Lakhasly

2.4.As a possible cause of MODY subtypes 7-14, eight genes have been suggested: Kruppel-like factor 11 (KLF11); carboxyl ester lipase; paired-box-containing gene 4 (PAX4); insulin (INS); B-lymphocyte kinase; adenosine triphosphate (ATP)-binding cassette, subfamily C (CFTR/MRP) number 8 (ABCC8); potassium channel, inwardly rectifying subfamily J, member 11 (KCNJ11); adaptor protein, phosphotyrosine interaction, PH domain, and leucine zipper containing (APPL1) [27].For T3cDM, characteristic parameters include the following: rare ketoacidosis, mild hyperglycemia, common hypoglycemia, increased peripheral insulin sensitivity, decreased hepatic insulin Int.T3cDM is associated with pancreatic diseases, such as pancreatic carcinoma, acute and chronic pancreatitis, cystic fibrosis, pancreatectomy and others [23].PDX1 is a transcription factor that is involved in the exocrine and endocrine development of the pancreas and affects pancreatic development and expression of the insulin gene [19,26,27].Maturity-Onset Diabetes of the Young Maturity-Onset Diabetes of the Young (MODY) is characterized by the onset of hyperglycemia detected at an early age, before age 25 years, although diagnosis may happen at older ages.2025, 26, 542 4 of 50 sensitivity, insulin, glucagon, PP and GIP levels are low, and any typical age of onset [20].The glucokinase gene is involved in the regulation of the amount of insulin produced by the pancreatic ?-cells in response to blood glucose levels.NEUROD1 is a basic-loop-helix transcription factor associated with pancreatic and neuronal development.This DM is secondary to pancreatic disease, due to diseases of the exocrine pancreas [19].This type of MODY causes only minor changes in blood glucose levels, resulting in a rare development of diabetic complications [19,26,27].MODY is often inherited as an autosomal dominant disease, in which at least 14 genes on different chromosomes are involved.Six genes encode proteins which correspond to MODY subtypes 1-6 [19,27].Type 3c Diabetes Mellitus Type 3c diabetes mellitus (T3cDM) is also known as pancreoprivic or pancreatogenic diabetes.Approximately 0.11% of patients with diseases of the exocrine pancreas have DM [24].It decreases the amount of insulin produced by the pancreas, causing diabetes.T3cDM affects approximately 9.2% of diabetic patients [25].The most commonly diagnosed types are MODY 1, MODY 2 and MODY 3 which account for 95% of cases [19,26].MODY 1--Hepatic Nuclear Factor 4 ?MODY 3--Hepatic Nuclear Factor 1 ?It may be misdiagnosed as T1DM, although patients are autoantibody negative [19,26,27].MODY 5--Hepatic Nuclear Factor 1 ?It is important to recognize, because MODY 5 may cause kidney problems in the form of renal cysts [26,27].It is involved in maturation and maintenance of the pancreatic ?-cell [26,27].Neonatal Diabetes Neonatal diabetes is a diabetes that occurs before 6 months of age.It affects 1-2% of diabetic patients.There are different subtypes of MODY (MODY 1 to MODY 14).MODY 2--Glucokinase.This subtype of MODY accounts for 70% of cases of MODY.MODY 3 is often related to a very strong family history of diabetes.MODY 4--PDX-MODY.(HNF-1?) is a very rare form of MODY.MODY 6--NEUROD1-MODY.J. Mol.Sci.(HNF-4?) is similar to HNF-1 ?, which is much less common [19,26,27].(HNF-1?).2.5.2.6.

2.4. Type 3c Diabetes Mellitus
Type 3c diabetes mellitus (T3cDM) is also known as pancreoprivic or pancreatogenic
diabetes. This DM is secondary to pancreatic disease, due to diseases of the exocrine
pancreas [19]. T3cDM is associated with pancreatic diseases, such as pancreatic carcinoma,
acute and chronic pancreatitis, cystic fibrosis, pancreatectomy and others [23]. For T3cDM,
characteristic parameters include the following: rare ketoacidosis, mild hyperglycemia,
common hypoglycemia, increased peripheral insulin sensitivity, decreased hepatic insulin
Int. J. Mol. Sci. 2025, 26, 542 4 of 50
sensitivity, insulin, glucagon, PP and GIP levels are low, and any typical age of onset [20].
Approximately 0.11% of patients with diseases of the exocrine pancreas have DM [24].
T3cDM affects approximately 9.2% of diabetic patients [25].
2.5. Maturity-Onset Diabetes of the Young
Maturity-Onset Diabetes of the Young (MODY) is characterized by the onset of hyperglycemia detected at an early age, before age 25 years, although diagnosis may happen
at older ages. It affects 1–2% of diabetic patients. There are different subtypes of MODY
(MODY 1 to MODY 14). The most commonly diagnosed types are MODY 1, MODY 2 and
MODY 3 which account for 95% of cases [19,26].
