Renal glycogen handling in diabetes: A narrative review of diabetic kidney disease pathogenesis

ABSTRACT

Kidney disease is a major microvascular complication of diabetes, affecting approximately 40% of individuals with diabetes, and is a leading cause of end‐stage renal disease. Besides the functional consequences of hyperglycemia; hemodynamic alterations are well understood. Activation of the sorbitol and hexosamine pathways, formation of advanced glycated products, and prevailing oxidative stress in the background of diabetic hyperglycemia are determinants of diabetic kidney disease (DKD) and its progression. The contribution of ectopic glycogen deposition remains unexplored. Glycogen metabolism in the kidneys is well regulated under physiological conditions, yet chronic hyperglycemia disrupts this balance across podocytes, tubular cells, and the glomerulus. Abnormal glycogen buildup has been observed in experimental diabetes models and human biopsy samples. GSK3β inactivation and mTORC1 upregulation emerge as central regulators. Metformin and SGLT2 inhibitors alter renal glycogen flow via AMPK‐dependent pathways, a potential avenue for therapeutic exploration. The significance of observational studies needs to be further explored for the potential involvement of glycogen buildup in the pathogenesis of DKD. This narrative review aims to provide a comprehensive understanding of glycogen metabolism, examine the dysregulation of key enzymes and signaling pathways, collate available evidence from animal and clinical studies and propose hypothesis that glycogen accumulation may have an additive role in the progression of DKD.

Abbreviations

AMPK‐5’

AMP‐activated protein kinase

BAX

Bcl‐2‐Associated X protein

BCL2

B‐Cell Lymphoma 2

BECN1

Beclin 1

DKD

Diabetic Kidney Disease

ECM

Extracellular Matrix

ESRD

End‐Stage Renal Disease

GAA

acid α‐glucosidase

GABARAPL1

GABA type A Receptor‐Associated Protein Like 1

GBM

Glomerular Basement Membrane

GLUT2

Glucose transporter 2

GP

Glycogen phosphorylase

GSK 3β

Glycogen synthase kinase 3β

GYG1

Glycogenin1

GYG2

Glycogenin2

GYS

Glycogen synthase

GYS1

Glycogen Synthase 1

IL‐1β

Interleukin 1β

LC3

Light Chain 3

mTOR

mammalian Target of Rapamycin

NF‐kB

Nuclear Factor‐Kappa‐light‐chain‐enhancer of activated B cells

NLRP3

Nod‐Like Receptor Protein 3

Nrf2

Nuclear factor erythroid 2‐related factor 2

OXPHOS

Oxidative Phosphorylation

PFKFB3

6‐phosphofructo‐2‐kinase/fructose‐2,6‐bisphosphatase 3

PKM2

Pyruvate Kinase M2

PRKAA1/2

protein kinase AMP‐activated catalytic subunit alpha 1/2

PYGL

Glycogen phosphorylase Liver isoform

SGLT2

Sodium–Glucose Cotransporter‐2

SGLT2i

Sodium–Glucose Cotransporter‐2 Inhibitors

STBD1

Starch Binding Domain‐containing Protein 1

TNF‐α

Tumor Necrosis Factor α

TXNIP

Thioredoxin‐Interacting Protein

v‐ATPase – AXIN – AMPK

Lysosomal Vacuolar‐type Proton ATPase – Axis Inhibition Protein – AMP‐Activated Protein Kinase pathway

INTRODUCTION

Diabetic kidney disease (DKD) is a chronic and severe illness affecting approximately 40% of individuals with diabetes. DKD is a severe microvascular complication in people with long‐standing diabetes and is also responsible for the progression to end‐stage renal disease (ESRD). ¹ , ² Pathogenesis of DKD is multifaceted, stems primarily from hyperglycemia, haemodynamic alterations, oxidative stress and structural changes (fibrosis). ³ DKD is characterized by pathological deposition of extracellular matrix (ECM), that is diagnosed as thickening of glomerular and basement membranes, and mesangium expansion. Type 1 diabetes, which accounts for 9–12% of diabetes cases and is also known as an autoimmune disease, primarily increases glucose levels by destroying insulin‐producing beta cells in the pancreas. This results in a lack of insulin secretion and an inability to effectively store glucose, leading to high blood glucose levels if untreated. In type 2 diabetes, which affects 87–91% of all diabetes patients, insulin resistance reduces glucose uptake in skeletal muscles and adipose tissues while also increasing glucose production in the liver. ⁴ , ⁵ This endogenous glucose synthesis, in turn, contributes to hyperglycemia. Structural aberrations in diabetic kidneys result in changes in functions like glomerular filtration, tubular reabsorption, the abrupt excretion of protein in urine, and the disturbed albumin to creatinine ratio. ³

