Genetic causes of type 2 diabetes

Last updated

Most cases of type 2 diabetes involved many genes contributing small amount to the overall condition. [1] As of 2011 more than 36 genes have been found that contribute to the risk of type 2 diabetes. [2] All of these genes together still only account for 10% of the total genetic component of the disease. [2]

Contents

There are a number of rare cases of diabetes that arise due to an abnormality in a single gene (known as monogenic forms of diabetes). [1] These include maturity onset diabetes of the young (MODY), Donohue syndrome, and Rabson–Mendenhall syndrome, among others. [1] Maturity onset diabetes of the young constitute 1–5% of all cases of diabetes in young people. [3]

Polygenic

Genetic cause and mechanism of type 2 diabetes is largely unknown. However, single nucleotide polymorphism (SNP) is one of many mechanisms that leads to increased risk for type 2 diabetes. To locate genes and loci that are responsible for the risk of type 2 diabetes, genome wide association studies (GWAS) was utilized to compare the genomes of diabetic patient group and the non-diabetic control group. [4] The diabetic patients’ genome sequences differ from the controls' genome in specific loci along and around numerous genes, and these differences in the nucleotide sequences alter phenotypic traits that exhibit increased susceptibility to the diabetes. GWAS has revealed 65 different loci (where single nucleotide sequences differ from the patient and control group's genomes), and genes associated with type 2 diabetes, including TCF7L2 , PPARG , FTO , KCNJ11 , NOTCH2 , WFS1 , IGF2BP2 , SLC30A8 , JAZF1 , HHEX, DGKB, CDKN2A, CDKN2B, KCNQ1, HNF1A, HNF1B MC4R, GIPR, HNF4A, MTNR1B, PPARG, ZBED3, SLC30A8, CDKAL1, GLIS3, GCK, GCKR, among others. [4] [5] [6] [7] KCNJ11 (potassium inwardly rectifying channel, subfamily J, member 11), encodes the islet ATP-sensitive potassium channel Kir6.2, and TCF7L2 (transcription factor 7–like 2) regulates proglucagon gene expression and thus the production of glucagon-like peptide-1. [8] In addition, there is also a mutation to the Islet Amyloid Polypeptide gene that results in an earlier onset, more severe, form of diabetes. [9] [10] However, this is not a comprehensive list of genes that affects the proneness to the diabetes.

SNP rs7873784 located in the 3′-untranslated region (3′-UTR) of TLR4 gene and associated with the development of type-2 diabetes mellitus. PU.1 binding to the minor C allele of rs7873784 may be responsible for elevated TLR4 expression in the monocytes of affected individuals, contributing to an inflammation-prone environment that predisposes minor allele carriers to development of certain pathologies with an inflammatory component. [11] rs7873784 was also associated with the abnormal metabolic phenotype accompanying T2DM (levels of fasting insulin and triglycerides, abnormal low-density lipoprotein and high-density lipoprotein cholesterol levels). However, there is growing evidence that T2DM is not only a purely metabolic, but also an inflammatory disorder. The link between certain TLR4 SNPs alleles and T2DM may be directly related to elevated TLR4 expression since its signaling can regulate diet-induced obesity and insulin resistance and, therefore, influence the pathogenesis of T2DM. TLR4 expression is elevated in adipose tissue of obese mice and its activation triggered insulin resistance in adipocytes. LPS-mediated TLR4 activation can suppress glucose-induced insulin secretion by β-cells. Monocytes from T2DM patients demonstrate increased TLR4 expression, NFκB activity, and production of proinflammatory cytokines and chemokines. A number of endogenous TLR4 ligands are elevated in patients with diabetes. Oxidized LDL upregulates TLR4 expression in macrophages and provokes TLR4-dependent inflammation in the arterial wall, further TLR4 activation results in a strong inhibition of cholesterol efflux from macrophages. The hepatic secretory glycoprotein fetuin-A correlates with increased risk of developing T2DM and may promote lipid-induced insulin resistance via TLR4 activation, resulting in production of proinflammatory cytokines. Additionally, mice with deficiencies in TLR4 signaling were protected from insulin resistance caused by high-fat diet and from secondary complications of T2DM such as atherosclerosis. [11]

Most SNPs that increase the risk of diabetes reside in noncoding regions of the genes, making the SNP's mechanism for increasing susceptibility largely unknown. However, they are thought to influence the susceptibility by altering the regulation of those gene expressions. Only few genes (PARG6, KCNJ11-ABCC8, SLC30A8, and GCKR) have SNPs in the open reading frame (ORF). [4] These SNPs in ORFs result in altering of the protein function, and the altered function and therefore compromise the performances of the protein product causes increased susceptibility to the type 2 diabetes.

