Chapter 3Genetic Factors in Type 2

Chapter 3Genetic Factors in Type 2 Diabetes
Created: July 7, 2004.

Type 2 diabetes has been loosely defined as "adult onset" diabetes, although as diabetes becomes more common throughout the world, cases of type 2 diabetes are being observed in younger people. It is increasingly common in children.

In determining the risk of developing diabetes, environmental factors such as food intake and exercise play an important role. The majority of individuals with type 2 diabetes are either overweight or obese. Inherited factors are also important, but the genes involved remain poorly defined.

In rare forms of diabetes, mutations of one gene can result in disease. However, in type 2 diabetes, many genes are thought to be involved. "Diabetes genes" may show only a subtle variation in the gene sequence, and these variations may be extremely common. The difficulty lies in linking such common gene variations, known as single nucleotide polymorphisms (SNPs), with an increased risk of developing diabetes.

One method of finding the diabetes susceptibility genes is by whole-genome linkage studies. The entire genome of affected family members is scanned, and the families are followed over several generations and/or large numbers of affected sibling-pairs are studied. Associations between parts of the genome and the risk of developing diabetes are looked for. To date only two genes, calpain 10 (CAPN10) and hepatocyte nuclear factor 4 alpha (HNF4A), have been identified by this method.

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The Sulfonylurea Receptor (ABCC8)

Summary

Sulfonylureas are a class of drugs used to lower blood glucose in the treatment of type 2 diabetes. These drugs interact with the sulfonylurea receptor of pancreatic beta cells and stimulate insulin release. The sulfonylurea receptor is encoded by the ABCC8 gene, and genetic variation of ABCC8 may impair the release of insulin.

Nomenclature

Official name: ATP-binding cassette, sub-family C, member 8
Official gene symbol: ABCC8
Alias: sulfonylurea receptor, SUR, SUR1

Background

The protein encoded by the ABCC8 gene is a member of the ATP-binding cassette transporters. These proteins use energy in the form of ATP to drive the transport of various molecules across cell membranes. ABCC8 belongs to a subfamily of transporters that contains the chloride channel that is mutated in cystic fibrosis (CFTR) and also the proteins that are involved in multi-drug resistance.

Read more: The Human ATP-Binding Cassette (ABC) Transporter Superfamily

The ABCC8 protein is also known as the sulfonylurea urea receptor (SUR). SUR is one of the proteins that composes the ATP-sensitive potassium channel (KATP channel) found in the pancreas (1). The other protein, called Kir6.2, forms the core of the channel and is encoded by the KCNJ11 gene. KATP channels play a central role in glucose-induced insulin secretion by linking signals derived from glucose metabolism (a rise in ATP) to membrane depolarization (due to KATP channels closing) and the secretion of insulin.

The activity of the KATP channel regulates the release of insulin. The sulfonylureas are drugs that can modulate KATP channel activity and are used in the treatment of type 2 diabetes. By binding to SUR, they inhibit the channel and stimulate the release of insulin. This leads to a lowering of blood glucose levels.

The activity of the KATP channel is also modulated by the subtype of SUR (SUR, also known as SUR1, is encoded by ABCC8; or SUR2A and SUR2B, which are encoded by ABCC9). In the pancreas, most KATP channels are thought to be a complex of four SUR1 proteins and four Kir6.2 proteins.

Mutations in either ABCC8 or KCNJ11 can result in up-regulated insulin secretion, a condition termed familial persistent hyperinsulinemic hypoglycemia of infancy (PHHI) (2-4). Genetic variation in ABCC8 has also been implicated in the impaired release of insulin that is seen in type 2 diabetes.

Molecular Information

ABC genes are found in many different eukaryotic species and are highly conserved between species, indicating that many of these genes existed early in eukaryotic evolution. A BLAST search using human ABCC8 as a query finds proteins in 30 different species, which include multicellular organisms (metazoans), fungi, and plants. Potential true homologous genes have been identified in the mouse and rat.

By fluorescence in situ hybridization, it was found that the ABBC8 gene maps to the short arm of chromosome 11 (Figure 1) (5). It has 41 exons (coding regions) that span over 84,000 bases (see evidence).

Figure 1. Location of ABCC8 on the human genome.
Figure 1

Location of ABCC8 on the human genome.
ABCC8 maps to chromosome 11, approximately between 17,370 and 17,470 kilobases (kb). Click Image maplink.jpg or here for a current and interactive view of the location of ABCC8 in the human genome. Note: this figure was (more...)
The ABC transporter proteins, such as ABCC8, typically contain two ATP-binding domains and two transmembrane domains (view domains).

