Renal Lipid Metabolism and Lipotoxicity in Diabetes

Thongnak, Laongdao; Pongchaidecha, Anchalee; Lungkaphin, Anusorn

doi:10.1016/j.amjms.2019.11.004

Cited by 95 publications

(79 citation statements)

References 91 publications

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“…37 Additionally, the diabetic kidney is characterized by the accumulation of glucose and lipid intermediates that are an important cause of oxidative and endoplasmic reticulum stress. Advanced glycation end products and free fatty acids can elicit a maladaptive unfolded protein response 38,39 and promote mitochondrial and peroxisomal dysfunction leading to the excessive generation of reactive oxygen species. 40 These cellular stresses would normally be mitigated by the ability of cells to enhance autophagy, a lysosome-dependent degradative process that mutes cytosolic stress and maintains cellular homeostasis.…”

Section: Hif-1α Upregulation and Hif-2α Downregulation In The Diabetimentioning

confidence: 99%

Mechanisms Leading to Differential Hypoxia-Inducible Factor Signaling in the Diabetic Kidney: Modulation by SGLT2 Inhibitors and Hypoxia Mimetics

Packer

2021

American Journal of Kidney Diseases

145

115

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Sodium/glucose cotransporter 2 (SGLT2) inhibitors exert important renoprotective effects in the diabetic kidney, which cannot be readily explained by their actions to lower blood glucose, blood pressure, or glomerular filtration pressures. Their effects to promote erythrocytosis suggest that these drugs act on hypoxia-inducible factors (HIFs; specifically, HIF-1α and HIF-2α), which may underlie their ability to reduce the progression of nephropathy. Type 2 diabetes is characterized by renal hypoxia, oxidative and endoplasmic reticulum stress, and defective nutrient deprivation signaling, which (acting in concert) are poised to cause both activation of HIF-1α and suppression of HIF-2α. This shift in the balance of HIF-1α/HIF-2α activities promotes proinflammatory and profibrotic pathways in glomerular and renal tubular cells. SGLT2 inhibitors alleviate renal hypoxia and cellular stress and enhance nutrient deprivation signaling, which collectively may explain their actions to suppress HIF-1α and activate HIF-2α and thereby augment erythropoiesis, while muting organellar dysfunction, inflammation, and fibrosis. Cobalt chloride, a drug conventionally classified as a hypoxia mimetic, has a profile of molecular and cellular actions in the kidney that is similar to those of SGLT2 inhibitors. Therefore, many renoprotective benefits of SGLT2 inhibitors may be related to their effect to promote oxygen deprivation signaling in the diabetic kidney. Complete author and article information provided before references.

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Section: Hif-1α Upregulation and Hif-2α Downregulation In The Diabetimentioning

confidence: 99%

Mechanisms Leading to Differential Hypoxia-Inducible Factor Signaling in the Diabetic Kidney: Modulation by SGLT2 Inhibitors and Hypoxia Mimetics

Packer

2021

American Journal of Kidney Diseases

145

115

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“…Cytoplasmatic lipid droplets accumulation influences the progression of inflammation and fibrosis in several genetic and metabolic pathologies [79]. These lipid mediators have been associated with the activation of the inflammatory response, ROS production, mitochondrial dysfunction, autophagy deregulation, endoplasmic reticulum stress (ER stress) and apoptosis [69,80,81]. This fact is mainly due to the accumulation of intermediary toxic metabolites, such as diacylglycerol, fatty acyl-CoA, ceramides, and sphingolipids, which are involved in protein kinase C (PKC) activation, triglyceride synthesis, and mitochondrial dysfunction [82,83].…”

Section: The Fatty Kidney In Dnmentioning

confidence: 99%

Lipotoxicity and Diabetic Nephropathy: Novel Mechanistic Insights and Therapeutic Opportunities

