scholarly journals Hepatic serine and lipid metabolism drive diabetic peripheral neuropathy

Author(s):  
Christian Metallo ◽  
Michal Handzlik ◽  
Jivani Gengatharan ◽  
Katie Frizzi ◽  
Grace McGregor ◽  
...  

Abstract Type 2 diabetes represents a disease spectrum in which chronic metabolic dysfunction damages multiple organ systems including liver, kidneys, and peripheral nerves1,2. While onset and progression of these co-morbidities are linked with insulin resistance, hyperglycaemia and dyslipidemia3-7, aberrant amino acid metabolism also contributes to pathogenesis of diabetes and potentially its complications8-10. Serine and glycine are closely related non-essential amino acids11,12 that are consistently reduced in patients with metabolic syndrome10,13-16, but the mechanistic drivers of serine deficiency and the downstream metabolic and phenotypic consequences remain unclear. Low systemic serine, a serine-opathy, is also emerging as a hallmark of macular and peripheral nerve disorders. Specifically, serine deficiency correlates positively with impaired visual acuity and peripheral neuropathy (PN)17-19. Here we demonstrate that aberrant serine homeostasis in the liver drives serine and glycine deficiencies in genetically obese and hyperglycaemic mice. This serine-opathy can be diagnosed with a serine tolerance test that quantifies systemic serine disposal. Mimicking these metabolic alterations via dietary serine/glycine restriction together with high fat intake dramatically accelerates thermal hypoalgesia in mice and reduces epidermal sensory nerve density, which are accompanied by extensive sciatic nerve lipid remodeling. These phenotypes were subsequently normalized by myriocin, linking serine-associated PN with sphingolipid biosynthesis. These findings identify systemic serine deficiency and dyslipidemia as novel risk factors for PN that may be exploited therapeutically.

Author(s):  
Christian Muschitz ◽  
Anita Trummert ◽  
Theresa Berent ◽  
Norbert Laimer ◽  
Lukas Knoblich ◽  
...  

SummarySevere acute respiratory syndrome coronavirus type 2 (SARS-CoV-2), the etiological agent of coronavirus disease 2019 (COVID-19), produces protean manifestations and causes indiscriminate havoc in multiple organ systems. This rapid and vast production of proinflammatory cytokines contributes to a condition termed cytokine storm. A 35-year-old, otherwise healthy, employed, male patient was tested positive for COVID-19. He was admitted to the hospital on disease day 10 due to retarded verbal reactions and progressive delirium. On account of these conditions and the need for noninvasive/invasive ventilation, a combination treatment with baricitinib and remdesivir in conjunction with standard of care was initiated. The cytokine storm was rapidly blocked, leading to a vast pulmonary recovery with retarded recovery of the central nervous system. We conclude that the rapid blockade of the COVID-19-induced cytokine storm should be considered of avail as a principle of careful decision-making for effective recovery.


Author(s):  
Melissa G. Farb ◽  
Noyan Gokce

AbstractObesity has emerged as one of the most critical health care problems globally that is associated with the development of insulin resistance, type 2 diabetes mellitus, metabolic dysfunction and cardiovascular disease. Central adiposity with intra-abdominal deposition of visceral fat, in particular, has been closely linked to cardiometabolic consequences of obesity. Increasing epidemiological, clinical and experimental data suggest that both adipose tissue quantity and perturbations in its quality termed “adiposopathy” contribute to mechanisms of cardiometabolic disease. The current review discusses regional differences in adipose tissue characteristics and highlights profound abnormalities in vascular endothelial function and angiogenesis that are manifest within the visceral adipose tissue milieu of obese individuals. Clinical data demonstrate up-regulation of pro-inflammatory and pro-atherosclerotic mediators in dysfunctional adipose tissue that may support pathological vascular changes not only locally in fat but also in multiple organ systems, including coronary and peripheral circulations, potentially contributing to mechanisms of obesity-related cardiovascular disease.