One of the examples of gene regulation in non-ORF SNPs that influences susceptibility is the changes in nucleotide sequence in microRNA (miRNA) binding site. miRNAs regulate gene expression by binding to the target mRNAs and physically block translation. SNPs on the miRNA-binding site can result in faulty levels of gene expression as miRNA fails to bind to the corresponding mRNA effectively, leading to excess amount of protein product overall. Although the protein structure of the genes with SNPs are identical to that of the normal gene product, due to their faulty level of expressions, those genes increase risk. Genes such as CDKN2A, CDKN2B, and HNF1B exhibit increase the risk phenotype with SNPs in their 3' UTR miRNA binding sites. As CDKN2A and B regulate the pancreatic beta-cell replication, [12] and HNF1B is homeodomain containing transcription factor that regulates other genes, [13] faulty regulations of those genes increase the risk of diabetes.

Another example of faulty gene regulation that influence the susceptibility is the SNPs in promoter regions of the genes. Gene like APOM and APM1 increase the risk of type 2 diabetes when there are SNPs in their proximal promoter regions. Promoters are sequences of DNA that allows proteins such as transcription factors to bind for gene expression, and when the sequences are modified, the proteins no longer bind as effectively, resulting in depressed level of gene expression. APOM is partly responsible for producing pre beta-high-density lipoprotein and cholesterol, [14] and APM1 is responsible for regulating glucose level in blood and fatty acid. [15] Decreasing the level these gene products reduce the body's ability to handle glucose, which leads to the increased risk of diabetes.

Since 2019 large sequencing studies have started to identify rare coding variants associated with type 2 diabetes risk, including variants in PAM and SLC30A8 . [16] Population-based sequencing studies have since identified numerous other genes harbouring rare large-effect variants for type 2 diabetes, including the known MODY gene GCK (over 14-fold increased odds) and the gene GIGYF1 (4-6 fold increased odds). [17] [18]

It is important to note that those discovered genes do not determine susceptibility to diabetes for all people or cases. As the risk of diabetes is combination of the gene regulations and the interplay between those gene products, certain genes may not pose a threat to increase the susceptibility. TCF7L2 is one of the well-studied genes for diabetes susceptibility in most populations. However, SNPs in TCF7L2 that would normally increase the risk of diabetes does not affect the susceptibility for Pima Indians. However, this gene is associated with regulating the BMI for Pima Indian population. [19]

Various hereditary conditions may feature diabetes, for example myotonic dystrophy and Friedreich's ataxia. Wolfram's syndrome is an autosomal recessive neurodegenerative disorder that first becomes evident in childhood. It consists of diabetes insipidus, diabetes mellitus, optic atrophy, and deafness, hence the acronym DIDMOAD. [20]

While obesity is an independent risk factor for type 2 diabetes that may be linked to lifestyle, obesity is also a trait that may be strongly inherited. [21] [22] Other research also shows that type 2 diabetes can cause obesity as an effect of the changes in metabolism and other deranged cell behavior attendant on insulin resistance. [23]

However, environmental factors (almost certainly diet and weight) play a large part in the development of type 2 diabetes in addition to any genetic component. Genetic risk for type 2 diabetes changes as humans first began migrating around the world, implying a strong environmental component has affected the genetic-basis of type 2 diabetes. [24] [25] This can be seen from the adoption of the type 2 diabetes epidemiological pattern in those who have moved to a different environment as compared to the same genetic pool who have not. Immigrants to Western developed countries, for instance, may be more prone to diabetes as compared to its lower incidence in their countries of origins. [26] Such developments can also be found in environments which have had a recent increase in social wealth, increasingly common throughout Asia.

See also

Related Research Articles

<span class="mw-page-title-main">Type 2 diabetes</span> Type of diabetes mellitus with high blood sugar and insulin resistance

Type 2 diabetes (T2D), formerly known as adult-onset diabetes, is a form of diabetes mellitus that is characterized by high blood sugar, insulin resistance, and relative lack of insulin. Common symptoms include increased thirst, frequent urination, fatigue and unexplained weight loss. Symptoms may also include increased hunger, having a sensation of pins and needles, and sores (wounds) that do not heal. Often symptoms come on slowly. Long-term complications from high blood sugar include heart disease, strokes, diabetic retinopathy which can result in blindness, kidney failure, and poor blood flow in the limbs which may lead to amputations. The sudden onset of hyperosmolar hyperglycemic state may occur; however, ketoacidosis is uncommon.

