Abstract

Hyperinsulinism hypoglycemia (HH) is a rare condition that affects newborn children in the postnatal period represented in dangerously low levels of blood glucose in a persistent manner, which puts the baby at high risk of multiple issues, especially on brain cells if the baby doesn’t take the appropriate medication or diagnosis. Hyperinsulinism hypoglycemia can happen due to an active or inactive mutation in 16 genes responsible of glucose metabolism and insulin secretion which are (GLUD1, GCK, SLC16A1, HK1, CACNA1D, KCNJ11, ABCC8, FOXA2, HNF1A, HNF4A, HADH, PGM1, UCP2, KCNQ1, PMM2, EIF2S3). These mutations can take place in many forms either defused or local, affecting several or all pancreatic beta cells respectively. This review articles summarizes genetic variations in hyperinsulinism hypoglycemia.

Keywords: Hyperinsulinism hypoglycemia; Genetic Variations; Glucose metabolism; Phosphorylation process; Diabetes mullites

Abbreviation: HH: Hyperinsulinism Hypoglycemia; ATP: Adenosine Triphosphate; GLUD1: Glutamate Dehydrogenase 1; NH3: Ammonia; NH4+: Ammonium ions; GDH: Glutamate Dehydrogenase; ADP: Adenosine Diphosphate; GTP: Guanosine Triphosphate; GCK: Glucokinase; GKRP: Glucokinase Regulatory Protein; GLUT: Glucose Transporter; PGM1: Phosphoglucomutase1; G1P: Glucose-1-Phosphate; HAD: Hydroxy Acyl-CoA Dehydrogenase; MODY: Maturity-Onset Diabetes of Youth; HNF14: Hepatocyte Nuclear Factor; MCT: Monocarboxylate Transporter

Introduction

Hyperinsulinism, idiopathic hypoglycemia of infancy, leucine-sensitive hypoglycemia, or nesidioblastosis, [1] are terms refer to a rare condition characterized by immediate severe persistent hypoglycemia in infants and newborn babies in the postnatal period. HH is considered a complex of disorders related to dysregulated in insulin secretion. It occurs when plasma glucose levels decrease, cells lead to inappropriate insulin secretion. This leads to hypoglycemia in children. HH affects the neurological system in patients because it causes a decrease in blood glucose concentration, it has a high risk of brain damage. There are different factors that lead to HH like birth asphyxia, intrauterine growth retardation, maternal diabetes mellitus and Beckwith-Wiedemann syndrome [2]. From this, the important diagnosis must be done to prevent some diseases like epilepsy and neuro-development defect [3].

The metabolism of insulin on glucose increases the neurological injury; when a human consumes a meal, it leads to glucose increases in bloodstream, this leading to activating glucose secretion pathways that play an important role in regulating blood glucose while and after eating. While eating, glucose level will be increases above its normal range activating the “triggering pathway” which induced by glucose metabolism to produce Adenosine triphosphate (ATP) molecules that trigger the production of insulin by causing the (KATP) channel to close, depolarize the beta cells membrane, and finally activate the calcium channels to enter the calcium to beta cells and binds to insulin granules to exocytic it to bloodstream, this pathway is known to be rapid in its response.

Even after some hours of eating the meal, the second pathway “amplifying pathway” will take its place to keep managing the glucose level by secreting insulin at sustained lower rates than the “triggering pathway”. On the other hand, insulin stimulates lipogenesis by inhibiting free fatty acid release, β-oxidation and ketone body formation which leads to brain injury. Although these phases aim the same goal, which is keeping blood glucose in a normal range all the time, they also differ in the insulin granules they trigger, the first phase “triggering phase” must be rapid so it uses the readily releasable insulin granules located on the beta cell membrane surface consuming only 1% of these granules, while in the other hand the “amplifying pathway” works after hours of eating so it uses the recruited granules from storage pool in addition to the membrane surface granules [4].

This review discusses how the insulin metabolism affects neurological system and leads to different diseases depending on different literature search on HH using PubMed database. And to investigates molecular and genetic mutations lead to HH whether activating or inactivating mutation with an example for each type.

