SPINA Team

New calculation offers simple and reliable early prediction of diabetes Diabetes often remains undetected until it has already damaged organs or nerves. This is partly due to the fact that diagnosis at an early stage is time-consuming and difficult.

Diagnosis of #diabetes mellitus and #prediabetes: A simple calculation may be better than a complex test.

🧪 🩺 #MedSky @medsky.social #Endosky #Endocrinology

medicalxpress.com/news/2024-01...

#SPINA_Thyr predicts the prognosis of #Takotsubo syndrome. Among all predictors, #SPINA-GD showed the most significant difference.

🧪 🩺 #MedSky @medsky.social #Endocrinology

Figure: Definition of clusters. Thyroid response and pituitary response curves denote the median of thyroid’s secretory capacity (SPINA-GT) and empirical thyrotropic pituitary response.

Figure: Association of clusters with total fatality (left) and time-course of survival (right).

Table: Characteristics of the three clusters. The figures in the first two lines refer to medoids of TSH and FT4 concentration as identified by the clustering algorithm.

#Takotsubo syndrome (TTS) is a poorly understood life-threatening #cardiomyopathy. With machine learning, we found 3 signatures of #thyroid #homeostasis heralding the prognosis of patients affected by TTS.

pubmed.ncbi.nlm.nih.gov/38502972/
doi.org/10.1016/j.eb...
www.livivo.de/doc/M38502972

<em>Journal of Internal Medicine</em> | Wiley Online Library Background Several reports have described Takotsubo syndrome (TTS) secondary to thyrotoxicosis. A complex interaction of central and peripheral catecholamines with thyroid homeostasis has been sugge...

Calculating #SPINA-GT has helped to distinguish two different ways leading to #thyroid-related #Takotsubo #cardiomyopathy.

www.livivo.de/doc/M33179374
pubmed.ncbi.nlm.nih.gov/33179374/
doi.org/10.1111/joim...

Figure: Bivariate null isokline plot of first measured FT4 and TSH serum concentrations per subject in relation to percentiles of subsystem responses of thyroid homeostasis. Shown are three different point clouds, representing three clusters: Normal controls (green dots in the center), critically-ill patients with acute coronary syndroms (black dots in the lower zone of TSH concentration) and patientes with Takotsubo syndrome (red dots in two cloucs with low and high TSH concentration).

Distribution (mean ± SEM) of measured and derived parameters in TTS during the first seven days of treatment. The shaded rectangles mark the reference ranges for the respective parameters. *P < 0.05, **P < 0.01, ***P < 0.001, *****P < 1e–5 compared to reference range with binomial test; P values are adjusted with the Benjamini–Hochberg method. SPINA-GT is elevated, and SPINA-GD is reduced during the first three days of Takotsubo syndrome. TTSI is elevated on day 3, representing a high set point of thyroid homeostasis as a consequence of type 2 allostatic load.

Abnormal thyroid function in Takotsubo syndrome is marked by two distinct phenotypes: an endocrine type representing primary hyperthyroidism and a stress type with an elevated set point of thyroid homeostasis. The results suggest a stress-dependent adaptive endocrine response or type 2 thyroid allostasis.

#Takotsubo syndrome is a dangerous stress-related #heart disease. Since #T3 upregulates β-receptors, we assumed a link to #thyroid homeostasis. With machine learning, we identified interesting allostatic patterns.

www.livivo.de/doc/M33179374
pubmed.ncbi.nlm.nih.gov/33179374/
doi.org/10.1111/joim...

Previsione precoce semplice e affidabile del diabete. Il diabete spesso rimane inosservato finché non ha già danneggiato organi o nervi. Ciò è in parte dovuto al fatto che la diagnosi in fase precoce è difficile e dispendiosa in termini di tempo. Un t…

Previsione precoce semplice e affidabile del diabete

blogpinali.wordpress.com/2024/01/23/p...

Information processing structure of the feedback model. [G](t): glucose concentration; S(t): insulin secretion rate; [I](t): insulin concentration; M(t): proximal insulin signalling; N(t) distal insulin signalling; P(t): constitutive glucose production rate; Q(t): regulated glucose production rate; W(t): intestinal glucose absorption rate; R(t): glucose arrival rate. G1 and G3 represent gains of ASIA elements. Units of measurement are displayed in the small, rounded boxes with red margins.