The ATP-binding domains are also known as nucleotide binding folds (NBFs), and mutations in either NBF1 or NBF2 can lead to PHHI (6). This suggests that both NBF regions of the SUR are needed for the normal regulation of KATP channel activity.

As found in all proteins that bind ATP, the nucleotide binding domains of the ABC family of proteins contain characteristic motifs called Walker A and B. The Walker A motif contains a lysine residue that is critical for activating the KATP channel. When this lysine residue is mutated in NBF1, but not NBF2, the KATP channel can no longer be activated (7). In addition, ABC genes also contain a signature C motif.

The transmembrane domains contain 6–11 membrane spanning helices, and the ABCC protein contains 6. These helices provide the protein with specificity for the molecule they transport across the membrane.

Several single nucleotide polymorphisms (SNPs) have been found within the ABCC8 gene. Usually SNPs linked with disease occur within the coding regions (exons) of the genes, and they result in a non-synonymous amino acid change. In ABCC8, there are seven such SNPs (at the time of writing) that cause a switch of amino acids in the mature protein (Figure 2). However, one of the SNPs of the ABCC8 gene that has been linked with diabetes (R1273R) does not cause an amino acid change (see below).

Figure 2. SNP positions of ABCC8 mapped to the 3D structure of a multidrug resistance ABC transporter homolog in Vibrio cholera.
Figure 2

SNP positions of ABCC8 mapped to the 3D structure of a multidrug resistance ABC transporter homolog in Vibrio cholera.
The figure shows the positions of non-synonymous amino acid changes (green residues) caused by SNPs in the coding sequence. (more...)
ABCC8 and Diabetes: Digest of Recent Articles

For a more complete list of research articles on ABCC8 and diabetes, search PubMed.

The two genes that encode the KATP channel, ABBC8 and KCNJ11, reside adjacent to one another on chromosome 11. A variant of ABCC8, called A1369S, is in almost complete linkage disequilibrium with a variant of KCNJ11 called E23K. This means that from the genetic evidence, it is difficult to determine whether it is the A1369S variant or the E23K variant that predisposes to type 2 diabetes (8).

A mutation in ABCC8 was observed to cause an extremely rare form of diabetes, autosomal dominant diabetes, in a Finnish family (9). The switch of glutamate to lysine at residue 1506 (E1506K) in the SUR1 protein caused a congenital hyperinsulinemia. The mutation reduced the activity of KATP channels, increasing insulin secretion. By early adulthood, the ability of the beta cells to secrete adequate amounts of insulin was exhausted, leading to diabetes (10).

A silent variant in exon 31 of the ABCC8 gene has been associated with high concentrations of insulin in non-diabetic Mexican Americans. The codon AGG is mutated to AGA, but this still codes for the residue arginine (R1273R). The normal and mutant alleles were called G and A, respectively. Among non-diabetics, those who were homozygous for the mutant allele (AA genotype) had higher levels of insulin when fasting, compared with heterozygotes (AG) and normal wild-type (GG). Because type 2 diabetes is more common in Mexican Americans than in the general US population, it has been proposed that individuals with the AA genotype are at a higher risk of diabetes because of an over-secretion of insulin (11).

Two common polymorphisms of the ABCC8 gene (exon 16-3t/c and exon 18 T/C) have been variably associated with type 2 diabetes. However, a recent large case control study in Britain revealed that these ABCC8 variants did not appear to be associated with diabetes (12).

Link Roundup for ABCC8

Live Searches

Diabetes and ABCC8 in PubMed | PubMed Central | Books

Background Information

ABCC8 in OMIM

The Human ATP-Binding Cassette (ABC) Transporter Superfamily on the Bookshelf

Molecular Biology

ABCC8 in Entrez Gene | Evidence Viewer | Map Viewer | Domains: Transmembrane region 1, ATPase 1, Transmembrane domain 2, ATPase 2 | SNPs | BLink | HomoloGene

References

Hasil (Bahasa Indonesia) 1:

Bab 3Genetic faktor dalam Diabetes Tipe 2Dibuat: 7 Juli 2004.Diabetes tipe 2 telah longgar ditetapkan sebagai "dewasa onset" diabetes, meskipun sebagai diabetes menjadi lebih umum di seluruh dunia, kasus-kasus diabetes tipe 2 sedang diamati pada orang muda. Hal ini semakin umum pada anak-anak.Dalam menentukan risiko mengembangkan diabetes, faktor-faktor lingkungan seperti asupan makanan dan latihan memainkan peran penting. Mayoritas individu dengan tipe 2 diabetes kelebihan berat badan atau obesitas. Faktor-faktor warisan juga penting, tetapi gen yang terlibat tetap didefinisikan dengan buruk.Dalam bentuk langka diabetes, mutasi gen satu dapat mengakibatkan penyakit. Namun, dalam diabetes tipe 2, banyak gen dianggap terlibat. "Diabetes gen" mungkin menunjukkan hanya variasi halus di urutan gen, dan variasi ini mungkin sangat umum. Kesulitan terletak di menghubungkan variasi gen tersebut umum, yang dikenal sebagai polimorfisme nukleotida tunggal (SNP), dengan peningkatan risiko mengembangkan diabetes.Salah satu metode mencari diabetes gen kerentanan adalah dengan studi keseluruhan-genom linkage. Genom seluruh anggota keluarga yang terkena scan, dan keluarga yang diikuti lebih dari beberapa generasi dan/atau jumlah besar terkena pasangan saudara kandung yang dipelajari. Asosiasi antara bagian dari genom dan risiko mengembangkan diabetes tampak untuk. Sampai saat ini hanya dua gen, calpain 10 (CAPN10) dan hepatosit nuklir faktor 4 alpha (HNF4A), telah diidentifikasi dengan metode ini.Pergi ke: pergi ke:Reseptor sulfonilurea (ABCC8)RingkasanSulfonylureas adalah kelas obat-obatan yang digunakan untuk menurunkan glukosa darah dalam pengobatan diabetes tipe 2. Obat ini berinteraksi dengan reseptor sulfonilurea sel beta pankreas dan merangsang pelepasan insulin. Sulfonilurea reseptor dikodekan oleh ABCC8 gen, dan variasi genetik yang ABCC8 dapat mengganggu melepaskan insulin.Tata namaNama resmi: ATP mengikat kaset, sub keluarga C, anggota 8 Simbol resmi gen: ABCC8Alias: sulfonilurea reseptor, SUR, SUR1Latar belakangProtein yang dikodekan oleh gen ABCC8 adalah anggota transporters kaset mengikat ATP. Protein ini menggunakan energi dalam bentuk ATP untuk mendorong transportasi berbagai molekul melintasi selaput sel. ABCC8 milik subfamili pengangkut yang berisi saluran klorida yang bermutasi di cystic fibrosis (CFTR) dan juga protein yang terlibat dalam resistensi multi-obat.Baca lebih lanjut: superfamili Transporter manusia ATP mengikat kaset (ABC)ABCC8 protein ini juga dikenal sebagai reseptor urea sulfonilurea (SUR). SUR adalah salah satu protein yang menyusun ATP-sensitif kalium saluran (KATP channel) ditemukan di pankreas (1). Protein lain, disebut Kir6.2, membentuk inti dari saluran dan dikodekan oleh KCNJ11 gen. KATP saluran memainkan peran sentral dalam sekresi insulin glukosa-diinduksi dengan menghubungkan sinyal berasal dari metabolisme glukosa (kenaikan ATP) ke membran depolarization (karena saluran KATP penutup) dan sekresi insulin.The activity of the KATP channel regulates the release of insulin. The sulfonylureas are drugs that can modulate KATP channel activity and are used in the treatment of type 2 diabetes. By binding to SUR, they inhibit the channel and stimulate the release of insulin. This leads to a lowering of blood glucose levels.The activity of the KATP channel is also modulated by the subtype of SUR (SUR, also known as SUR1, is encoded by ABCC8; or SUR2A and SUR2B, which are encoded by ABCC9). In the pancreas, most KATP channels are thought to be a complex of four SUR1 proteins and four Kir6.2 proteins.Mutations in either ABCC8 or KCNJ11 can result in up-regulated insulin secretion, a condition termed familial persistent hyperinsulinemic hypoglycemia of infancy (PHHI) (2-4). Genetic variation in ABCC8 has also been implicated in the impaired release of insulin that is seen in type 2 diabetes.Molecular InformationABC genes are found in many different eukaryotic species and are highly conserved between species, indicating that many of these genes existed early in eukaryotic evolution. A BLAST search using human ABCC8 as a query finds proteins in 30 different species, which include multicellular organisms (metazoans), fungi, and plants. Potential true homologous genes have been identified in the mouse and rat.By fluorescence in situ hybridization, it was found that the ABBC8 gene maps to the short arm of chromosome 11 (Figure 1) (5). It has 41 exons (coding regions) that span over 84,000 bases (see evidence).Figure 1. Location of ABCC8 on the human genome.Figure 1Location of ABCC8 on the human genome. ABCC8 maps to chromosome 11, approximately between 17,370 and 17,470 kilobases (kb). Click Image maplink.jpg or here for a current and interactive view of the location of ABCC8 in the human genome. Note: this figure was (more...)The ABC transporter proteins, such as ABCC8, typically contain two ATP-binding domains and two transmembrane domains (view domains).The ATP-binding domains are also known as nucleotide binding folds (NBFs), and mutations in either NBF1 or NBF2 can lead to PHHI (6). This suggests that both NBF regions of the SUR are needed for the normal regulation of KATP channel activity.As found in all proteins that bind ATP, the nucleotide binding domains of the ABC family of proteins contain characteristic motifs called Walker A and B. The Walker A motif contains a lysine residue that is critical for activating the KATP channel. When this lysine residue is mutated in NBF1, but not NBF2, the KATP channel can no longer be activated (7). In addition, ABC genes also contain a signature C motif.The transmembrane domains contain 6–11 membrane spanning helices, and the ABCC protein contains 6. These helices provide the protein with specificity for the molecule they transport across the membrane.Several single nucleotide polymorphisms (SNPs) have been found within the ABCC8 gene. Usually SNPs linked with disease occur within the coding regions (exons) of the genes, and they result in a non-synonymous amino acid change. In ABCC8, there are seven such SNPs (at the time of writing) that cause a switch of amino acids in the mature protein (Figure 2). However, one of the SNPs of the ABCC8 gene that has been linked with diabetes (R1273R) does not cause an amino acid change (see below).
Figure 2. SNP positions of ABCC8 mapped to the 3D structure of a multidrug resistance ABC transporter homolog in Vibrio cholera.
Figure 2