Mutations in Hyperinsulinism hypoglycemia

Islets of Langerhans and their functions

Many mutations in different 16 key genes, that are known to be responsible for regulating insulin secretion from beta-cells of pancreas, would cause in a dangerous condition of (HH). As well as multiple different syndromes are also associated with hyperinsulinism hypoglycemia [5]. Islets of Langerhans are the functional units of the pancreas ranging from (1 to 15 million) each containing 2000 endocrine hormone-producing cells, that play important roles in the glucose regulating process including (alpha-cells, beta-cells, polypeptide cells, somatostatin cells, ghrelin cells) each has a specific function (Table 1).

Hyperinsulinism hypoglycemia forms

Hyperinsulinism hypoglycemia can manifest in three distinct forms: the diffuse form which is characterized by hypertrophic beta cells affecting all the islet cells, it occurs mostly due to a mutation in the (KATP) channel’s subunits genes and is known to be unresponsive for diazoxide treatment [9]. The focal form, where hyperactive beta cells undergo changes within localized adenomatoid hyperplastic regions due to a parentally inherited mutation on the (KATP) channel’s subunits genes and this type can affect any region of the pancreas, especially at the tail and the body of pancreas [10]. The atypical form, which is considered to happen due to an enlargement of the pancreatic beta cells nuclei leading to an up normality in glucose metabolism [11].

Molecular changes in Hyperinsulinism

Mutations could be activating some genes and inactivating others leading to over-secretion of insulin causing dangerous hypoglycemia [5,12]. Activating mutations lead to increases in the activity or the function of a gene or its protein product, resulting in a gain-of-function alternation, those mutations are relatively rare among autosomal gene mutations. Many of these mutations occur in the regulatory region of the gene rather than the coding region [13].

In this case, activating mutation can arise in 5 genes (GLUD1, GCK, SLC16A1, HK1, CACNA1D) that play a role in the insulin secretion process, leading to hyperinsulinism hypoglycemia [14,15]. Inactive mutations are the most common type of autosomal mutations, they are known to reduce or even eliminate the protein function resulting in loss-of-function alternation in the gene affected with it. These mutations are frequently recessive because when a heterozygous individual carries two copies of the gene one of them is mutant while the other is not, which will enable the production of a fully functional protein which in turn compensates for the effect of the mutant one [13]. In hyperinsulinism hypoglycemia, 11 genes could be affected with this type of mutation leading to an uncontrolled dangerous insulin secretion process and they are: (KCNJ11, ABCC8, FOXA2, HNF1A, HNF4A, HADH, PGM1, UCP2, KCNQ1, PMM2, EIF2S3) [1,15-19].

Activating mutations cause Hyperinsulinism (Table 2)

Glutamate dehydrogenase 1 (GLUD1) gain-of-function mutation leads to (HI)

Glutamate dehydrogenase 1(GLUD1) is important because it encodes the mitochondrial glutamate dehydrogenase (GDH) enzyme, which is responsible for catalyzing a biochemical reaction that converts nicotinamide adenine (NADP) or its phosphate form into (NADPH), glutamate into alpha-ketoglutarate, and NH4+(ammonium ions) into NH3 (ammonia) [20].

This enzyme becomes functional after 6 identical monomers assemble to form a hexametric configuration, but if these hexametric structures are high in concentration, they can even bind together forming a larger structure. The (GDH) enzyme has 4 activators which are: (leucine, adenosine diphosphate (ADP), succinyl-CoA, 2aminobicyclo hebtan-2-carboxylic acid (BCH) and 2 inhibitors which are: (guanosine triphosphate (GTP), and palmitoyl-CoA) [21].

