Molecular pathogenesis of diabetes:Study of diabetic genetic epidemiology and pancreatic beta cell functions
Date Issued
2006
Date
2006
Author(s)
DOI
zh-TW
Abstract
Diabetes is a big challenge of global public health
By the end of the 20th century the worldwide diabetes pandemic had affected an estimated 151 million persons, distributed among both developed and developing countries. At the societal level, the burden of diabetes worldwide is great and continues to grow. Overall, 90–95% of diabetes is type 2, and this form of the disease (historically considered rare in youth) is now increasingly affecting children and adolescents. While it is estimated that 30–50% of diabetes cases remain undiagnosed, there were approximately 30 million people worldwide diagnosed with diabetes in 1985. By 1995 this number had increased to 135 million (4.0% of the world population), and projections indicate there may be 300 million people with diabetes (5.4% of the world population) by 2025. Between 1995 and 2025, the number of people with diabetes will increase 42% (from 51 to 72 million) in industrialized countries, but will increase 170% (from 84 to 228 million) in industrializing countries.
Diabetes is a lifelong condition that seriously affects a person’s quality of life. Individuals with the disease have to make major lifestyle changes and learn to live with monitoring blood glucose, using multiple drugs and injections, and dealing with complications of the disease and their treatment. Diabetes is a complex and multifactorial disease that is associated with considerable mortality, morbidity, and loss of quality of life. Diabetes is a leading cause of death, new cases of end-stage renal disease (ESRD), lower-limb amputations, blindness, and cardiovascular disease (CVD). Around 25% of people with diabetes in the United States have some visual impairment. Of those with disease for 15 years, 10% develop severe visual impairment and 2% become blind. Diabetes accounts for 35% of all new ESRD cases in the United States. The most common cause of death among people with diabetes is CVD, and approximately 50% of people with diabetes in the United States die from coronary heart disease. About 10% of diabetic individuals in the United States report having had a stroke and 20–30% have some peripheral vascular disease (PVD). Furthermore, people with diabetes have extraordinarily high levels of CVD risk factors, including hypertension, dyslipidemia, and obesity. Between 30 and 60% of Americans with diabetes have neuropathy, 50% have considerable physical disability, and diabetes is also associated with higher risk of dental disease and complications of pregnancy. The burden of diabetes complications is similarly large worldwide. Based on data from several countries, the World Health Organization (WHO) estimates that in year 2000, between 30 and 45% of people with diabetes worldwide have retinopathy, 10–20% have nephropathy, 20–35% has neuropathy and 10–25% has CVD.
At the national level, diabetes exerts a substantial toll on the direct health care costs in all countries. A person with diabetes costs the health care sector 2.5 times more than a person without the disease. The estimated total annual direct health care cost of diabetes in 1998 in industrialized countries varied from US$ 0.54 billion in Denmark to US$ 60 billion in the United States. One study, estimated the annual direct cost of diabetes in India at US$ 2.2 billion.
Diabetes is an inheritable disease
Type 1 diabetes is an autoimmune disease that leads to the destruction of pancreatic β cells and insulin deficiency. It is common in childhood and adolescence but can occur at any age. Although most cases lack a family history, first-degree relatives have a higher risk of developing type 1 diabetes than does the general population. Within families, susceptibility depends on the degree of genetic identity with the proband. The highest risk is observed in identical twins. The disease concordance rate in twins can be up to 70% in studies with the longest follow-up period. Although siblings have, on average, a lower prevalence of approximately 6%, this rate is still higher than the 0.4% observed in the white population in the United States, confirming a significant familiar clustering. Empirically, type 2 diabetes mellitus has been considered a partially inheritable disease, as suggested either by the studies of life-time risk of around 40% for the development of the disease in non-diabetic offspring, siblings and dizygotic twins and increasing to 70% if both parents have type 2 diabetes mellitus or by the studies of the concordance of type 2 diabetes mellitus in dizygotic and monozygotic twins. The recurrence risk (λs) of type 2 diabetes for monozygotic twins has been estimated as high as 10 and around 3 in first-degree relatives. The best evidence that heredity plays an important role comes from the following observations: (i)Concordance rates for type 2 diabetes and its predecessor, impaired glucose tolerance, are consistently higher in monozygotic than in dizygotic twin pairs; (ii) sibling recurrence rates are consistently higher than population prevalence rates, although the reported excess is modest; (iii) groups of patients labeled as having type 2 diabetes include individuals suffering from unrecognized monogenic and digenic disorders; and (iv) certain common single-nucleotide polymorphisms (SNPs) appear to influence diabetes risk.
