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Role of cAMP in double switch of glucagon secretion
Jan Zmazek, Vladimir Grubelnik, Rene Markovič, Marko Marhl, 2021, izvirni znanstveni članek

Opis: Glucose metabolism plays a crucial role in modulating glucagon secretion in pancreatic alpha cells. However, the downstream effects of glucose metabolism and the activated signaling pathways influencing glucagon granule exocytosis are still obscure. We developed a computational alpha cell model, implementing metabolic pathways of glucose and free fatty acids (FFA) catabolism and an intrinsically activated cAMP signaling pathway. According to the model predictions, increased catabolic activity is able to suppress the cAMP signaling pathway, reducing exocytosis in a Ca2+ -dependent and Ca2+ independent manner. The effect is synergistic to the pathway involving ATPdependent closure of KATP channels and consequent reduction of Ca2+. We analyze the contribution of each pathway to glucagon secretion and show that both play decisive roles, providing a kind of "secure double switch". The cAMP-driven signaling switch plays a dominant role, while the ATP-driven metabolic switch is less favored. The ratio is approximately 60:40, according to the most recent experimental evidence.
Ključne besede: pancreatic alpha cell, glucagon, cAMP, mathematical model, diabetes, cellular bioenergetics
Objavljeno v DKUM: 06.06.2024; Ogledov: 28; Prenosov: 0
.pdf Celotno besedilo (2,58 MB)
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Attachment in close relationships and glycemic outcomes in children with type 1 diabetes
Simona Klemenčič, Jasna Klara Lipovšek, Anja Turin, Klemen Dovč, Nataša Bratina, Yael Shmueli-Goetz, Katarina Trebušak Podkrajšek, Barbka Repič-Lampret, Barbara Jenko Bizjan, Sašo Karakatič, Tadej Battelino, Maja Drobnič Radobuljac, 2023, izvirni znanstveni članek

Opis: Background: Our aim was to determine whether child attachment to parents, parent attachment style, and morning cortisol levels were related to diabetes outcomes measured by average glycated hemoglobin (HbA1c), HbA1c variability over 4 years and time in range (TIR) in children with type 1 diabetes (T1D). Research design and methods: 101 children with T1D and one of their parents were assessed at baseline for child attachment (Child Attachment Interview; CAI) and parent attachment (Relationship Structures Questionnaire; ECR-RS). Serum samples were collected for cortisol measurements before the interviews. HbA1c levels were measured during a 4-year follow-up period at regular 3-monthly visits, and data for TIR were exported from blood glucose measuring devices. Multivariate linear regression models were constructed to identify independent predictors of glycemic outcomes. Results: More girls than boys exhibited secure attachment to their mothers. The results of the regression models showed that securely attached girls (CAI) had higher average HbA1c than did insecurely attached girls (B = -0.64, p = 0.03). In boys, the more insecure the parent's attachment style, the worse the child's glycemic outcome: the higher the average Hb1Ac (B = 0.51, p = 0.005), the higher the HbA1c variability (B = 0.017, p = 0.011), and the lower the TIR (B = -8.543, p = 0.002). Conclusions: Attachment in close relationships is associated with glycemic outcomes in children with T1D, and we observed significant differences between sexes. A sex- and attachment-specific approach is recommended when treating children with less favorable glycemic outcomes. Special attention and tailored support should be offered to securely attached girls in transferring responsibility for diabetes care and at least to male children of insecurely attached parents to prevent suboptimal glycemic control. Further studies in larger samples and more daily cortisol measurements may help us better understand the links between stress response, attachment and T1D.
Ključne besede: attachment, childhood and adolescence, cortisol, diabetes control, time in range
Objavljeno v DKUM: 21.05.2024; Ogledov: 63; Prenosov: 1
.pdf Celotno besedilo (980,31 KB)
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Modeling the amino acid effect on glucagon secretion from pancreatic alpha cells
Jan Zmazek, Vladimir Grubelnik, Rene Markovič, Marko Marhl, 2022, izvirni znanstveni članek

