Pheochromocytomas and paragangliomas (PPGLs) have emerged as one of the most common endocrine tumors. It epitomizes fascinating crossroads of genetic, metabolic, and endocrine oncology, providing a canvas to explore the molecular intricacies of tumor biology. Predominantly rooted in the aberration of metabolic pathways, particularly the Krebs cycle and related enzymatic functionalities, PPGLs manifest an intriguing metabolic profile, highlighting elevated levels of oncometabolites like succinate and fumarate, and furthering cellular malignancy and genomic instability. This comprehensive review aims to delineate the multifaceted aspects of tumor metabolism in PPGLs, encapsulating genetic factors, oncometabolites, and potential therapeutic avenues, thereby providing a cohesive understanding of metabolic disturbances and their ramifications in tumorigenesis and disease progression. Initial investigations into PPGLs metabolomics unveiled a stark correlation between specific genetic mutations, notably in the succinate dehydrogenase complex (SDHx) genes, and the accumulation of oncometabolites, establishing a pivotal role in epigenetic alterations and hypoxia-inducible pathways. By scrutinizing voluminous metabolic studies and exploiting technologies, novel insights into the metabolic and genetic aspects of PPGLs are perpetually being gathered elucidating complex interactions and molecular machinations. Additionally, the exploration of therapeutic strategies targeting metabolic abnormalities has burgeoned harboring potential for innovative and efficacious treatment modalities. This review encapsulates the profound metabolic complexities of PPGLs, aiming to foster an enriched understanding and pave the way for future investigations and therapeutic innovations in managing these metabolically unique tumors.
Childhood-onset obesity has emerged as a major public healthcare challenge across the globe, fueled by an obesogenic environment and influenced by both genetic and epigenetic predispositions. This has led to an exponential rise in the incidence of type 2 diabetes mellitus in children and adolescents. The looming wave of diabetes-related complications in early adulthood is anticipated to strain the healthcare budgets in most countries. Unless there is a collective global effort to curb the devastation caused by the situation, the impact is poised to be pro-found. A multifaceted research effort, governmental legislation, and effective social action are crucial in attaining this goal. This article delves into the current epidemiological landscape, explores evidence concerning potential risks and consequences, delves into the pathobiology of childhood obesity, and discusses the latest evidence-based management strategies for diabesity.
Sodium glucose cotransporter-2 inhibitors (SGLT-2i) are antidiabetic medications with remarkable cardiovascular (CV) benefits proven by multiple randomised controlled trials and real-world data. These drugs are also useful in the prevention of CV disease (CVD) in patients with diabetes mellitus (DM). Although DM as such is a huge risk factor for CVD, the CV benefits of SGLT-2i are not just because of antidiabetic effects. These molecules have proven beneficial roles in prevention and management of nondiabetic CVD and renal disease as well. There are various molecular mechanisms for the organ protective effects of SGLT-2i which are still being elucidated. Proper understanding of the role of SGLT-2i in prevention and management of CVD is important not only for the cardiologists but also for other specialists caring for various illnesses which can directly or indirectly impact care of heart diseases. This clinical review compiles the current evidence on the rational use of SGLT-2i in clinical practice.
There has been an exponential increase in the global prevalence of fatty liver disease in recent years in association with the obesity pandemic worldwide. 'Metabolic dysfunction-associated fatty liver disease', the new terminology adopted by an international panel of experts in 2020 to largely replace the old term 'non-alcoholic fatty liver disease', has now been accepted by most hepatologists and diabetologists across the globe. The term metabolic dysfunction-associated fatty liver disease was created to better reflect the metabolicand liver-specific manifestations and complications of fatty liver disease. It is important to disseminate our current understanding of this enigmatic disease among the global scientific fraternity. Recent publications, including articles from the latest issue of Endocrinology & Metabolism Clinics of North America, are attempting to fill this knowledge gap.