Circular Maps of the correlation networks of novel biomarkers for insulin-glucose homeostasis with anthropometric and experimental data in the NHANES cohort (A) and the clamp study (B). Shown are significant correlations (p < 0.05) only, and line thickness indicates the strength of negative (blue) or positive (red) correlation. A green segment in the inner ring indicates a reduction of the corresponding biomarker in subjects with diabetes.

Plot of SPINA-GBeta against SPINA-GR, suggesting a compensatory rise of beta cell function in the case of declining insulin sensitivity in subjects with normal glucose homeostasis (green dots). This ability of beta cell compensation is partly lost in subjects with prediabetes (orange dots) or diabetes (red dots).

Mathematical modelling of #insulin-#glucose #homeostasis delivers new and improved methods for metabolic endotyping. #prediabetes #diabetes #metabolic_syndrome #betacell pubmed.ncbi.nlm.nih.gov/36271244/ doi.org/10.1038/s415...

Molecular Mechanisms in gestational diabetes mellitus (GDM). Pregnancy-induced insulin resistance is driven by placental hormones (human placental lactogen (hPL), placental growth hormone, estrogen, progesterone, cortisol) and inflammatory cytokines (tumour necrosis factor α (TNF α), interleukin 6 (IL-6), interleukin 1β (IL-1β)). Inadequate β-cell adaptation due to mitochondrial dysfunction, and impaired incretin signaling leads to hyperglycemia. Dysregulated adipokines (decreased adiponectin, increased leptin, resistin, visfatin), oxidative stress, and epigenetic modifications (deoxyribonucleic acid (DNA) methylation, non-coding ribonucleic acids (RNAs)) further exacerbate disease and contribute to adverse maternal and fetal outcomes.

Gestational #diabetes mellitus (GDM) is linked to significant adverse outcomes for both mothers and their offspring. Since #SPINA-GBeta outperforms #HOMA-Beta, its use is advised as a preferred calculated #biomarker for the evolution and pathophysiology of #GDM.

pubmed.ncbi.nlm.nih.gov/40943638/

Screenshot of the web site of the Research Topic "Mechanistic, Machine Learning and Hybrid Models of the 'Other' Endocrine Regulatory Systems in Health and Disease: Volume II" in Frontiers in Systems Endocrinology

Are you researching #endocrine #feedback control systems?

Our Research Topic "Mechanistic, Machine Learning and Hybrid Models of the 'Other' Endocrine Regulatory Systems in Health and Disease: Volume II" is still open for submission.

www.frontiersin.org/research-top...

#endocrinology #cybernetics

Table showing increased risk of dementia, atrial fibrillation and fatality in patients with treated hypothyroidism in a follow-up of 20 years

Forest plot showing increased risk of dementia in patients with treated hypothyroidism

Table with the results of multivariable regression analysis, showing significantly increased risk for dementia and fatality in monotherapy with L-T4 compared to combination therapy of L-T4 and L-T3 or DTE

Table showing increased risk for dementia, atrial fibrillation and fatality in patients receiving monotherapy with L-T4 compared to combination therapy consisting of L-T4 and L-T3 or DTE.

Patients with #hypothyroidism, even when treated with levothyroxine (L-T4), face increased risk of #dementia and #fatality. Fortunately, the risk can be lowered again by a combination therapy with L-T4 and L-T3, as shown by a recent study.

pubmed.ncbi.nlm.nih.gov/40579157/
doi.org/10.1210/clin...

#SPINA_Thyr helps in decision-making to implement this algorithm.

Sketch of pituitary-thyroid feedback control (HPT axis) maintaining thyroid homeostasis. This figure provides an overview of biomarkers for TR-alpha (Heart rate, ECG QT interval, JT interval, Tp-e interval and ostase concentration, painted in cyan) and TR-beta (concentrations of ceruloplasmin, copper, SHBG, CK, lipids, painted in orange) signalling and of functional biomarkers (SPINA-GT, SPINA-GD, Jostel’s TSH index, TTSI, TFQI, rounded boxes).

