Comparison of Comorbidities between Adults and Children with Glycogen Storage Disease Type Ia (GSDIA)

Objectives: Glycogen Storage Disease Type Ia (GSDIa) is a rare inherited disorder resulting in acute hypoglycemia due to impaired release of glucose from glycogen. Despite dietary management practices to prevent hypoglycemia in patients with GSDIa, complications still occur in children and throughout adulthood. This retrospective cohort study compared the prevalence of complications in adults and children with GSDIa. Method(s): Using ICD-10 diagnosis codes, the IQVIA Pharmetrics Plus database was searched for patients with >=2 GSDI claims (E74.01) from January 2016 through February 2020, with >=12 months continuous enrollment beginning prior to March 2019 (for one year of follow-up before COVID-19), and no inflammatory bowel disease diagnoses (indicative of GSDIb). Complication prevalence in adults and children with GSDIa was summarized descriptively. Result(s): In total, 557 patients with GSDIa were identified (adults, 67%;male, 63%), including 372 adults (median age, 41 years) and 185 children (median age, 7 years). Complications occurring only in adults were atherosclerotic heart disease (8.6%), pulmonary hypertension (3.0%), primary liver cancer (1.9%), dialysis (0.8%), and focal segmental glomerulosclerosis (0.3%). Other complications with the greatest prevalence in adults/children included gout (11.8%/0.5%), insomnia (10.0%/1.1%), osteoarthritis (22.0%/2.7%), severe chronic kidney disease (4.3%/0.5%), malignant neoplasm (10.8%/1.6%), hypertension (49.7%/8.7%), acute kidney failure (15.3%/2.7%), pancreatitis (3.0%/0.5%), gallstones (7.8%/1.6%), benign neoplasm (37.4%/8.1%), hepatocellular adenoma (7.0%/1.6%), neoplasm (41.1%/9.7%), and hyperlipidemia (45.2%/10.8%). Complications with the greatest prevalence in children/adults included poor growth (22.2%/1.9%), gastrostomy (29.7%/3.2%), kidney hypertrophy (2.7%/0.8%), seizure (1.6%/0.5%), hypoglycemia (27.0%/11.3%), hepatomegaly (28.7%/15.9%), kidney transplant (1.6%/1.1%), diarrhea (26.5%/18.6%), nausea and/or vomiting (43.8%/35.8%), acidosis (20.0%/17.2%), and anemia due to enzyme disorders (43.8%/40.6%). Conclusion(s): GSDIa is associated with numerous, potentially serious complications. Compared with children, adults with GSDIa had a greater prevalence of chronic complications, potentially indicating the progressive nature of disease. Children with GSDIa had more acute complications related to suboptimal metabolic control.Copyright © 2023

The use of alanine, free carnitine and IGFBP-1 as potential biomarkers for glycogen storage disease type I

Background: Glycogen Storage Disease Ia (GSDIa) and Ib (GSDIb) are inborn errors of carbohydrate metabolism due to a deficiency of glucose-6-phosphatase (G6Pase) or glucose-6-phosphate translocase (G6PT), respectively. Consuming prescribed amounts of uncooked cornstarch (UCCS) to prevent hypoglycemia is the standard of care for GSDIa and GSDIb. Patients followed in our GSD Program are admitted to the hospital annually for evaluation of their metabolic control by measuring glucose and lactate levels and revising treatment regimens accordingly. Lack of bed space due to the COVID-19 pandemic has created a need for alternate markers of metabolic control as lactate measurements are unreliable in the outpatient setting. This research aims to identify alternative biomarkers to show degree of metabolic control in individuals with GSDI. Method(s): A retrospective chart review was conducted on 45 adults and children with GSDI using data from January 1, 2014 toMay 6, 2021. Plasma alanine and free carnitine levels were compared with laboratory reference ranges. Results from the three tests were not available on every subject. Plasma alanine was evaluated on 24 subjects (16-GSDIa, 8-GSDIb) and free carnitine was evaluated on 25 subjects (17-GSDIa, 8-GSDIb). Result(s): Alanine levels in subjects with GSDIa ranged from 378 to 786 umol/L, while alanine levels in subjects with GSDIb ranged from 254 to 506 umol/L (reference range = 103-528 umol/L). Free carnitine levels ranged from26 to 72 umol/L in subjects with GSDIa and from 44 to 90 umol/L in subjects with GSDIb (reference range = 19-55 umol/L). Conclusion(s): Our analysis showed that plasma alanine and free carnitine have potential to be used as biomarkers of metabolic control. For plasma alanine, there seemed to be differences between subjects with GSDIa and GSDIb, as the majority of subjects with GSDIa had elevations in plasma alanine, while subjects with GSDIb did not. Elevated plasma alanine levels indicate lactic acidosis. For GSDIb, we hypothesize that there may be some type of G6Pase enzyme activity that occurs outside of the endoplasmic reticulum. When looking at both groups, free carnitine levels were mostly elevated. This indicates that there could be inhibition of fatty acid oxidation.Copyright © 2022 Elsevier Inc. All rights reserved.