All these ligands don’t need to undergo chemical alternation to bind to their sites on this enzyme in addition the binding sites of these ligands are overlapping leading one activator or one inhibitor in some cases to displace the other causing overactivation or over-inhibition of (GDH) enzyme. 80% OF GDH-HI cases are due to de novo mutations in GLUD1 and 20% from the cases are due to autosomal dominant mutations which leads to missense amino acid substitutions in GLUD1 affecting the GTPbinding site. The overlapping of the Lucien activator makes the GDH extremely sensitive to it leading to the over-activating of this enzyme and more insulin will be released causing Lucien-sensitive hypoglycemia. Another mutation affects the GDH when it’s increased in activity, this leads to oxidation reaction of glutamate to alpha-ketoglutarate. Alpha- ketoglutarate enters the Krebs cycle which increases NADH, FADH2 and ATP levels. Increased ATP levels leads to insulin secretion as mentioned before [20].

Glucokinase (GCK) gain-of-function mutations lead to (HI)

Glucokinase (GCK), is an important protein that plays a crucial role in catalyzing the phosphorylation process of glucose into glucose-6-phosphate (G6P), initiating the pivotal entry point for glucose into various metabolic processes, in pancreatic beta cells it assumes a distinctive role as a “glucose sensor.” This protein exerts regulating control over the glucose-stimulatedinsulin- secretion-threshold (GSIS-T) and various mutations on this protein gene, either active or inactive, that known to be a reason for different types of diabatic due to its effect on (GSIS-T) by increase or decrease it [22].

Also, researchers have discovered eight different mutations which are (p.S64P, p.E67V, p.S69_E70insVPL, p.S69P, p.V91L, p.W99C, p.Y215C, p.R447L) that can affect the (GCK) protein near to the allosteric site, but four of them (p.S64P, p.S69P, p.S69_ E70insVPL, p.W99C) found in a specific part called the “loop structure” which extend from the 41 residues to 71 which helps different parts of the protein to work together, by facilitating the cooperativity between the large and the small domain of (GCK).

Shortening or lengthening of this loop leads to a dysregulated function of the enzyme, the lengthening of the loop at 69 and 70 positions can boost the enzyme activity as in mutation p.S69- E70insVPL, while the shortening can impair the enzyme function [23].

Glucokinase (GCK) has two main properties, which make it a reason for (HI) if it was affected by an active mutation, the first one displays a low affinity for glucose, with an active mutation this affinity will be heightened, which in turn enable the (GCK) to dynamically modulate its enzymic activity in response to the concentration of glucose across the phycological range (4-15 mmol/l). The second property of (GCK) is that it can remain impervious to inhibition by its product the glucose-6-phosphate (G6P), and with an active mutation this property will alter the threshold of the inhibition process and (GCK) will become less susceptible to the inhibition by glucose-6-phosphate (G6P), leading to a continuous catalyzing of the phosphorylation process indeed increasing insulin secretion even when blood glucose is low and at this stage, the patient will be in a dangerous condition of hyperinsulinism hypoglycemia [24].

Drawing upon the insight of a new novel has studied ten patients from eight families with glucokinase hyperinsulinism hypoglycemia (GCK-HI), revealed that in addition to the effect of the activation mutation on the (GSIS-T) by lowering it, it can affect the counter-regulatory glucagon secretory response in the liver by decreasing it. They could detect that when glucose concentration was 3 and 6 millimole per liter(mM), with the presence of glucokinase regulatory protein (GKRP) in a 1:1 ratio with (GCK) there was a clear notable inhibition in the wild type (GCK) activity with a percentage of 20%, and this percentage mitigated by half settling at approximately 10% when glucose elevated to 12(mM). However, this ratio had no inhibitory effect on the activating of two specific activating GCK mutants (p.V91L, p.S69-E70insVPL) across multiple glucose concentrations.

Even when this ratio increases there wasn’t any inhibitor effect in the (p.V91L) variant, while only partial reduction in activity was discernible in the (p.S69-E70insVPL) variant. This diminished responsive to GKRP-mediated inhibition within select (GCK) mutants implicit a border mechanistic framework underlying (GCK-HH) this framework extends beyond islet dysfunction, suggesting a potential role for the liver where the (GKRP) exerts its regulatory control over (GCK) activity in pathophysiology of hyperinsulinism [25].

