Exploration of Endocrine and Metabolic Diseases

23 results in Exploration of Endocrine and Metabolic Diseases

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Editorial

Message of welcome from the editor-in-chief

Stefan R. Bornstein

Published: April 01, 2024 Explor Endocr Metab Dis. 2024;1:1–3
DOI: https://doi.org/10.37349/eemd.2023.00001

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Review

Application of chimeric antigen receptor-natural killer cells for the treatment of type 1 diabetes
For the past 100 years, insulin supplementation has been the mainstay of treatment for type 1 diabetes (T1D), which is characterized by progressive autoimmune-mediated loss of insulin-producing β c [...] Read more.

For the past 100 years, insulin supplementation has been the mainstay of treatment for type 1 diabetes (T1D), which is characterized by progressive autoimmune-mediated loss of insulin-producing β cells in the islets of Langerhans over the last decades, technological advances in glucose monitoring and therapeutics have greatly improved the care and management of these patients. However, morbidity, mortality, and quality of life remain challenges for patients with T1D. Islet transplantation has been successfully performed, but there are several limiting factors, such as the lack of cadaveric donors and the need for lifelong immunosuppressive therapy. Therefore, there is a great medical need for alternative therapeutic approaches. In the current review, the current knowledge on novel approaches for the treatment of T1D with a focus on the potential of using chimeric antigen receptor (CAR)-T cells and natural killer (NK) cells is summarized.

Charlotte Steenblock ... Stefan R. Bornstein

Published: April 01, 2024 Explor Endocr Metab Dis. 2024;1:4–11
DOI: https://doi.org/10.37349/eemd.2023.00002

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For the past 100 years, insulin supplementation has been the mainstay of treatment for type 1 diabetes (T1D), which is characterized by progressive autoimmune-mediated loss of insulin-producing β cells in the islets of Langerhans over the last decades, technological advances in glucose monitoring and therapeutics have greatly improved the care and management of these patients. However, morbidity, mortality, and quality of life remain challenges for patients with T1D. Islet transplantation has been successfully performed, but there are several limiting factors, such as the lack of cadaveric donors and the need for lifelong immunosuppressive therapy. Therefore, there is a great medical need for alternative therapeutic approaches. In the current review, the current knowledge on novel approaches for the treatment of T1D with a focus on the potential of using chimeric antigen receptor (CAR)-T cells and natural killer (NK) cells is summarized.

Open Access

Commentary

Unique original endocrine findings: the endoplasmic reticulum-mitochondrial unit in steroid producing cells

Stefan R. Bornstein ... Waldemar Kanczkowski

Published: April 01, 2024 Explor Endocr Metab Dis. 2024;1:12–15
DOI: https://doi.org/10.37349/eemd.2023.00003
This article belongs to the special issue The HPA Axis in Health and Disease

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Open Access

Review

Recent advances in artificial intelligence-assisted endocrinology and diabetes
Artificial intelligence (AI) has gained attention for various reasons in recent years, surrounded by speculation, concerns, and expectations. Despite being developed since 1960, its widespread appli [...] Read more.

Artificial intelligence (AI) has gained attention for various reasons in recent years, surrounded by speculation, concerns, and expectations. Despite being developed since 1960, its widespread application took several decades due to limited computing power. Today, engineers continually improve system capabilities, enabling AI to handle more complex tasks. Fields like diagnostics and biology benefit from AI’s expansion, as the data they deal with requires sophisticated analysis beyond human capacity. This review showcases AI’s integration in endocrinology, covering molecular to phenotypic patient data. These examples demonstrate AI’s potential and power in research and medicine.

Ioannis T. Oikonomakos ... Stefan R. Bornstein

Published: April 01, 2024 Explor Endocr Metab Dis. 2024;1:16–26
DOI: https://doi.org/10.37349/eemd.2023.00004

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Artificial intelligence (AI) has gained attention for various reasons in recent years, surrounded by speculation, concerns, and expectations. Despite being developed since 1960, its widespread application took several decades due to limited computing power. Today, engineers continually improve system capabilities, enabling AI to handle more complex tasks. Fields like diagnostics and biology benefit from AI’s expansion, as the data they deal with requires sophisticated analysis beyond human capacity. This review showcases AI’s integration in endocrinology, covering molecular to phenotypic patient data. These examples demonstrate AI’s potential and power in research and medicine.

Open Access

Original Article

Development of adrenal 3-dimensional spheroid cultures: potential for the treatment of adrenal insufficiency and neurodegenerative diseases
Aim: Regenerative and curative strategies would be desirable for neurodegenerative and adrenal diseases, and multipotent adrenal stem cells are considered as promising biological tools for this p [...] Read more.

Aim: Regenerative and curative strategies would be desirable for neurodegenerative and adrenal diseases, and multipotent adrenal stem cells are considered as promising biological tools for this purpose. Stem-like cells with the potential to proliferate and differentiate in vivo and in vitro were discovered in both cortex and medulla of the adrenal gland. Previously, it was demonstrated that nestin-positive progenitors in the cortex and medulla, play an important role under stress. In the present study, the cultivation of these cells was optimized and their growth in vitro was characterized. Methods: Primary cells from the adrenal cortex and medulla from Nes-GFP mice were isolated and the in vitro culture conditions promoting the growth of stem and progenitor cells using different 3-dimensional (3D) spheroid culture models were optimized. Results: Both cortical and medullary cells could be cultured for at least one month under several different low-adherence conditions maintaining their viability and potential to differentiate. Medullary cells grew faster than cortical cells. Endothelin did not affect the cultures. Conclusions: Adrenomedullary and adrenocortical nestin-positive progenitor cells can be cultured long-term in 3D cultures maintaining their proliferation and differentiation capabilities. Such multidimensional models can potentially be used for drug screening to develop personalized medicines or for transplantation to treat neurodegenerative disorders or adrenal diseases, such as adrenal insufficiency.

Charlotte Steenblock ... Nicole Bechmann

Published: April 01, 2024 Explor Endocr Metab Dis. 2024;1:27–38
DOI: https://doi.org/10.37349/eemd.2023.00005

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Aim: Regenerative and curative strategies would be desirable for neurodegenerative and adrenal diseases, and multipotent adrenal stem cells are considered as promising biological tools for this purpose. Stem-like cells with the potential to proliferate and differentiate in vivo and in vitro were discovered in both cortex and medulla of the adrenal gland. Previously, it was demonstrated that nestin-positive progenitors in the cortex and medulla, play an important role under stress. In the present study, the cultivation of these cells was optimized and their growth in vitro was characterized. Methods: Primary cells from the adrenal cortex and medulla from Nes-GFP mice were isolated and the in vitro culture conditions promoting the growth of stem and progenitor cells using different 3-dimensional (3D) spheroid culture models were optimized. Results: Both cortical and medullary cells could be cultured for at least one month under several different low-adherence conditions maintaining their viability and potential to differentiate. Medullary cells grew faster than cortical cells. Endothelin did not affect the cultures. Conclusions: Adrenomedullary and adrenocortical nestin-positive progenitor cells can be cultured long-term in 3D cultures maintaining their proliferation and differentiation capabilities. Such multidimensional models can potentially be used for drug screening to develop personalized medicines or for transplantation to treat neurodegenerative disorders or adrenal diseases, such as adrenal insufficiency.

