Diuretics: a review of the pharmacology and effects on glucose homeostasis

Abstract

Thiazides, thiazide-like and loop diuretics are commonly prescribed to manage hypertension and heart failure. The main mechanism of action of these diuretics involve inhibition of Na⁺ reabsorption in the kidneys, leading to increased urine production. While effective, diuretics, particularly hydrochlorothiazide, have been linked to altered glucose metabolism and other metabolic issues. These disruptions in fuel homeostasis are not clearly related to their primary action of fluid management, raising concerns for patients with metabolic syndrome, in which high blood pressure coexists with obesity, insulin resistance, glucose intolerance and dyslipidemia. In this review, we conducted an extensive examination of existing literature on these classes of diuretics, covering publications from the late 1950s to the present. Our objective was to investigate the origins, development and current understanding of the widely recognized association between the use of diuretics in general and their potential negative impact on glucose homeostasis. We focused on the clinical and experimental evidence of the most commonly prescribed diuretics: hydrochlorothiazide, chlorthalidone, bumetanide and furosemide. On one hand, the clinical evidence supports the hypothesis that the metabolic effects on glucose homeostasis are primarily linked to hydrochlorothiazide, with little, if any impact observed in other diuretics. In addition, these metabolic effects do not appear to be related to their diuretic action or intended pharmacological targets, raising concerns about the long-term metabolic impact of specific diuretics, particularly in vulnerable populations, including those with metabolic syndrome. On the other hand, the experimental evidence using animal models suggest variable effects of diuretics in insulin secretion and general glucose metabolism. Although the mechanisms involved are not clearly understood, further research is needed to uncover the molecular mechanisms by which certain diuretics disrupt fuel metabolism and contribute to metabolic disturbances.

Keywords: diabetes; hyperglycemia; hypertension; insulin; loop diuretics; metabolic syndrome; overweight; thiazides.

FIGURE 1

Overview of blood glucose regulation. The liver, muscles and kidneys are major modulators of blood glucose levels by releasing glucose through glycogenolysis (liver, muscle) and gluconeogenesis (liver and kidneys), in turn orchestrated by insulin (purple arrows) and glucagon (green arrows) secreted by β- and α-cells of the pancreatic islet, respectively. Glycogenolysis breaks down stored glycogen into glucose-6-phosphate, then free glucose after dephosphorylation, while gluconeogenesis forms glucose-6-phosphate from various non-hydrocarbon precursors (e.g., pyruvate, lactate, glycerol, glutamine). Only the liver, kidneys and small intestines (not represented) can release glucose from glucose-6-phosphate due to the presence of glucose-6-phosphatase activity. Hepatic glycogen breakdown releases glucose, while muscle glycogen breakdown releases lactate, a substrate that can be converted back into glucose by the liver and kidneys after conversion to pyruvate. The kidneys use glucose mainly in the renal medulla and release it from the renal cortex, due to enzyme differences alone the nephron. Renal medulla cells, like neurons, can accumulate glycogen but cannot release glucose. Renal cortex cells can produce and release glucose but cannot synthesize glycogen. In adipocytes, insulin promotes the uptake of glucose and its transformation into fat.

FIGURE 2

Oversimplified model of insulin secretion. Described is a β-cell containing glucose transporters (Glut), K_ATP-channels, voltage-gated Ca²⁺ channels, bumetanide-sensitive Cl⁻ loaders (e.g., NKCC2, NKCC1), furosemide-sensitive Cl⁻ extruders (e.g., KCC1, KCC2, KCC3, KCC4) and Cl⁻ channels [e.g., volume-regulated anion channels, (VRAC), Ca²⁺ activated Cl⁻ channels (ANO1) and others]. Note that Cl⁻ loaders and extruders help maintain the intracellular Cl⁻ concentration above thermodynamic equilibrium, making possible the electrogenic exiting of Cl⁻ ions, when Cl⁻ channels are opened, contributing to plasma membrane depolarization. When glucose is transported into the β-cell, it undergoes glycolysis, generating ATP and metabolites that affect cellular osmolarity and cell volume. ATP closes K_ATP-channels, reducing K⁺ permeability and causing plasma membrane depolarization. Metabolites and Ca²⁺ open Cl⁻ channels triggering inward Cl⁻ currents (Cl⁻ exits the cell). Many Cl⁻ channels likely contribute to these currents which together with reduced K⁺ permeability are responsible for the activation of voltage-gated Ca²⁺ channels, thus leading to Ca²⁺ influx, action potentials, electrical activity and insulin release. Note: hydrochlorothiazide can inhibit mitochondrial carbonic anhydrase Vb (CAV), which limits the supply of HCO₃ ⁻ to pyruvate carboxylase (and other carboxylases) reducing the biosynthesis of oxaloacetate, an intermediary of the tricarboxylic acid (TCA) cycle potentially reducing ATP and contributing to reduced K_ATP-channel closure. The consensus model of insulin secretion is greyed.

FIGURE 3

Renal de novo gluconeogenesis and glucose reabsorption. (A) Renal de novo gluconeogenesis is the process by which the kidneys produce glucose from non-carbohydrate sources (e.g., lactate, glycerol, amino acids). This process mainly occurs in the renal cortex and is particularly important during periods of fasting or intense exercise. Lactate or glutamine (from muscle) generate glucose in the kidneys after being transported into renal tubular cells, where they undergo enzymatic reactions to form pyruvate, which then is converted into oxaloacetate via pyruvate carboxylase (PC, which uses HCO₃ ⁻ provided by carbonic anhydrases, some of them potentially inhibited by hydrochlorothiazide). Oxaloacetate, through phosphoenolpyruvate carboxykinase (PEPCK) forms phosphonolpyruvate (PEP). Glycerol (from adipocytes), can enter the gluconeogenic process as a precursor of glyceraldehyde-3-phosphate (G3P) by the enzymes glyceraldehyde 3-phosphate dehydrogenase (GAPDH) and triose phosphate isomerase (TPI). G3P combined with dihydroxyacetone-phosphate, via aldolase B, forms fructose-1,6-bisphosphate (F1,6BP). Note: GAPDH was reported inhibited by furosemide and ethacrynic acid, and aldolase B can directly regulate NKCC2 functional expression. F1,6BP is then dephosphorylated to fructose-6-phosphate via fructose-1,6-bisphosphatase (F1,6BPase) and isomerized to form glucose-6-phosphate. (B) Renal glucose reabsorption primarily occurs in the proximal tubule of the nephron, ensuring that glucose is conserved and returned to the bloodstream rather than excreted in urine. This process involves two main types of glucose transporters: SGLTs and GLUTs. In particular, SGLT2, located in the apical side of epithelium of the proximal convoluted tubule uses the Na⁺ gradient to reabsorb ∼90% of glucose from the filtrate back into the cells lining the tubule. The remaining glucose filtered is absorbed by SGLT1 further down the proximal tubule. Once in the tubular cell, GLUT2, located in the basolateral side of the tubular epithelium, transports glucose into the bloodstream.