Pathologically, DKD is marked by thickening of the glomerular basement membrane (GBM), expansion of the mesangium, interstitial infiltration, and the notable Kimmelstiel–Wilson lesions. Usually, healthy kidneys contain very little glycogen; however, kidneys affected by poorly controlled diabetes contain a significant buildup of glycogen. Histologically, these lesions are identified as Armanni–Ebstein lesions, located near the apex of the proximal tubules, and appear either diffusely or as focal nodular sclerosis, along with arteriolar hyalinosis. ⁶ , ⁷ , ⁸ The dense uptake of periodic acid Schiff (PAS) stain suggests the accumulation of glycogen, although fat vacuoles have also been identified. Armanni–Ebstein lesions are historically associated with ketoacidosis of diabetes, starvation, or alcoholic origin, as indicators of acute metabolic stress. ⁸

The postprandial glucose is sequestered and stored as glycogen. Glucose residues are connected by α‐1,4‐glycosidic bonds in linear chains and by α‐1,6‐glycosidic bonds at branch points. The metabolism of glycogen is regulated by two critical enzymes: Glycogen synthase (GYS) and Glycogen phosphorylase (GP). ⁹ , ¹⁰ Another pivotal enzyme, Glycogen synthase kinase 3β (GSK3β), is a protein kinase that plays a role in the insulin signaling pathway and negatively regulates glycogen synthesis by phosphorylating key enzymes, such as GYS. ¹¹ , ¹² Glycogen, a branched polymer of glucose, is generally stored in the liver and muscles, with very little in other tissues. Animal studies have provided evidence of glycogen deposition in the kidneys. Its presence, however, remains uncertain as to whether it is harmful, beneficial, or neutral in the context of DKD. ⁷ , ⁸ , ¹³ , ¹⁴ This review provides an understanding of glycogen metabolism in the kidneys in a broader context by discussing both established observations and unresolved hypotheses of renal glycogen alterations in DKD.

GLYCOGEN STRUCTURE AND FUNCTION IN THE KIDNEY

Glycogen, a storage form of glucose, is organized into β particles (basic granules) and α‐particles (aggregates of β‐particles). These particles have three structural levels. Level 1 contains α‐1,4‐glycosidic bonds in linear chains and α‐1,6‐glycosidic bonds at branch points. Level 2 assembles the branched structure (Glycogen) into β particles, and each has a glycogenin, a protein core necessary for glycogen synthesis. Level 3 comprises multiple β particles that aggregate into α particles by an unknown mechanism. ¹⁵ , ¹⁶ The α particles form a large, complex, spherical structure approximately 200–300 nm in size. Structure of glycogen primarily depends on organ type; the liver contains α particles, which are stable and perform the function of steady release of glucose, while the skeletal muscle, adipose tissues and the heart contain larger β particles, which have a higher surface area to volume ratio allowing faster glycogenolysis, making glucose available on demand. ¹⁷ , ¹⁸ As mentioned, the mechanism of formation of α and β particles remains unknown and to address this, there are various hypotheses. ¹⁶ One hypothesis called ‘budding’ suggests that during the formation of β particles, few additional long chains move away from the radius of β particles and these chains form buds attaching themselves to the parent β particle. Repeated such a process ultimately results in the formation of α particles. ¹⁹ Another hypothesis called ‘protein glue’ suggests that the size and shape of glycogen particles are not affected by glycogenin alone, but there could be other proteins in the α particles that act as glue. Initially, glycogenin itself was considered a protein core, but gene knockout experiments found that proteases do not affect glycogenin, and the shape of the glycogen molecule is not affected by glycogenin. ²⁰ This indicates that glycogenin may not be the cause of α particle formation, while it can enhance the quality. As understood, α particles are pivotal for organisms, and finding a mechanism that could help our understanding of α and β particles is an important area for future studies.

Figure 1 illustrates glycogen structure, showing how β‐particles aggregate into α‐particles, and highlights that in DKD these α‐particles may become fragile and dissociate to β‐particles, which fail to undergo normal enzymatic breakdown, leading to glycogen deposition (β particles). ¹⁶ , ¹⁷ , ¹⁸ , ¹⁹

Figure 1.

Structural organization and pathological deposition of glycogen in diabetic kidney disease (DKD). (a) Glucose is polymerized by GYS and GBE to form branched glycogen polymers. (b) These polymers organize into β‐particles, each containing a glycogenin protein core, and aggregate into compact or fragile α‐particles. (c) Under DKD conditions (oxidative stress, hyperglycemia, and inflammation), fragile α‐particles readily dissociate into β‐particles. Normally, β‐particles are degraded by glycogen phosphorylase and the debranching enzyme, but in DKD this process is impaired, leading to β‐particle accumulation and glycogen deposition in podocytes and tubular cells, thereby driving metabolic stress, inflammation, and renal injury. GYS, glycogen synthase; GBE, glycogen branching enzyme; DKD, diabetic kidney disease.