Positive and negative biomarkers for thyroid hormone action in tissues. Positive biomarkers for TR-alpha signalling include bone-specific alkaline phosphatase (ostase) and heart rate, negative biomarkers for TR-alpha signalling comprise QT interval, JT interval and TP-e interval in the ECG. Positive biomarkers for TR-beta signalling are 3-methylhistidine, coeruloplasmin, copper and sex-hormone binding globulin (SHBG), negative biomarkers for TR-beta signalling include lipids (total cholesterol, low-density lipoprotein [LDL], high-density lipoprotein [HDL], lipoprotein a [Lp(a)] and triglycerides) and creatine kinase (CK).

For the diagnosis and management of #hypothyroidism, measuring #TSH (thyrotropin) concentration is necessary, but it isn’t sufficient. Additional #biomarkers help to improve diagnostic power and to identify #endotypes of dysregulation.

doi.org/10.1007/978-...

🧪 🩺 #MedSky

European flag

SPINA apps are also available from European servers, provided by #CERN's #zenodo:

doi.org/10.5281/zeno...
doi.org/10.5281/zeno...

‪@cern.bsky.social‬

#SPINA_Thyr and #SPINA_Carb, two implementations of the structure parameter inference approach (SPINA), provide evidence-based improved methods for diagnosis and endotyping of endocrine diseases. Now, thoroughly tested apps for Mac and Windows are available for free download.

spina.sf.net

Screenshot of SPINA Carb 5.1.0 Cycline on macOS 15.5 Sequoia, showing two Windows (entry and results).

SPINA Carb 5.1.0 Cyclone has been released in its final version.

#SPINA-GBeta #SPINA-GR #SPINA-DI #SPINA_Carb #insulin #glucose #homeostasis #prediabetes #diabetes

sourceforge.net/projects/spi...

doi.org/10.5281/zeno...

doi.org/10.5281/zeno...

Screenshot of release candidate 3 of SPINA Carb 5.1 Cyclone on mac OS 15.5 Sequoia

Release candidate 3 for the software SPINA Carb Cyclone is available for macOS, Windows and Linux.

sourceforge.net/projects/spi...

doi.org/10.5281/zeno...

doi.org/10.5281/zeno...

#SPINA_Carb #SPINA-GBeta #SPINA-GR #SPINA-DI #HOMA

Hypothalamic–pituitary–thyroid regulation is implemented by multiple feedforward motifs and feedback loops.

Demonstration of attainment of perfect FT3 homeostasis in hypothalamic–pituitary–thyroid axis regulation in a mathematical model. The interactive loops of the hypothalamic–pituitary–thyroid axis regulation enable the actions of TRH (not shown), TSH, and FT4 to cooperate in a way to produce an equilibrium solution of perfect homeostasis for FT3. This is an example of relational stability. The strengths of all limbs have been normalised.

Multiple feedforward motifs and feedback loops maintain #thyroid #homeostasis and #allostasis. The mechanism of relational stability maintains T3 in a balanced and safe range, even in conditions of declining thyroid function.

doi.org/10.1007/978-...

🧪 🩺 #MedSky

Table: Characteristics of euthyroid subjects with benign disease or differentiated thyroid cancer. Patients with cancer have lower SPINA-GT and a higher set point (TSHI and TT4RI) than patients with benign nodules.

Table: Association between thyroid parameters (per SD change) and differentiated thyroid cancer in total subjects. SPINA-GT is negatively associated with the presence of cancer.

In patients undergoing #thyroid surgery due to nodules, #SPINA-GT is lower (and the set point of the homeostatic system higher) in cases of thyroid cancer compared to benign nodules.

doi.org/10.3389/fend...

Table from the book "Hypothyroidism – a Paradigm Shift" by Hoermann and Dietrich: Four receptor types (THRalpha1, THRbeta1, THRbeta2, THRbeta3, p43 and alphaVbeta3) convey thyroid signals in different tissues.

Table from the book "Hypothyroidism – a Paradigm Shift" by Hoermann and Dietrich: Eleven types of transporters with different hormone- and tissue-specificity carry thyroid hormones through cell membranes.

Figure from the book "Hypothyroidism – a Paradigm Shift" by Hoermann and Dietrich, showing an opened cell with the interaction of different thyroid hormones, transporters, deiodinases and signaling types.