Opis: Type 2 Diabetes Mellitus (T2DM) is a burdensome problem in modern society, and intensive research is focused on better understanding the underlying cellular mechanisms of hormone secretion for blood glucose regulation. T2DM is a bi-hormonal disease, and in addition to 100 years of increasing knowledge about the importance of insulin, the second hormone glucagon, secreted by pancreatic alpha cells, is becoming increasingly important. We have developed a mathematical model for glucagon secretion that incorporates all major metabolic processes of glucose, fatty acids, and glutamine as the most abundant postprandial amino acid in blood. In addition, we consider cAMP signaling in alpha cells. The model predictions quantitatively estimate the relative importance of specific metabolic and signaling pathways and particularly emphasize the important role of glutamine in promoting glucagon secretion, which is in good agreement with known experimental data.
Ključne besede: diabetes, hormone secretion, glucose, amino acid, cAMP
Objavljeno v DKUM: 21.05.2024; Ogledov: 109; Prenosov: 2
.pdf Celotno besedilo (1,82 MB)
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Age-related changes in lipid and glucose levels associated with drug use and mortality : an observational study
Rene Markovič, Vladimir Grubelnik, Helena Blažun Vošner, Peter Kokol, Matej Završnik, Karmen Janša, Marjeta Zupet, Jernej Završnik, Marko Marhl, 2022, izvirni znanstveni članek

Opis: 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.
Ključne besede: diabetes, metabolic syndrome, hematological data, aging
Objavljeno v DKUM: 21.05.2024; Ogledov: 97; Prenosov: 1
.pdf Celotno besedilo (2,12 MB)
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Lipotoxicity in a vicious cycle of pancreatic beta cell exhaustion
Vladimir Grubelnik, Jan Zmazek, Matej Završnik, Marko Marhl, 2022, izvirni znanstveni članek

Opis: 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.
Ključne besede: diabetes, insulin secretion, lipids, PEP cycle, uncoupling proteins, mitochondrial dysfunction
Objavljeno v DKUM: 20.05.2024; Ogledov: 76; Prenosov: 2
.pdf Celotno besedilo (2,47 MB)
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Uporaba večceličnih modelov in mrežnih analiz za preučevanje kolektivne celične dinamike v Langerhansovih otočkih : doktorska disertacija po skandinavskem modelu
Marko Šterk, 2024, doktorska disertacija

Opis: V doktorski disertaciji smo se osredotočili na pereča vprašanja s področja fiziologije Langerhansovih otočkov, ki igrajo ključno vlogo pri uravnavanju glukozne homeostaze v telesu. Z uporabo inovativnih računalniških tehnik smo analizirali vpliv 3D citoarhitekture otočkov na večcelično dinamiko v opazovani 2D optični rezini, vpliv inhibicije NMDA receptorjev na kolektivno dinamiko celic beta, različne subpopulacije celic beta in njihov vpliv na kolektivno dinamiko ter vpliv metabolne sklopitve celic na kompleksnost funkcionalnih omrežij. Ugotovili smo, da je pri analizi medceličnih kalcijevih valov treba upoštevati 3D citoarhitekturo Langerhansovih otočkov, saj velik delež medceličnih kalcijevih valov izvira izven opazovane optične rezine, kar vpliva na opazovano hitrost širjenja valovne fronte. Nadalje je naša analiza pokazala, da inhibicija NMDA receptorjev blagodejno vpliva na delovanje posameznih celic beta kakor tudi na njihovo kolektivno dinamiko, kar se odraža v povečani stabilnosti poteka medceličnih kalcijevih valov. Podrobna analiza subpopulacij celic beta je razkrila, da centralne celice in celice, ki sprožajo valove, igrajo ključno vlogo pri širjenju medceličnih valov in sinhronosti celic, kar je izjemnega pomena za zagotavljanje normalne fiziološke funkcije. Naši izsledki kažejo, da ti dve vrsti celic predstavljata različni subpopulaciji, ki se med seboj ne prekrivata. Poleg tega s teoretičnim raziskovanjem mehanizmov sinhronizacije celic beta podrobneje prikazujemo, da je za koordinirano aktivnost celic beta dovolj samo električna sklopitev, vendar dodatna metabolna sklopitev še dodatno okrepi sinhrono delovanje in s tem vpliva na lastnosti pridobljenih funkcionalnih omrežij, zaradi česar so ta bolj podobna tistim, ki jih opazimo v eksperimentih. Z izvedenimi raziskavami smo prispevali k razumevanju, kako je vzpostavljeno koordinirano delovanje v kolektivih celic beta, kar odpira nove možnosti za razvoj zdravil za sladkorno bolezen tipa 2.
Ključne besede: celice beta, kompleksna omrežja, diabetes tipa 2, večcelični modeli, celična dinamika
Objavljeno v DKUM: 25.04.2024; Ogledov: 179; Prenosov: 16
.pdf Celotno besedilo (39,68 MB)