After a comprehensive analysis was done to compare normal islets (GCK-HH) and mutant’s islets (p.S69_E70insVPL, p.W99C, p.R447L) to distinguish the insulin secretion dynamics in the (GCK-HI) islets the results showed that:
i. The (GCK-HI) islets exhibit a conspicuous augmentation in (GSIS-T) under heightened glucose concentration (25mM) coupled with a noteworthy reduction of the (GSIS-T) with (p.S69_E70insVPL, p.W99C, p.R447L) mutants’ thresholds were (1.9mM, 3.1mM, 1.2mM) in order. In contrast, the normal islets the threshold was 6.9 mM [25].
ii. (GCK-HH) islets didn’t exhibit a substantial elevation in the basal insulin release unlike the HI caused by a mutation in the voltage-gated potassium channel (KATP) (Lek M et al., 2016).
iii. (GCK-HH) islets displayed conspicuously subdued basal glucagon secretion. Stimulation with a 4mM amino acid mixture failed to elicit glucagon secretion from these islets’ alpha-cells. In contrast, in normal control islets when they were exposed to a 4mM amino acid mixture they resulted in a nearly 4-fold surge in glucagon secretion, with a minimal impact of insulin release, and when 3 mM amino acid mixture glucagon secretion was repressed, the introduction of 16.7 mM glucose further dampened glucagon secretion while concurrently provoking biphasic insulin secretion [26].

(GCK-HI) has three phenotypes which are:

• Asymptotic (GCK-HH): Individuals with (GCK) mutation may have a genetic predisposition that leads to low blood sugar levels with an absence of noticeable symptoms like (shakiness, sweating, or confusion) [24].
• Medically unresponsive (GCK-HH): Known as (hyperinsulinism of infancy) where the diazoxide therapy or other treatment cannot effectively control the insulin secretion on this level, which can pose significant challenges in managing this condition and prevent the dangerously low blood sugar surge episodes [24].
• Mild responsive hyperinsulinism hypoglycemia: Where a significant proportion of cases involve patients with active (GCK) mutations who experience a mild HH and are positively responsive to the diazoxide treatment [24]. so, 2022 a case study was done by Anojina Koneshamoorthy et al on an adult patient and his mother who were suffering from hypoglycemia, a genetic test that resulted in a genetic variation of GCK gene, computer tools were used in the analysis suggests that a genetic cause would be a reason of the hypoglycemia, which wasn’t known if it is significant or not, so to get more clarity this test was done on the patient’s sister and her son, and the results of them were the same genetic changes in (GCK) gene.

Finally, it was significant that the hypoglycemia was due to a crucial genetic change after it was uncertain. This means that testing and considering genetic factors when adults experience hypoglycemia is not less important than doing these tests only for children [27].

Hexokinase (HK1) gain-of-function mutation leads to HH

Hexokinase is an enzyme that catalysis the first step of glucose metabolism, the phosphorylation process, which converts the glucose molecule into glucose-6-phosphate(G6P), this enzyme is encoded by the (HK1) gene on chromosome number 10 [15]. Hexokinase is normally “silenced” or “forbidden” from expression in the pancreatic beta cells, which helps prevent the stimulation of the insulin secretion process when the glucose level is low in the bloodstream [1,28].

According to this, if an active mutation affects this gene, this will lead to an inappropriate and dangerous insulin secretion leading to hyperinsulinism hypoglycemia. The mutation of this gene is mainly located in a non- coding regulatory region of HK1 (in intron 2) which reflecting the enzyme action leads to insulin secretion during hypoglycemia. A family was identified to be affected with idiopathic-hypoglycemia-of-infancy due to an active gain-of-function mutation on the (HK1) gene [29]. Another in vitro study showed inappropriate (HK1) expression which was a reason for (HH) and uncontrolled insulin secretion with the normal functioning of ATP-sensitive-potassium-channel (KATP) [30].

