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Review
. 2020 Aug 31;21(17):6286.
doi: 10.3390/ijms21176286.

Fanconi-Bickel Syndrome: A Review of the Mechanisms That Lead to Dysglycaemia

Sanaa Sharari  1   2 , Mohamad Abou-Alloul  3 , Khalid Hussain  2 , Faiyaz Ahmad Khan  2
Affiliations
Review

Fanconi-Bickel Syndrome: A Review of the Mechanisms That Lead to Dysglycaemia

Sanaa Sharari et al. Int J Mol Sci. .

Abstract

Accumulation of glycogen in the kidney and liver is the main feature of Fanconi-Bickel Syndrome (FBS), a rare disorder of carbohydrate metabolism inherited in an autosomal recessive manner due to SLC2A2 gene mutations. Missense, nonsense, frame-shift (fs), in-frame indels, splice site, and compound heterozygous variants have all been identified in SLC2A2 gene of FBS cases. Approximately 144 FBS cases with 70 different SLC2A2 gene variants have been reported so far. SLC2A2 encodes for glucose transporter 2 (GLUT2) a low affinity facilitative transporter of glucose mainly expressed in tissues playing important roles in glucose homeostasis, such as renal tubular cells, enterocytes, pancreatic β-cells, hepatocytes and discrete regions of the brain. Dysfunctional mutations and decreased GLUT2 expression leads to dysglycaemia (fasting hypoglycemia, postprandial hyperglycemia, glucose intolerance, and rarely diabetes mellitus), hepatomegaly, galactose intolerance, rickets, and poor growth. The molecular mechanisms of dysglycaemia in FBS are still not clearly understood. In this review, we discuss the physiological roles of GLUT2 and the pathophysiology of mutants, highlight all of the previously reported SLC2A2 mutations associated with dysglycaemia, and review the potential molecular mechanisms leading to dysglycaemia and diabetes mellitus in FBS patients.

Keywords: Fanconi–Bickel Syndrome (FBS); GLUT2 dysfunction; SLC2A2 mutation; birth weight; cAMP; dysglycaemia; hepatomegaly; insulin secretion; liver; pancreatic β cell.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Role of glucose transporter 2 (GLUT2) in pancreatic β cell glucose-stimulated insulin secretion. Glucose enters the β-cells facilitated by GLUT2, which is then phosphorylated by glucokinase (GK) and metabolized by glycolysis and tricarboxylic acid cycle (TCA), leading to increased generation of ATP. Glucagon like peptide-1 (GLP1), glucagon, and GIP (gastric inhibitory polypeptide) activation of G protein-coupled receptors (GPCRs) responsive adenylyl cyclases (AC), leading to increased formation of cyclic adenosine monophosphate (cAMP). cAMP activates protein kinase A (PKA) and epac2 (cAMP-regulated guanine nucleotide exchange factor) to potentiate glucose-stimulated secretion of insulin. Increased ratio of ATP/ADP due to increased glucose metabolism closes the ATP-gated K+ channel (KATP), causing membrane depolarization, and voltage-dependent calcium channels (VDCC) opening, leading to Ca2+ influx via VDCC, which activates insulin secretion. This action of Ca2+ is potentiated by PKA. For exocytosis of insulin from β-cells, Rab3a and Rab27a GTPases are important signaling mediators that become activated by this mechanism and contribute to the exocytosis of insulin from glucose-stimulated cells.
Figure 2
Figure 2
Regulation of glycogen metabolism in liver by GLUT2. The insulin-independent GLUT2 facilitates glucose transport across the cell membranes. Sodium-glucose cotransporter (SGLT) transport activity can be regulated by protein kinases including PKA (protein kinase A) and PKC (protein kinase C). PKA activation positively regulates SGLT1 expression and activity. Increased glucose concentration causes conformational change and activation of glucokinase (GK), which phosphorylates glucose to glucose-6-phosphate (G6P) and serves as a substrate for glycogen synthesis or glycolysis. In hepatic glycogen metabolism, G6P serves as the central intermediate. During glycolysis, utilization of G6P provides energy in the form of pyruvate, NADH and ATP. Acetyl-CoA produced from pyruvate, enters the mitochondrial tricarboxylic acid cycle (TCA). During fasting, G6P serves as a substrate for synthesis of glucose during gluconeogenesis or glycogenolysis. Glycogen phosphorylase (GP) catalyze glycogenolysis, activated by AMP or PKA, and inhibited by insulin. GSK-3β (a serine/threonine kinase) is a downstream element of PI3K/AKT pathway, whose activity can be inhibited by protein kinase B (PKB)-mediated phosphorylation at Ser9 of GSK-3β. Glycogen synthase (GS) is phosphorylated and inactivated by GSK3. SGLT: sodium-glucose cotransporter; G: glucose. Green arrows (stimulation); Red arrows (inhibition); Green Sp (phosphorylated serine): activating phosphorylation; Red Sp: inhibiting phosphorylation. Dashed lines indicate many steps not listed in the gluconeogenesis and glycogenolysis pathways to glucose.
Figure 3
Figure 3
Human glucose transporter 2 (GLUT2) structural topology including location of variants and conserved amino acids. GLUT2 is a glucose transporter containing 12 transmembrane domains (524 amino acids) connected with extracellular and intracellular loops, facilitating the movement of glucose across the cell membranes. It has high capacity but low affinity (high km) for glucose, and functions as a glucose sensor. GLUT2 mediates bidirectional glucose transport, and is mostly expressed in pancreatic β-cells, liver, small intestine, brain and renal tubular cells.
Figure 4
Figure 4
GLUT2-mediated glucose transport across cell membranes and communication to different organs. GLUT2 is a low affinity and high capacity glucose transporter and facilitates the transport of glucose in intestinal cells. SGLTs are high-affinity and low capacity transporters, capable of transporting glucose against a concentration gradient. Ghrelin increases the GLUT2 expression by modulating the GLUT2 transcription via GHS-R1 (growth hormone secretagogue receptor 1a) and PLC/PKC pathway. Ghrelin also stimulates translocation of GLUT2 to the surfaces of intestinal cell from intracellular vesicles, leading to increased glucose absorption. GLUT2 is highly expressed in the liver, pancreas, brain and kidney cells. Activation of nervous signals, induces the first phase of insulin release from pancreatic β-cells induced by increased glucose transport to pancreatic β-cells. These signals also induce other physiological processes. In the liver, GLUT2 maintains the glucose homeostasis during fasting and fed state by regulating the expression of glucose-sensitive genes. GLUT2 is more highly expressed in rodent β-cells than in human β-cells. In the brain, glucose-sensing cells expressing GLUT2, regulate glucose by parasympathetic and sympathetic systems. GLUT2-dependent glucose-sensing cells also regulate leptin sensitivity and regulate the expressions of uncoupling protein 1 (UCP1) and thermogenesis. Homozygous GLUT2 mutation leads to a dysfunctional and reduced expression of GLUT2, which causes FBS. Dysfunctional GLUT2 causes fasting hypoglycemia, postprandial hyperglycemia, glucose and galactose intolerance, hepatomegaly, glucosuria, reduced GSIS (glucose-stimulated insulin secretion), rickets, GH (growth hormone) deficiency and poor, growth. (G; glucose).
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