The bidirectional association between type 2 diabetes mellitus (T2DM) and periodontitis is now well established, resulting in periodontal disease being considered as the 6th major complication of diabetes mellitus (DM) after car-diovascular disease, eye disease, neuropathy, nephropathy, and peripheral vascular disease. DM can worsen the virulence and invasiveness of pathogenic oral microbial flora aggravating the local inflammation and infection in those with periodontal disease. On the other hand, the chemical and immunological mediators released into the circulation as part of periodontal inflammation worsen the systemic insulin resistance with worsening of T2DM. Periodontitis if undiagnosed or left untreated can also result in eventual tooth loss. A study by Xu et al in the World Journal of Diabetes examined the predictive factors associated with periodontitis in Chinese patients with T2DM. The prevalence of periodontitis was found to be 75.7% in this study. Based on logistic regression analysis, the predictive factors for higher risk were low tooth brushing frequency [odds ratio (OR) = 4.3], high triglycerides (TG; OR = 3.31), high total cholesterol (TC; OR = 2.87), higher glycated hemoglobin (HbA1c; OR = 2.55), and higher age (OR = 1.05) while higher education level was protective (OR = 0.53). However, the most influential variables were HbA1c followed by age, TC, TG, low education level, brushing frequency, and sex on the random forest model (this model showed higher sensitivity for predicting the risk). A good understanding of the predictors for periodontitis in T2DM patients is important in prevention, early detection of susceptible patients, and intervention to improve periodontal health and enable long-term glycaemic control as observed by Xu et al.
While chronic hyperglycaemia resulting from poorly controlled diabetes mellitus (DM) is a well-known precursor to complications such as diabetic retinopathy, neuropathy (including autonomic neuropathy), and nephropathy, a paradoxical intensification of these complications can rarely occur with aggressive glycemic management resulting in a rapid reduction of glycated haemoglobin. Although, acute onset or worsening of retinopathy and treatment induced neuropathy of diabetes are more common among these complications, rarely other problems such as albuminuria, diabetic kidney disease, Charcot's neuroarthropathy, gastroparesis, and urinary bladder dysfunction are also encountered. The World Journal of Diabetes recently published a rare case of all these complications, occurring in a young type 1 diabetic female intensely managed during pregnancy, as a case report by Huret et al. It is essential to have a comprehensive understanding of the pathobiology, prevalence, predisposing factors, and management strategies for acute onset, or worsening of microvascular complications when rapid glycemic control is achieved, which serves to alleviate patient morbidity, enhance disease management compliance, and possibly to avoid medico-legal issues around this rare clinical problem. This editorial delves into the dynamics surrounding the acute exacerbation of microvascular complications in poorly controlled DM during rapid glycaemic control.
BACKGROUND: Sodium glucose cotransporter-2 inhibitors (SGLT-2i) are a class of drugs with modest antidiabetic efficacy, weight loss effect, and cardiovascular benefits as proven by multiple randomised controlled trials (RCTs). However, real-world data on the comparative efficacy and safety of individual SGLT-2i medications is sparse. AIM: To study the comparative efficacy and safety of SGLT-2i using real-world clinical data. METHODS: We evaluated the comparative efficacy data of 3 SGLT-2i drugs (dapagliflozin, canagliflozin, and empagliflozin) used for treating patients with type 2 diabetes mellitus. Data on the reduction of glycated hemoglobin (HbA1c), body weight, blood pressure (BP), urine albumin creatinine ratio (ACR), and adverse effects were recorded retrospectively. RESULTS: Data from 467 patients with a median age of 64 (14.8) years, 294 (62.96%) males and 375 (80.5%) Caucasians were analysed. Median diabetes duration was 16.0 (9.0) years, and the duration of SGLT-2i use was 3.6 (2.1) years. SGLT-2i molecules used were dapagliflozin 10 mg (n = 227; 48.6%), canagliflozin 300 mg (n = 160; 34.3%), and empagliflozin 25 mg (n = 80; 17.1). Baseline median (interquartile range) HbA1c in mmol/mol were: dapagliflozin - 78.0 (25.3), canagliflozin - 80.0 (25.5), and empagliflozin - 75.0 (23.5) respectively. The respective median HbA1c reduction at 12 months and the latest review (just prior to the study) were: 66.5 (22.8) & 69.0 (24.0), 67.0 (16.3) & 66.0 (28.0), and 67.0 (22.5) & 66.5 (25.8) respectively (P < 0.001 for all comparisons from baseline). Significant improvements in body weight (in kilograms) from baseline to study end were noticed with dapagliflozin - 101 (29.5) to 92.2 (25.6), and canagliflozin 100 (28.3) to 95.3 (27.5) only. Significant reductions in median systolic and diastolic BP, from 144 (21) mmHg to 139 (23) mmHg; (P = 0.015), and from 82 (16) mmHg to 78 (19) mmHg; (P < 0.001) respectively were also observed. A significant reduction of microalbuminuria was observed with canagliflozin only [ACR 14.6 (42.6) at baseline to 8.9 (23.7) at the study end; P = 0.043]. Adverse effects of SGLT-2i were as follows: genital thrush and urinary infection - 20 (8.8%) & 17 (7.5%) with dapagliflozin; 9 (5.6%) & 5 (3.13%) with canagliflozin; and 4 (5%) & 4 (5%) with empagliflozin. Diabetic ketoacidosis was observed in 4 (1.8%) with dapagliflozin and 1 (0.63%) with canagliflozin. CONCLUSION: Treatment of patients with SGLT-2i is associated with statistically significant reductions in HbA1c, body weight, and better than those reported in RCTs, with low side effect profiles. A review of large-scale real-world data is needed to inform better clinical practice decision making.