Open Access

Review

Adult-onset testosterone deficiency: the usefulness of hormone replacement in reducing mortality in men with this common age-related condition
Adult-onset testosterone deficiency (TD) in men is diagnosed by the finding of low serum testosterone levels and recognised, associated symptoms. The condition has high prevalence in men over 50 yea [...] Read more.

Adult-onset testosterone deficiency (TD) in men is diagnosed by the finding of low serum testosterone levels and recognised, associated symptoms. The condition has high prevalence in men over 50 years of age, particularly those with type 2 diabetes (T2DM). Accumulating data show adult-onset TD is associated with increased mortality risk. We review the literature and consider the evidence suggesting testosterone therapy (TTh) reduces mortality, especially in men with T2DM. We previously reported that in the Burntwood Lichfield Atherstone Sutton Coldfield Tamworth (BLAST) study screened cohort of men with adult-onset TD and T2DM adult-onset TD was associated with increased mortality with TTh decreasing this higher mortality. The data hinted that the effect was greater in older men. We confirmed this observation with statistical analyses to study the effect of age on the association between adult-onset TD and mortality; Cox regression analysis demonstrated that the reduced risk (hazard ratio: 0.61, 95% CI: 0.38–0.96) following TTh was restricted to men above the median age of 65.89 years. Finally, we speculate on putative mechanisms that may mediate these associations. Heterogeneity in men with adult-onset TD is expected in view of its definition of low testosterone levels together with associated clinical phenotypes that are not always directly related. Many of these classifying phenotypes are associated with increased mortality. Thus, it is perhaps possible that mechanism(s) of all-cause mortality reduction following TTh is via the impact on these associated phenotypes such as the metabolic syndrome (MetS), hyperglycaemia, hypertension, dyslipidaemia, low haematocrit, sex hormone binding levels, erectile dysfunction, etc. We propose that further research studying the effect of TTh takes heterogeneity into account.

Amar Mann ... Sudarshan Ramachandran

Published: June 28, 2024 Explor Endocr Metab Dis. 2024;1:83–100
DOI: https://doi.org/10.37349/eemd.2024.00010
This article belongs to the special issue The Fountain of Youth: Decoding the Hormonal Regulation of Aging

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Adult-onset testosterone deficiency (TD) in men is diagnosed by the finding of low serum testosterone levels and recognised, associated symptoms. The condition has high prevalence in men over 50 years of age, particularly those with type 2 diabetes (T2DM). Accumulating data show adult-onset TD is associated with increased mortality risk. We review the literature and consider the evidence suggesting testosterone therapy (TTh) reduces mortality, especially in men with T2DM. We previously reported that in the Burntwood Lichfield Atherstone Sutton Coldfield Tamworth (BLAST) study screened cohort of men with adult-onset TD and T2DM adult-onset TD was associated with increased mortality with TTh decreasing this higher mortality. The data hinted that the effect was greater in older men. We confirmed this observation with statistical analyses to study the effect of age on the association between adult-onset TD and mortality; Cox regression analysis demonstrated that the reduced risk (hazard ratio: 0.61, 95% CI: 0.38–0.96) following TTh was restricted to men above the median age of 65.89 years. Finally, we speculate on putative mechanisms that may mediate these associations. Heterogeneity in men with adult-onset TD is expected in view of its definition of low testosterone levels together with associated clinical phenotypes that are not always directly related. Many of these classifying phenotypes are associated with increased mortality. Thus, it is perhaps possible that mechanism(s) of all-cause mortality reduction following TTh is via the impact on these associated phenotypes such as the metabolic syndrome (MetS), hyperglycaemia, hypertension, dyslipidaemia, low haematocrit, sex hormone binding levels, erectile dysfunction, etc. We propose that further research studying the effect of TTh takes heterogeneity into account.

Open Access

Review

Genome editing in the adrenal gland: a novel strategy for treating congenital adrenal hyperplasia
Congenital adrenal hyperplasia due to 21-hydroxylase deficiency leads to high morbidity and mortality, despite the availability of life-saving corticosteroid replacement therapy. Gene therapy repres [...] Read more.

Congenital adrenal hyperplasia due to 21-hydroxylase deficiency leads to high morbidity and mortality, despite the availability of life-saving corticosteroid replacement therapy. Gene therapy represents a promising potential treatment for monogenic disorders such as congenital adrenal hyperplasia, overcoming the limitations of corticosteroid replacement approaches. Adeno-associated viral vectors are currently the leading vector for direct in vivo gene delivery. However, physiological properties of the adrenal gland limit the application of adeno-associated viral vector-based gene addition strategies. To achieve durable correction in the adrenal gland, gene editing must be employed to stably introduce a genetic modification into the CYP21A2 locus. The safety of this and other gene editing approaches could be greatly improved by using lipid nanoparticles for the delivery of editing machinery mRNA. While little data exists regarding adrenocortical lipid nanoparticle targeting, physiological features of this organ (such as high relative blood flow, fenestrated endothelium, and cholesterol uptake) indicate the promise of these delivery vectors for the treatment of monogenic diseases of the adrenal cortex. This review discusses the complexities of developing gene therapy for congenital adrenal hyperplasia and explores the viability of novel gene therapy strategies in this application.

Eva B. van Dijk ... Lara E. Graves

Published: July 09, 2024 Explor Endocr Metab Dis. 2024;1:101–121
DOI: https://doi.org/10.37349/eemd.2024.00011
This article belongs to the special issue The HPA Axis in Health and Disease

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Congenital adrenal hyperplasia due to 21-hydroxylase deficiency leads to high morbidity and mortality, despite the availability of life-saving corticosteroid replacement therapy. Gene therapy represents a promising potential treatment for monogenic disorders such as congenital adrenal hyperplasia, overcoming the limitations of corticosteroid replacement approaches. Adeno-associated viral vectors are currently the leading vector for direct in vivo gene delivery. However, physiological properties of the adrenal gland limit the application of adeno-associated viral vector-based gene addition strategies. To achieve durable correction in the adrenal gland, gene editing must be employed to stably introduce a genetic modification into the CYP21A2 locus. The safety of this and other gene editing approaches could be greatly improved by using lipid nanoparticles for the delivery of editing machinery mRNA. While little data exists regarding adrenocortical lipid nanoparticle targeting, physiological features of this organ (such as high relative blood flow, fenestrated endothelium, and cholesterol uptake) indicate the promise of these delivery vectors for the treatment of monogenic diseases of the adrenal cortex. This review discusses the complexities of developing gene therapy for congenital adrenal hyperplasia and explores the viability of novel gene therapy strategies in this application.

