Association of the renin-angiotensin system gene polymorphism with nephropathy in type II diabetes

Diabetic nephropathy is the most frequent cause of end-stage renal failure. One of the crucial factors in a development of renal and cardiovascular complications of diabetes is genetic predisposition. The genes of the renin-angiotensin system are important group of candidate genes involved in pathogenesis of chronic renal diseases. The purpose of our study was the evaluation of a possible role of genetic polymorphisms of some of the RAS system genes in the nephropathy in type 2 diabetes. The study was performed in 117 patients with diabetic nephropathy, compared with 200 healthy subjects as a control group. The following polymorphisms: insertion/deletion (I/D) of the angiotensin-converting enzyme gene (ACE), M235T of the angiotensinogen gene (AGT) and A1166C of the angiotensin II type 1 receptor gene (AT1R) were evaluated by polymerase chain reaction (PCR). No statistically significant differences between groups were found in the allele frequency and genotype distribution for ACE and AGT polymorphisms. The results for the AT1R gene polymorphism revealed significant differences in allele and genotype frequencies. The homozygous CC genotype was more frequent in patients with diabetic nephropathy than in control group. Both genotypes with the C allele (AC + CC) were found in 56% of patients compared to 38% in control group. These results suggest increased susceptibility to diabetic nephropathy in individuals carrying the CC genotype. Therefore, the A1166C polymorphism of the AT1R gene could be a potential genetic marker for increased susceptibility to renal complications in type 2 diabetes.     

Human leucocyte antigen and insulin gene regions and nephropathy in Type I diabetes

Abstract Aims/hypothesis. Diabetic nephropathy seems to have a strong genetic component. Genes involved in the genetic susceptibility to Type I (insulin-dependent) diabetes have been suggested to have a role in the development of diabetic nephropathy. This study aimed to examine the role of human leucocyte antigen and insulin genes in susceptibility to nephropathy in patients with Type I diabetes. Methods. We carried out a genetic association study examining insulin gene polymorphisms using three large cohorts of patients with Type I diabetes: nephropathy (n = 258), long duration non-nephropathy (n = 153) and a recently diagnosed (sporadic) diabetic cohort (n = 264). Human leucocyte antigen typing results were obtained in a smaller number due to assay failures (n = 182, 126 and 200 respectively). Results. No significant difference was seen in the distribution of human leucocyte antigen A, B, C, DR, DQA1 and DQB1 haplotypes and alleles between the three diabetic cohorts. No significant difference was seen in insulin ’ + ' and ’–' genotypes and alleles between the three diabetic cohorts. Conclusion/interpretation. Human leucocyte antigen and insulin gene loci are unlikely to have a major role in the susceptibility to nephropathy in Caucasian patients with Type I diabetes in the United Kingdom. [Diabetologia (1999) 42: 1017–1020] Received: 6 November 1998 and in final revised form: 31 March 1999     

Examination of two genetic polymorphisms within the renin-angiotensin system: no evidence for an association with nephropathy in IDDM

Summary Premature cardiovascular disease is common in insulin-dependent diabetic (IDDM) patients who develop diabetic nephropathy. Genetic polymorphism within the renin-angiotensin system has been implicated in the aetiology of a number of cardiovascular disorders; these loci are therefore candidate genes for susceptibility to diabetic renal disease. We have examined the angiotensin converting enzyme insertion/deletion polymorphism and angiotensinogen methionine 235 threonine polymorphism in a large cohort of Caucasian patients with IDDM and diabetic nephropathy. Patients were classified as having nephropathy by the presence of persistent dipstick positive proteinuria (in the absence of other causes), retinopathy and hypertension (n=242). Three groups were examined for comparison: ethnically matched non-diabetic subjects (n=187); a geographically defined cohort of newly diagnosed diabetic patients (n=341); and IDDM patients with long duration of disease (>15 years) and no evidence of overt nephropathy (n=166). No significant difference was seen in distribution of angiotensin converting enzyme or angiotensinogen genotypes between IDDM patients with nephropathy and recently diagnosed diabetic subjects (p=0.282 and 0.584, respectively), nor the long-duration non-nephropathy diabetic subjects (p=0.701 and 0.190, respectively). We conclude that these genetic loci are unlikely to influence susceptibility to diabetic nephropathy in IDDM in the United Kingdom.Abbreviations IDDM Insulin-dependent diabetes mellitus - ACE angiotensin converting enzyme - PCR polymerase chain reaction - LDNN long duration-non-nephropathy group - I/D insertion/deletion - RAS renin-angiotension system     

A genetic analysis of type 2 (non-insulin-dependent) diabetes mellitus in Punjabi Sikhs and British Caucasoid patients

A genetic analysis of diabetic and non-diabetic Punjabi Sikhs (n = 164) was made for markers of non-insulin-dependent diabetes mellitus using insulin receptor, insulin, and HLA-D alpha chain gene probes. Additionally British Caucasoids (n = 163) were studied using the insulin receptor probe. Insulin receptor gene restriction fragment length polymorphisms were defined using Southern blot techniques and the restriction enzyme Bgl II and BAm Hl. In Punjabi Sikhs and British Caucasoids neither of the restriction fragment length polymorphisms distinguished non-insulin-dependent diabetes mellitus subjects from controls. In the Sikhs no association with non-insulin-dependent diabetes mellitus was seen with the hypervariable region of the insulin gene or with HLA-DR/DQ/DX alpha chain restriction fragment length polymorphisms. We therefore conclude that despite the high prevalence of non-insulin-dependent diabetes mellitus in Asians we were unable to find any genetic markers for this disease using the available cloned gene probes.     