<span class="mw-page-title-main">Single-nucleotide polymorphism</span> Single nucleotide in genomic DNA at which different sequence alternatives exist

In genetics and bioinformatics, a single-nucleotide polymorphism is a germline substitution of a single nucleotide at a specific position in the genome that is present in a sufficiently large fraction of considered population.

<span class="mw-page-title-main">Adiponectin</span> Mammalian protein found in Homo sapiens

Adiponectin is a protein hormone and adipokine, which is involved in regulating glucose levels and fatty acid breakdown. In humans, it is encoded by the ADIPOQ gene and is produced primarily in adipose tissue, but also in muscle and even in the brain.

<span class="mw-page-title-main">Resistin</span> Mammalian protein found in Homo sapiens

Resistin also known as adipose tissue-specific secretory factor (ADSF) or C/EBP-epsilon-regulated myeloid-specific secreted cysteine-rich protein (XCP1) is a cysteine-rich peptide hormone derived from adipose tissue that in humans is encoded by the RETN gene.

Slowly evolving immune-mediated diabetes, or latent autoimmune diabetes in adults (LADA), is a form of diabetes that exhibits clinical features similar to both type 1 diabetes (T1D) and type 2 diabetes (T2D), and is sometimes referred to as type 1.5 diabetes. It is an autoimmune form of diabetes, similar to T1D, but patients with LADA often show insulin resistance, similar to T2D, and share some risk factors for the disease with T2D. Studies have shown that LADA patients have certain types of antibodies against the insulin-producing cells, and that these cells stop producing insulin more slowly than in T1D patients.

<span class="mw-page-title-main">Agouti-signaling protein</span> Protein-coding gene in the species Homo sapiens

Agouti-signaling protein is a protein that in humans is encoded by the ASIP gene. It is responsible for the distribution of melanin pigment in mammals. Agouti interacts with the melanocortin 1 receptor to determine whether the melanocyte produces phaeomelanin, or eumelanin. This interaction is responsible for making distinct light and dark bands in the hairs of animals such as the agouti, which the gene is named after. In other species such as horses, agouti signalling is responsible for determining which parts of the body will be red or black. Mice with wildtype agouti will be grey, with each hair being partly yellow and partly black. Loss of function mutations in mice and other species cause black fur coloration, while mutations causing expression throughout the whole body in mice cause yellow fur and obesity.

The thrifty gene hypothesis, or Gianfranco's hypothesis is an attempt by geneticist James V. Neel to explain why certain populations and subpopulations in the modern day are prone to diabetes mellitus type 2. He proposed the hypothesis in 1962 to resolve a fundamental problem: diabetes is clearly a very harmful medical condition, yet it is quite common, and it was already evident to Neel that it likely had a strong genetic basis. The problem is to understand how disease with a likely genetic component and with such negative effects may have been favoured by the process of natural selection. Neel suggested the resolution to this problem is that genes which predispose to diabetes were historically advantageous, but they became detrimental in the modern world. In his words they were "rendered detrimental by 'progress'". Neel's primary interest was in diabetes, but the idea was soon expanded to encompass obesity as well. Thrifty genes are genes which enable individuals to efficiently collect and process food to deposit fat during periods of food abundance in order to provide for periods of food shortage.

<span class="mw-page-title-main">Zinc transporter 8</span> Protein found in humans

Zinc transporter 8 (ZNT8) is a protein that in humans is encoded by the SLC30A8 gene. ZNT8 is a zinc transporter related to insulin secretion in humans. In particular, ZNT8 is critical for the accumulation of zinc into beta cell secretory granules and the maintenance of stored insulin as tightly packaged hexamers. Certain alleles of the SLC30A8 gene may increase the risk for developing type 2 diabetes, but a loss-of-function mutation appears to greatly reduce the risk of diabetes.

<span class="mw-page-title-main">FTO gene</span> Protein-coding gene in the species Homo sapiens

Fat mass and obesity-associated protein also known as alpha-ketoglutarate-dependent dioxygenase FTO is an enzyme that in humans is encoded by the FTO gene located on chromosome 16. As one homolog in the AlkB family proteins, it is the first mRNA demethylase that has been identified. Certain alleles of the FTO gene appear to be correlated with obesity in humans.