Open Access

Review

Hypothetical involvement of stress hormones-induced reprograming of adult stem/progenitor cells in tumorigenesis
Stress is a state of threatened or perceived as threatened homeostasis that can be induced by various external and internal stimuli such as psychosocial factors, inflammatory or injurious conditions [...] Read more.

Stress is a state of threatened or perceived as threatened homeostasis that can be induced by various external and internal stimuli such as psychosocial factors, inflammatory or injurious conditions, and infections. In order to restore body homeostasis, adrenal glands produce and secrete glucocorticoids (GCs) and catecholamines (CAs), which are the main stress hormones that support the survival and adaptation of the organisms to the new environment. In contrast to the rather beneficial impact of acute and short-lasting stress, chronic stress and related dysregulation of the stress system is implicated in the development of many non-communicable diseases, including cancer. Particularly, ever-increasing experimental and clinical evidence implicates the involvement of CAs and GCs as well as the overexpression of their receptors in the activation of the major pathways involved in tumour development, metastasis, and resistance to various therapies. More importantly, results of experimental and epidemiological studies revealed that overexposure to stress hormones during pre- and early postnatal life might induce life-long or even transgenerational dysregulation of the stress system and predispose it to the development of various tumours. Although the exact mechanisms involved in the latter process are not yet fully known, it has been demonstrated that GC-induced epigenetic modifications can change the expression of several key genes involved in the regulation of the stress system, tumour initiation, and epigenetic imprinting. When such alterations occur in stem/progenitor cells (SPCs), this might not only lead to long-term dysfunction of the stress system but might promote the generation of cancer stem cells (CSCs). This review article discusses a hypothesis that stress hormones-mediated epigenetic reprograming of various SPCs during sensitive developmental periods, might contribute to their dysfunction and increased sensitivity to malignant transformation, thereby promoting tumorigenesis.

Waldemar Kanczkowski ... George P. Chrousos

Published: July 15, 2024 Explor Endocr Metab Dis. 2024;1:122–157
DOI: https://doi.org/10.37349/eemd.2024.00012
This article belongs to the special issue The HPA Axis in Health and Disease

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Stress is a state of threatened or perceived as threatened homeostasis that can be induced by various external and internal stimuli such as psychosocial factors, inflammatory or injurious conditions, and infections. In order to restore body homeostasis, adrenal glands produce and secrete glucocorticoids (GCs) and catecholamines (CAs), which are the main stress hormones that support the survival and adaptation of the organisms to the new environment. In contrast to the rather beneficial impact of acute and short-lasting stress, chronic stress and related dysregulation of the stress system is implicated in the development of many non-communicable diseases, including cancer. Particularly, ever-increasing experimental and clinical evidence implicates the involvement of CAs and GCs as well as the overexpression of their receptors in the activation of the major pathways involved in tumour development, metastasis, and resistance to various therapies. More importantly, results of experimental and epidemiological studies revealed that overexposure to stress hormones during pre- and early postnatal life might induce life-long or even transgenerational dysregulation of the stress system and predispose it to the development of various tumours. Although the exact mechanisms involved in the latter process are not yet fully known, it has been demonstrated that GC-induced epigenetic modifications can change the expression of several key genes involved in the regulation of the stress system, tumour initiation, and epigenetic imprinting. When such alterations occur in stem/progenitor cells (SPCs), this might not only lead to long-term dysfunction of the stress system but might promote the generation of cancer stem cells (CSCs). This review article discusses a hypothesis that stress hormones-mediated epigenetic reprograming of various SPCs during sensitive developmental periods, might contribute to their dysfunction and increased sensitivity to malignant transformation, thereby promoting tumorigenesis.

Open Access

Commentary

The 2024 American Diabetes Association guidelines on Standards of Medical Care in Diabetes: key takeaways for laboratory
The escalating prevalence of diabetes poses a significant health concern. Uncontrolled diabetes leads to a multitude of complications. A comprehensive management plan and continual adaptation of gui [...] Read more.

The escalating prevalence of diabetes poses a significant health concern. Uncontrolled diabetes leads to a multitude of complications. A comprehensive management plan and continual adaptation of guidelines is needed. The American Diabetes Association (ADA) is a guiding force in this domain, providing diabetes care recommendations for clinicians, laboratorians, researchers, and policymakers since 1989. The latest ADA guidelines present both challenges and opportunities for laboratories. The increased emphasis on glycated hemoglobin (HbA1c) testing for early diagnosis and personalized monitoring is expected to increase testing volumes, potentially leading to a rise in point-of-care testing. Ensuring standardized testing procedures becomes paramount to maintaining consistent and reliable results across laboratories. Moreover, laboratories may need to expand their test menus to accommodate the growing demand for personalized medicine approaches and collaborate closely with healthcare providers to support informed decision-making. This commentary provides a focused analysis of the 2024 ADA guidelines for the laboratory assessment of diabetes.

Dipti Tiwari, Tar Choon Aw

Published: July 23, 2024 Explor Endocr Metab Dis. 2024;1:158–166
DOI: https://doi.org/10.37349/eemd.2024.00013

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The escalating prevalence of diabetes poses a significant health concern. Uncontrolled diabetes leads to a multitude of complications. A comprehensive management plan and continual adaptation of guidelines is needed. The American Diabetes Association (ADA) is a guiding force in this domain, providing diabetes care recommendations for clinicians, laboratorians, researchers, and policymakers since 1989. The latest ADA guidelines present both challenges and opportunities for laboratories. The increased emphasis on glycated hemoglobin (HbA1c) testing for early diagnosis and personalized monitoring is expected to increase testing volumes, potentially leading to a rise in point-of-care testing. Ensuring standardized testing procedures becomes paramount to maintaining consistent and reliable results across laboratories. Moreover, laboratories may need to expand their test menus to accommodate the growing demand for personalized medicine approaches and collaborate closely with healthcare providers to support informed decision-making. This commentary provides a focused analysis of the 2024 ADA guidelines for the laboratory assessment of diabetes.

Open Access

Original Article

Glycemic trends, app engagement and achievement of gestational diabetes guideline targets using a diabetes app and Bluetooth^® connected blood glucose meters
Aim: Current diabetes guidelines recommend people with gestational diabetes mellitus (PwGDM) use primarily blood glucose meters (BGM) for diabetes management. We evaluated glycemic trends and gui [...] Read more.