Accelerator hypothesis : Type 1 and type 2 diabetes as the same disorder of insulin resistance, set against different genetic backgrounds
The prevalence of diabetes is increasing rapidly in industrialized countries. Although most attention has focused on the increase in type 2 diabetes, there has been a parallel increase in type 1 diabetes, which requires explanation. Type 2 diabetes is believed to result from the loss of β cell function in association with insulin resistance. The “Accelerator Hypothesis” regards type 1 diabetes in the same way. Awareness of overlap between type 1 and type 2 diabetes is not new. There has long been interest in insulin resistance in type 1 diabetes, although related more to its implications for management and outcome than to its pathogenesis. The term “type one-and-a-half” diabetes, referring to the progression in some from type 2 to type 1 diabetes, was coined years ago and remains an area of lively debate. In a modern context, the increasing difficulty in distinguishing type 1 from type 2 diabetes in obese young people has given rise to the designation “double diabetes,” in which recognition is given to the coexistence of autoimmunity and insulin resistance. Insulin resistance upregulates the β cells metabolically and accelerates their loss through glucotoxicity. The tempo is normally slow. The “Accelerator Hypothesis” argues that people in whom type 1 diabetes develops are subject to the same weight increase, the same insulin resistance, the same metabolic upregulation, and the same acceleration in β cell loss as those with type 2 diabetes. They are, in addition, genetically susceptible to mounting an aggressive immune response to metabolically upregulated β cells. Depending on the genotype, this further accelerator can greatly increase the tempo of β cell loss. Those with type 1 diabetes nevertheless remain a subset of type 2 diabetes, sharing the same basic accelerator: insulin resistance. Indeed, the “Accelerator Hypothesis” predicts that if people inwhom type 1 diabetes would develop lacked the immunogenetic accelerator, they would still be at risk for type 2 diabetes at a later time.
It is already known that people in whom type 1 diabetes develops are heavier in early childhood than nondiabetic people and tend to be taller. Moreover, the prevalence and titer of GAD antibodies are also related to BMI both in first-degree relatives of type 1 diabetic subjects and in the normal population. The “Accelerator Hypothesis” goes further and predicts that, among those who develop type 1 diabetes, the heavier children will do so at a younger age, in the same way that greater body mass accelerates the onset of type 2 diabetes. It goes on to suggest a mechanism whereby insulin resistance could interact with the type 1 diabetes susceptibility genotype to further accelerate β cell loss. Because only a defined subgroup of the population is genetically susceptible, the “Accelerator Hypothesis” predicts that increasing obesity in children would cause the age at presentation to decrease without necessarily changing lifetime risk. Recent epidemiological data suggest that this may be the case.
The associated genes of type 1 diabetes
Association studies and linkage analysis have been used to identify susceptibility loci. So far, three loci are well characterized, and much progress has been made in elucidating the mechanisms by which alleles at these loci modulate type 1 diabetes susceptibility. These loci are IDDM1, corresponding to the human leukocyte antigen (HLA) genes HLA-DR and HLA-DQ; IDDM2, corresponding to the insulin gene INS; and IDDM12, corresponding to the CTLA4 gene. A description of these loci follows.