Monitoring the healing progress of diabetic foot ulcers is a challenging process. Accurate segmentation of foot ulcers can help podiatrists to quantitatively measure the size of wound regions to assist prediction of healing status. The main challenge in this field is the lack of publicly available manual delineation, which can be time consuming and laborious. Recently, methods based on deep learning have shown excellent results in automatic segmentation of medical images, however, they require large-scale datasets for training, and there is limited consensus on which methods perform the best. The 2022 Diabetic Foot Ulcers segmentation challenge was held in conjunction with the 2022 International Conference on Medical Image Computing and Computer Assisted Intervention, which sought to address these issues and stimulate progress in this research domain. A training set of 2000 images exhibiting diabetic foot ulcers was released with corresponding segmentation ground truth masks. Of the 72 (approved) requests from 47 countries, 26 teams used this data to develop fully automated systems to predict the true segmentation masks on a test set of 2000 images, with the corresponding ground truth segmentation masks kept private. Predictions from participating teams were scored and ranked according to their average Dice similarity coefficient of the ground truth masks and prediction masks. The winning team achieved a Dice of 0.7287 for diabetic foot ulcer segmentation. This challenge has now entered a live leaderboard stage where it serves as a challenging benchmark for diabetic foot ulcer segmentation.
Diabetes Mellitus , Diabetic Foot , Humans , Diabetic Foot/diagnostic imaging , Neural Networks, Computer , Benchmarking , Image Processing, Computer-Assisted/methods
Managing diabetes during pregnancy is challenging, given the significant risk it poses for both maternal and foetal health outcomes. While traditional methods involve capillary self-monitoring of blood glucose level monitoring and periodic HbA1c tests, the advent of continuous glucose monitoring (CGM) systems has revolutionized the approach. These devices offer a safe and reliable means of tracking glucose levels in real-time, benefiting both women with diabetes during pregnancy and the healthcare providers. Moreover, CGM systems have shown a low rate of side effects and high feasibility when used in pregnancies complicated by diabetes, especially when paired with continuous subcutaneous insulin infusion pump as hybrid closed loop device. Such a combined approach has been demonstrated to improve overall blood sugar control, lessen the occurrence of preeclampsia and neonatal hypoglycaemia, and minimize the duration of neonatal intensive care unit stays. This paper aims to offer a comprehensive evaluation of CGM metrics specifically tailored for pregnancies impacted by type 1 diabetes mellitus.
