DiseasesAcidosis and type 2 diabetes — a hidden mechanism of the disease?
- M. S. Sater i H. A. Giha — Toll of Chronic Metabolic Acidosis at Molecular, Cellular, and Systemic Levels: A Conceptual Framework to Revisit Type 2 Diabetes (T2D) Pathophysiology
- M. Williamson i N. Moustaid-Moussa i L. Gollahon — Frontiers | The Molecular Effects of Dietary Acid Load on Metabolic Disease (The Cellular PasaDoble: The Fast-Paced Dance of pH Regulation)
- Bracia Rodzeń — Keto
M. S. Sater and H. A. Giha suggest that chronic metabolic acidosis may be an underappreciated factor in the development of type 2 diabetes.
- Insulin resistance may contribute to cell acidification, which may further weaken insulin’s effects, creating a vicious cycle.
- It has not yet been tested in a sufficiently large study whether correcting pH improves treatment outcomes, and alkalizing the whole body carries risks.
What the authors write
M. S. Sater i H. A. Giha
Chronic metabolic acidosis may be an underappreciated factor in the development of type 2 diabetes.
„Chronic metabolic acidosis in diabetes represents an underappreciated but mechanistically coherent contributor to T2D pathophysiology. The three-tier framework presented here illustrates how mild, sustained reductions in intracellular pH disrupt glycolytic enzymes, ion transporters, and buffering proteins at the molecular level, and how this disruption spreads through insulin signaling, inflammatory and apoptotic cascades, and combines with established contributing mechanisms to cause metabolic dysfunction at the organ level.”Chronic metabolic acidosis of diabetes represents an underappreciated but mechanistically coherent contributor to T2D pathophysiology. The three-tier framework presented here illustrates how mild, sustained reductions in intracellular pH dysregulate glycolytic enzymes, ion transporters, and buffering proteins at the molecular level propagate disruption through insulin signaling, inflammatory and apoptotic cascades, and converge with established co-operating mechanisms to produce organ-level metabolic dysfunction.
M. Williamson i N. Moustaid-Moussa i L. Gollahon
Insulin resistance may indirectly acidify cells by hindering lactate metabolism and proton removal.
„Reduced insulin sensitivity, or insulin resistance, can cause indirect acidosis by preventing lactate metabolism and the associated extrusion of protons. Chronic intracellular acidosis (pH 7.1) inhibits IRS-1 and Pi3K binding in muscle cells, impairing insulin signaling and insulin’s ability to inhibit proteolysis ().”Reduced insulin sensitivity or insulin resistance can cause indirect acidosis by preventing lactate metabolism and associated proton extrusion. Chronic intracellular acidosis (pH 7.1) inhibits IRS-1 and Pi3K binding in muscle cells, impairing insulin signaling and insulin’s ability to inhibit proteolysis ().
M. Williamson i N. Moustaid-Moussa i L. Gollahon
Chronic cell acidification may weaken insulin signaling in muscles.
„Chronic intracellular acidosis (pH 7.1) inhibits IRS-1 and Pi3K binding in muscle cells, impairing insulin signaling and insulin’s ability to inhibit proteolysis (). Acidosis stimulates OGR1-activated PLC-calcium signaling, which enhances glucose-stimulated insulin secretion and contributes to resistance (; ).”Chronic intracellular acidosis (pH 7.1) inhibits IRS-1 and Pi3K binding in muscle cells, impairing insulin signaling and insulin’s ability to inhibit proteolysis (). Acidosis stimulates OGR1 activated PLC-calcium signaling, which enhances glucose stimulated insulin secretion and contribute to resistance (; ).
M. S. Sater i H. A. Giha
Insulin resistance may worsen acidosis, and acidosis may in turn deepen insulin resistance, creating a self-perpetuating vicious cycle.
„Crucially, this relationship is bidirectional: insulin resistance deepens acidosis, which in turn amplifies insulin resistance, creating a self-perpetuating cycle with clear parallels to the well-characterized inflammation-IR axis.
The evidence reviewed ranges from established human data to preclinical inference, and this heterogeneity calls for caution in interpretation.”Critically, this relationship is bidirectional: insulin resistance deepens acidosis, which in turn amplifies insulin resistance, creating a self-perpetuating cycle with clear parallels to the well-characterized inflammation-IR axis.
The evidence reviewed ranges from established human data to preclinical inference, and this heterogeneity demands interpretive restraint.
M. S. Sater i H. A. Giha
Acidification may activate inflammatory pathways that weaken insulin’s effects, but direct evidence of this in people with diabetes is limited.
„At the same time, acidosis promotes NF-κB activation [3], driving the transcription of pro-inflammatory cytokines, including TNF-α and IL-6 [91] (Supported: an association between acidosis and the NF-κB pathway has been demonstrated in inflammatory cell models; direct demonstration in human diabetic tissue is limited).”Concurrently, acidosis promotes NF-κB activation [3], driving transcription of pro-inflammatory cytokines including TNF-α and IL-6 [91] (Supported: association between acidosis and NF-κB pathway demonstrated in inflammatory cell models; direct demonstration in human diabetic tissue limited).
M. S. Sater i H. A. Giha
It has not yet been tested in a sufficiently large study whether deliberately correcting pH improves type 2 diabetes outcomes; alkalizing the whole body carries risks.
„No pH-directed intervention has been tested in an adequately powered trial specifically targeting T2D outcomes, and systemic alkalinization carries clinically meaningful risks that must inform the design of any future intervention. Nevertheless, pH homeostasis in T2D is a testable hypothesis with a strong molecular rationale.”No pH-directed intervention has been tested in an adequately powered trial specifically targeting T2D outcomes, and systemic alkalinization carries clinically meaningful risks that must inform any future interventional design. Nevertheless, pH homeostasis in T2D constitutes a testable hypothesis with strong molecular rationale.
Bracia Rodzeń
Diabetic ketoacidosis occurs mainly in people with type 1 diabetes who do not take insulin; it is associated with dangerously high blood sugar and ketone levels.
„Diabetic ketoacidosis occurs mainly in people with type 1 diabetes if they do not take insulin. In diabetic ketoacidosis, blood sugar and ketone levels rise to dangerous levels, disrupting the delicate acid-base balance of the blood.”Kwasica ketonowa występuje głównie u osób z cukrzycą typu 1, jeśli nie przyjmują one insuliny. W cukrzycowej kwasicy ketonowej poziom cukru i ciał ketonowych we krwi wzrasta do niebezpiecznego poziomu, co zaburza delikatną równowagę kwasowo-zasadową krwi.
Bracia Rodzeń
According to the author, diabetic ketoacidosis is practically impossible in most people who can produce insulin.
„However, people with diabetic ketoacidosis often have BHB levels of 10 mmol/l or higher, which is directly linked to their inability to produce insulin.
However, diabetic ketoacidosis is practically impossible in most people who can produce insulin.”Jednak osoby z cukrzycową kwasicą ketonową często mają poziom BHB wynoszący 10 mmol/l lub wyższy, co jest bezpośrednio związane z ich niezdolnością do wytwarzania insuliny.
Jednak, w przypadku większości osób zdolnych do wytwarzania insuliny, kwasica ketonowa jest praktycznie niemożliwa.
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