2019 ◽  
Vol 6 (1) ◽  
pp. 59-63 ◽  
Author(s):  
Md Fakruddin

Diabetes Mellitus (DM), one of the most non-communicable diseases, is increasing day by day in an alarming way. More than 140 million people are suffering from diabetes throughout the world. It is not a single disease entity, but rather a group of metabolic disorders sharing the common underlying feature of hyperglycemia. Hyperglycemia in diabetes results from defects in insulin secretion, insulin action, or, most commonly, both. The chronic hyperglycemia and attendant metabolic deregulation may be associated with secondary damage in multiple organ systems, especially the kidneys, eyes, nerves, and blood vessels. The pathophysiology of diabetes is not fully elucidated. Insulin secretory dysfunction and insulin resistance or both is main candidate for this metabolic disorder, moreover various genetic and environmental factors may also involve in this process. Racial variations play also an important role as evidenced by various studies. However, the interrelationships between the molecular and metabolic mechanisms in these parameters contributing this life threatening disease still remain a mystery to the scientists. Journal of Current and Advance Medical Research 2019;6(1):59-63


Cells ◽  
2021 ◽  
Vol 10 (8) ◽  
pp. 2131
Author(s):  
Daire J. Hurley ◽  
Mustapha Irnaten ◽  
Colm O’Brien

Glaucoma is the leading cause of irreversible blindness globally. With an aging population, disease incidence will rise with an enormous societal and economic burden. The treatment strategy revolves around targeting intraocular pressure, the principle modifiable risk factor, to slow progression of disease. However, there is a clear unmet clinical need to find a novel therapeutic approach that targets and halts the retinal ganglion cell (RGC) degeneration that occurs with fibrosis. RGCs are highly sensitive to metabolic fluctuations as a result of multiple stressors and thus their viability depends on healthy mitochondrial functioning. Metformin, known for its use in type 2 diabetes, has come to the forefront of medical research in multiple organ systems. Its use was recently associated with a 25% reduced risk of glaucoma in a large population study. Here, we discuss its application to glaucoma therapy, highlighting its effect on fibrotic signalling pathways, mitochondrial bioenergetics and NAD oxidation.


2021 ◽  
Vol 17 ◽  
Author(s):  
Siska Darmayanti ◽  
Ronny Lesmana ◽  
Anna Meiliana ◽  
Rizky Abdulah

Background: There is a continuous rise in the prevalence of Diabetes Mellitus Type 2 (T2DM) worldwide and most patients are unaware of the presence of this chronic disease at the early stages. T2DM is associated with complications related to long-term damage and failure of multiple organ systems caused by vascular changes associated with glycated end products, oxidative stress, mild inflammation, and neovascularization. Among the most frequent complications of T2DM observed in about 20-40% of T2DM patients is Diabetes Nephropathy (DN). Method: Literature search was done in view of highlighting the novel application of genomics, proteomics and metabolomics, as the new prospective strategy for predicting DN in T2DM patients. Results: The complexity of DN requires a comprehensive and unbiased approach to investigate the main causes of disease and identify the most important mechanisms underlying its development. With the help of evolving throughput technology, rapidly evolving information can now be applied to clinical practice. Discussion: DN is also the leading cause of end-stage renal disease, and comorbidity independent of T2DM. In terms of the comorbidity level, DN has many phenotypes; therefore, timely diagnosis is required to prevent these complications. Currently, urine albumin-to-creatinine ratio and estimated glomerular filtration rate (eGFR) are gold standards for assessing glomerular damage and changes in renal function. However, GFR estimation based on creatinine is limited to hyperfiltration status; therefore, this makes albuminuria and eGFR indicators less reliable for early-stage diagnosis of DN. Conclusion: The combination of genomics, proteomics, and metabolomics assays as suitable biological systems that can provide new and deeper insights into the pathogenesis of diabetes, as well as to discover prospects for developing suitable and targeted interventions.


2012 ◽  
Vol 1 ◽  
pp. 5 ◽  
Author(s):  
Xiumei Zhang ◽  
Kunzhu Huang ◽  
Yanshan Gu

<p><strong>Objective:</strong> To discuss the curative effects of foot care on type 2 diabetes peripheral neuropathy (DPN).<strong> Methods:</strong> This study selected 80 cases of type 2 diabetes peripheral neuropathy, and divided them into two groups randomly: the experimental group and the control group, both of the two groups were treated with standard hypoglycemic therapy plus promoting blood circulation and removing blood stasis drugs and nutritional nerve medicine therapy and regular nursing, the observation group was conducted foot care, education and guidance on the basis of these measures in 3 months. Assessed the improvement of the double lower limbs symptoms and the speed of lower limbs sensory nerve conduction velocity. <strong>Results:</strong> The curative effects of the observation group were more significant than the control group (<em>p </em>&lt; 0.01), the overall efficiency was 86%, and the improvement of the lower limbs sensory nerve conduction velocity was superior to the control group (<em>p </em>&lt; 0.01, <em>p </em>&lt; 0.05). <strong>Conclusion:</strong> The foot care can improve the microcirculation, promote the repair of the damaged nerve, improve the DPN symptoms, and prevent the occurrence of the diabetic foot.<strong></strong></p>


