Insulin Resistance the kidney and its mitochondria
We alert people in the ED frequently that diabetes damages blood vessels ultimately affecting the brain, the heart and the kidney. This research paper in Nature discusses some specifics and postulates an affect on the energy demands on the powerhouse of the cell; the mitochondria.
The Intricacies of Diabetic Nephropathy (DN)
Diabetic nephropathy (DN), a formidable adversary, stands as a predominant cause of morbidity and mortality among diabetes patients. It's closely linked with chronic and terminal stages of renal disease. Elevated plasma glucose levels can initiate a cascade of cellular malfunctions, disrupting energy dynamics and leading to mitochondrial anomalies.
The Kidney's Energy Demands
The kidney, a powerhouse organ, consumes vast amounts of ATP, primarily due to its intricate re-absorption mechanism. Within this complex, the renal cortex’s proximal tubules heavily rely on oxidative phosphorylation (OXPHOS) for ATP synthesis. In contrast, glomerular cells have a subdued oxidative capacity. This distinction means that proximal renal tubular cells, with their high mitochondrial content, are especially vulnerable to disruptions when faced with hyperglycemia.
Unraveling Mitochondrial Mysteries
The enigma of mitochondrial operation in kidney physiology remains. Some theories suggest that uncovering these mitochondrial issues could lead to tailor-made therapies or specific protein targets to rejuvenate renal function. Moreover, a concerning revelation has emerged: many patients show no signs of albuminuria even years after a diabetes diagnosis, indicating that DN might advance silently and challenging the traditional trust in albuminuria as a reliable biomarker.
The Role of Insulin Resistance (IR)
Prolonged hyperglycemia is a major player, inciting inflammation and hastening insulin resistance (IR)—a clear indicator of renal damage. What’s more, IR isn't a diabetes-exclusive issue. It's found in non-diabetic individuals during early stages of chronic kidney disease and becomes even more prevalent as the disease progresses. Essentially, IR represents a state where cells resist insulin, leading to elevated blood glucose levels.
Decoding the Impact of Fatty Acids
Elevated free fatty acids (FFA) and triglycerides characterize dyslipidemia in diabetic individuals. At the core of many kidney issues, especially IR, is lipotoxicity due to excessive FFA levels. FFAs interfere with insulin signaling, making glucose absorption and glycogen synthesis harder. Palmitate, an abundant saturated fatty acid in human serum, is implicated in lipid accumulation, IR, oxidative stress, and cellular death. However, its exact role, especially when coupled with IR, remains unclear.
Researching Mitochondrial Bioenergetics
Investigations into mitochondrial bioenergetics in relation to DN progression are limited. Many studies merely contrast physiological and diabetic states. In this context, our research seeks to understand the effects of various hyperglycemia levels and IR on renal epithelial cells, focusing on their metabolic and mitochondrial dynamics.
Patrícia C. Braga, Raquel L. Bernardino, Bárbara Guerra-Carvalho, David F. Carrageta, Pedro F. Oliveira, Anabela S. Rodrigues, Marco G. Alves, The progression from mild to severe hyperglycemia coupled with insulin resistance causes mitochondrial dysfunction and alters the metabolic secretome of epithelial kidney cells, Experimental Cell Research, 2023, ISSN 0014-4827.
Here is yet another example showing how tipping the sugar scales in the wrong direction leads to cellular damage and this time specific to the kidney. Given the importance of this organ to filtering out toxins, managing blood pressure, and managing fluid balance. Although people feel like they "have to have their cookies, sweets, and carbohydrates" this is contributing to overall damage as we age. . .and it doesn't have to be that way. HRT improves insulin resistance leading to improvement and prevention of this level of damage. Jason & Rita...aka Dr. De Leon and Dr. Gillespie.