The liver is the major storage organ for glycogen. Free glucose is generated during the process of metabolism by the action of the enzyme Glucose 6‐Phosphatase, which is an imperative enzyme of glycogenolysis and gluconeogenesis. This enzyme is predominantly found in the liver and to a small extent in the kidneys, while plasma glucose concentration is largely maintained by the liver. The contribution of the kidney via both glycogen degradation and gluconeogenesis cannot be ignored. GYS is expressed as GYS1, observed in muscle, kidney, and other tissues, where GYS2 is active in the liver. The glycogen phosphorylase (GP) contains three isoenzymes: PYGL, PYGB, and PYGM, expressed in liver, brain, and muscle. GP exists in interconvertible forms: the active (phosphorylated) and inactive (dephosphorylated) forms. Both GYS and GP are covalently regulated along with several factors mentioned in (Table 1). ¹⁰ , ²¹ , ²² , ²³ , ²⁴ , ²⁵ As mentioned earlier, glycogenin, a protein that functions as a self‐transfer of glucose units, initiates glycogen synthesis and is expressed in humans as GYG1 and GYG2. ¹⁰ GYG1 is predominantly found in the heart and muscle, and to a lesser extent in the kidney and lung, while GYG2 is found in the liver. ²⁵

Table 1.

Key enzymes and regulators of renal glycogen metabolism

Component	Primary renal location	Function	Regulation	Net effect on glycogen in the kidney
Glycogen synthase (GYS1)	Cortex and medulla	Catalyzes the addition of glucose molecules from UDP‐glucose to form glycogen	Activated by dephosphorylation (insulin, Protein phosphatase 1 (PP1)); allosterically by G6P; inhibited by phosphorylation (GSK3, PKA, epinephrine)	Promotes glycogen synthesis and deposition of medullary glycogen stores, especially in diabetes
Glycogen phosphorylase (PYGL)	Primarily in Cortex and limited in medulla	Releases glucose‐1‐phosphate from glycogen to form glucose	Activated by phosphorylation (PKA cascade); allosterically by AMP; inhibited by ATP and G6P	Promotes glycogen breakdown to support glycolysis
Glycogenin1 (GYG1)	Renal medulla	Autoglucosylation for glycogen formation	Insulin and PPI activate GYG1; PKA inhibits	Initiation of renal glycogen synthesis; altered expression linked to abnormal deposition
Glycogenin2 (GYG2)	Renal medulla	Stimulates glycogen breakdown; glucose homeostasis; promotes formation of alpha glycogen particles	Interacts with the inactive form of GYS in the formation of the GS‐GYG2 complex	Limited activity; repressing GYS activity
GSK3β	Peripheral end of the renal tubules and the glomerulus	Phosphorylates and inhibits GYS1	Inhibited by insulin signaling; pharmacologically modulated	Regulates glycogen synthesis, influencing medullary glycogen levels in diabetes through its activation or inhibition

The liver oversees the kidneys' contribution to blood glucose. Considering that glycogen is stored in the renal medulla (loop of Henle) and the renal cortex is the site for gluconeogenesis, ⁶ , ¹⁵ , ²⁶ , ²⁷ it may be possible that the contribution of the kidneys to homeostasis of glucose in the blood may be due to gluconeogenesis because of the prevailing hypoxic condition in the medulla, which may not be conducive to glycogenolysis. A single glycogen molecule contains about 55,000 glucose units and a glycogenin protein, involved in glycogen synthesis. ²⁸

TISSUE‐SPECIFIC GLYCOGEN METABOLISM

Glycogen metabolism exhibits distinct characteristics in various tissues. Liver, the principal organ for glycogen storage in its soluble form, readily degrades to give glucose and is responsible for 80% endogenous glucose production, followed by skeletal muscle. ²⁹ The liver glycogen aids in maintaining the systemic blood glucose, and in skeletal muscle, it helps release glucose during muscle contraction. ²⁹ , ³⁰ Other tissues like kidneys, heart, and adipose tissue also exhibit glycogen deposition that corresponds to specific functions as detailed in (Table 2). ²¹ , ³¹ , ³² , ³³ , ³⁴ , ³⁵

Table 2.