Monocarboxylate transporter (MCT1) gene (SLC16A1) gain-of-function mutation leads to (HH)

This gene encodes a normal unexpressed enzyme in pancreatic beta cells which is the monocarboxylate transporter (MCT1), that transports the insulin secretomotor (pyruvate and lactate) helping beta cells by preventing insulin secretion in response to them [31]. Autosomal dominant gain-of-function mutation within the promoter region of (SLC16A1) results in heightened expression of (MCT1) within the pancreatic beta cells. Consequently, this prompts a persistent influx of glycolysis-produced pyruvate into the Kreps cycle, thereby provoking insulin secretion in instances of low blood glucose, notably during anaerobic exercise and particularly strenuous physical exertion [28,32].

Calcium voltage-gated channel subunit alpha 1D(CACNA1D) gain-of-function-mutation can be caused (HH)

This gene encodes the L-type calcium voltage-gated channel subunit alpha 1D. It has a crucial role in the insulin secretion process, it allows the calcium ions to inter the beta cells after the depolarization of membrane (specifically the depolymerization of potassium channel) due to increase ATP production in result of fuel metabolism, in which these molecules attach to the insulin vesicles and move them to the membrane surface for exocytosis of insulin, this gene is prominently expressed in pancreatic beta cells [14,33]. A second case was reported by Flanagan SE et al, a patient harboring a pathogenic CACNA1D variant necessitated prolonged diazoxide therapy for condition control. They exhibited a satisfactory clinical response during the initial 18 months of life [34].

Inactivating mutations cause Hyperinsulinism (Table 3)

The coding genes of the ATP-sensitive-potassiumchannel (KATP) subunits (Kir6.2 and SUR1) the (KCNJ11, ABCC8) loss-of-function mutation leads to (HH)

These two genes (KCNJ11, ABCC8) are the coding genes of the ATP-sensitive-potassium-channel (KATP) subunits (Kir6.2 and SUR1) respectively are located on the short arm of chromosome 11 (11p15.1), if these genes alternate their activity due to an inactive mutation this will lead to the most common type of hyperinsulinism hypoglycemia the (KATP-HH) accounting 40- 50% of cases (Kapoor RR et al.,2013).

Adenosine triphosphate-sensitive-potassium channel (KATP) plays a very important role in the glucose-stimulated insulin secretion pathway. After the glucose level increases in the blood, it will pass through the glucose transporter (GLUT), and then the glycolysis process will occur in the cytosol of the beta cells producing (pyruvate, ATP, NADH), which in turn will go through the citric acid cycle to produce (ATP, NADH, FADH2) in the mitochondria of the pancreatic beta cells, finally, the phosphorylation process takes its place for generating the largest amount of the adenosine triphosphate (ATP) [7].

After these adenosine triphosphates (ATP) molecules accumulate inside the pancreatic beta cells leading to change in the adenosine triphosphate: adenosine diphosphate ratio (ATP: ADP ratio), they activate the adenosine triphosphate-sensitivepotassium channel (KATP) by binding to it, inducing the closure of (KATP) channel subunits, which in turn leads to the depolarization of the membrane by the entry of sodium ions (Na₊). After that the voltage-dependent-calcium channels will open letting the calcium (Ca₂₊) to enter the cell, and finally, these ions induce the insulin secretion from the pancreatic beta cells by binding to the insulin vesicles found in beta cells taking them to the membrane surface then insulin will exocytosis into the bloodstream to control the high blood glucose [33].