(1) IDDM1: DR and DQ regions of HLA
The major susceptibility locus lies within he HLA complex on chromosome 6 and provides up to 40% to 50% of the inheritable diabetes risk. The HLA-DR and HLA-DQ loci in the class II region have the strongest influence on type 1 diabetes risk. Most patients carry the HLA-DR3 or HLA-DR4 class II antigens, and approximately 30% of these are DR3/ DR4 heterozygotes. The DR3/ DR4 genotype confers the highest risk, with a synergistic mode of action, followed by DR4 and DR3 homozygosity, respectively. In the white population, the HLA-DQ heterodimers encoded by DQA1*0301, DQB1*0302, DQA1*0501, and DQB1*0201 have the strongest association with diabetes. However, the HLA-DQ locus also harbors type 1 diabetes protective alleles. Among the commonest DR2 haplotypes observed in white , the DQA1*0102, DQB1*0602, and DRB1*1501 haplotype is negatively associated with type 1 diabetes in several populations.
(2) IDDM2: insulin gene
The IDDM2 locus maps to a variable number of tandem repeats (VNTR) located approximately 0.5 kilobase (kb) upstream of the insulin gene (INS). Two main classes of VNTR alleles are defined based on the number of repeats: short alleles (class I) and long alleles (class III); intermediate size (class II) are rare in the white population. Homozygosity for class VNTR I alleles is found in 75% to 85% of the patients, compared with a frequency of 50% to 60% in the general population, and it increases the likelihood that identical tween will be concordant for type 1 diabetes. The relative risk ratio of the I/I genotype versus I/III or III/III has been reported to the moderate (in the 3 to 5 range), and it accounts for approximately 10% of the familial clustering of type 1 diabetes.
(3) IDDM12: CTLA4 gene.
The 2q33 chromosomal region contains a cluster of genes coding for proteins involved in T-cell costimulation, such as CTLA4 (cytotoxic T-lymphocyte-associated 4), CD28, and ICOS. Linkage with CTLA4 came from a multiethnic collection of families from Spain, France, China, Korea, and Mexican Americans. The transmission disequilibrium test (TDT) revealed deviation for alleles at the (AT)n microsatellite and the A→G polymorphism. Additional evidence suggesting that CTLA4 is the etiologic variant at the IDDM12 locus came from another study of a multiethnic collection nof 178 simplex and 350 multiplex families. The TDT revealed association/linkage with threee markers within CTLA4 and two flanking markers on each side of CTLA4 but not with more distant markers near CD28.
The associated genes of type 2 diabetes
Genomewide linkage mapping for type 2 diabetes or related quantitative metabolic traits have provided a number of different chromosomal loci, among which the chromosomes 1q, 2q, 8p, 10q, 12q and 20q seem to be the most consistent, but so far only the NIDDM1 locus on chromosome 2q37, with the identification of calpain-10 (CAPN10) as a diabetes susceptibility gene, has been a successful example of positional cloning of a common gene for type 2 diabetes. It appears that the most consistent findings in nonmendelian type 2 diabetes are the two common coding variants: Pro12Ala of the PPAR-g gene and Glu23Lys of Kir6.2, both of which may confer a modest relative increased risk of diabetes (odds ratio about 1.2). However, due to the high frequency of the two risk alleles, they contribute with a large population attributable to diabetes risk. The latter gene variant was recently by a second-look shown to be associated with impaired glucose-induced insulin release during an oral glucose tolerance test, impaired glucose-induced suppression of glucagon secretion and to associate with type 2 diabetes. Oligogenic (digenic) inheritance of severe insulin resistance and type 2 diabetes has been reported in a human pedigree with double mutations in the PPP1R3 and PPAR-g genes. Interestingly, several other gene variants have inconsistently been shown to associate with type 2 diabetes including a non-coding intronic variant of the SUR1 gene, IVS15-3t/c, Trp64Arg of the b3-adrenergic receptor, Gly972Arg of the IRS-1, PP1ARE of the PPP1R3 and Gly482Ser of the PGC-1. The potential role of these susceptibility genes deserves further cautious investigations applying SNP genotyping and haplotyping in sufficiently powered and well-characterized study materials.