Glycogen content, roles, and G6Pase expression in key tissues

Tissue/cells	~concentration	Primary function	G6Pase presence?
Liver	5–6%	Systemic blood glucose homeostasis	Yes
Skeletal muscle	1–2%	Immediate energy for muscle contraction	No
Cardiac muscle	~2%	Regulator in hypoxic conditions or stress	No
Kidney	Negligible amounts	Utilized by the renal medulla mostly (obligate user)	Yes
Glial cells	Very low	Energy reservoir for astrocytes	No
Adipose tissue	Small amounts	Releases free glucose during starvation	No
Others (RBC, WBC)	Trace amounts	More pivotal in diseases (type IIIGSD) in RBCs Energy for phagocytosis, chemotaxis, and internal metabolic needs in WBCs	No

G6Pase expression reflects the potential for systemic glucose release, highlighting its critical role in various metabolic processes.

Glycogen deposition markedly varies across the tissues, presenting unique functions (Table 2). Liver (5–6%) and kidney express G6Pase for systemic glucose release, while muscle (~1–2%) and glial cells use it locally without G6Pase. While the significance of glycogen metabolism is distinct across tissues, the kidney exhibits unique features that are particularly relevant in the context of diabetes.

GLYCOGEN METABOLISM IN THE KIDNEY

The kidneys produce approximately 20% of body glucose under standard conditions through G6Pase activity in the renal cortex, while the liver generates about 80%. The body switches to a 60–40 kidney superiority after the liver exhausts all its glycogen stores. Proximal tubules accomplish almost complete glucose reabsorption of freely filtered glucose (~160 g/day) through their insulin‐independent SGLT1/2 and GLUT1/2 transport systems. ²⁷ , ²⁸ , ³⁶ , ³⁷ , ³⁸ , ³⁹ In the postprandial period, kidneys release glucose into the bloodstream at rates that match liver glucose production. In diabetes, hyperglycemia elevates filtration to ~450 g/day, ⁴⁰ , ⁴¹ , ⁴² hinders insulin breakdown (~40% daily renal contribution), and promotes excessive medullary glycogen buildup alongside upregulated gluconeogenesis. As presented in Figure 2, elevated renal glucose reabsorption under chronic hyperglycemia contributes to intracellular overload of glycogen in the medulla. ²⁷ , ²⁸ , ⁴⁰ , ⁴¹ , ⁴²

Figure 2.

Hepatorenal shift in glucose homeostasis: Physiological vs diabetic states. The comparative contributions of liver and kidney to systemic glucose production, alongside renal glucose handling and glycogen dynamics, in healthy (physiological) vs diabetic conditions. GLUT2, glucose transporter 2; SGLT2, sodium–glucose cotransporter‐2.

Glycogen synthesis (glycogenesis) and its accumulation occur predominantly in medullary segments. As noted earlier, Glycogen metabolism is regulated by several enzymes, allosteric factors, and hormones (Table 2). ¹⁰ , ²² , ²³ , ²⁴ , ²⁵ In the medulla, the prevailing hypoxic environment favors the glycogenic enzymes, further abetted by Hypoxia Inducible Factors1/2 (HIF1/2). The renal medulla and the thick ascending limb rely on these stores for energy. While glycogen stores are minimal under physiological conditions, pathological states such as diabetes can lead to aberrant glycogen accumulation. This is not solely due to increased glycolytic flux, but rather a combination of enhanced glucose uptake, impaired glycogen metabolism, and dysregulated signaling pathways, including insulin‐AKT‐GSK3β and glycophagy mechanisms. ²³

Renal proximal tubular cells show increased glucose inflow via the glucose‐sensing basolateral GLUT2 receptors, followed by reabsorption of the glucose by apical SGLT2 receptors and STBD1‐initiated phagolysosome release of glucose from glycogen, resulting in intracellular glucose overload under hyperglycemic conditions. As the glycogen‐targeting receptor, STBD1 binds glycogen via its carbohydrate‐binding module and recruits autophagosome machinery through GABARAPL1 contact to initiate glycophagy, a selective autophagy pathway for glycogen degradation. ⁴³ , ⁴⁴ While mature phagolysosomes (via GAA lysosomal enzyme) break down glycogen particles absorbed by glycophore structures, releasing glucose for cellular energy or efflux (through the bidirectional GLUT2) and reducing the toxic accumulation of glycogen in the renal medulla, AMPK activation phosphorylates STBD1 to improve glycogen association and initiate autophagosome formation. Figure 3 shows the STBD1‐mediated glycophagy facilitating glycogen clearance in renal cells. Under hyperglycemic conditions, each of the above mechanisms is exaggerated, leading to disruption in these processes ⁴³ , ⁴⁴ with a pathological buildup of glycogen.

Figure 3.