<span class="mw-page-title-main">TCF7L2</span> Protein-coding gene in humans

Transcription factor 7-like 2 , also known as TCF7L2 or TCF4, is a protein acting as a transcription factor that, in humans, is encoded by the TCF7L2 gene. The TCF7L2 gene is located on chromosome 10q25.2–q25.3, contains 19 exons. As a member of the TCF family, TCF7L2 can form a bipartite transcription factor and influence several biological pathways, including the Wnt signalling pathway.

<span class="mw-page-title-main">Endothelial NOS</span> Protein and coding gene in humans

Endothelial NOS (eNOS), also known as nitric oxide synthase 3 (NOS3) or constitutive NOS (cNOS), is an enzyme that in humans is encoded by the NOS3 gene located in the 7q35-7q36 region of chromosome 7. This enzyme is one of three isoforms that synthesize nitric oxide (NO), a small gaseous and lipophilic molecule that participates in several biological processes. The other isoforms include neuronal nitric oxide synthase (nNOS), which is constitutively expressed in specific neurons of the brain and inducible nitric oxide synthase (iNOS), whose expression is typically induced in inflammatory diseases. eNOS is primarily responsible for the generation of NO in the vascular endothelium, a monolayer of flat cells lining the interior surface of blood vessels, at the interface between circulating blood in the lumen and the remainder of the vessel wall. NO produced by eNOS in the vascular endothelium plays crucial roles in regulating vascular tone, cellular proliferation, leukocyte adhesion, and platelet aggregation. Therefore, a functional eNOS is essential for a healthy cardiovascular system.

<span class="mw-page-title-main">CAPN10</span> Protein-coding gene in the species Homo sapiens

Calpain-10 is a protein that in humans is encoded by the CAPN10 gene.

<span class="mw-page-title-main">5′ flanking region</span>

The 5′ flanking region is a region of DNA that is adjacent to the 5′ end of the gene. The 5′ flanking region contains the promoter, and may contain enhancers or other protein binding sites. It is the region of DNA that is not transcribed into RNA. Not to be confused with the 5′ untranslated region, this region is not transcribed into RNA or translated into a functional protein. These regions primarily function in the regulation of gene transcription. 5′ flanking regions are categorized between prokaryotes and eukaryotes.

TOX high mobility group box family member 3, also known as TOX3, is a human gene.

<span class="mw-page-title-main">CDKN2BAS</span> Non-coding RNA in the species Homo sapiens

CDKN2B-AS, also known as ANRIL is a long non-coding RNA consisting of 19 exons, spanning 126.3kb in the genome, and its spliced product is a 3834bp RNA. It is located within the p15/CDKN2B-p16/CDKN2A-p14/ARF gene cluster, in the antisense direction. Single nucleotide polymorphisms (SNPs) which alter the expression of CDKN2B-AS are associated with human healthy life expectancy, as well as with multiple diseases, including coronary artery disease, diabetes and many cancers. It binds to chromobox 7 (CBX7) within the polycomb repressive complex 1 and to SUZ12, a component of polycomb repression complex 2 and through these interactions is involved in transcriptional repression.

<span class="mw-page-title-main">CDKAL1</span> Protein-coding gene in the species Homo sapiens

CDKAL1 is a gene in the methylthiotransferase family. The complete physiological function and implications of this have not been fully determined. CDKAL1 is known to code for CDK5, a regulatory subunit-associated protein 1. This protein CDK5 regulatory subunit-associated protein 1 is found broadly across tissue types including neuronal tissues and pancreatic beta cells. CDKAL1 is suspected to be involved in the CDK5/p35 pathway, in which p35 is the activator for CDK5 which regulates several neuronal functions.

In recent years it has become apparent that the environment and underlying mechanisms affect gene expression and the genome outside of the central dogma of biology. It has been found that many epigenetic mechanisms are involved in the regulation and expression of genes such as DNA methylation and chromatin remodeling. These epigenetic mechanisms are believed to be a contributing factor to pathological diseases such as type 2 diabetes. An understanding of the epigenome of Diabetes patients may help to elucidate otherwise hidden causes of this disease.