Different types of mutations on (KATP) channel subunits genes can cause multiple types of Diabetes, one of them is hyperinsulinism hypoglycemia (HH) which could happen due to an inactive mutation on the (KATP) channel subunits genes, these mutations can be divided into four forms:
• Recessive (KATP) mutations: These mutations disrupt (KATP) channel biogenesis by impeding various intracellular processes, leading to a complete absence of functional (KATP) channels in the plasma membrane, which results from interference with the correct trafficking of channel subunits [1]. As a result of the absence of the channel, the beta cell membrane will stay in the depolarizing status like when it is present and enclosed in response to the (ATP), so this will lead to an uncontrolled continuous insulin secretion of insulin. However, in all cases mothers should be screened and test for the presence of recessive mutations to avoid diffuse or focal disease in future pregnancies [33].
• Dominant (KATP) mutations: Dominant KATP mutations manifest as missense defects allowing normal subunit trafficking to the plasma membrane, but they will act as dominant negative factors within the hetero-octameric (KATP) complex [1]. This type of mutation severely compromises channel activity and remains unresponsive to the diazoxide, and somatostatin would help in this case [34,35]. Dominant heterozygous mutations have 50% while recessive homozygous mutations have 25% of disease recurrency [36].
• Diazoxide-responsive dominant (KATP) channel mutations: Certain dominant (KATP)mutations exhibit partial preservation of (KATP) channel activity, rendering them amenable to modulation by diazoxide intervention. These three forms of (KATP-HH) are known to be diffuse and affect all pancreatic beta cells. Generally, genetic, pedigree of patients and in vitro functional studies must be done to discover the cases [1].
• Focal form of (KATP-HH): This form includes the inheritance of recessive (KATP) mutations transmitted from the parental side, coupled with secondary postzygotic events, that lead to loss of the maternal heterozygosity for the 11p15.1 genomic rejoin intricate interplay of genetic factors culminates in the localized manifestation of (HH) within the pancreas while in diffuse form the entire pancreas is affected [37,38].

There is difficulty in detecting a patient’s infection by focal or diffuse disease. But there are some methods like PET imaging using F-fluoro-L-DOPA and genetic information from the parents to detect the type of disease. 95% of focal disease has a recessive mutation in ABCC8 or KCNJ11. In most cases, diffuse form needs pancreatectomy to avoid other complications of hypoglycemia if the patients don’t respond to treatment [39].

Forkhead box protein A2 (FOXA2) loss-of-function mutation on its gene can cause (HH)

Foxa2 is located on chromosome 20 (20p11). Mutations in the Forkhead box protein A2 (FOXA2) have been identified as responsible for a set of medical conditions including hypopituitarism, congenital hyperinsulinism hypoglycemia (CHH), and various structural anomalies within endodermderived organs [14]. Foxa2, considered as DNA-binding proteins, plays a role in multiple tissue development. Mutation in this gene -loss of function- leads to embryonic lethal. There is a connection between Foxa2, ABCC8 and KCNJ11 in regulation of insulin secretion. Any mutation in any of these genes leads to HH [40].

Children affected by these mutations exhibit a unique clinical profile characterized by manifestations of hypopituitarism, (CHH), dysmorphic facial characteristics, as well as aberrations affecting vital organs such as the liver, pancreas, heart, and gastrointestinal system. Also, Foxa2 plays a major role in morphogenesis of the central nervous system by controlling the expression of Gli2, SHH and Nkx2 [16].

Hepatocyte nuclear factor genes (HNF1A, HNF4A) lossof- function mutation causes (HH)

Hepatocyte nuclear factor genes, namely (HNF14, and HNF4A) encode the HNF-1 alpha and HNF-4 alpha respectively, and they are transcription factors that play a pivotal role in glucose-insulinsecretion in pancreatic beta cells. They are normally expressed in these cells, and it is considered as autosomal dominant disease that manifest in youth [28]. Loss-of-function mutations in these genes have been identified in individuals with maturity-onset diabetes of young (MODY) and autosomal dominant diabetes type typically diagnosed before age 25. Inactivating mutations in HNF1A and HNF4A cause the maturity-onset diabetes of youth (MODY)-3 and (MODY)-1 forms of monogenic diabetes respectively (Colclough K et al.,2013).

Mutations on (HNF1) were described to be the second most common reason for having (HH) after the (KATP-HH) [7]. (HNF4A) mutations have a unique impact, causing a two-phase phenotype, with some individuals initially experiencing macrosomia and transient neonatal hypoglycemia followed by diabetes later in life [41].