Aim: Current diabetes guidelines recommend people with gestational diabetes mellitus (PwGDM) use primarily blood glucose meters (BGM) for diabetes management. We evaluated glycemic trends and guideline-recommended glycemic targets achieved in PwGDM using a diabetes app with a family of Bluetooth® connected BGMs. Methods: Anonymized glucose and app analytics data from 26,382 PwGDM were sourced from a server. Data from their first 7-days using the app with connected BGMs was compared to 7-days prior to a 10-week timepoint. Results: Percent fasting readings in range (RIR, < 5.3 mmol/L) improved by +20.3 percentage points in the overall population. Improved glucose RIR (3.5 to 7.8 mmol/L) (+8.3 percentage points), mean blood glucose (BG, –0.59 mmol/L), and fasting RIR (+33.2 percentage points) were observed in those with baseline mean BG ≥ 6.1 mmol/L. Improvements in mean BG of –0.32 to –2.36 mmol/L, and RIR of +3.0 to +38.3 percentage points correlated with higher baseline mean BG ≥ 6.1 to ≥ 7.8 mmol/L. Only 58.5% of PwGDM with baseline mean BG ≥ 6.1 mmol/L had > 80% RIR at baseline, which improved to 79.5% at 10 weeks. PwGDM averaged 17 app sessions and 90 minutes per week on the app. Conclusions: PwGDM engaged with the diabetes app and connected BGM, facilitating attainment of glycemic targets, an especially important outcome for those with higher mean glucose at baseline.

Mike Grady ... Elizabeth Holt

Published: July 24, 2024 Explor Endocr Metab Dis. 2024;1:167–176
DOI: https://doi.org/10.37349/eemd.2024.00014
This article belongs to the special issue The Impact of Digitalization To Improve Nutrition and Self-Management in Patients With Diabetes

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Aim: Current diabetes guidelines recommend people with gestational diabetes mellitus (PwGDM) use primarily blood glucose meters (BGM) for diabetes management. We evaluated glycemic trends and guideline-recommended glycemic targets achieved in PwGDM using a diabetes app with a family of Bluetooth® connected BGMs. Methods: Anonymized glucose and app analytics data from 26,382 PwGDM were sourced from a server. Data from their first 7-days using the app with connected BGMs was compared to 7-days prior to a 10-week timepoint. Results: Percent fasting readings in range (RIR, < 5.3 mmol/L) improved by +20.3 percentage points in the overall population. Improved glucose RIR (3.5 to 7.8 mmol/L) (+8.3 percentage points), mean blood glucose (BG, –0.59 mmol/L), and fasting RIR (+33.2 percentage points) were observed in those with baseline mean BG ≥ 6.1 mmol/L. Improvements in mean BG of –0.32 to –2.36 mmol/L, and RIR of +3.0 to +38.3 percentage points correlated with higher baseline mean BG ≥ 6.1 to ≥ 7.8 mmol/L. Only 58.5% of PwGDM with baseline mean BG ≥ 6.1 mmol/L had > 80% RIR at baseline, which improved to 79.5% at 10 weeks. PwGDM averaged 17 app sessions and 90 minutes per week on the app. Conclusions: PwGDM engaged with the diabetes app and connected BGM, facilitating attainment of glycemic targets, an especially important outcome for those with higher mean glucose at baseline.

Open Access

Original Article

Testosterone undecanoate is associated with improved ageing male symptoms score in men with type 2 diabetes and adult-onset testosterone deficiency: re-analyzed results from a randomised controlled trial
Aim: To evaluate changes in quality of life via the ageing male symptom scale (AMSS) and somatic, psychological, and sexual sub-scales following testosterone undecanoate (TU) or placebo (P) treat [...] Read more.

Aim: To evaluate changes in quality of life via the ageing male symptom scale (AMSS) and somatic, psychological, and sexual sub-scales following testosterone undecanoate (TU) or placebo (P) treatment in men with type 2 diabetes mellitus (T2DM) and adult-onset testosterone deficiency (TD) via a re-analysis of the BLAST (Burntwood, Lichfield, Atherstone, Sutton Coldfield, and Tamworth) randomised controlled trial (RCT). Methods: Analysis of data from the BLAST RCT in men with T2DM and adult-onset TD was performed. Summation baseline and study-end AMSS data were available in 170 men (94: P; 76: TU) with subscale data available in 82 men. Rank-sum and sign-rank tests determined inter/intra-group differences, whilst linear/multiple regression models identified predictors of AMSS change. Results: AMSS improved significantly in P [–2 (median), p = 0.010] and TU [–6 (median), p < 0.0001)] arms, with greater improvement observed in men on TU (p = 0.014). No significant change was seen in either arm with baseline AMSS < 27 (asymptomatic). TU was significantly associated with AMSS improvement in all symptomatic AMSS categories. Improvement in the P arm was confined to men with baseline AMSS > 49. In the cohort with subscale AMSS data, TU was associated with improvements in somatic, psychological, and sexual subscales, whilst improvement was limited to the somatic subscale in the men on P. TU (reference: P) and higher baseline AMSS were significantly and independently associated with AMSS improvement. The improvement in summation AMSS associated with TU (reference: P) was only evident in men with mild depression and no anxiety (based on baseline Hospital Anxiety and Depression Scale data). Conclusions: TU appeared associated with improved AMSS (summation and subscales) in men with T2DM and adult-onset TD demonstrating symptoms (AMSS ≥ 27) with this benefit mediated by levels of depression and anxiety (European Union Clinical Trials Register, EudraCT 2008-000931-16).

Pravinath Ramachandran ... Geoffrey Hackett

Published: August 13, 2024 Explor Endocr Metab Dis. 2024;1:177–190
DOI: https://doi.org/10.37349/eemd.2024.00015
This article belongs to the special issue The Fountain of Youth: Decoding the Hormonal Regulation of Aging

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Aim: To evaluate changes in quality of life via the ageing male symptom scale (AMSS) and somatic, psychological, and sexual sub-scales following testosterone undecanoate (TU) or placebo (P) treatment in men with type 2 diabetes mellitus (T2DM) and adult-onset testosterone deficiency (TD) via a re-analysis of the BLAST (Burntwood, Lichfield, Atherstone, Sutton Coldfield, and Tamworth) randomised controlled trial (RCT). Methods: Analysis of data from the BLAST RCT in men with T2DM and adult-onset TD was performed. Summation baseline and study-end AMSS data were available in 170 men (94: P; 76: TU) with subscale data available in 82 men. Rank-sum and sign-rank tests determined inter/intra-group differences, whilst linear/multiple regression models identified predictors of AMSS change. Results: AMSS improved significantly in P [–2 (median), p = 0.010] and TU [–6 (median), p < 0.0001)] arms, with greater improvement observed in men on TU (p = 0.014). No significant change was seen in either arm with baseline AMSS < 27 (asymptomatic). TU was significantly associated with AMSS improvement in all symptomatic AMSS categories. Improvement in the P arm was confined to men with baseline AMSS > 49. In the cohort with subscale AMSS data, TU was associated with improvements in somatic, psychological, and sexual subscales, whilst improvement was limited to the somatic subscale in the men on P. TU (reference: P) and higher baseline AMSS were significantly and independently associated with AMSS improvement. The improvement in summation AMSS associated with TU (reference: P) was only evident in men with mild depression and no anxiety (based on baseline Hospital Anxiety and Depression Scale data). Conclusions: TU appeared associated with improved AMSS (summation and subscales) in men with T2DM and adult-onset TD demonstrating symptoms (AMSS ≥ 27) with this benefit mediated by levels of depression and anxiety (European Union Clinical Trials Register, EudraCT 2008-000931-16).