Glucose and Glycogen handling in the renal cell. The schematic figure illustrates renal cell glucose handling. Glycogen builds up when glucose reaches renal tubular cells through SGLT2. Glycogen is drawn into glycophagosomes by STBD1‐mediated glycophagy. Glycophagosomes merge with lysosomes to break down GAA and release glucose, while AMPK and GABARAPL1 regulate this process to maintain glycogen balance in kidney cells. GLUT2, Glucose transporter 2; SGLT2, sodium–glucose cotransporter‐2; AMPK‐5′, AMP‐activated protein kinase; GAA, acid α‐glucosidase; STBD1, starch binding domain‐containing protein 1; GABARAPL1, GABA type A receptor‐associated protein like 1.

GLYCOGEN DEPOSITION IN DIABETIC CONDITIONS

Normally, kidneys accumulate very little glycogen and utilize it to maintain homeostasis. ²⁴ , ²⁵ Animal studies have demonstrated glycogen collection in renal tubules and glomerulus in short‐term diabetes‐affected rats and the expression of GYS and G6P were also increased in them. ¹⁴ , ⁴⁵ Other studies presented glycogen deposition in the ascending loop of Henle ¹⁵ , ²¹ , ²⁶ and the increased levels of GYS1 were accompanied by increased expression of genes responsible for inflammation specific to kidneys such as IL6, TNF‐α, and TGF‐β. ¹⁴ , ⁴⁵ , ⁴⁶ , ⁴⁷ Further, the use of heterogenic transgenic (Ren 2), streptozotocin‐induced diabetic rats showed increased glycogen content and higher levels of GYG in diabetic kidney. ⁴⁸ Predominantly found in the glomerulus, the hematoxylin‐eosin staining and the PAS staining identified the buildup as glycogen. ⁴⁹ Glycogen extracted from diabetic kidneys consisted of β‐particles and the chain length was similar to that of muscle glycogen molecule suggesting it as metabolically active and not similar to polyglucan bodies seen in glycogen storage disorders. ²⁷

More recent studies observed increased presence of GSK3β protein in the urinary cells of type 2 diabetes mellitus patients and expression of GYS1 in the cortex, supported by histology and immunohistochemical findings. ⁵⁰ , ⁵¹ People with poorly controlled diabetes are at a high risk of glycogen buildup, which can lead to prominent Armanni–Ebstein lesions in the tubules (proximal tubules). ⁵⁰ The glomerular visceral epithelial cells (podocytes) hold the glomerular filtration barrier. Alterations in the podocytes and their slit diaphragms (SD) compromise the function of glomerular filtration, leading to proteinuria. ⁵² Glomerular basement membrane (GBM) and mesangial cells, along with podocytes, are highly vulnerable to high glucose.

The resultant production of ROS and the release of inflammatory proteins damage the complex three‐dimensional architecture. ⁵³ , ⁵⁴ , ⁵⁵ Prolonged hyperglycemia of diabetes increases the production of advanced glycation end products (AGEs), resulting in podocyte injury. ⁵³ , ⁵⁶ The impaired insulin signaling pathways resulting from nonresponsive GLUT4 and GLUT8 pave way for chronic glucose influx via insulin‐independent transporters like GLUT1, worsening the glucotoxicity. ⁵⁵ , ⁵⁷ , ⁵⁸ Podocytes usually rely on anaerobic glycolysis that converts glucose to lactate, which in turn aids glycogen synthesis in podocytes as confirmed by a recent study. ⁵⁹ Whether this glycogen formed is detrimental or beneficial remains unknown.

METABOLIC ALTERATIONS IN DKD

Chronic hyperglycemia disrupts the structural and functional integrity of podocytes, glomerular cells, and tubular cells. In vitro and in vivo models of diabetes‐induced kidney injury have shown a decrease in the activity of GSK‐3β, which is associated with mTORC1 activation and glycogen deposition in the extracellular matrix and podocytes, largely driven by the insulin signaling cascade. GSK3β is a serine/threonine kinase activated by phosphorylation of tyrosine residues at the 216th position and inactivated by phosphorylation of serine at the 9th site. ⁵⁹ Studies reported that high glucose levels phosphorylate serine at the 9th site, thereby inhibiting GSK 3β and lifting the inhibitory effect on GYS. ²¹