Opazo-Ríos

Mas

Marín-Royo

et al. 2020

IJMS

211

147

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Lipotoxicity is characterized by the ectopic accumulation of lipids in organs different from adipose tissue. Lipotoxicity is mainly associated with dysfunctional signaling and insulin resistance response in non-adipose tissue such as myocardium, pancreas, skeletal muscle, liver, and kidney. Serum lipid abnormalities and renal ectopic lipid accumulation have been associated with the development of kidney diseases, in particular diabetic nephropathy. Chronic hyperinsulinemia, often seen in type 2 diabetes, plays a crucial role in blood and liver lipid metabolism abnormalities, thus resulting in increased non-esterified fatty acids (NEFA). Excessive lipid accumulation alters cellular homeostasis and activates lipogenic and glycogenic cell-signaling pathways. Recent evidences indicate that both quantity and quality of lipids are involved in renal damage associated to lipotoxicity by activating inflammation, oxidative stress, mitochondrial dysfunction, and cell-death. The pathological effects of lipotoxicity have been observed in renal cells, thus promoting podocyte injury, tubular damage, mesangial proliferation, endothelial activation, and formation of macrophage-derived foam cells. Therefore, this review examines the recent preclinical and clinical research about the potentially harmful effects of lipids in the kidney, metabolic markers associated with these mechanisms, major signaling pathways affected, the causes of excessive lipid accumulation, and the types of lipids involved, as well as offers a comprehensive update of therapeutic strategies targeting lipotoxicity.

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“…16 In addition, lipid metabolism disorder also plays an important role in the occurrence and development of DKD. [17][18][19][20][21] Lipid metabolism disorder is common in diabetic patients, and insulin resistance can aggravate lipid metabolism disorder, while lipid metabolism abnormality can also enhance insulin resistance in various ways. 22 In this vicious cycle, excessive lipid heterotopia is deposited in liver, kidney, pancreas and other non-adipose tissues and organs, leading to lipid toxicity.…”

Section: Discussionmentioning

confidence: 99%

The Predictive Value of Visceral Adiposity Index and Lipid Accumulation Index for Microalbuminuria in Newly Diagnosed Type 2 Diabetes Patients

Qi¹,

Kang²,

Li³

et al. 2021

DMSO

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This study aims to investigate the predictive value of visceral adiposity index (VAI) and lipid accumulation index (LAP) for microalbuminuria (MAU) in patients with newly diagnosed Type 2 diabetes (T2DM). Patients and Methods: This study included 335 patients with newly diagnosed T2DM patients from Hebei General Hospital. All the patients aged from 18 to 65 years old include 226 males and 109 females. Patients information and blood indicators were Collected and calculated the LAP and VAI scores. All the patients were divided into males (group A) and females (group B), and these groups were then further subdivided into A1 group which arises microalbuminuria, and A2 group which does not. With the same method, women were divided into B1 group and B2 group. Results: Baseline data analysis showed that LAP and VAI levels in A1 and B1 groups were significantly higher than those in A2 and B2 groups (P<0.05). Logistic regression analysis showed that fasting blood glucose, waist circumference, LAP, and VAI were independent risk factors for the occurrence of microalbuminuria in both males and females. ROC showed that the area under curve (AUC) of waist circumference, fasting blood glucose, LAP and VAI in male patients were 0.626, 0.676, 0.760 and 0.742, respectively, and in female patients were 0.703, 0.685, 0.787 and 0.764, respectively. In addition, the area under the curve of both LAP and VAI was higher in females than in males. Conclusion: This study confirmed that both LAP and VAI had predictive values for the occurrence of urinary microalbumin in newly diagnosed T2DM patients. The predictive value was higher in the female group and the suggestion was more applicable to female patients.

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Renal Lipid Metabolism and Lipotoxicity in Diabetes

Cited by 95 publications

References 91 publications

Mechanisms Leading to Differential Hypoxia-Inducible Factor Signaling in the Diabetic Kidney: Modulation by SGLT2 Inhibitors and Hypoxia Mimetics

Mechanisms Leading to Differential Hypoxia-Inducible Factor Signaling in the Diabetic Kidney: Modulation by SGLT2 Inhibitors and Hypoxia Mimetics

Lipotoxicity and Diabetic Nephropathy: Novel Mechanistic Insights and Therapeutic Opportunities

The Predictive Value of Visceral Adiposity Index and Lipid Accumulation Index for Microalbuminuria in Newly Diagnosed Type 2 Diabetes Patients

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