Open Access

Review

Endogenous glucocorticoids during skeletal ageing
Stress hormones, namely glucocorticoids, have diverse actions throughout the body in regulating development, tissue metabolism, inflammation, circadian rhythms, and skeletal homeostasis. While endog [...] Read more.

Stress hormones, namely glucocorticoids, have diverse actions throughout the body in regulating development, tissue metabolism, inflammation, circadian rhythms, and skeletal homeostasis. While endogenous glucocorticoid levels are important to support bodily homeostasis, chronically elevated levels can cause damage to tissues and drive diseases including bone loss (i.e., osteoporosis), myopathy (i.e., sarcopenia) and metabolic disturbances (i.e., glucose intolerance, diabetes, and abnormal fat accrual). There is substantial evidence that basal glucocorticoid levels increase during ageing while at the same time the amplitude of the diurnal variation in glucocorticoid secretion decreases. However, the significance of these changes for skeletal health is not well understood and has only recently been studied in more detail. Evidence from genetically modified mouse models indicates that changes in glucocorticoid signaling associated with ageing induce bone loss, sarcopenia and drive osteoarthritic joint disease. These studies provide important insights into the role of glucocorticoids in age-related skeletal diseases which will aid in the development of novel treatments especially needed for osteoarthritis which disproportionally affects the elderly.

Eugenie Macfarlane ... Markus Joachim Seibel

Published: August 16, 2024 Explor Endocr Metab Dis. 2024;1:191–212
DOI: https://doi.org/10.37349/eemd.2024.00016
This article belongs to the special issue The Fountain of Youth: Decoding the Hormonal Regulation of Aging

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Stress hormones, namely glucocorticoids, have diverse actions throughout the body in regulating development, tissue metabolism, inflammation, circadian rhythms, and skeletal homeostasis. While endogenous glucocorticoid levels are important to support bodily homeostasis, chronically elevated levels can cause damage to tissues and drive diseases including bone loss (i.e., osteoporosis), myopathy (i.e., sarcopenia) and metabolic disturbances (i.e., glucose intolerance, diabetes, and abnormal fat accrual). There is substantial evidence that basal glucocorticoid levels increase during ageing while at the same time the amplitude of the diurnal variation in glucocorticoid secretion decreases. However, the significance of these changes for skeletal health is not well understood and has only recently been studied in more detail. Evidence from genetically modified mouse models indicates that changes in glucocorticoid signaling associated with ageing induce bone loss, sarcopenia and drive osteoarthritic joint disease. These studies provide important insights into the role of glucocorticoids in age-related skeletal diseases which will aid in the development of novel treatments especially needed for osteoarthritis which disproportionally affects the elderly.

Open Access

Original Article

Epigenetics in etiopathology of hyperprolactinemia
Aim: Epigenetic alterations have been reported in patients with pituitary tumors and those on antipsychotic drugs, which are also responsible for hyperprolactinemia. This suggests a possible role [...] Read more.

Aim: Epigenetic alterations have been reported in patients with pituitary tumors and those on antipsychotic drugs, which are also responsible for hyperprolactinemia. This suggests a possible role of epigenetics in the etiopathology of hyperprolactinemia. Methods: The study recruited 83 hyperprolactinemia cases with prolactin > 100 ng/mL and 65 controls. Global DNA methylation status was studied by MethylFlash Methylated DNA Quantification Kit and genome-wide methylation analysis (GWMA) by Infinium Methylation EPIC BeadChip 850K array. Results: Hyperprolactinemia cases showed significant global DNA hypermethylation compared to controls. Around 66.67% of hypomethylated and 12.9% of hypermethylated cases were on antipsychotics. Gene enrichment analysis of 5-cytosine-phosphate-guanine-3 (CpG) site-associated genes demonstrated significantly enriched major histocompatibility complex (MHC)-related protein classes and cellular components. Conclusions: The study suggested the role of epigenetics in the etiopathology of hyperprolactinemia.

Amanpreet Kaur Kalsi ... Jai Bhagwan Sharma

Published: May 22, 2024 Explor Endocr Metab Dis. 2024;1:39–55
DOI: https://doi.org/10.37349/eemd.2024.00006
This article belongs to the special issue The HPA Axis in Health and Disease

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Aim: Epigenetic alterations have been reported in patients with pituitary tumors and those on antipsychotic drugs, which are also responsible for hyperprolactinemia. This suggests a possible role of epigenetics in the etiopathology of hyperprolactinemia. Methods: The study recruited 83 hyperprolactinemia cases with prolactin > 100 ng/mL and 65 controls. Global DNA methylation status was studied by MethylFlash Methylated DNA Quantification Kit and genome-wide methylation analysis (GWMA) by Infinium Methylation EPIC BeadChip 850K array. Results: Hyperprolactinemia cases showed significant global DNA hypermethylation compared to controls. Around 66.67% of hypomethylated and 12.9% of hypermethylated cases were on antipsychotics. Gene enrichment analysis of 5-cytosine-phosphate-guanine-3 (CpG) site-associated genes demonstrated significantly enriched major histocompatibility complex (MHC)-related protein classes and cellular components. Conclusions: The study suggested the role of epigenetics in the etiopathology of hyperprolactinemia.

Open Access

Perspective

Diabetes and cancer: two epidemic diseases requiring an opposite therapeutic approach to target cells
Diabetes and cancer are two chronic metabolic diseases with ever-increasing incidence rates worldwide. These disorders can often occur together, as diabetes presents an important risk factor for can [...] Read more.

Diabetes and cancer are two chronic metabolic diseases with ever-increasing incidence rates worldwide. These disorders can often occur together, as diabetes presents an important risk factor for cancer and some cancers could in turn lead to diabetes. In this perspective article, many more commonalities between diabetes and cancer are highlighted, including the role of lifestyle and environmental factors in the pathogenesis, the presence of a rather long latency period before clinical diagnosis of invasive disease, as well as the ultimate progression to diabetic complications or malignant metastases. Moreover, both of these devastating disorders still lack curative treatment options, whereas several currently approved antidiabetic and anticancer drugs have been originally derived from different natural sources. However, while in the case of diabetes, the main therapeutic goal is to maintain the pancreatic islet mass by preserving β-cells survival, the major purpose of cancer therapy is to kill malignant cells and reduce the neoplastic mass of solid tumors. It is expected that both diabetes and cancer, two systemic diseases with epidemic proportions, would be managed more effectively through an integral approach, considering many different aspects related to their pathogenesis, including also lifestyle changes and dietary modifications.

