: Our results suggest that medications and mortality are important factors affecting population statistics and must be considered when studying metabolic disorders such as dyslipidemia and hyperglycemia using laboratory data.

Item banks are generally considered the basis of a new generation of educational measurement. In combination with specialized software, they can facilitate the computerized assembling of multiple pre-equated test forms. However, for advantages of item banks to become fully realized it is important that the item banks store a relatively large number of valid test items. In this paper, we demonstrate how the Rasch model is used for integrating new items into an existing wave optics item bank. First, we identified and applied a set of criteria for selecting 18 linking items from our initial item bank. In order to integrate 12 newly developed items, we combined the 18 linking items with the 12 newly developed ones into one test and administered this test to 106 postinstruction physics students from 4 universities in Slovenia, Croatia, and Bosnia and Herzegovina. It was determined that the 12 new items measure the same construct as items from the initial item bank. In addition, all items exhibited good item fit, item reliability was excellent and person reliability was fair. The ratio of standard deviations of linking item difficulties for the new test and existing item bank amounted to 0.89 and correlation of these difficulties amounted to 0.93 which indicated good linking precision. We could conclude that good linking precision can be obtained if linking items are chosen based on the following set of criteria: number of items, item fit, range and spacing of item difficulties, content representativeness, position in test form and interuniversity DIF contrasts.

Hyperlipidemia is a common metabolic disorder in modern society and may precede hyperglycemia and diabetes by several years. Exactly how disorders of lipid and glucose metabolism are related is still a mystery in many respects. We analyze the effects of hyperlipidemia, particularly free fatty acids, on pancreatic beta cells and insulin secretion. We have developed a computational model to quantitatively estimate the effects of specific metabolic pathways on insulin secretion and to assess the effects of short- and long-term exposure of beta cells to elevated concentrations of free fatty acids. We show that the major trigger for insulin secretion is the anaplerotic pathway via the phosphoenolpyruvate cycle, which is affected by free fatty acids via uncoupling protein 2 and proton leak and is particularly destructive in long-term chronic exposure to free fatty acids, leading to increased insulin secretion at low blood glucose and inadequate insulin secretion at high blood glucose. This results in beta cells remaining highly active in the “resting” state at low glucose and being unable to respond to anaplerotic signals at high pyruvate levels, as is the case with high blood glucose. The observed fatty-acid-induced disruption of anaplerotic pathways makes sense in the context of the physiological role of insulin as one of the major anabolic hormones.