Custom parenteral nutrition for critically ill patients with aminoacidopathies

Background: Nutrition therapy is crucial in the management of aminoacidopathies. The goal during critical illness is to reverse catabolism by providing sufficient energy and non-offending amino acids (AAs). If the patient's condition is unstable, tolerance of adequate enteral nutrition (EN) to promote anabolism may not be feasible. Parental nutrition (PN) may be necessary to meet nutrition goals, however standard preparations of PN are contraindicated. Integrity Compounding Pharmacy [Sandy Springs, GA] offers specialty compounding options tailored to provide PN to critically ill patients with aminoacidopathies void of offending AAs. Method(s): Retrospective chart review was performed. Patient Awas a 4-day old twin female born at 31-weeks gestation with phenylketonuria (PKU) hospitalized for prematurity and respiratory failure. Patient B was a 4-day old female, sibling of patient A, also with PKU hospitalized due to prematurity, respiratory failure and ductal dependent pulmonic stenosis. Patient C was a 26 year old male with maple syrup urine disease (MSUD) admitted for metabolic decompensation and respiratory failure in the setting of novel Covid-19 virus. Patient Dwas an 8 year old female with MSUD presenting with nausea and vomiting in the setting of novel Covid-19 virus. All four patients experienced elevated blood levels of offending AAs and inadequate EN intake. Custom PN from Integrity Compounding Pharmacy was utilized in all four patients ranging from 6 to 11 days. Patient A, B and D received custom PN as sole source nutrition for a period of time while transitioning to EN. Patient C tolerated a small amount of EN as well as custom PN to meet nutrition goals. Result(s): The Integrity custom PN provided appropriate AAs to optimize nutrition until full EN could be tolerated. This essential nutrition therapy helped reverse catabolism, achieve metabolic control and prevent further sequelae. Conclusion(s): Custom PN should be considered in critically ill patients with aminoacidopathies that have significant EN intolerance.Copyright © 2022 Elsevier Inc. All rights reserved.

Successful Outpatient Transition to Extended-Release Cornstarch in Patients with Glycogen Storage Disease

Background: The use of uncooked cornstarch every four hours remains the most efficient treatment to prevent recurrent hypoglycemia in individuals with glycogen storage diseases (GSD). However, children must wake up overnight for therapy, and delayed administration of cornstarch can be associated with hypoglycemia, seizures, neurologic injury, and death. Since the introduction of extended-release, waxy maize cornstarch (ER-CS) Glycosade as a medical food, patients and families have benefited from ER-CS by avoiding the overnight dose while maintaining metabolic control. It is recommended that individuals with GSD transitioning to ER-CS be admitted to the hospital for two nights for initial evaluation of the ER-CS dose. This recommendation was made to minimize the risk of hypoglycemia. During this hospitalization, it is recommended glucose levels be measured hourly. The ER-CS package insert states that outpatient transition may be considered if the patient has history of adherence to recommendations, good metabolic control, and the calculated dose falls within the recommended range. Detailed guidance of home transition was not provided. During the COVID-19 pandemic, our clinic developed an outpatient protocol for ER-CS transition. The goal of this protocol was to prevent unnecessary hospitalizations while safely transitioning individuals with GSD to ER-CS. Method(s): We identified patients followed in the Metabolic Genetics Clinic at Texas Children's Hospital with liver GSD who require overnight uncooked cornstarch, have a history of adherence to recommendations, and good metabolic control. Each had a working glucometer, test strips for three nights of hourly blood glucose tests, emergency rescue glucose products, and a personalized hypoglycemia action plan. The trial took place over three nights. During the first 24 h of the trial, the patient followed their previous uncooked cornstarch regimen and feeding schedule with pre-prandial glucose measures. If euglycemia was documented, ER-CS was subsequently used on nights #2 and #3. Patients were monitored with hourly blood glucose measurements and hourly ketones in GSD III or IX. ER-CS doses were calculated following the standard insert packet recommendations. If hypoglycemia was detected on either night, the dose of ER-CS was increased prior to continuing the trial. Families communicated the results of nightly blood glucose logs with the metabolic dietician on the subsequent mornings. Result(s): Three patients with GSD III and one patient with GSD Ia attempted the home ER-CS trial. All patients passed the trial. All glucose levels and ketone levels were obtained as directed. One patient had a documented blood glucose level of 69 at hour eight on the third night of the trial. The dose of ER-CS was subsequently increased. The trial was extended to a fourth night and euglycemia was maintained. No further side effects were reported in the other patients. Conclusion(s): We report successful outpatient ER-CS transitions of multiple patients with GSDs. No adverse events or significant hypoglycemic episodes were recorded during at-home trials. Thus, in patients with GSDs who are compliant with medical recommendations and under good metabolic control, at-home transition to ER-CS can be done safely and effectively without need for hospitalization.Copyright © 2023