Insulin-dependent diabetes mellitus (IDDM) is a genetic heterogenouse autoimmune disorder, which is triggered by genetic predisposition and environmental factors. The prevalence of insulin-dependent diabetes mellitus (IDDM) among children and young adult from Europe is approximately 0.4%. Insulin-dependent diabetes mellitus (IDDM) is characterized by acute onset and insulin deficiency. Patients with insulin-dependent diabetes mellitus (IDDM) are found with gradual loss of the pancreatic islet beta cells and therefore not able to produce insulin. As a result, they usually need exogenous insulin to maintain their life.

Predictive genomics is at the intersection of multiple disciplines: predictive medicine, personal genomics and translational bioinformatics. Specifically, predictive genomics deals with the future phenotypic outcomes via prediction in areas such as complex multifactorial diseases in humans. To date, the success of predictive genomics has been dependent on the genetic framework underlying these applications, typically explored in genome-wide association (GWA) studies. The identification of associated single-nucleotide polymorphisms underpin GWA studies in complex diseases that have ranged from Type 2 Diabetes (T2D), Age-related macular degeneration (AMD) and Crohn's disease.

References

  1. 1 2 3 Williams textbook of endocrinology (12th ed.). Philadelphia: Elsevier/Saunders. 2011. pp. 1371–1435. ISBN   978-1-4377-0324-5.
  2. 1 2 Herder, C; Roden, M (Jun 2011). "Genetics of type 2 diabetes: pathophysiologic and clinical relevance". European Journal of Clinical Investigation. 41 (6): 679–92. doi:10.1111/j.1365-2362.2010.02454.x. PMID   21198561. S2CID   43548816.
  3. ↑ "Monogenic Forms of Diabetes: Neonatal Diabetes Mellitus and Maturity-onset Diabetes of the Young". National Diabetes Information Clearinghouse (NDIC). National Institute of Diabetes and Digestive and Kidney Diseases, NIH. Archived from the original on 2008-07-04. Retrieved 2008-08-04.
  4. 1 2 3 Gaulton, Kyle (Dec 2015). "Genetic fine mapping and genomic annotation defines causal mechanisms at type 2 diabetes susceptibility loci". Nature Genetics. 47 (12): 1415–25. doi:10.1038/ng.3437. PMC   4666734 . PMID   26551672.
  5. ↑ Lyssenko V, Jonsson A, Almgren P, et al. (November 2008). "Clinical risk factors, DNA variants, and the development of type 2 diabetes". The New England Journal of Medicine . 359 (21): 2220–32. doi: 10.1056/NEJMoa0801869 . PMID   19020324.
  6. ↑ McCarthy, M. I. (December 2010). Feero, W. G.; Guttmacher, A. E. (eds.). "Genomics, Type 2 Diabetes, and Obesity". The New England Journal of Medicine . 363 (24): 2339–50. doi: 10.1056/NEJMra0906948 . PMID   21142536.
  7. ↑ Ayub, Qasim (Feb 6, 2014). "Revisiting the Thrifty Gene Hypothesis via 65 Loci Associated with Susceptibility to Type 2 Diabetes". American Journal of Human Genetics. 94 (2): 176–85. doi:10.1016/j.ajhg.2013.12.010. PMC   3928649 . PMID   24412096.
  8. ↑ Rother KI (April 2007). "Diabetes treatment—bridging the divide". The New England Journal of Medicine . 356 (15): 1499–501. doi:10.1056/NEJMp078030. PMC   4152979 . PMID   17429082.
  9. ↑ Sakagashira S, Sanke T, Hanabusa T, et al. (September 1996). "Missense mutation of amylin gene (S20G) in Japanese NIDDM patients". Diabetes. 45 (9): 1279–81. doi:10.2337/diabetes.45.9.1279. PMID   8772735.
  10. ↑ Cho YM, Kim M, Park KS, Kim SY, Lee HK (May 2003). "S20G mutation of the amylin gene is associated with a lower body mass index in Korean type 2 diabetic patients". Diabetes Res. Clin. Pract. 60 (2): 125–9. doi:10.1016/S0168-8227(03)00019-6. PMID   12706321.