Table from the book "Hypothyroidism – a Paradigm Shift" by Hoermann and Dietrich: Three types of deiodinases mediate step-up and step-down reactions interconverting thyroid hormones and leading to activation and inactivation.

Signalling via #thyroid hormones is more than T3 and T4. It involves 27 molecules based on the thyronine skeleton, 10 transmembrane transporters, 3 deiodinases, 6 receptors, and 4 types of action, unfolding a complex firework of possibilities, explaining health and disease.

doi.org/10.1007/978-...

A stack with several printed books, "Hypothyroidism – A Paradigm Shift" by Rudolf Hoermann and Johannes W. Dietrich.

Flyer for the book "Hypothyroidism – A Paradigm Shift" by Rudolf Hoermann and Johannes W. Dietrich. Use the code SPRAUT to get a discount of 20% at Springer Nature.

Our book is now available in printed form. Use the code SPRAUT to get a discount of 20% at Springer Nature.

link.springer.com/book/9789819...

Figure from the book "Hypothyroidism: A Paradigm Shift" by Hoermann and Dietrich: Combination of peripheral and central mechanisms leading to the low-T3 syndrome. The activities of peripheral (GD1) and central (GD2) deiodinases diverge to cause the low-T3 phenotype. The graph shown has been produced by computer simulation with the free app SimThyr.

Computer simulations with #SimThyr enhance our understanding of the physiology of hypothalamic-pituitary-thyroid feedback control. This applies, for example, to the evolution of #TACITUS syndrome.

#thyroid #hypothyroidism #NTIS #biocybernetics

doi.org/10.1007/978-...

Title page of the book "Hypothyroidism" by Hoermann and Dietrich. This book revolutionizes our understanding of the regulation of the hypothalamic-pituitary-thyroid axis and the homeostasis of the thyroid system, offering a groundbreaking framework for diagnosing and treating hypothyroidism. By challenging conventional approaches, it addresses the pressing need for improved treatment quality, especially for patients experiencing persistent symptoms despite standard levothyroxine therapy. Delve into a comprehensive exploration of hypothyroidism, from its definition and pathophysiology to patient presentation and endocrine regulation. The chapters illuminate critical topics such as iodine metabolism, thyroid hormone signaling, and the intricacies of the hypothalamic-pituitary-thyroid axis. With contributions from leading experts, this book presents a paradigm shift in clinical care by integrating recent advances in thyroid regulation into practical treatment strategies. Readers will uncover why many patients fail to respond adequately to current treatments and discover innovative approaches to diagnosis and therapy. Ideal for medical professionals, researchers, clinicians, and specialists interested in thyroid disease, this book is also invaluable for general practitioners and informed patients seeking deeper insights into their condition. Aspiring endocrinologists will find it particularly educational, aligning with curriculum requirements while offering a fresh perspective on thyroid health. With its focus on cutting-edge research and practical applications, this volume is indispensable for anyone dedicated to improving patient care in the field of endocrinology.

Our eBook on #hypothyroidism has been published. The new cybernetic theory presented here summarises our scientific work of more than 20 years and lays the foundation for improved diagnosis and therapy of #thyroid disorders.

The book is available in EPUB and PDF formats.

doi.org/10.1007/978-...

Screenshot of SPINA Carb 5.1.0 (Cyclone) RC2 on macOS Ventura 13.7.5.

Release candidate 2 of #SPINA_Carb is available for testing.

sourceforge.net/projects/spi...

doi.org/10.5281/zeno...

doi.org/10.5281/zeno...

You may be right.

Figure 1. Effect of the rs3811787 of UCP1 gene in human adaptation to cold: (a) The levels of FT3 as a function of rs3811787 genotypes of the UCP1 gene; (b) Association analysis of the TT rs3811787 genotype between SPINA-GD; (c) Association analysis of the TT rs3811787 genotype between BSA; (d) The geographical distribution of the frequencies of the T rs3811787 (UCP1) allele in global human populations to identify signals of natural selection for cold climate adaptation.