Efficacy and safety of metabolic interventions for the treatment of severe COVID-19: in vitro, observational, and non-randomized open-label interventional study.

Background: Viral infection is associated with a significant rewire of the host metabolic pathways, presenting attractive metabolic targets for intervention. Methods: We chart the metabolic response of lung epithelial cells to SARS-CoV-2 infection in primary cultures and COVID-19 patient samples and perform in vitro metabolism-focused drug screen on primary lung epithelial cells infected with different strains of the virus. We perform observational analysis of Israeli patients hospitalized due to COVID-19 and comparative epidemiological analysis from cohorts in Italy and the Veteran's Health Administration in the United States. In addition, we perform a prospective non-randomized interventional open-label study in which 15 patients hospitalized with severe COVID-19 were given 145 mg/day of nanocrystallized fenofibrate added to the standard of care. Results: SARS-CoV-2 infection produced transcriptional changes associated with increased glycolysis and lipid accumulation. Metabolism-focused drug screen showed that fenofibrate reversed lipid accumulation and blocked SARS-CoV-2 replication through a PPARα-dependent mechanism in both alpha and delta variants. Analysis of 3233 Israeli patients hospitalized due to COVID-19 supported in vitro findings. Patients taking fibrates showed significantly lower markers of immunoinflammation and faster recovery. Additional corroboration was received by comparative epidemiological analysis from cohorts in Europe and the United States. A subsequent prospective non-randomized interventional open-label study was carried out on 15 patients hospitalized with severe COVID-19. The patients were treated with 145 mg/day of nanocrystallized fenofibrate in addition to standard-of-care. Patients receiving fenofibrate demonstrated a rapid reduction in inflammation and a significantly faster recovery compared to patients admitted during the same period. Conclusions: Taken together, our data suggest that pharmacological modulation of PPARα should be strongly considered as a potential therapeutic approach for SARS-CoV-2 infection and emphasizes the need to complete the study of fenofibrate in large randomized controlled clinical trials. Funding: Funding was provided by European Research Council Consolidator Grants OCLD (project no. 681870) and generous gifts from the Nikoh Foundation and the Sam and Rina Frankel Foundation (YN). The interventional study was supported by Abbott (project FENOC0003). Clinical trial number: NCT04661930.