2005 ◽  
Vol 33 (4) ◽  
pp. 442-453 ◽  
Author(s):  
R Matsutomo ◽  
K Takebayashi ◽  
Y Aso

Measurement of current perception threshold (CPT) using the Neurometer® at 2000, 250 and 5 Hz assesses function in three different nerve fibre types. This method was used to investigate peripheral neuropathy in 116 patients with type 2 diabetes mellitus and 38 healthy controls. The CPT at 2000 Hz was significantly higher in diabetic patients than in controls, and showed a significant negative correlation with motor and sensory nerve conduction velocities. At 250 Hz, CPT showed a significant positive correlation with the vibration perception threshold. At 5 Hz, the change in systolic blood pressure in the Schellong test in patients with hypoaesthesia tended to be less than in those with normal sensation or hyperaesthesia. Significantly higher CPT values were obtained in patients with proliferative diabetic retinopathy and macroalbuminuria. These data suggest that CPT is useful in detecting abnormalities of myelinated as opposed to unmyelinated nerve fibres in patients with type 2 diabetes.


Author(s):  
T. L. Benning ◽  
P. Ingram ◽  
J. D. Shelburne

Two benzofuran derivatives, chlorpromazine and amiodarone, are known to produce inclusion bodies in human tissues. Prolonged high dose chlorpromazine therapy causes hyperpigmentation of the skin with electron-dense inclusion bodies present in dermal histiocytes and endothelial cells ultrastructurally. The nature of the deposits is not known although a drug-melanin complex has been hypothesized. Amiodarone may also cause cutaneous hyperpigmentation and lamellar lysosomal inclusion bodies have been demonstrated within the cells of multiple organ systems. These lamellar bodies are believed to be the product of an amiodarone-induced phospholipid storage disorder. We performed transmission electron microscopy (TEM) and energy dispersive x-ray microanalysis (EDXA) on tissue samples from patients treated with these drugs, attempting to detect the sulfur atom of chlorpromazine and the iodine atom of amiodarone within their respective inclusion bodies.A skin biopsy from a patient with hyperpigmentation due to prolonged chlorpromazine therapy was fixed in 4% glutaraldehyde and processed without osmium tetroxide or en bloc uranyl acetate for Epon embedding.


2010 ◽  
Vol 15 (3) ◽  
pp. 1-7
Author(s):  
Richard T. Katz

Abstract This article addresses some criticisms of the AMA Guides to the Evaluation of Permanent Impairment (AMA Guides) by comparing previously published outcome data from a group of complete spinal cord injury (SCI) persons with impairment ratings for a corresponding level of injury calculated using the AMA Guides, Sixth Edition. Results of the comparison show that impairment ratings using the sixth edition scale poorly with the level of impairments of activities of daily living (ADL) in SCI patients as assessed by the Functional Independence Measure (FIM) motor scale and the extended FIM motor scale. Because of the combinations of multiple impairments, the AMA Guides potentially overrates the impairment of paraplegics compared with that of quadriplegics. The use and applicability of the Combined Values formula should be further investigated, and complete loss of function of two upper extremities seems consistent with levels of quadriplegia using the SCI model. Some aspects of the AMA Guides contain inconsistencies. The concept of diminishing impairment values is not easily translated between specific losses of function per organ system and “overall” loss of ADLs involving multiple organ systems, and the notion of “catastrophic thresholds” involving multiple organ systems may support the understanding that variations in rating may exist in higher rating cases such as those that involve an SCI.


2020 ◽  
Vol 7 (3) ◽  
pp. 5-19
Author(s):  
Nikhil Nair ◽  
Ronith Chakraborty ◽  
Zubin Mahajan ◽  
Aditya Sharma ◽  
Sidarth Sethi ◽  
...  

Tuberous sclerosis complex (TSC) is a genetic condition caused by a mutation in either the TSC1 or TSC2 gene. Disruption of either of these genes leads to impaired production of hamartin or tuberin proteins, leading to the manifestation of skin lesions, tumors and seizures. TSC can manifests in multiple organ systems with the cutaneous and renal systems being the most commonly affected. These manifestations can secondarily lead to the development of hypertension, chronic kidney disease, and neurocognitive declines. The renal pathologies most commonly seen in TSC are angiomyolipoma, renal cysts and less commonly, oncocytomas. In this review, we highlight the current understanding on the renal manifestations of TSC along with current diagnosis and treatment guidelines.


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