Figure 2. Effect of the rs1800849 of UCP3 gene on human adaptation to cold: (a) The levels of FT3 as a function of rs1800849 genotypes of the UCP3 gene; (b) Association analysis of TT rs1800849 genotype between SPINA-GD; (c) Association analysis of TT rs1800849 genotype between BSA; (d) The geographical distribution of frequencies of the T rs1800849 (UCP3) allele in global human populations to identify signals of natural selection for cold climate adaptation.

Figure 3. The mechanism of BAT-mediated regulation of thyroid hormones and basal metabolic rate from the allelic variants rs3811787 of the UCP1 gene. Note. In the carriers of the T allele, with the active form of the UCP1 protein, brown adipocytes mitochondria use higher concentrations of T3 for increased heat generation during adaptive thermogenesis, which increases T3 clearance and in response increases peripheral deiodination (SPINA-GD), which raises blood levels of FT3 and basal metabolic rate. In carriers of the C allele, with a less active form of the protein, brown adipocytes will use less T3, which will not significantly increase SPINA-GD and blood levels of FT3, hence the metabolic rate will not significantly improve.

#Thyroid hormones play a pivotal role in #thermoregulation and the attunement to hot and cold #climate​s. Recent research found global patterns of variants in the UCP1 and UCP3 genes and #SPINA-GD (step-up #deiodinase activity), suggesting integrated adaptation.

🧪 🩺 #MedSky

doi.org/10.3390/biol...

Screenshot of SPINA Carb Release Candidate 1 for macOS

After intensive internal testing, the release candidate 1 of the #SPINA_Carb app is available. This is the "sister" app for #SPINA_Thyr, and it is provided for purposes of testing.

sourceforge.net/projects/spi...

doi.org/10.5281/zeno...

doi.org/10.5281/zeno...

Box plots showing SPINA GT actual vs predicted values (a) in all euthyroid children divided in groups by quartiles of TSH values and (b) in children with normal TSH in the upper 2 quartiles and children with mild and severe SH (**P < 0.001, *P<0.01). The comparison with predicted results rules out that this association is due to spurious correlation.

Table: TSH concentrations (min and max) in euthyroid (by quartiles) and children with SH and their corresponding SPINA-GT value (median and mean) along with the frequency of thyroid antibody positivity.

Calculating #SPINA-GT is useful in paediatrics, as recently shown in a research paper by the Medical School of Patras.

SPINA-GT is significantly reduced in subclinical hypothyroidism and even in the upper 2 quartiles of normal TSH.

pubmed.ncbi.nlm.nih.gov/40230485/
doi.org/10.3389/fend...

Thyroid hormone signalling involves four different mechanisms. T4 is a prohormone with respect to genomic signaling, but a true fast-acting hormone regarding type 4 action (which is inhibited by the iodothyroacetate TETRAC). Genomic action (type 1, type 2 and mitochondrial signaling) occurs on a slow time scale, whereas non-genomic effects (type 3 and type 4 signaling) represent a fast response (A). Thyroid hormone receptors (THR) usually act as heterodimers. Without thyroid hormone bound they block the transcription together with corepressors. Iodothyronines displace the corepressors and stimulate gene expression together with coactivators (B). Tissue specific distributions of THRs further contribute to the diversity of signaling patterns in the organism (C). AF-1, activation function 1; AF-2, activation function 2; D2, type 2 deiodinase; DBD, DNA-binding domain; HAT, histone acetyl-transferase; HDAc, histone deacetylase; LBD, ligand-binding domain; RXR, retinoid X receptor; TRE, thyroid-hormone response element.

Thyroid hormones have a profound effect on the intracellular processes of rhythm generation. The figure shows mechanisms of rhythm generation in cardiomyocytes based on a model by Maltsev et al. Two loops, an external membrane loop and an internal calcium loop, independently ensure the generation of impulses. Therefore, they provide some redundancy, but they are also intertwined at the stage of slow L-type Ca2+ current (ICaL) activation. Thyroid hormone signalling can modulate both loops simultaneously via interfaces at several sites, and direct myocardial effects of TSH are largely opposing. gK, ionic conductance for K+; INCX, Na+/Ca2+ exchange current; ICaT, T-type Ca2+ current; If , hyperpolarisation-activated “funny” current; IK, voltage-gated K+ current; Ist , sustained non-selective current; Ito, transient outward potassium current; LCR, local Ca2+ release; SERCA, sarcoendoplasmic reticulum Ca2+-ATPase; SR, sarcoplasmic reticulum.