In 2017 a case study was performed by Jonna Yuet et al. who reported that even when (HNF1A, and HNF4A) weren’t statically significantly different between individuals with mutations on these genes, notably those with inactive mutations on (HNF4A) gene were highly probable to be born with large weight for gestational age than those with an inactive mutation on (HNF1A) gene. The inheritance of (HNF1A) mutation was mostly from the father side, while the percentage of inheriting (HNF4A) mutations from both parents was close in this study and only one case was described to be “de novo” mutation [18]. The third common cause of diazoxide-responsive congenital hyperinsulinism is mutation in HNF4A [42].

The HADH gene, which encodes the Short Chain L-3 hydroxy Acyl-CoA Dehydrogenase (SCHAD), inactive mutation leads to (HH)

(HADH) is the recessive mutations in gene encoded the hydroxy Acyl-CoA Dehydrogenase that encoding SCHAD enzyme 3- hydroxy acyl-CoA dehydrogenase, which is the inhibitor for the Glutamate dehydrogenase (GDH) enzyme catalyzes the oxidative deamination of glutamate into alpha-ketoglutarate and ammonia process. HADH is located on chromosome 4 (4 q 22-26) with 8 exons, it’s known to be highly expressed in the pancreatic beta cells under the transcription factors controlled. If a deficiency of this short-chain inhibitor occurs this will lead to a loss of the inhibition process to the (GDH) enzyme. This will happen due to inactive mutation on the (SCHAD) binding site encoded gene the (HADH) on (GDH)enzyme. At the same time, it is binding to the (BCH) activator [11,20].

In summary to what happened in this case, the (GDH) enzyme is binding to the activator (BCH) leading to catalyzing the oxidative deamination of the glutamate, which in turn leads to an increase in alpha-ketoglutarate amount, NADH, and NADPH in the mitochondria, these elevated levels of these products will inhibit the isocitrate dehydrogenase enzyme, which will cause to an accumulation of citrate without being converted into isocitrate after this citrate will be transported from the mitochondria to the cytosol where the citrate utilize to synthesize the short and long chain of Acyl-CoA, that is known to be an insulin secretion signaling molecules. Finally, when the glucose level rises and stimulates the insulin secretion, while there is also a high amount of citrate, this will be a reason to start an uncontrolled insulin secretion process causing (HH) [20]. Most patients who are affected by this type of (HH) are diazoxide-responsive. In rare cases, patients with HADH deficiency suffer from elevated in plasma 3- hydroxy butyryl- carnitine levels. Genetic testing of (HADH) gene is also recommended in this case which are negative for (KATP) mutations [42].

Phosphoglucomutase1 (PGM1) loss-of-function mutation leads to (HH)

Phosphoglucomutase1 (PGM1), is a crucial enzyme that is responsible for the reversible conversion between glucose-6- phosphate (G6P) and glucose-1-phosphate (G1P), also it plays a vital role in different biological processes such as glucagon formation, glycogenesis, and protein glycosylation [11]. PGM1 is located on chromosome 1 (1p31). Loss - of- function mutations on this enzyme when inherited in a recessive manner can lead to rare disorders characterized by various clinical features including hyperinsulinism hypoglycemia; because PGM1 mutations lead to decrease glucose mediated insulin secretion from pancreas [43].

Patients have mutations in PGM1 show symptoms like glycogenesis (type XIV) and glycosylation (CDG type 1t). Children affected with this enzyme mutations suffer from both fasting ketonic hypoglycemia (which is low blood glucose with elevated ketone levels), symptomatic postprandial hypoketotic (which is characterized by low blood glucose levels without elevated ketone levels), short stature, dilated cardiomyopathy, and cardiac arrest [44].

Mitochondrial carrier protein (UCP2) inactive mutation and (HH).