Microbial Dysbiosis and Epithelial Dysfunction in Vitamin A-Deficient Lungs

Once believed to be sterile, recent studies now show microbes inhabiting healthy lungs that are dysregulated in patients with chronic obstructive pulmonary disease (COPD), asthma, tuberculosis (TB), and SARS-CoV-2 infection. Other studies have shown an increase in pulmonary disease and recurrent respiratory infections in malnourished patients. According to the World Health Organization, vitamin A deficiency (VAD) is now a major public health issue in low-income communities and many developing countries. While VAD has been shown to alter gene expression and tissue morphology in humans and mice, research suggests the lung microbiome plays an intimate role in the metabolic regulation, pathogen inhibition, and inflammatory responses in the lung. Whether dysbiosis is a cause or consequence of chronic respiratory conditions, or whether retinoic acid (RA) - the bioactive metabolite of Vitamin A - is essential for lung microbiome homeostasis, remains unknown. Therefore, we hypothesize that dietary VAD leads to epithelial remodeling which promotes microbial dysbiosis;the dysbiosis then perpetuates epithelial remodeling via host-microbe interactions. Our preliminary results show anatomical/pathological changes to the epithelium in VAD adult mouse lungs compared to controls (VAS). Using our Nkx2- 1creERT2/dnRAR Rosa26 tdTomato transgenic mouse model that selectively induces VAD in the adult lung epithelium following tamoxifen injections, our data supports the hypothesis that host epithelial aberration associated with dietary VAD is induced locally in the lung and not via distal or systemic mechanisms. Our data also indicates the onset of dysbiosis in adult mouse lungs as early as three weeks post-diet modulation as observed through changes in microbial composition in VAD mice compared to controls. Finally, our bulk RNAseq analysis of host and microbial gene signatures has uncovered mechanisms associated with microbial metabolic functions, ciliopathy, host cellular polarity, and immune response to infection, that are dysregulated in the absence of vitamin A. Further, we have also identified altered transcriptional activity of microbes that are traditionally symbiotic or pathobiotic under normal homeostasis. This work indicates the presence of specific host-microbe interactions that are essential for lung homeostasis and protection against lung infection and disease that are dysregulated or lost in the absence of dietary vitamin A.

DEMPOWER STUDY: EVALUATION OF THE EFFECT OF A PATIENT EMPOWERMENT AND COMMUNICATION DIGITAL TOOL ON METABOLIC CONTROL IN T2DM PATIENTS

Background and Aims: There is still a high number of inadequately controlled T2DM patients. Therefore, it is essential to develop innovative solutions to improve patient's empowerment by increasing patient-physician communication and their selfmanagement. The aim of this study was to analyze the effect of a home digital patient empowerment tool (Figure 1), on metabolic control in T2DM patients. Methods: Multicentric, randomized prospective clinical trial including adult T2DM patients without adequate glycemic control treated according to usual clinical practice across Spain. Figure 2 summarizes the study design and study population. The primary endpoint was the comparison of the proportion of patients who did not achieve the study glycemic target (defined as HbA1c levels ≤7.5% with a reduction in HbA1c ≥0.5 from baseline) at week 24 between groups 1 and 2. It was also performed a comparison of mean HbA1c changes from baseline to week 24 between groups 1 and 2. Results: The COVID-19 pandemic led to a premature study closure since patient's enrollment and follow-up were active during the 2020 lockdown. In total, 50 patients completed week 24 visit. Figure 3 shows the main study results. 46% patients from group 1 achieved study glycemic target vs 18% in group 2 (p = 0.067), whereas the difference in the HbA1c reduction between group 1 and 2 was -0.66% (p < 0.05). Conclusions: Our results suggest the patient empowerment through a home digital tool might allow an improvement in metabolic control and consequently a more effective management of T2DM.

EFFECT OF THE COVID-19 PANDEMIC ON METABOLIC CONTROL IN INSULIN PUMP USERS IN A DIABETES CENTER IN COLOMBIA

Background and Aims: The COVID-19 pandemic has led to changes in the management of insulin pump patients, requiring the use of telemedicine as a follow-up strategy. This study aimed to describe the metabolic control before and during the pandemic following the implementation of a teleconsultation program. Methods: Observational study of a cohort of insulin pump users at the Diabetes Center, Fundación Santa Fe de Bogotá from January 2020 to July 2021. Changes in HbA1c, time in range, episodes of hypoglycemia in both, pre-pandemic ( January to April 2020). and the pandemic (April to July 2021) period were evaluated. Results: During the study period, 44 patients were included, 22 males (50%), with a mean age of 41 years and time of diabetes 20.9 years. Micro-infusion systems incluided paradigm754 (11%), veo640 (72%), and veo670 (15%). No significant changes in metabolic control or time in the range were observed in the patients under follow-up (Table 1). Table 1 Conclusions: The implementation of a telemedicine program for follow-up of patients on insulin pumps provided maintenance of metabolic control.