β cell function declined gradually with time
Patients with Type 2 diabetes are characterized by peripheral insulin resistance, aberrant pancreatic insulin secretion and enhanced hepatic glucose output. Pancreatic beta cell function has been shown to decline with increasing duration of diabetes, regardless the use of different existing therapies including sulphonylureas, biguanides and insulin as demonstrated in the prospective study of UKPDS. A longitudinal study in Pima Indian demonstrated that transition from NGT to IGT was associated with an increase in body weight, a decline in insulin-stimulated glucose disposal, and a decline in the acute insulin secretory response (AIR) to intravenous glucose, but no change in EGO. Progression from IGT to diabetes was accompanied by a further increase in body weight, further decreases in insulin-stimulated glucose disposal and AIR, and an increase in basal EGO. Thirty-one subjects who retained NGT over a similar period also gained weight, but their AIR increased with decreasing insulin-stimulated glucose disposal. Thus, defects in insulin secretion and insulin action occur early in the pathogenesis of diabetes. Intervention to prevent diabetes should target both abnormalities.
The specific aims of this study
Both type 1 and type 2 diabetes were considered as polygenic disease，and it has been reported that certain genetic polymorphism will be associated with incidence rate, age of onset or the decline of β cell function。Recently, “Accelerator Hypothesis” was postulated, and it was considered that both type 1 and type 2 diabetes was the same, which have insulin resistance associated hyper secretion of insulin, and then accelerate the β cell loss. Therefore, there maybe the same genetic susceptibility to warrant between type 1 and type 2 diabetes. Besides, the defects in β cell secretory function and insulin resistance existed early in the prediabetic stage, and they were aggravated with time. Therefore, it is very important to investigate how to prevent and delay the loss of β cell function.
Therefore the thesis will be divided into three parts: (1) The association study between vitamin D receptor (VDR) gene polymorphism and susceptibility to type 1 diabetes in Taiwanese population (2) The association study between β2-adrenoreceptor (ADRB2) gene polymorphism and susceptibility to type 2 diabetes (3) The molecular mechanism of thiazolidinediones (TZDs) to improve the insulin secretory capacity of islet β cells.
First part: The association study between vitamin D receptor (VDR) gene polymorphism and susceptibility to type 1 diabetes in Taiwanese population
OBJECTIVE: Vitamin D and its receptor have been suggested to play a role in the pathogenesis of type 1 diabetes mellitus. We have therefore studied the influence of vitamin D receptor (VDR) gene polymorphisms on susceptibility to type 1 diabetes, and rates of glutamic acid decarboxylase (GAD65) autoantibody and islet cell autoantibody (ICA512) positivity.
SUBJECTS AND MEASUREMENTS: One hundred and fiffty-seven type 1 diabetic patients and 248 unrelated normal controls were recruited for this study. Genomic DNA was extracted from peripheral blood leucocytes. All type 1 diabetic patients and controls were genotyped using polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP), for three restriction sites in the VDR gene, BsmI, ApaI and TaqI. The x2 test was used to compare the frequency of the VDR gene polymorphisms in patients and normal controls. The association of VDR gene polymorphisms in type 1 diabetes with the presence of GAD65 and ICA512 autoantibodies were also examined using the χ2 test.
RESULTS: The allele frequency of the BsmI and ApaI polymorphisms, but not TaqI polymorphism, differed between patients and controls (BsmI P=0.015; ApaI P= 0.018; TaqI P= 0.266). However, after correction for the three different polymorphisms tested, only the BsmI was significant (pc=0.045).
CONCLUSIONS: Vitamin D receptor gene polymorphisms were associated with type 1 diabetes in a Taiwanese population. However, functional studies are needed to establish the role of the vitamin D receptor in the pathogenesis of type 1 diabetes mellitus.
Second Part: The association study between β2-adrenoreceptor (ADRB2) gene polymorphism and susceptibility to type 2 diabetes
OBJECTIVE: The significance of the association of amino terminal polymorphisms in β2-adrenoreceptor (ADRB2) with obesity and type 2 diabetes is controversial and differs among ethnic groups. In this study, the association of ADRB2 with risk and age of onset of type 2 diabetes has been examined in a Taiwanese population.
DESIGN: The study design is a case–control study to investigate the impact of the two amino acid polymorphisms in ADRB2
.