Katrin Sak

Published: May 23, 2024 Explor Endocr Metab Dis. 2024;1:56–61
DOI: https://doi.org/10.37349/eemd.2024.00007

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Diabetes and cancer are two chronic metabolic diseases with ever-increasing incidence rates worldwide. These disorders can often occur together, as diabetes presents an important risk factor for cancer and some cancers could in turn lead to diabetes. In this perspective article, many more commonalities between diabetes and cancer are highlighted, including the role of lifestyle and environmental factors in the pathogenesis, the presence of a rather long latency period before clinical diagnosis of invasive disease, as well as the ultimate progression to diabetic complications or malignant metastases. Moreover, both of these devastating disorders still lack curative treatment options, whereas several currently approved antidiabetic and anticancer drugs have been originally derived from different natural sources. However, while in the case of diabetes, the main therapeutic goal is to maintain the pancreatic islet mass by preserving β-cells survival, the major purpose of cancer therapy is to kill malignant cells and reduce the neoplastic mass of solid tumors. It is expected that both diabetes and cancer, two systemic diseases with epidemic proportions, would be managed more effectively through an integral approach, considering many different aspects related to their pathogenesis, including also lifestyle changes and dietary modifications.

Open Access

Original Article

Four hepatic steatosis indices in predicting quantitative computed tomography-based metabolic dysfunction-associated fatty liver disease
Aim: To evaluate the prediction ability for quantitative computed tomography (QCT)-based metabolic dysfunction-associated fatty liver disease (MAFLD) of four widely known hepatic steatosis algori [...] Read more.

Aim: To evaluate the prediction ability for quantitative computed tomography (QCT)-based metabolic dysfunction-associated fatty liver disease (MAFLD) of four widely known hepatic steatosis algorithms, namely the fatty liver index (FLI), the hepatic steatosis index (HSI), the Framingham Steatosis index (FSI) and the Zhejiang University index (ZJU index). Methods: From July 2020 to June 2022, health checkup subjects who accepted liver fat quantification with QCT at the Health Management Center of the Second Affiliated Hospital of Chongqing Medical University were recruited in this study. MAFLD was diagnosed by using QCT-based liver fat quantification. The prediction performance of FLI, HSI, FSI, and ZJU index on MAFLD was evaluated using the area under the receiver operating characteristic curve (AUC). Results: Of a total of 4,566 subjects enrolled in this study, 48.7% were diagnosed with MAFLD. The AUC values of FLI, HSI, FSI, and ZJU index were 0.819, 0.792, 0.822 and 0.826, respectively. FLI exhibited the highest sensitivity (SN) of 79.42%, while the ZJU index demonstrated the highest specificity (SP) of 75.35%. Conclusions: All four indices (FLI, HSI, FSI, and ZJU index) have acceptable predictive performance for patients with QCT-based MAFLD. Our study suggests that the above indices have a stable ability for detecting MAFLD.

Bingwu Xu ... Yong Zhang

Published: May 23, 2024 Explor Endocr Metab Dis. 2024;1:62–76
DOI: https://doi.org/10.37349/eemd.2024.00008
This article belongs to the special issue Regulators of Glucose Homeostasis, Lipid Metabolism and Energy Balance

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Aim: To evaluate the prediction ability for quantitative computed tomography (QCT)-based metabolic dysfunction-associated fatty liver disease (MAFLD) of four widely known hepatic steatosis algorithms, namely the fatty liver index (FLI), the hepatic steatosis index (HSI), the Framingham Steatosis index (FSI) and the Zhejiang University index (ZJU index). Methods: From July 2020 to June 2022, health checkup subjects who accepted liver fat quantification with QCT at the Health Management Center of the Second Affiliated Hospital of Chongqing Medical University were recruited in this study. MAFLD was diagnosed by using QCT-based liver fat quantification. The prediction performance of FLI, HSI, FSI, and ZJU index on MAFLD was evaluated using the area under the receiver operating characteristic curve (AUC). Results: Of a total of 4,566 subjects enrolled in this study, 48.7% were diagnosed with MAFLD. The AUC values of FLI, HSI, FSI, and ZJU index were 0.819, 0.792, 0.822 and 0.826, respectively. FLI exhibited the highest sensitivity (SN) of 79.42%, while the ZJU index demonstrated the highest specificity (SP) of 75.35%. Conclusions: All four indices (FLI, HSI, FSI, and ZJU index) have acceptable predictive performance for patients with QCT-based MAFLD. Our study suggests that the above indices have a stable ability for detecting MAFLD.

Open Access

Case Report

Hypoparathyroidism, deafness and renal dysplasia syndrome with bilateral cataract and bicornuate uterus caused by a de novo GATA3 mutation
Hypoparathyroidism, deafness and renal dysplasia (HDR) syndrome is a rare genetic disorder caused by haploinsufficiency of the GATA3 gene. A very limited number of cases have been reported in the li [...] Read more.

Hypoparathyroidism, deafness and renal dysplasia (HDR) syndrome is a rare genetic disorder caused by haploinsufficiency of the GATA3 gene. A very limited number of cases have been reported in the literature to date. Diagnosis is challenging as the phenotypic expression has wide heterogeneity due to variable penetrance of the underlying genetic mutation. Although the condition is inherited in an autosomal dominant pattern, sporadic cases do occur. This report presents a case of a 22-year-old female diagnosed with HDR syndrome, featuring bilateral cataract and bicornuate uterus. The GATA3 mutation detected in the patient was not identified in the family, suggesting it to be arising de novo. The present case report describes the rare phenotypic findings of bilateral cataract and bicornuate uterus associated with HDR, thus expanding the clinical spectrum of the syndrome.

Rajesh Chetiwal ... Priyank Rastogi

Published: May 27, 2024 Explor Endocr Metab Dis. 2024;1:77–82
DOI: https://doi.org/10.37349/eemd.2024.00009

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Hypoparathyroidism, deafness and renal dysplasia (HDR) syndrome is a rare genetic disorder caused by haploinsufficiency of the GATA3 gene. A very limited number of cases have been reported in the literature to date. Diagnosis is challenging as the phenotypic expression has wide heterogeneity due to variable penetrance of the underlying genetic mutation. Although the condition is inherited in an autosomal dominant pattern, sporadic cases do occur. This report presents a case of a 22-year-old female diagnosed with HDR syndrome, featuring bilateral cataract and bicornuate uterus. The GATA3 mutation detected in the patient was not identified in the family, suggesting it to be arising de novo. The present case report describes the rare phenotypic findings of bilateral cataract and bicornuate uterus associated with HDR, thus expanding the clinical spectrum of the syndrome.

Open Access

Case Report

Beta thalassemia minor: a potential risk factor for osteopenia and osteoporosis
A 74-year-old male patient with beta thalassemia minor presented in 2022 for a follow-up of osteoporosis diagnosed prior to 2004. At the time of presentation, his medical history included: radiation [...] Read more.