EVALUATION OF GLYCAEMIC CONTROL IN PATIENTS WITH DIABETES MELLITUS HOSPITALIZED DUE TO COVID-ASSOCIATED PNEUMONIA

Background and Aims: Glycaemic control during a COVID- 19 pneumonia is affected by illness severity and required therapeutic measures (e.g. corticosteroids) in patients with diabetes. The aim is to compare glycaemic control and therapeutic changes during the inpatient stay in patients with HbA1c <7.0% compared to those with ≥7.0 on admission. Methods: Clinical data of 59 patients with diabetes, who were hospitalized between October 15th-December 31th 2020 at our pulmonary department due to a COVID-19 illness, were retrospectively collected and stratified according to their metabolic control at admission (HbA1c<7.0% or ≥7.0%) Results: Compared to patients with sufficient metabolic control (HbA1c<7.0%,n = 24), patients with HbA1c≥7.0% (n = 35) had longer duration of diabetes (p = 0.013), were more often male (74%vs.46%,p = 0.032) and were more frequently treated with metformin (74%vs.46%,p = 0.032) and DDP4- inhibitors (34%vs.8%, p = 0.029). The average glucose on admission (175vs.225mg/dl) worsened during inpatient stay in both groups. Patients with higher baseline HbA1c consistently showed higher glucose values during their stay (299vs.205mg/dl, p <0.001). Insulin requirement increased in both groups, whereby the maximum insulin dose per day over observation period was 13 IU in patients with baseline HbA1c<7.0% and 52 IU in patients with HbA1c≥7.0% (p < 0.001). In contrast, there was no difference in hospital mortality (17%vs.26%,p = 0.529). Using logistic regression, the patient's age was identified as a significant risk factor for hospital mortality (OR:1.07, 95%CI:1.01-1.14, p = 0.034). Conclusions: Patients with diabetes, particularly those with HbA1c ≥7.0 on admission, and severe COVID-19 disease show a significant deterioration in their glycaemic control during their inpatient stay. Increasing age in patients with diabetes is associated with a higher risk of mortality.

THE IMPACT OF COVID-19 PANDEMIC IN PATIENTS WITH TYPE 2 DIABETES

Background and Aims: In order to reduce the spread of COVID-19, a lockdown was imposed in Tunisia with movement restrictions, social distancing and home confinement, which has affected routine healthcare activities and everyday life. The aim of this study was to examine the impact of the COVID-19 lockdown on glycemic control in patients with type 2 diabetes (T2D). Methods: Seventy-eight patients were evaluated in the period of three months after lockdown ending . Clinical metabolic profile, glycemic and metabolic control ( fasting glucose, Hba1c, lipid parameters) were evaluated in patients with type 2 diabetes Results: A total of seventy-eight participants took part in the study, of which 32 (41%) were men and 46(59%) women. Clinical characteristics were shown a weight gain (+ 3,2 kg), an increase in abdominal circumference by 2,7 cm but not change in hypertension profile. Biological parameters found a worsening in diabetes control: meaning fasting glucose was increased by 1,9 mmol/l and HbA1C increased by 1,1% ( 36 have not attend their glycemic targets , compared to 23 in the period before lockdown). six patients report to be hospitalized during this period for major hyperglycemia. Conclusions: A short-term variation of daily habits induced by the COVID-19 lockdown significantly worsened metabolic control in a relevant number of patients with type 2 diabetes. The recent increase in covid 19 spread suggests serious intervention to anticipate such deleterious effect.

Mitochondria Can Cross Cell Boundaries: An Overview of the Biological Relevance, Pathophysiological Implications and Therapeutic Perspectives of Intercellular Mitochondrial Transfer.

Mitochondria are complex intracellular organelles traditionally identified as the powerhouses of eukaryotic cells due to their central role in bioenergetic metabolism. In recent decades, the growing interest in mitochondria research has revealed that these multifunctional organelles are more than just the cell powerhouses, playing many other key roles as signaling platforms that regulate cell metabolism, proliferation, death and immunological response. As key regulators, mitochondria, when dysfunctional, are involved in the pathogenesis of a wide range of metabolic, neurodegenerative, immune and neoplastic disorders. Far more recently, mitochondria attracted renewed attention from the scientific community for their ability of intercellular translocation that can involve whole mitochondria, mitochondrial genome or other mitochondrial components. The intercellular transport of mitochondria, defined as horizontal mitochondrial transfer, can occur in mammalian cells both in vitro and in vivo, and in physiological and pathological conditions. Mitochondrial transfer can provide an exogenous mitochondrial source, replenishing dysfunctional mitochondria, thereby improving mitochondrial faults or, as in in the case of tumor cells, changing their functional skills and response to chemotherapy. In this review, we will provide an overview of the state of the art of the up-to-date knowledge on intercellular trafficking of mitochondria by discussing its biological relevance, mode and mechanisms underlying the process and its involvement in different pathophysiological contexts, highlighting its therapeutic potential for diseases with mitochondrial dysfunction primarily involved in their pathogenesis.