Electrodermal activity and heart rate variability for detection of peripheral abnormalities in type 2diabetes : a review
Matej Žnidarič, Dominik Škrinjar, Alen Kapel, 2023, izvirni znanstveni članek

Opis: Modern medicine exhibits an upward trend towards non-invasive methods for early detection of disease and long-term monitoring of patients’ health. Diabetes mellitus and its complications are a promising area for implementation of new medical diagnostic devices. One of the most serious complications of diabetes is diabetic foot ulcer. The main causes responsible for diabetic foot ulcer are ischemia caused by peripheral artery disease and diabetic neuropathy caused by polyol pathway-induced oxidative stress. Autonomic neuropathy impairs function of sweat glands, which can be measured by electrodermal activity. On the other hand, autonomic neuropathy leads to changes in heart rate variability, which is used to assess autonomic regulation of the sinoatrial node. Both methods are enough sensitive to detect pathological changes caused by autonomic neuropathy and are promising screening methods for early diagnosis of diabetic neuropathy, which could prevent the onset of diabetic ulcer.
Ključne besede: diabetes mellitus, diabetic foot ulcer, autonomic neuropathy, electrodermal activity, heart rate variability
Objavljeno v DKUM: 22.04.2024; Ogledov: 93; Prenosov: 6
.pdf Celotno besedilo (1,02 MB)
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Perceptions of the primary health care team about the implementation of integrated care of patients with type 2 diabetes and hypertension in Slovenia : qualitative study
Nataša Stojnić, Zalika Klemenc-Ketiš, Majda Mori-Lukančič, Črt Zavrnik, Tonka Poplas-Susič, 2023, izvirni znanstveni članek

Opis: Background Integrated care involves good coordination, networking, and communication within health care services and externally between providers and patients or informal caregivers. It affects the quality of services, is more cost-effective, and contributes to greater satisfaction among individuals and providers of integrated care. In our study, we examined the implementation and understanding of integrated care from the perspective of providers - the health care team - and gained insights into the current situation. Methods Eight focus groups were conducted with health care teams, involving a total of 48 health care professionals, including family physicians, registered nurses, practice nurses, community nurses, and registered nurses working in a health education center. Prior to conducting the focus groups, a thematic guide was developed based on the literature and contextual knowledge with the main themes of the integrated care package. The analysis was conducted using the NVivo program. Results We identified 12 main themes with 49 subthemes. Health care professionals highlighted good accessibility and the method of diagnostic screening integrated with preventive examinations as positive aspects of the current system of integrated care in Slovenia. They mentioned the good cooperation within the team, with the involvement of registered nurses and community nurses being a particular advantage. Complaints were made about the high workload and the lack of workforce. They feel that patients do not take the disease seriously enough and that patients as teachers could be useful. Conclusion Primary care teams described the importance of implementing integrated care for diabetes and hypertension patients at four levels: Patient, community, care providers, and state. Primary care teams also recognized the importance of including more professionals from different health care settings on their team.
Ključne besede: integrated health care system, type-2-diabetes, Hypertension, Health care team, interdisciplinary primary care, qualitative research
Objavljeno v DKUM: 19.04.2024; Ogledov: 148; Prenosov: 5
.pdf Celotno besedilo (1007,00 KB)
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