A 74-year-old male patient with beta thalassemia minor presented in 2022 for a follow-up of osteoporosis diagnosed prior to 2004. At the time of presentation, his medical history included: radiation exposure to his head and neck, goiter, prostate cancer status post resection in 2019 without a history of anti-androgen therapy, and atrial fibrillation, for which he had been prescribed apixaban since 2021. Treatment with risedronate occurred from approximately 2004 to about 2011, with improvement in bone density to osteopenia. He had also taken vitamin D and calcium supplementation and engaged in regular weight-bearing exercise. The patient had no other known risk factors for decreased bone mineral density preceding the onset of his osteoporosis, and a previous workup for secondary causes of his osteoporosis etiology proved negative. We propose that beta thalassemia minor is potentially a risk factor for osteopenia and osteoporosis, and that bisphosphonates can be considered for management when therapeutic intervention is indicated. Even in the absence of other known risk factors, clinicians should consider periodically screening beta thalassemia minor patients with DXA for evaluation of bone health.

Felicia Woron ... Parvathy Madhavan

Published: October 31, 2024 Explor Endocr Metab Dis. 2024;1:213–217
DOI: https://doi.org/10.37349/eemd.2024.00017

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A 74-year-old male patient with beta thalassemia minor presented in 2022 for a follow-up of osteoporosis diagnosed prior to 2004. At the time of presentation, his medical history included: radiation exposure to his head and neck, goiter, prostate cancer status post resection in 2019 without a history of anti-androgen therapy, and atrial fibrillation, for which he had been prescribed apixaban since 2021. Treatment with risedronate occurred from approximately 2004 to about 2011, with improvement in bone density to osteopenia. He had also taken vitamin D and calcium supplementation and engaged in regular weight-bearing exercise. The patient had no other known risk factors for decreased bone mineral density preceding the onset of his osteoporosis, and a previous workup for secondary causes of his osteoporosis etiology proved negative. We propose that beta thalassemia minor is potentially a risk factor for osteopenia and osteoporosis, and that bisphosphonates can be considered for management when therapeutic intervention is indicated. Even in the absence of other known risk factors, clinicians should consider periodically screening beta thalassemia minor patients with DXA for evaluation of bone health.

Open Access

Original Article

Waist-to-height ratio as a novel marker of metabolic syndrome in patients with type 2 diabetes mellitus
Aim: Metabolic syndrome (MetS) is associated with chronic conditions, including type 2 diabetes mellitus (T2DM) and cardiovascular disorders. New markers are needed for the early detection and su [...] Read more.

Aim: Metabolic syndrome (MetS) is associated with chronic conditions, including type 2 diabetes mellitus (T2DM) and cardiovascular disorders. New markers are needed for the early detection and successful treatment of MetS, especially in patients with T2DM. The serum uric acid-to-creatinine ratio (UCR) and waist-to-height ratio (WHR) are novel markers in various chronic metabolic disorders. We aimed to compare WHR, UCR, and other metabolic and laboratory markers in T2DM patients with and without MetS. Methods: Patients with T2DM who visited the outpatient clinics of our institution were enrolled in the study. Total diabetic subjects were 239 of which 180 were in MetS group while 59 were in without MetS group. Data from both study groups were compared. Results: The serum UCR in the MetS and control groups was 6.3 ± 2.1 and 5.8 ± 1.6, respectively (p = 0.04). The WHR in the MetS and control groups was 0.65 (0.47–0.87) and 0.62 (0.35–0.84), respectively (p < 0.001). Significant positive correlations were observed between UCR and triglycerides (r = 0.17, p = 0.009), waist circumference (r = 0.13, p = 0.046), hip circumference (r = 0.18, p = 0.006), BMI (r = 0.2, p = 0.002), and GFR (r = 0.4, p < 0.001). Similarly, significant positive correlations were noted between WHR and systolic blood pressure (r = 0.12, p = 0.049), weight (r = 0.5, p < 0.001), BMI (r = 0.7, p < 0.001), and UCR (r = 0.12, p = 0.047). In the ROC analysis, the sensitivity and specificity of WHR (when higher than 0.64) in detecting MetS were 72% and 54%, respectively (AUC: 0.69, p < 0.001, 95% CI: 0.61–0.77). Conclusions: We propose that WHR and UCR could be valuable tools for the early detection of MetS in patients with T2DM. The ease and low cost of evaluating WHR and UCR make them practical markers for monitoring and diagnosing MetS.

Elif Basaran, Gulali Aktas

Published: January 10, 2025 Explor Endocr Metab Dis. 2025;2:101421
DOI: https://doi.org/10.37349/eemd.2025.101421
This article belongs to the special issue Current Views on Pathogenesis, Diagnosis and Management of Type 2 Diabetes Mellitus and Its Complications and Related Conditions

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Aim: Metabolic syndrome (MetS) is associated with chronic conditions, including type 2 diabetes mellitus (T2DM) and cardiovascular disorders. New markers are needed for the early detection and successful treatment of MetS, especially in patients with T2DM. The serum uric acid-to-creatinine ratio (UCR) and waist-to-height ratio (WHR) are novel markers in various chronic metabolic disorders. We aimed to compare WHR, UCR, and other metabolic and laboratory markers in T2DM patients with and without MetS. Methods: Patients with T2DM who visited the outpatient clinics of our institution were enrolled in the study. Total diabetic subjects were 239 of which 180 were in MetS group while 59 were in without MetS group. Data from both study groups were compared. Results: The serum UCR in the MetS and control groups was 6.3 ± 2.1 and 5.8 ± 1.6, respectively (p = 0.04). The WHR in the MetS and control groups was 0.65 (0.47–0.87) and 0.62 (0.35–0.84), respectively (p < 0.001). Significant positive correlations were observed between UCR and triglycerides (r = 0.17, p = 0.009), waist circumference (r = 0.13, p = 0.046), hip circumference (r = 0.18, p = 0.006), BMI (r = 0.2, p = 0.002), and GFR (r = 0.4, p < 0.001). Similarly, significant positive correlations were noted between WHR and systolic blood pressure (r = 0.12, p = 0.049), weight (r = 0.5, p < 0.001), BMI (r = 0.7, p < 0.001), and UCR (r = 0.12, p = 0.047). In the ROC analysis, the sensitivity and specificity of WHR (when higher than 0.64) in detecting MetS were 72% and 54%, respectively (AUC: 0.69, p < 0.001, 95% CI: 0.61–0.77). Conclusions: We propose that WHR and UCR could be valuable tools for the early detection of MetS in patients with T2DM. The ease and low cost of evaluating WHR and UCR make them practical markers for monitoring and diagnosing MetS.

Open Access

Review

A brief approach to hypertension in type 2 diabetes mellitus
Type 2 diabetes mellitus (DM) and hypertension (HT) are common major cardiovascular disease (CVD) risk factors. They share common pathophysiological mechanisms and are commonly co-existent. Prevalen [...] Read more.