Glucose metabolism (glycolysis) and oxidative phosphorylation are the main sources of energy in the renal cells. Compared with glycolysis, OXPHOS is a more efficient generator of ATP, but glycolysis occurs 100‐fold faster than OXPHOS, and this increases exponentially in the presence of high glucose concentration, as is seen in uncontrolled diabetes patients, leading to a mismatched channeling of metabolites into the electron transport chain (ETC) via the Krebs cycle, potentially contributing to the pathology of DKD. ⁶⁰ The diabetic milieu increases the transportation of glucose intracellularly by GLUTs and SGLTs. Glomerular cells express the isoforms of GLUT1, and proximal tubular cells reabsorb filtered glucose by the SGLT2 transporter. This increases the glycolytic flux and progresses to intensify the mechanical and physiological stress in the kidneys. Given the relative hypoxic environment in the kidneys, there is a shift to anaerobic glycolysis for rapid ATP production to meet energy demands; this is termed ‘metabolic switch’ where high glucose levels along with mitochondrial stress upregulates key glycolytic genes and shunts glucose intermediates to alternate non‐glycolytic pathways such as hexosamine, protein kinase C (PKC), and polyol pathways that promote harmful products and further damage the kidney. The production of lactic acid by anaerobic glycolysis also exacerbates kidney injury. ²¹ , ⁵⁹ , ⁶⁰

Thioredoxin‐interacting protein (TXNIP) is an important regulator for glucose homeostasis involved in high glucose‐mediated DKD progression. ⁶¹ As an upstream protein, TXNIP binds to the ligand thioredoxin (TBP) and inhibits the thiol oxidoreductase thioredoxin and GLUT2 transporter activity, thereby integrating high glucose‐sensing signals to activate downstream cascades that contribute to renal inflammation, fibrosis, and tubular injury. ⁶² TXNIP upregulation in glucose metabolism causes metabolic alterations like the release of reactive oxygen species and caspase‐3, activation of the NLRP3 inflammasome, apoptosis, and autophagy impairment, which is linked to disruption of glycogen metabolism through shared pathways like mTOR signaling and glucose handling. Figure 4 shows that TXNIP‐mediated mTOR activation promotes inflammation and fibrosis under hyperglycemia, demonstrating its dual role in DKD. ⁶⁰ , ⁶¹ , ⁶²

Figure 4.

TXNIP‐mediated crosstalk between glucose handling, NLRP3 inflammasome‐mediated inflammation, and mitochondrial apoptosis via ROS, NF‐kB, and caspase‐3 signaling. Proposed mechanism connecting renal cell inflammation and apoptotic signaling to glucose‐induced glycogen buildup. HG activates TXNIP through GLUT in kidney cells, which inhibits PI3K/AKT signaling, causes excessive mTORC1 activation that hinders autophagy, and starts the activation of the NF‐kB/NLRP3 inflammasome, which promotes inflammation and fibrosis. TXNIP, thioredoxin‐interacting protein; mTOR, mammalian target of rapamycin; GYS1, glycogen synthase 1; NLRP3, Nod‐like receptor protein 3; NF‐kB, nuclear factor‐kappa‐light‐chain‐enhancer of activated B cells; IL‐1β, interleukin 1β; TNF‐α‐, tumor necrosis actor α.

Metabolic alterations in Podocytes

The energy requirements of the podocytes are met both by anaerobic glucose metabolism and through OXPHOS. ⁶³ Podocytes undergo a specialized mechanism called ‘bioenergetic de‐differentiation’ in diabetic conditions in the high glucose environment, stimulating aerobic ‘glycolytic switch’. ⁶⁴ Further, the high glucose‐mediated oxidative stress and inflammatory response decrease the key glycolytic enzymes, and this results in the accumulation of intermediates such as dihydroxyacetone phosphate, rerouting the metabolites toward glycogen synthesis and its subsequent accumulation in podocytes. As a consequence, injury‐related signaling pathways such as pyruvate kinase M2 (PKM2), 6‐phosphofructo‐2‐kinase/fructose‐2,6‐bisphosphatase 3 (PFKFB3), 5’ AMP‐activated protein kinase (AMPK), mechanistic target of rapamycin (mTOR), and nuclear factor erythroid 2‐related factor 2 (Nrf2) may contribute to apoptosis and autophagy in podocytes. ⁶⁵ , ⁶⁶ Figure 5 illustrates the metabolic reprogramming of podocytes that reroutes the metabolites toward glycogen synthesis, contributing to abnormal glycogen buildup in DKD.

Figure 5.

GSK3β and PFKFB3‐driven pathological mechanisms linking hyperglycemia to podocyte dysfunction in diabetic kidney disease. Metabolic reprogramming and glycogen dysregulation interact with structural and inflammatory signaling in podocytes. PKM2, pyruvate kinase M2, PFKFB3, 6‐phosphofructo‐2‐kinase/fructose‐2,6‐bisphosphatase 3; Nrf2, nuclear factor erythroid 2‐related factor 2; BCL2, B‐cell lymphoma 2; BECN1, Beclin 1; LC3, light chain 3; BAX, Bcl‐2‐associated X protein.