Despite the advent of relatively reliable modalities of diagnosing diabetic peripheral neuropathy (DPN), such as nerve conduction studies, there is still a knowledge gap about the pathophysiology, and thus limited available interventions for symptom control and curtailing disease progression. The pharmacologic aspect of management is mainly centred on pain control, however, there are several important aspects of DPN such as loss of vibration sense, pressure sense, and proprioception which are associated with risks to lower limb health, which pharmacotherapy does not address. Furthermore, published evidence suggests non-pharmacologic interventions such as glycaemic control through dietary modification and exercise need to be combined with other measures such as psychotherapy, to reach a desired, however modest effect. Acupuncture is emerging as an important treatment modality for several chronic medical conditions including neuropathic and other pain syndromes. In their study published in the World Journal of Diabetes on the potential of acupuncture to reduce DPN symptoms and enhance nerve conduction parameters, Hoerder et al have been able to demonstrate that acupuncture improves sensory function and that this effect is likely sustained two months after treatment cessation. Although previous studies also support these findings, larger multi-center randomized control trials including a sham-controlled arm accounting for a placebo effect are required. Overall, given the satisfactory safety profile and the positive results found in these studies, it is likely that acupuncture may become an important aspect of the repertoire of effective DPN management.
The prevalence of metabolic-associated fatty liver disease (MAFLD) has increased substantially in recent years because of the global obesity pandemic. MAFLD, now recognized as the number one cause of chronic liver disease in the world, not only increases liver-related morbidity and mortality among sufferers but also worsens the complications associated with other comorbid conditions such as cardiovascular disease, type 2 diabetes mellitus, obstructive sleep apnoea, lipid disorders and sarcopenia. Understanding the interplay between MAFLD and these comorbidities is important to design optimal therapeutic strategies. Sarcopenia can be either part of the disease process that results in MAFLD (e.g., obesity or adiposity) or a consequence of MAFLD, especially in the advanced stages such as fibrosis and cirrhosis. Sarcopenia can also worsen MAFLD by reducing exercise capacity and by the production of various muscle-related chemical factors. Therefore, it is crucial to thoroughly understand how we deal with these diseases, especially when they coexist. We explore the pathobiological interlinks between MAFLD and sarcopenia in this comprehensive clinical update review article and propose evidence-based therapeutic strategies to enhance patient care.
SOURCE CITATION: Pavlou V, Cienfuegos S, Lin S, et al. Effect of time-restricted eating on weight loss in adults with type 2 diabetes: a randomized clinical trial. JAMA Netw Open. 2023;6:e2339337. 37889487.
Diabetes Mellitus, Type 2 , Adult , Humans , Diabetes Mellitus, Type 2/complications , Obesity/complications , Weight Gain , Weight Loss , Randomized Controlled Trials as Topic
Metabolic dysfunction-associated fatty liver disease (MAFLD) has now affected nearly one-third of the global population and has become the number one cause of chronic liver disease in the world because of the obesity pandemic. Chronic hepatitis resulting from hepatitis B virus (HBV) and hepatitis C virus (HCV) remain significant challenges to liver health even in the 21st century. The co-existence of MAFLD and chronic viral hepatitis can markedly alter the disease course of individual diseases and can complicate the management of each of these disorders. A thorough understanding of the pathobiological interactions between MAFLD and these two chronic viral infections is crucial for appropriately managing these patients. In this comprehensive clinical review, we discuss the various mechanisms of chronic viral hepatitis-mediated metabolic dysfunction and the impact of MAFLD on the progression of liver disease.
OBJECTIVE: Conduct a multicenter proof-of-concept clinical evaluation to assess the accuracy of an artificial intelligence system on a smartphone for automated detection of diabetic foot ulcers. METHODS: The evaluation was undertaken with patients with diabetes (n = 81) from September 2020 to January 2021. A total of 203 foot photographs were collected using a smartphone, analysed using the artificial intelligence system, and compared against expert clinician judgement, with 162 images showing at least one ulcer, and 41 showing no ulcer. Sensitivity and specificity of the system against clinician decisions was determined and inter- and intra-rater reliability analysed. RESULTS: Predictions/decisions made by the system showed excellent sensitivity (0.9157) and high specificity (0.8857). Merging of intersecting predictions improved specificity to 0.9243. High levels of inter- and intra-rater reliability for clinician agreement on the ability of the artificial intelligence system to detect diabetic foot ulcers was also demonstrated (Kα > 0.8000 for all studies, between and within raters). CONCLUSIONS: We demonstrate highly accurate automated diabetic foot ulcer detection using an artificial intelligence system with a low-end smartphone. This is the first key stage in the creation of a fully automated diabetic foot ulcer detection and monitoring system, with these findings underpinning medical device development.