UCP2, an inner mitochondrial carrier protein encoded by the (UCP2) gene, exhibits widespread tissue expression including pancreatic cells. It functions as a mediator of proton leak across the inner mitochondrial membrane, thus impeding ATP generation through mitochondrial oxidative metabolism. This in turn exerts a negative regulatory influence on glucose-insulin-mediated secretion [45-47]. When (UCP2) gene has inactivating mutations that make it less effective, which in turn can lead to increased glucose metabolism due to the increase in ATP production causing (HH). This type of (HH) caused by loss-of-function on the (UCP2) gene can range from short-term to long-lasting episodes [46,48,49].

A previous study that was done in 2017 by Laver TW et al showed that 206 diazoxide-responsive patients didn’t have any significant (UCP2) mutations, only a common genetic variation [50]. Only one case showed a positive result for a mutation of the (UCP2) gene among 211 patients who were diazoxide-responsive in a study that was done by Ferrara et al [48].

Eukaryotic translation initiation factor 2 subunit 3 (eIF2S3) loss-of-function mutation and (HH)

Eukaryotic translation factor 2 subunit 3 is a heterotrimeric GTP- binding protein with 40 S ribosomal subunit and methionyltRNA with start codon to initiate the protein synthesis. It’s located on chromosome X (Xp22.11) and it has three subunits. Mutations in this translation factor affect translation initiation near starting codon like AUU and UUG leads to different diseases. Individuals with variants in (eIF2S3) display an unusual pattern of glucose regulation. They experience fluctuations between being responsive to diazoxide for (HH) and experiencing postprandial hyperglycemia. Additionally, these individuals exhibit learning difficulties and hypopituitarism [51].

Phosphomannomutase 2 (PMM2) mutation and (HH)

Phosphomannomutase 2 encoding gene (PMM2) plays a pivotal role in the N-glycosylation process led to glycoprotein synthesis significantly influencing insulin secretion in pancreatic cells [8]. N- glycosylation means: glycans carbohydrates are covalently attached to protein from N-terminal side which improves protein stability. PMM2 gene located on chromosome 16 (16p13.2). PMM2 enzyme which is encoded by PMM2 gene transfer mannose 6- phosphate to mannose 1 phosphate in glycosylation process. Homozygous recessive mutation in PMM2 leads to disease related to CDG type 1a. As mentioned early, HH is a part of CDG type 1a, mutations in PMM2 gene promoter significantly influencing insulin secretion in pancreatic cells leads to hyperinsulinism hypoglycemia and polycystic kidney diseases because this mutation specifically affect the formation of chromatin loop which change the gene expression of organ. Patients are usually born larger than normal in gestational age, and experience hypoglycemia in early life but usually respond to diazoxide treatment [14,52].

Conclusion

In conclusion, the classification of the genes causing hyperinsulinism hypoglycemia is according to the mutation types they could go through. Firstly, the active mutations which can affect 5 genes (GLUD1, GCK, SLC16A1, HK1, CACNA1D), with minimal research on (CACNA1D) gene. Secondly, the inactive mutations that can affect 11 genes: (KCNJ11, ABCC8, FOXA2, HNF1A, HNF4A, HADH, PGM1, UCP2, KCNQ1, PMM2, EIF2S3) including the most common cause of hyperinsulinism hypoglycemia which is the mutation on (KCNJ11, ABCC8) genes and limited research on (KCNQ1) gene with only one case on (UCP2) gene.Respectively all these genes play an important role in glucose metabolism and insulin secretion individually and collectively to maintain blood glucose in the normal range.

Recommendations

Considering all genetic causes of hyperinsulinism hypoglycemia (HH) in its different types, there are still many genes that need to be studied more such as (UCP2), (KCNQ1) and (CACN1D) to encode its enhancing role in continuous low blood glucose in the early years of life. Since there are multiple studies focusing on the genetic variations connected with hyperinsulinism hypoglycemia (HH), there are many other questions about the epigenetic variations related to it, which have always been done to be related only to the general types of diabetes mullites. In addition to that we need to know more about how to avoid the effect of (HH) in the later life of patients, and what other technology could be practice limiting these mutations from happening in an early stage to those people with a history of diabetes mullites, and how to check it in early stages.

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