In this context, GYS and phosphorylase, along with GSK 3β and AKT regulation, favor glycogen deposition in podocytes and correlate with glomerular damage observed in diabetic kidneys. ⁶⁷

Metabolic alterations in tubular cells

Glycogen metabolism dysregulation in tubular cells, primarily the proximal tubular cells, manifests as a pathological feature in DKD. The condition leads to a shift from fatty acid oxidation to glycolysis, which has been associated with hypertrophy, lipid accumulation, inflammation, and fibrosis through mTORC1 activation and GSK3β inactivation, suggesting metabolic reprogramming. In mouse models, activation of GSK 3β was found to lower albuminuria and decrease deposition of extracellular matrix proteins, without any effect on the blood glucose levels. ⁶⁷ As SGLT2 transporters are expressed in renal tubular cells, exposure to high glucose overloads the transporters leading to glycogen deposition by reabsorption which are visible by PAS staining in 6‐month‐old diabetic rats. ⁷ This deposition aligns with tubular hypertrophy and correlates with glucose/lipids dysregulation, NLRP3 inflammasome activation via GPX1. ⁶⁸ Apart from GYS1, GSK3β, and AKT certain other proteins such as protein kinase AMP‐activated catalytic subunit alpha 1/2 (PRKAA1/2) indirectly upregulates the glycogen storage in DKD tubules are described in Table 3. The other glucose/lipid nodes tied to glycogen include phosphoglycerate kinase 1 (PGK1), hexokinase (HK1/2), sodium/glucose cotransporter 2 (SLC5A2), and ceramide glucosyltransferase (UGCG) proteins that act as precursors that pull high glucose toward glycogen. ⁶⁸

Table 3.

Comparisons of different cell types across the glomerulus and tubules

Cell type	Glycogen deposition	Key proteins involved	Outcome
Podocytes	Increased accumulation as polyglucosan bodies	GYS1, GSK3β	Proteinuria
Mesangial cells	Minimal/None	SGLT2, PKC	Hypertrophy
Tubular cells	Accumulation observed as granules in the periphery of proximal tubules (Armanni–Ebstein lesions) and the center of distal tubules	GSK3β, GYS1, mTOR	Hypertrophy and fibrosis

Podocytes exhibit polyglucosan body accumulation via GYS1/GSK3β dysregulation, driving proteinuria; mesangial cells show minimal glycogen but SGLT2/PKC‐mediated hypertrophy and overproduction of extracellular matrix proteins (collagen and fibronectin); proximal/distal tubular cells display peripheral/central granular deposits linked to GSK3β/GYS1/mTOR activation, culminating in hypertrophy and fibrosis.

EVIDENCE LINKING GLYCOGEN ACCUMULATION IN DKD PHENOTYPES TO EXPERIMENTAL AND HUMAN STUDIES

Experimental studies and animal models demonstrate glycogen deposition in diabetic kidneys. In rats with chronic hyperglycemia‐induced diabetes, showed significant glycogen buildup in their kidneys compared with normal rats, with electron microscopy revealing large glycogen clusters located toward renal tubules, suggesting prolonged hyperglycemia is the primary driver. ⁸ , ⁶⁹ Given that GSK3β regulates glycogen metabolism, data from in vitro models and DKD participants have demonstrated that GSK3β mediates podocyte injury by integrating multiple podocytopathic signaling pathways. ⁷⁰ , ⁷¹ , ⁷² These findings are significantly more pronounced in chronic hyperglycemia compared with acute exposure. The glycolytic switch from OXPHOS to anaerobic glycolysis observed under hyperglycemic conditions probably served as a protective mechanism to overcome short phases of elevated ambient glycemia; however, it becomes detrimental in a chronic hyperglycemia atmosphere, favoring glycogen deposition. The function of this glycogen needs to be comprehended. ⁷³

The intrarenal accumulation of glycogen was identified as polyglucosan bodies in the kidney biopsy specimens of DKD patients. ⁴⁷ However, they have been identified as glycogen aggregates by fluorescence‐assisted electrophoresis and electron microscopy. These results have shifted the perspective on renal glycogen from being a passive buildup to its causal role in DKD. Despite evidence, there is still a dearth of information on whether kidney damage is directly caused by glycogen buildup. As can be expected from the ectopic accumulation of any substance, excessive glycogen in the kidneys of diabetic patients can galvanize an inflammatory response, further fueling the DKD damage.