Diabetes Mellitus , Diabetic Foot , Humans , Diabetic Foot/diagnosis , Artificial Intelligence , Reproducibility of Results , Smartphone , Sensitivity and Specificity
Type 1 diabetes mellitus (T1DM) is one of the important causes of chronic kidney disease (CKD) and end-stage renal failure (ESRF). Even with the best available treatment options, management of T1DM poses significant challenges for cli nicians across the world, especially when associated with CKD and ESRF. Substantial increases in morbidity and mortality along with marked rise in treatment costs and marked reduction of quality of life are the usual consequences of onset of CKD and progression to ESRF in patients with T1DM. Simultaneous pancreas-kidney transplant (SPK) is an attractive and promising treatment option for patients with advanced CKD/ESRF and T1DM for potential cure of these diseases and possibly several complications. However, limited availability of the organs for transplantation, the need for long-term immunosuppression to prevent rejection, peri- and post-operative complications of SPK, lack of resources and the expertise for the procedure in many centers, and the cost implications related to the surgery and postoperative care of these patients are major issues faced by clinicians across the globe. This clinical update review compiles the latest evidence and current recommendations of SPK for patients with T1DM and advanced CKD/ESRF to enable clinicians to care for these diseases.
Metabolic-associated fatty liver disease (MAFLD), formerly known as nonalcoholic fatty liver disease, is highly associated with the metabolic syndrome. Given its high heterogeneity in patients along with unpredictable clinical outcomes, MAFLD is difficult to diagnose and manage. MAFLD is associated with obesity, diabetes, metabolic derangements, lipid disorders, cardiovascular disorders, sleep apnea, sarcopenia, gut dysbiosis, and sex hormone-related disorders. Identification of risk factors is imperative in understanding disease heterogeneity and clinical presentation to reliably diagnose and manage patients. The complexity of MAFLD pathobiology is discussed in this review in relation to its association with common metabolic and nonmetabolic disorders.
Cardiovascular Diseases , Metabolic Syndrome , Non-alcoholic Fatty Liver Disease , Humans , Non-alcoholic Fatty Liver Disease/diagnosis , Non-alcoholic Fatty Liver Disease/etiology , Non-alcoholic Fatty Liver Disease/therapy , Risk Factors , Obesity
The pathobiology of MAFLD is such a big puzzle, and many of the metabolic and other health consequences of the disease are not yet fully elucidated. In their review on "Pathobiology of metabolic-associated fatty liver disease," Fouda and colleagues update the current evidence on the disease characteristics. The prevalence of MAFLD has reached epidemic proportions in children and young adults in the recent years, with figures reaching as high as 15% owing to the global obesity pandemic. Vespoli and colleagues in their review "MAFLD in childhood and adolescence" portray the latest updates and new emerging therapies for pediatric MAFLD. Gofton and colleagues update the association between metabolically unhealthy visceral adiposity and MAFLD in individuals with "normal body weight" in their review "Lean MAFLD." The pathobiological link between dyslipidemia and MAFLD is elaborated by Anwar and colleagues with the therapeutic algorithms. Ren and colleagues summarize evidence surrounding cardiovascular disease and MAFLD and analyze management strategies focusing on prevention of cardiovascular disease in MAFLD. Another important review by Kapoor and Kalra discusses the hot topic of diabetes and MAFLD and portrays the latest management strategies for both diseases. Barber and colleagues thoroughly review the gut-liver axis in the context of gut dysbiosis in MAFLD. Sarcopenia and MAFLD is the theme of the review by Bali and colleagues. This article emphasizes the importance of early identification of sarcopenia in patients with MAFLD and vice versa. Obstructive sleep apnea and MAFLD are often underdiagnosed and inadequately managed. Preshy and Brown in their review highlight the association between these common disorders to enhance the global awareness with updated evaluation and management strategies in their review. Mandato and colleagues review current literature on pregnancy and MAFLD and update the best clinical approach in their article. The interlink between polycystic ovary syndrome and MAFLD, their coexistence, diagnosis, and current management strategies are critically apprised by Vidal-Cevallos and colleagues in their review. Venkatesan and Haroon successively provide more important evidence for the clinical management of MAFLD with additional focus on minority groups and currently available therapies.