  11. 1 2 Korneev, Kirill V.; Sviriaeva, Ekaterina N.; Mitkin, Nikita A.; Gorbacheva, Alisa M.; Uvarova, Aksinya N.; Ustiugova, Alina S.; Polanovsky, Oleg L.; Kulakovskiy, Ivan V.; Afanasyeva, Marina A.; Schwartz, Anton M.; Kuprash, Dmitry V. (March 2020). "Minor C allele of the SNP rs7873784 associated with rheumatoid arthritis and type-2 diabetes mellitus binds PU.1 and enhances TLR4 expression". Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease. 1866 (3): 165626. doi: 10.1016/j.bbadis.2019.165626 . PMID   31785408.
  12. ↑ Wang, Xiaojing (Oct 2015). "Association study of the miRNA-binding site polymorphisms of CDKN2A/B genes with gestational diabetes mellitus susceptibility". Acta Diabetologica. 52 (5): 951–8. doi:10.1007/s00592-015-0768-2. PMID   25990668. S2CID   21203147.
  13. ↑ Goda, Naoki (Sep 2, 2015). "Polymorphism in microRNA-binding site in HNF1B influences the susceptibility of type 2 diabetes mellitus: a population based case-control study". BMC Medical Genetics. 16: 75. doi: 10.1186/s12881-015-0219-5 . PMC   4557749 . PMID   26329304.
  14. ↑ Niu, Nifang (Jan 2007). "Single nucleotide polymorphisms in the proximal promoter region of apolipoprotein M gene (apoM) confer the susceptibility to development of type 2 diabetes in Han Chinese". Diabetes/Metabolism Research and Reviews. 23 (1): 21–5. doi:10.1002/dmrr.641. PMID   16572495. S2CID   21156244.
  15. ↑ Gu, HF (Feb 2004). "Single nucleotide polymorphisms in the proximal promoter region of the adiponectin (APM1) gene are associated with type 2 diabetes in Swedish Caucasians". Diabetes. 53 (Suppl 1): S31–5. doi: 10.2337/diabetes.53.2007.S31 . PMID   14749263.
  16. ↑ Flannick (2019). "Exome sequencing of 20,791 cases of type 2 diabetes and 24,440 controls". Nature. 570 (7759): 71–76. Bibcode:2019Natur.570...71F. doi:10.1038/s41586-019-1231-2. PMC   6699738 . PMID   31118516.
  17. ↑ Jurgens (2022). "Analysis of rare genetic variation underlying cardiometabolic diseases and traits among 200,000 individuals in the UK Biobank". Nature Genetics. 54 (3): 240–250. doi:10.1038/s41588-021-01011-w. PMC   8930703 . PMID   35177841.
  18. ↑ Deaton (2021). "Gene-level analysis of rare variants in 379,066 whole exome sequences identifies an association of GIGYF1 loss of function with type 2 diabetes". Scientific Reports. 11 (1): 21565. doi:10.1038/s41598-021-99091-5. PMC   8566487 . PMID   34732801.
  19. ↑ Guo, Tingwei (Dec 2007). "TCF7L2 is not a major susceptibility gene for type 2 diabetes in Pima Indians". Diabetes. 56 (12): 3082–8. doi: 10.2337/db07-0621 . PMID   17909099.
  20. ↑ Barrett TG (September 2001). "Mitochondrial diabetes, DIDMOAD and other inherited diabetes syndromes". Best Practice & Research. Clinical Endocrinology & Metabolism. 15 (3): 325–43. doi:10.1053/beem.2001.0149. PMID   11554774.
  21. ↑ Walley AJ, Blakemore AI, Froguel P (October 2006). "Genetics of obesity and the prediction of risk for health". Human Molecular Genetics. 15 Spec No 2: R124–30. doi: 10.1093/hmg/ddl215 . PMID   16987875.
  22. ↑ "Can Diabetes Type II be inherited?". Dw.com . 25 August 2017. Retrieved 29 August 2017.
  23. ↑ Camastra S, Bonora E, Del Prato S, Rett K, Weck M, Ferrannini E (December 1999). "Effect of obesity and insulin resistance on resting and glucose-induced thermogenesis in man. EGIR (European Group for the Study of Insulin Resistance)". Int. J. Obes. Relat. Metab. Disord. 23 (12): 1307–13. doi:10.1038/sj.ijo.0801072. PMID   10643689.
  24. ↑ Corona, Erik. "Geneworld". World Wide Patterns of Genetic Risk for Disease. Stanford University. Retrieved 11 September 2013.
  25. ↑ Gibbons, Ann (4 November 2011). "Diabetes Genes Decline Out of Africa". Science. 334 (6056): 583. Bibcode:2011Sci...334..583G. doi:10.1126/science.334.6056.583. PMID   22053022.
  26. ↑ Cotran, Kumar, Collins; Robbins Pathologic Basis of Disease, Saunders Sixth Edition, 1999; 913-926.
This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.