EFFECTS OF METFORMIN AND SGLT2 INHIBITORS ON GLYCOGEN METABOLISM IN DIABETIC KIDNEY DISEASE

Metformin is an indispensable hypoglycemic agent prescribed to most type 2 diabetes patients as the first‐line therapy, because of its safety, efficacy, anti‐diabetic effect, and its versatility in preventing cardiovascular events, kidney disease, neurological dysfunction, cancer prevention, and other possible roles which are being actively investigated. Metformin decreases high blood glucose levels by inhibiting gluconeogenesis in hepatocytes and by increasing insulin sensitivity in peripheral tissues. ⁷⁴ , ⁷⁵ , ⁷⁶ , ⁷⁷ The oral pharmacological preparation activates the AMPK via lysosomal v‐ATPase–AXIN–AMPK pathway, which inhibits the glycogen phosphorylase activity thereby stimulating glycogen synthesis by dephosphorylation. ⁷⁸ In the context of DKD, this pathway partially reduces the ATP, recruiting LKB1 to phosphorylate AMPKα‐Thr172 thereby curbing glycogen buildup. ⁷⁸ , ⁷⁹ However, study on type 2 diabetes mellitus patients receiving metformin also reported the decrease in glycogen buildup by reducing the glucose precursors like pyruvate and lactate. ⁸⁰ The action of metformin in preventing/retarding chronic kidney disease is primarily through activation of AMPK pathway resulting in decreased oxidative stress, inflammation, and renal fibrosis. The action of glycogen production, however, in view of DKD, must be explored.

SGLT2 inhibitors like dapagliflozin increase renal glucosuria, thereby preventing glycogen buildup via the mTOR‐AMPK pathway, which shifts renal metabolism toward ketogenesis and fat utilization. ⁸⁰ SGLT2i monotherapy evidently amplified the lipolysis, glycogenolysis, gluconeogenesis, fatty acid oxidation, and prominently ketogenesis in the kidney. ⁸⁰ SGLT2i are gaining popularity as monotherapy choices, particularly in patients with renal disorder, obesity, and cardio‐renal disease. When both SGLT2i and Metformin are given as a dual regimen, marked attenuation of the protein catabolism and gluconeogenesis in the kidney in db mice was observed. ⁸¹ It may be hypothesized that dual therapy balances the glycogen flux and helps lower DKD progression, outperforming monotherapy in real‐world cohorts. This, however, must be ascertained in systematic studies.

Taken together, as both metformin and dapagliflozin appear promising in modulating downstream targets relevant to glycogen metabolism, the observations are preclinical and preliminary. Most human studies are observational, and secondary analyses could not draw mechanistic or clinical conclusions. However, novel studies could involve modulation of glycogen metabolism regulators, GSK3β, mTORC1 signaling, glycophagy receptor, STBD1, and GABARAPL1, experimental evaluation of glycogen metabolism enzymes and genes using siRNA, or pharmacological upregulation of AMPK protein for glycogen balance, and development of imaging probes for abnormal glycogen buildup. Whether the benefit from SGLT2 inhibitors is also in part due to the alterations in glycogen handling remains to be ascertained.

CONCLUSIONS

Although contemporarily it is understood that glycogen metabolism is reciprocally controlled by GYS and glycogen phosphorylase, the regulatory kinases have been shown to exhibit highly complex adaptations/alterations during metabolic stress, particularly glucose overload. Focus thus far has been on the role of dysregulated glucose on various tissues/organs in diabetes mellitus. One of the flip effects of attempts at regulating blood glucose either by physiological processes or pharmacological aids is the conversion of excess glucose to glycogen and its deposition in non‐native organs. The recent pique in interest in this area is relevant considering the complex interplay of cellular adaptations between striking a balance in maintaining glucose homeostasis and preventing the ectopic buildup of glycogen, which is likely to stimulate the very same pathways that high glucose would. This review brings out the possibility of glycogen metabolism as an emerging and underexplored feature of DKD. While glycogen deposition is observed in diabetic kidneys, current evidence does not establish whether it is a causal driver, a compensatory response, or a consequence remains to be studied.

Throughout the literature, there exists a wide consensus that glycogen deposition occurs in podocytes and tubular cells, and GSK3β inactivation and mTORC1 activation act as central regulators. However, its functional significance remains to be ascertained. Major knowledge gaps include the limited human biopsy data, heterogeneous patient populations, mechanistic studies distinguishing causality from association, and inadequate understanding of glycophagy in renal cells. In addition, systemic studies of glycogen metabolism should be assessed carefully to avoid any unintended effects in the liver and skeletal muscle. These limitations constrain our ability to draw firm conclusions about causality. Future research could prioritize resolving these mechanisms in human tissue and evaluate therapeutic strategies to determine whether targeting glycogen metabolism can significantly modulate DKD and its progression.

DISCLOSURE

The authors declare no conflict of interest.

Approval of the research protocol: N/A.

Informed consent: N/A.

Registry and the registration no. of the study/trial: N/A.

Animal studies: N/A.

DATA AVAILABILITY STATEMENT

Data sharing not applicable to this article as no datasets were generated or analyzed during the current study.