MODY 1—Hepatic Nuclear Factor 4 α (HNF-4α) is similar to HNF-1 α, which is much
less common [19,26,27].
MODY 2—Glucokinase. The glucokinase gene is involved in the regulation of the
amount of insulin produced by the pancreatic β-cells in response to blood glucose levels.
This type of MODY causes only minor changes in blood glucose levels, resulting in a rare
development of diabetic complications [19,26,27].
MODY 3—Hepatic Nuclear Factor 1 α (HNF-1α). This subtype of MODY accounts
for 70% of cases of MODY. It decreases the amount of insulin produced by the pancreas,
causing diabetes. MODY 3 is often related to a very strong family history of diabetes. It
may be misdiagnosed as T1DM, although patients are autoantibody negative [19,26,27].
MODY 4—PDX-MODY. PDX1 is a transcription factor that is involved in the exocrine and endocrine development of the pancreas and affects pancreatic development and
expression of the insulin gene [19,26,27].
MODY 5—Hepatic Nuclear Factor 1 β (HNF-1β) is a very rare form of MODY. It
is important to recognize, because MODY 5 may cause kidney problems in the form of
renal cysts [26,27].
MODY 6—NEUROD1-MODY. NEUROD1 is a basic-loop-helix transcription factor
associated with pancreatic and neuronal development. It is involved in maturation and
maintenance of the pancreatic β-cell [26,27].
As a possible cause of MODY subtypes 7–14, eight genes have been suggested:
Kruppel-like factor 11 (KLF11); carboxyl ester lipase; paired-box-containing gene 4 (PAX4);
insulin (INS); B-lymphocyte kinase; adenosine triphosphate (ATP)-binding cassette, subfamily C (CFTR/MRP) number 8 (ABCC8); potassium channel, inwardly rectifying subfamily J, member 11 (KCNJ11); adaptor protein, phosphotyrosine interaction, PH domain,
and leucine zipper containing (APPL1) [27].
MODY is often inherited as an autosomal dominant disease, in which at least 14 genes
on different chromosomes are involved. Six genes encode proteins which correspond to
MODY subtypes 1–6 [19,27].
2.6. Neonatal Diabetes
Neonatal diabetes is a diabetes that occurs before 6 months of age. Therefore, it is
termed as “neonatal” or “congenital”. T1DM rarely occurs before 6 months of age. This
type of DM may be either transient or permanent [19]. The first form, transient neonatal
diabetes, is most often caused by overexpression of genes located on chromosome 6q24,
and in about half of cases it is recurrent. The second form, permanent neonatal diabetes,
is most commonly caused by autosomal dominant mutation in the genes which encode
the Kir.2 subunit (KCNJ11) and SUR1 subunit (ABCC8) of the β-cell KATP channel and by
mutation in gene EIF2B1 affecting eIF2 signaling [28]. The second, most common cause of
permanent neonatal diabetes is associated with mutations in the insulin gene, which are
also predominantly inherited [19].
Int. J. Mol. Sci. 2025, 26, 542 5 of 50
2.7. Latent Autoimmune Diabetes in Adults (LADA)
LADA, also termed 1.5 diabetes mellitus [29], accounts for 2–12% of all patients with
adult-onset DM. Patients with LADA exhibit a slowly progressive form of autoimmune
diabetes with immune markers of type 1 diabetes mellitus in serum. Diagnostic criteria
for LADA are the following: adult-onset DM (>30 years at diagnosis), presence of autoantibodies associated with diabetes, and no requirement for insulin for least 6 months after
diagnosis [29]. Several autoantibodies are detected in LADA patients, such as autoantibody
against glutamic acid decarboxylase (GADA), which is the most sensitive marker used
for screening. Other autoantibodies include those acting against islet cells (ICA), protein
tyrosine phosphatase IA-2 (IA-2A), insulin (IAA), the islet-specific zinc transporter isoform 8 (ZnT8A), tetraspanin 7, and others [30–32]. There is also another, similar type of
slowly progressive form of diabetes that is diagnosed in early-onset cases, called Latent
Autoimmune Diabetes in the Young (LADY) [33].