PATIENTS AND MEASUREMENTS: This study includes 130 patients with type 2 diabetes [female : male = 1 : 1, age: 52.4 ± 10.0 years; body mass index (BMI): 24.2 ± 2.9 kg/m2 ; mean ± SD] and 130 controlled subjects matched for gender, age and BMI with normal glucose tolerance (female : male = 1 : 1, age: 51.7 ± 10.6 years; BMI: 23.9 ± 2.7 kg/m2). The Arg16Gly and Gln27Glu polymorphisms of ADRB2 were determined by polymerase chain reaction-restriction fragment length polymorphism (PCR–RFLP) assays. The genotypic and allelic frequencies between two groups were compared and the relationship between the genotypes and clinical phenotypes was examined.
RESULTS: A difference in genotypic frequency in the Arg16Gly polymorphism was noted between groups in this gender-, age- and BMI-matched case–control study (P= 0.039). Multivariate regression analysis revealed that the Arg16Gly polymorphism was the only independent factor for development of type 2 diabetes(P= 0.021). In addition, we utilized the log-rank test to compare the differences in age of onset between wildtype and nonwild-type polymorphisms. The Arg16Gly polymorphism was independently associated with age of onset in type 2 diabetes (P= 0.017). There was no difference in the Gln27Glu polymorphism between diabetic and control groups in this study.
CONCLUSIONS: In a Taiwanese population, homozygosity of Arg16 in the ADRB2 gene was associated with a higher frequency (odds ratio 1.87, 95% confidence interval 1.34–2.40) for development of type 2 diabetes. Moreover, this polymorphism was also associated with an earlier onset of type 2 diabetes. However, the Glu27Gln polymorphism had no impact on either BMI or type 2 diabetes in a Taiwanese population.
Third Part: The molecular mechanism of thiazolidinediones (TZDs) to improve the insulin secretory capacity of islet β cells
To elucidate the direct effect of rosiglitazone (RSG), a new thiazolidinedione antihyperglycemic agent, on pancreatic insulin secretion, an in situ investigation by rat pancreatic perfusion was performed. At a basal glucose concentration of 6 mmol/l, RSG (0.045–4.5 μmol/l) stimulated insulin release in a dose-dependent manner. In addition, 4.5 μmol/l RSG potentiated the glucose (10 mmol/l)-induced insulin secretion. Both the first and second phases of glucose-induced insulin secretion were significantly enhanced by RSG, by 80.7 and 52.4%, respectively. The effects of RSG on insulin secretion were inhibited by a phosphatidylinositol 3-kinase (PI3K) inhibitor, LY294002. In contrast, the glucose-stimulated insulin secretion was not affected by LY294002. The potentiation effect of RSG on glucose-stimulated insulin secretion, in both the first and second phases, was significantly blocked by LY294002. These results suggest that RSG has a direct potentiation effect on insulin secretion in the presence of 10 mmol/l glucose, mediated through PI3K activity. The inability of LY294002 to inhibit glucose-induced insulin secretion suggests that different pathways are responsible for glucose and RSG signaling.
To further elucidate the molecular mechanism of RSG on potentiating the glucose-stimulated insulin secretion, we found that rosiglitazone could activate AMP-activated protein kinase (AMPK), downstream of PI3K activation in pancreatic beta cells. Using a pharmacological activator of AMPK, 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR), we showed that AICAR inhibited ATP-sensitive potassium channel conductance by whole cell voltage clamp techniques and potentiate glucose-stimulated insulin secretion in the primary rat islets. To confirm the role of this signaling pathway in insulin secretion in vivo, we also found that AICAR could stimulate insulin secretion in the presence of basal and high glucose concentration in isolated pancreatic perfusion studies. Taken together, we conclude that PI3K-dependent activation of the AMPK is required for the insulin secretory response induced by rosiglitazone in pancreatic beta cells. AMPK may serve as a potential therapeutic target of insulin secretion for the treatment of diabetes mellitus.
Subjects
糖尿病
遺傳流行病學
胰島beta 細胞功能
diabetes
genetic epidemiology
islet beta cell function
SDGs
Type
text
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