Type 2 diabetes mellitus (DM) and hypertension (HT) are common major cardiovascular disease (CVD) risk factors. They share common pathophysiological mechanisms and are commonly co-existent. Prevalence of HT is increased among diabetic patients but also DM is more common in hypertensive patients. CVD risk increases multiplicatively in coexistence of HT and DM. Lowering blood pressure (BP) has been shown to be associated with improved morbidity related to both macro- and micro-vascular complications. Although there is debate about target BP levels, in many randomized controlled trials and guidelines a goal of < 130/80 mmHg is advocated in patients with DM, if well tolerated. However, an individualized approach should be cared for depending on risk factors, co-morbidities, and frailty of patients. Lifestyle modifications including weight loss, regular exercise, avoiding smoking and excessive alcohol consumption, and a healthy diet including limitation of salt and fat and total energy intake, are important both as a part of preventive therapy and treatment modality for both DM and HT. Among antihypertensive drugs angiotensin-converting enzyme inhibitors (ACEIs)/angiotensin receptor blockers (ARBs) are warranted due to their potential advantages for slowing albuminuria and progression to kidney failure which is more common in DM. Usually, their combination with calcium-channel blockers (CCBs) or thiazide/thiazide-like diuretics, in a step-wise manner, is recommended. Resistant HT is more common in DM and requires the addition of mineralocorticoid receptor antagonists (MRAs). New antidiabetic drugs like glucagon-like peptide 1 (GLP-1) agonists and sodium-glucose cotransporter 2 (SGLT2) inhibitors have been found to lower BP. Apart from their antihypertensive effects they also improve CVD and renal outcomes. There’re ongoing new trials for new agents. Development of more potent and longer-term effective BP lowering drugs, single pill multiple drug combinations of antiHT agents and combination of antiHT agents with glucose-lowering and antilipidemic agents will probably improve compliance to treatment and achievement of goals in diabetic patients.

Yilmaz Gunes

Published: February 04, 2025 Explor Endocr Metab Dis. 2025;2:101422
DOI: https://doi.org/10.37349/eemd.2025.101422
This article belongs to the special issue Current Views on Pathogenesis, Diagnosis and Management of Type 2 Diabetes Mellitus and Its Complications and Related Conditions

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Type 2 diabetes mellitus (DM) and hypertension (HT) are common major cardiovascular disease (CVD) risk factors. They share common pathophysiological mechanisms and are commonly co-existent. Prevalence of HT is increased among diabetic patients but also DM is more common in hypertensive patients. CVD risk increases multiplicatively in coexistence of HT and DM. Lowering blood pressure (BP) has been shown to be associated with improved morbidity related to both macro- and micro-vascular complications. Although there is debate about target BP levels, in many randomized controlled trials and guidelines a goal of < 130/80 mmHg is advocated in patients with DM, if well tolerated. However, an individualized approach should be cared for depending on risk factors, co-morbidities, and frailty of patients. Lifestyle modifications including weight loss, regular exercise, avoiding smoking and excessive alcohol consumption, and a healthy diet including limitation of salt and fat and total energy intake, are important both as a part of preventive therapy and treatment modality for both DM and HT. Among antihypertensive drugs angiotensin-converting enzyme inhibitors (ACEIs)/angiotensin receptor blockers (ARBs) are warranted due to their potential advantages for slowing albuminuria and progression to kidney failure which is more common in DM. Usually, their combination with calcium-channel blockers (CCBs) or thiazide/thiazide-like diuretics, in a step-wise manner, is recommended. Resistant HT is more common in DM and requires the addition of mineralocorticoid receptor antagonists (MRAs). New antidiabetic drugs like glucagon-like peptide 1 (GLP-1) agonists and sodium-glucose cotransporter 2 (SGLT2) inhibitors have been found to lower BP. Apart from their antihypertensive effects they also improve CVD and renal outcomes. There’re ongoing new trials for new agents. Development of more potent and longer-term effective BP lowering drugs, single pill multiple drug combinations of antiHT agents and combination of antiHT agents with glucose-lowering and antilipidemic agents will probably improve compliance to treatment and achievement of goals in diabetic patients.

Open Access

Case Report

Whole-exome sequencing uncovered the 3-hydroxy-3-methylglutaryl-CoA lyase deficiency as the cause of lethal in a Vietnamese infant
Metabolic disorders are due to a deficiency of enzymes, which can severely impact health or cause serious complications without treatment. This study aimed to identify the molecular causes of an inf [...] Read more.

Metabolic disorders are due to a deficiency of enzymes, which can severely impact health or cause serious complications without treatment. This study aimed to identify the molecular causes of an infant death who had been hospitalized with complicated health problems and metabolism syndrome. Whole-exome sequencing (WES) was used to screen pathogenic variants in the patient’s genome, followed by examination of variants segregation in her parents. The WES analysis identified two homozygous variants, c.[614C>G; 649A>G] in the HMGCL gene of the patient. These two variants co-locate within the exon 7 of the HMGCL gene, resulting in 2 amino acid substitutions, p.[T205S; M217V], in the conservative region of enzyme protein. Sanger sequencing showed that the patient’s unaffected mother and father carried one mutant allele of the HMGCL gene containing two c.[614C>G; 649A>G] variants. The HMGCL gene encodes the 3-hydroxy-3-methylglutaryl-CoA lyase enzyme, which is critical in the ketogenic pathway. The deficiency of this enzyme was reported to be a life-threatening illness in the neonatal period, and two variants detected in this study were also found in a Japanese patient with sudden, unexpected death in infancy. The frequency of these two variants in the Vietnamese in-hour database and their further functional analysis were also reported in this study. The results of this study have explored the molecular etiology that causes the severe, deadly condition of the patient and provide an understanding of the risk of disease in her family.

Hong Thu Nguyen-Huu ... Hai Ha Nguyen

Published: February 13, 2025 Explor Endocr Metab Dis. 2025;2:101423
DOI: https://doi.org/10.37349/eemd.2025.101423

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Metabolic disorders are due to a deficiency of enzymes, which can severely impact health or cause serious complications without treatment. This study aimed to identify the molecular causes of an infant death who had been hospitalized with complicated health problems and metabolism syndrome. Whole-exome sequencing (WES) was used to screen pathogenic variants in the patient’s genome, followed by examination of variants segregation in her parents. The WES analysis identified two homozygous variants, c.[614C>G; 649A>G] in the HMGCL gene of the patient. These two variants co-locate within the exon 7 of the HMGCL gene, resulting in 2 amino acid substitutions, p.[T205S; M217V], in the conservative region of enzyme protein. Sanger sequencing showed that the patient’s unaffected mother and father carried one mutant allele of the HMGCL gene containing two c.[614C>G; 649A>G] variants. The HMGCL gene encodes the 3-hydroxy-3-methylglutaryl-CoA lyase enzyme, which is critical in the ketogenic pathway. The deficiency of this enzyme was reported to be a life-threatening illness in the neonatal period, and two variants detected in this study were also found in a Japanese patient with sudden, unexpected death in infancy. The frequency of these two variants in the Vietnamese in-hour database and their further functional analysis were also reported in this study. The results of this study have explored the molecular etiology that causes the severe, deadly condition of the patient and provide an understanding of the risk of disease in her family.
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