Cardiovascular Diseases , Non-alcoholic Fatty Liver Disease , Sarcopenia , Adolescent , Female , Pregnancy , Young Adult , Humans , Child , Non-alcoholic Fatty Liver Disease/epidemiology , Non-alcoholic Fatty Liver Disease/etiology , Non-alcoholic Fatty Liver Disease/therapy , Algorithms , Obesity
The diagnosis of adrenal insufficiency (AI) requires a high index of suspicion, detailed clinical assessment including detailed drug history, and appropriate laboratory evaluation. The clinical characteristics of adrenal insufficiency vary according to the cause, and the presentation may be myriad, e.g. insidious onset to a catastrophic adrenal crisis presenting with circulatory shock and coma. Secondary adrenal insufficiency (SAI) often presents with only glucocorticoid deficiency because aldosterone production, which is controlled by the renin angiotensin system, is usually intact, and rarely presents with an adrenal crisis. Measurements of the basal serum cortisol at 8 am (<140 nmol/L or 5 mcg/dL) coupled with adrenocorticotrophin (ACTH) remain the initial tests of choice. The cosyntropin stimulation (short synacthen) test is used for the confirmation of the diagnosis. Newer highly specific cortisol assays have reduced the cut-off points for cortisol in the diagnosis of AI. The salivary cortisol test is increasingly being used in conditions associated with abnormal cortisol binding globulin (CBG) levels such as pregnancy. Children and infants require lower doses of cosyntropin for testing. 21-hydoxylase antibodies are routinely evaluated to rule out autoimmunity, the absence of which would require secondary causes of adrenal insufficiency to be ruled out. Testing the hypothalamic-pituitary-adrenal (HPA) axis, imaging, and ruling out systemic causes are necessary for the diagnosis of AI. Cancer treatment with immune checkpoint inhibitors (ICI) is an emerging cause of both primary AI and SAI and requires close follow up. Several antibodies are being implicated, but more clarity is required. We update the diagnostic evaluation of AI in this evidence-based review.
The global prevalence of obesity is increasing rapidly with an exponential rise in incidence of type 2 diabetes mellitus in recent years. 'Diabesity', the term coined to show the strong interlink between obesity and diabetes, is the direct cons-equence of the obesity pandemic, and poses significant challenges in the management of the disease. Without addressing the clinical and mechanistic complications of obesity such as metabolic-associated fatty liver disease and obstructive sleep apnoea, a rational management algorithm for diabesity cannot be developed. Several classes of anti-diabetic medications including insulins, sulphonylureas, thiazolidinediones and meglitinides are associated with the risk of weight gain and may potentially worsen diabesity. Therefore, appropriate selection of antidiabetic drug regimen is crucial in the medical management of diabesity. The role of non-pharmacological measures such as dietary adjustments, exercise interventions and bariatric procedures should also be emphasised. Unfortunately, the importance of appropriate and optimal management of diabesity is often overlooked by medical professionals when achieving adequate glycemic control which results in inappropriate management of the disease and its complications. This review provides a narrative clinical update on the evidence behind the management of diabesity.
Diabetes care is often difficult without a proper collaboration between the patient and the care provider as the disease is mostly self-managed by patients through adjustments in their lifestyles, and medication doses to optimise glycaemic control. Most clinical guidelines on the management of diabetes mellitus (DM) provide only broad principles on diabetes care, and the blind follow-up of such principles without a proper review and consideration of patient characteristics often results in inadequate glycaemic control and diabetes complications consequently. Therefore, a proper understanding of the pathobiology, clinical situation, and comorbidities of the individual case is of paramount importance to tailoring the most appropriate management strategy in real-world diabetes care. With the aid of five unique cases of DM [(1) Medically managed type 2 diabetes mellitus (T2DM) with severe obesity; (2) Management of T2DM with unreliable glycated haemoglobin (HbA1c); (3) Obesity in a patient with type 1 diabetes mellitus (T1DM); and (4) Late diagnosis and subsequent management of monogenic diabetes and 5. Sudden worsening of well-controlled T2DM)] we elaborate on the importance of individualised diabetes care and the practicalities in these situations. The review also provides an evidence update on the management of different forms of DM to guide physicians in optimising the care of their patients in day-to-day clinical practice.