Selected mechanisms of arrhythmogenesis by thyroid hormones at the cellular level. T3 (and other active thyroid hormones) upregulate the gene expression of beta1 and beta2 adrenoceptors via classical genomic signaling, but downregulate protective beta3 adrenoceptor expression. The transcription of critical genes for the formation of gap junctions is downregulated as well. Potassium channels are regulated via classical type 1 signaling and via non-genomic effects (type 4 action) as well. Purple arrows indicate the effects of gene expression (transcription, translation and associated processing steps), green arrows visualize the impact of T3-agonistic thyroid hormones.

On a macroscopic level, elevated concentrations of thyroid hormones promote arrhythmia by slowing down electrical conduction and reducing the effective refractory period. (A,B) Simplified model of the effects of thyroid hormone signalling facilitating disorders of impulse conduction. Iodothyronine action reduces both the effective refractory period (ERP) and the conduction velocity (θ). As a consequence, the wavelength of excitation λ = ERP x θ may get shorter than the dimensions of a potential re-entry circuit, thus giving rise to re-entrant tachycardia.

#Thyroid hormones profoundly impact the #cardiovascular system. They act at all levels, ranging from the tier of ion currents over cellular processes to the macroscopic levels of myocardial tissue and even the whole organism.

🧪 🩺 #MedSky

doi.org/10.3389/fcvm...

pubmed.ncbi.nlm.nih.gov/36046184/

Table showing endotypes of insulin-glucose homeostasis in patients with hidradenitis suppurative (HS or acne inversa) and different expressions of haptoglobin concentration. In persons with HS and a high haptoglobin concentration, insulin sensitivity (SPINA-GR) and beta-cell function (SPINA-GBeta) are similar but combine to provide a reduced disposition index (SPINA-DI).

Plot of SPINA-GBeta versus SPINA-GR in patients with HS and controls: The majority of patients with HS and diabetes are faced with rather low insulin sensitivity and a lack of dynamic compensation via pancreatic beta-cell function, resulting in a reduced disposition index.

#Hidradenitis suppurativa (acne inversa) is linked to #diabetes mellitus. In the affected, #SPINA-GR is reduced and not compensated by #SPINA-GBeta, resulting in low #SPINA-DI. This phenomenon may be mediated by #inflammation, as shown by ties to #haptoglobin.

pubmed.ncbi.nlm.nih.gov/40217596/

Fig. 1. Simplified block diagram of the pituitary-thyroid feedback loop. The thyroid produces the hormones T3 and T4. On the one hand, this process is stimulated by TSH, a hormone secreted from the pituitary. On the other hand, this process is inhibited by Methimazole (MMI), an antithyroid agent (i.e., a medication), which constitutes the control input in this work. The hormone T4 gets converted into T3 by the enzymes 5’-deiodinase type I (D1) and 5’-deiodinase type II (D2). Finally, TRH (which is a natural hormone, and not a medication) stimulates the production of TSH.

Fig. 2. Illustration of the guidelines given by the American Thyroid association (ATA) (Ross et al., 2016). The treating physician may encounter many difficulties to select one precise dosage using these (rather vague) recommendations.

Fig. 3. Simulation results of an exemplary treatment based on the guidelines introduced in Ross et al. (2016). We apply the mean medication dosage for each interval, e.g., if the concentration of FT4 (which is proportional to T4) is within 27−42 pmol/L, we apply 7.5 mg. As disturbances, we consider forgotten dosages and measurement noise as explained in Section 3.

Fig. 4. Course of the hormone concentrations and the corresponding MMI dosages that are taken orally once per day. The dosages are determined by the MPC scheme introduced in Subsection 2.2. As explained in Section 3, we consider forgotten dosages, a model-plant mismatch, and some measurement noise as disturbances.

Medical treatment of #hyperthyroidism, i.e. #thyrotoxicosis due to overproduction of #thyroid hormone, remains a challenge. We developed a new dosage methodology based on model predictive control (MPC), which is faster and more stable than the usual trial-and-error approach. doi.org/10.1016/j.if...