Perceptions of lifestyles changes in people with type 1 diabetes during the SARS-COV-2 pandemic in Chile

Introduction: It is unknown if lifestyles changes forced by SARSCOV- 2 interfere with the treatment in people with T1D. Objectives: To assess the perceptions of lifestyle changes in patients with T1D during the pandemic in Chile. Methods: A specific survey was created and piloted. It was distributed by a national educational NGO during 2020 July and August. The instrument evaluated changes regarding the pre-pandemic habits in alimentation, sleep, physical activity, and emotionality through a Likert questions Results: 776 people with T1D or their parents answered. The median age was 12 years (range 2-68). 44% referred care in child/youth centers. 51% were from public health and 49% from private. The average of last HbA1c recorded was 6.9%. 40% referred economic burden during the pandemic and 30% have participated in diabetes support networks. 36% of surveyed reported they maintain pre-pandemic routine, while 51% generated a new routine. 81% reported practicing less physical activity during the period and 9% more. 35% of people believe that they eat more and 12% less, being less healthy for 26% and healthier for 13%. 41% report they modified their sleep “many times” or “always” and 30% report problems falling asleep;66% refer the change has impacted their treatment. 51% report emotions that interfered with treatment-related behavior. 49% report anger, 46% frustration, 46% sadness and 43% nervousness. Change of routine also generated positives aspects: 46% referred more time with the family, 22% more supervision and 17% restructuring of schedules;14% reported they do not see any positive aspects. Conclusions: People with T1D in Chile changed their lifestyle during the SARS-CoV-2 pandemic. Alimentation, physical activity, and sleep have been disadvantaged aspects. Negative emotions are experienced by half of the respondents, interfering with diabetes care. Despite this, there are positive aspects that have emerged. It must be evaluated whether these factors will condition a change in the metabolic control of these persons.

GLP1-RA/basal insulin vs basal bolus in CoViD-19 type 2 diabetes in patients

Background: During the CoViD-19 pandemic in type 2 diabetic patients (T2DM pts) present in our Medicine wards we administered a big amount of s.c. insulin through the basal bolus regimen in order to obtain a good metabolic control;often difficult to reach both for the septic state and steroid therapy. Since we administered almost 60 to 80 units/insulin per day (TDD), not always obtaining a good metabolic control, we thought to switch some of our in-patients treated with basal bolus insulin regimen to a bolus plus a fixed ratio combination of GLP1-RA/basal insulin trying to take advantage of both the antiinflammatory and slimming effect of GLP1-RA. Results: Between October and December 2020 we evaluated 54 T2DM in-patients with CoViD-19 pneumonia.They were 41 males and 13 females aged 70±5 yrs, BMI 31±3kg/sm with an average HbA1c 8.3±1.2 and an insulin TDD of 70±11 s.c. compared to 40 matched (for sex, age, BMI and insulin TDD) control pts treated with basal bolus regimen. Conclusions:We detected in the fixed ratio combination of GLP1- RA/basal insulin a faster and stable good metabolic control vs the basal bolus treated pts. We reduced the average amount of insulin TDD of 34% with great satisfaction of pts and nurses.

Loneliness: An Immunometabolic Syndrome.

Loneliness has been defined as an agonizing encounter, experienced when the need for human intimacy is not met adequately, or when a person's social network does not match their preference, either in number or attributes. This definition helps us realize that the cause of loneliness is not merely being alone, but rather not being in the company we desire. With loneliness being introduced as a measurable, distinct psychological experience, it has been found to be associated with poor health behaviors, heightened stress response, and inadequate physiological repairing activity. With these three major pathways of pathogenesis, loneliness can do much harm; as it impacts both immune and metabolic regulation, altering the levels of inflammatory cytokines, growth factors, acute-phase reactants, chemokines, immunoglobulins, antibody response against viruses and vaccines, and immune cell activity; and affecting stress circuitry, glycemic control, lipid metabolism, body composition, metabolic syndrome, cardiovascular function, cognitive function and mental health, respectively. Taken together, there are too many immunologic and metabolic manifestations associated with the construct of loneliness, and with previous literature showcasing loneliness as a distinct psychological experience and a health determinant, we propose that loneliness, in and of itself, is not just a psychosocial phenomenon. It is also an all-encompassing complex of systemic alterations that occur with it, expanding it into a syndrome of events, linked through a shared network of immunometabolic pathology. This review aims to portray a detailed picture of loneliness as an "immunometabolic syndrome", with its multifaceted pathology.