2.8. Alström Syndrome
Alström syndrome (ALMS1) is a rare autosomal recessive genetic disorder. Its prevalence is from 1 in 500,000 to 1 in 1,000,000 [34]. It has been identified worldwide in
approximately 1200 cases [35] and this syndrome affects both sexes equally [36]. It is due
to mutation in the ALMST1 gene, located on chromosome 2p13. Mutations in this gene are
due to insertions, deletions and nonsense mutations, detected primarily in exons 8, 10 and
16. ALMS1 was first described in 1959 [37,38]. This gene encodes the ALMS1 protein that is
found in centrosomes, basal bodies and cytosol [39]. This protein is involved in the function
of cilia and its absence causes impairment of the formation of cilia [40]. The ALMS1 protein
is also associated with homeostasis of energy metabolism, control of cell cycles, ciliary
signaling pathways and intracellular trafficking [41]. Alström syndrome is also classified
as a ciliopathy, because it causes abnormal cilia function and formation [42,43]. Diagnosis
of Alström syndrome is difficult because some features begin at birth, whereas others are
detected as the child develops [44]. Within and among families, symptoms differ between
patients with this syndrome [44]. In children, the major phenotypes include cone-rod
retinal dystrophy that begins in infancy and may cause juvenile blindness, sensorineural
hearing, impairment obesity, insulin resistance, and congestive heart failure caused by
dilated cardiomyopathy. In adolescence T2DM, hyperinsulinemia, hypertriglyceridemia,
short stature, scoliosis, alopecia, and progressive renal, pulmonary and hepatic dysfunction
are observed. Fibrosis of unknown etiology may develop in multiple organs. In adulthood,
male patients exhibit hypogonadism and female patients, hyperandrogenism. Patients
with Alström syndrome rarely exceed the age of 50 [36,39,44].
2.9. Wolfram Syndrome
Wolfram syndrome (WS) is a rare, progressive neurodegenerative disease. It is an autosomal recessive disorder [45,46]. This disease is also described by the acronym DIDMOAD
(Diabetes insipidus, early-onset non-autoimmune insulin-dependent Diabetes Mellitus, Optic
Atrophy and Deafness) [47]. According to the draft International Classification of Diseases
(ICD-11), it is categorized as a rare specific diabetes mellitus, subcategory 5A16.1, Wolfram
Syndrome [48]. Its global prevalence is one in 500,000 [49], or, based on other observations, it is
estimated to afflict about 1 in 160,000–770,000 [50,51]. Patients with WS exhibit juvenile-onset
diabetes mellitus, diabetes insipidus, optic nerve atrophy, sensorineural deafness, hearing loss,
abnormal urinary tract function, neurodegeneration and neuropsychiatric disorders [43,52].
The first manifestation of WS is DM, usually diagnosed around age 6 [51]. The prognosis of WS
is currently poor. Most patients die prematurely with severe neurological disabilities as a result
of brain stem atrophy. The average life of patients with WS is approximately 30 years (full
Int. J. Mol. Sci. 2025, 26, 542 6 of 50
range 25–49 years) [51,53]. There are two phenocopies of WS: Wolfram Syndrome type 1 (WS1)
and Wolfram Syndrome type 2 (WS2), which are due to homozygous mutations of WFS1 and
CISD2 genes, respectively [52]. It is also the Autosomal Dominant Wolfram-like syndrome due
to heterozygous mutations in the WFS1 gene [52]. Wolfram Syndrome 1, commonly referred
to as Wolfram syndrome, was first described in 1938 by Wolfram and Wagener in a family of
eight siblings. Four had optic nerve atrophy and juvenile diabetes mellitus [54]. Its prevalence
differs in dependence on the geographical region: from 1/54,478 in North-Eastern Sicily [55] to
1/700,000 in the general population and 1/500,000 in the pediatric population of the UK [48].
As mentioned above, WS1 is due to mutations in the WFS1 gene, located on chromosome
4p16.1. It encodes the glycoprotein wolframin. To date, more than 200 mutations have been
identified, mainly located in exon 8 [56]. It was found that nonsense and frameshift mutations
had more severe phenotypic presentation in comparison with missense mutations [57]. Wolframin is a membrane glycoprotein located in the endoplasmic reticulum. It is involved in
Ca2+ homeostasis and regulation of the endoplasmic reticulum stress response [58]. Wolframin
is highly expressed in brain regions, such as the hippocampus, amygdala, allocortex, and
olfactory bulb, as well as in pancreatic cells, heart, lung and placenta [47,59]. Mutations in the
gene that encodes wolframin causes dysfunction of endoplasmic reticulum and mitochondria,
resulting in apoptosis and cell death [60]. WS2 is a rarer form of WS due to mutation in the
CISD2 gene, located on chromosome 4p22–q24 [61]. It codes the zinc-finger protein called
endoplasmic reticulum intermembrane small protein (ERIS). This protein is involved in the
integrity of endoplasmic reticulum and mitochondrial membrane, as well as in the functional
interaction between these two cellular compartments [62]. ERIS is expressed in several tissues,
such as brain and pancreas [59,63].