SNP positions of ABCC8 mapped to the 3D structure of a multidrug resistance ABC transporter homolog in Vibrio cholera.
The figure shows the positions of non-synonymous amino acid changes (green residues) caused by SNPs in the coding sequence. (more...)
ABCC8 and Diabetes: Digest of Recent Articles

For a more complete list of research articles on ABCC8 and diabetes, search PubMed.

The two genes that encode the KATP channel, ABBC8 and KCNJ11, reside adjacent to one another on chromosome 11. A variant of ABCC8, called A1369S, is in almost complete linkage disequilibrium with a variant of KCNJ11 called E23K. This means that from the genetic evidence, it is difficult to determine whether it is the A1369S variant or the E23K variant that predisposes to type 2 diabetes (8).

A mutation in ABCC8 was observed to cause an extremely rare form of diabetes, autosomal dominant diabetes, in a Finnish family (9). The switch of glutamate to lysine at residue 1506 (E1506K) in the SUR1 protein caused a congenital hyperinsulinemia. The mutation reduced the activity of KATP channels, increasing insulin secretion. By early adulthood, the ability of the beta cells to secrete adequate amounts of insulin was exhausted, leading to diabetes (10).

A silent variant in exon 31 of the ABCC8 gene has been associated with high concentrations of insulin in non-diabetic Mexican Americans. The codon AGG is mutated to AGA, but this still codes for the residue arginine (R1273R). The normal and mutant alleles were called G and A, respectively. Among non-diabetics, those who were homozygous for the mutant allele (AA genotype) had higher levels of insulin when fasting, compared with heterozygotes (AG) and normal wild-type (GG). Because type 2 diabetes is more common in Mexican Americans than in the general US population, it has been proposed that individuals with the AA genotype are at a higher risk of diabetes because of an over-secretion of insulin (11).

Two common polymorphisms of the ABCC8 gene (exon 16-3t/c and exon 18 T/C) have been variably associated with type 2 diabetes. However, a recent large case control study in Britain revealed that these ABCC8 variants did not appear to be associated with diabetes (12).

Link Roundup for ABCC8

Live Searches

Diabetes and ABCC8 in PubMed | PubMed Central | Books

Background Information

ABCC8 in OMIM

The Human ATP-Binding Cassette (ABC) Transporter Superfamily on the Bookshelf

Molecular Biology

ABCC8 in Entrez Gene | Evidence Viewer | Map Viewer | Domains: Transmembrane region 1, ATPase 1, Transmembrane domain 2, ATPase 2 | SNPs | BLink | HomoloGene

References