Genetic variants of the renin-angiotensin system, diabetic nephropathy and hypertension

Summary Recent studies have suggested an association between a deletion (D) variant of the angiotensin-converting-enzyme (ACE) gene and diabetic nephropathy. However, this finding has not been confirmed by all investigators. Furthermore, an M235T variant of the angiotensinogen (AGT) gene has been associated with hypertension, an important risk factor for the development and progression of diabetic nephropathy. The objective of our study was therefore to examine the relationship between these genetic variants of the renin-angiotensin system and diabetic nephropathy and hypertension, respectively, in a large (n = 661) group of Caucasian patients with insulin-dependent (n = 360) or non-insulin-dependent (n = 301) diabetes mellitus. The study had a power of 0.8 to detect a doubling of risk of nephropathy or hypertension in patients with the ACE-DD or AGT-235TT genotype, respectively. Allelic frequencies of the ACE-D and AGT-235T alleles were similar between patients with and without nephropathy in either type of diabetes, and accordingly, there was no significant association between diabetic nephropathy and the ACE or AGT genotype. Likewise, there was no significant association between the ACE or AGT genotype and hypertension. Thus, our data, in this large and ethnically homogeneous group of patients, do not support the hypothesis that these genetic variants of the renin-angiotensin system are strongly associated with either nephropathy or hypertension in patients with insulin-dependent or non-insulin-dependent diabetes mellitus. These genetic markers are therefore unlikely to serve as clinically useful predictors of either nephropathy or hypertension in Caucasian patients with diabetes. [Diabetologia (1997) 40: 193–199] Received: 16 July 1996 and in revised form: 17 October 1996     

Molecular mechanism of insulin resistance in type 2 diabetes mellitus: role of the insulin receptor variant forms

Type 2 diabetes is a heterogeneous and polygenic disorder resulting from interaction of genetic factors with environmental influences. Numerous candidate genes for insulin signaling proteins have been screened, but no single major susceptibility gene for type 2 diabetes has been identified. Due to its pivotal role in insulin action, the insulin receptor was considered a plausible candidate gene. The insulin receptor exists in two isoforms differing by the absence (Ex11^?) or presence (Ex11⁺) of a 12 amino acid sequence in the COOH‐terminus of the α‐subunit, as a consequence of alternative splicing of exon 11. The Ex11^? binds insulin with two‐fold higher affinity than the Ex11⁺. This difference is paralleled by a decreased sensitivity for metabolic actions of insulin. Some, but not all, studies have reported that expression of the low‐affinity Ex11⁺ is increased in target tissues from type 2 diabetic patients, thus suggesting that alterations in abundance of the two isoforms might contribute to insulin resistance. Insulin and type 1 IGF receptors have been shown to form hybrid receptors in tissues co‐expressing both molecules. Hybrid receptors bind IGF‐I, but not insulin, with high affinity, and behave as IGF‐I holoreceptors, rather than insulin receptors, in terms of receptor autophosphorylation, and hormone internalization. It has been shown that the abundance of hybrid receptors is increased in skeletal muscle and adipose tissue from type 2 diabetic patients, and is negatively correlated with in vivo insulin sensitivity. Mutations in the insulin receptor gene have been identified in studies which examined an appropriately sized population of patients with type 2 diabetes. The prevalence of mutations in the insulin receptor gene ranged from 0.4%–7.8%. This review will focus on the structural and functional heterogeneity of the insulin receptor, and will discuss the pathogenetic role of insulin receptor variant forms and polymorphisms in the development of the common form of type 2 diabetes. Copyright © 2001 John Wiley & Sons, Ltd.     

The amino acid sequence of the insulin receptor is normal in an insulin-resistant Pima Indian

Insulin resistance is an early predictor of development of noninsulin-dependent diabetes mellitus (NIDDM) in Pima Indians, a population with the highest reported prevalence of NIDDM. The insulin receptor plays a central role in mediating insulin action, and previous studies have demonstrated that mutations in the insulin receptor gene may cause insulin resistance. Therefore, we have cloned the insulin receptor cDNA from an insulin-resistant Pima Indian to determine if there is a mutation in the patient's insulin receptor gene. We obtained nine cDNA clones spanning exons 4-10 and 12-22 of the patient's insulin receptor gene. Polymorphisms in the nucleotide sequences for codons 523 (Ala), 1058 (His), and 1062 (Leu) provided useful markers to differentiate the patient's two alleles of the insulin receptor gene. These substitutions were silent, in that they did not alter the predicted amino acid sequence. The sequence of exons 1-3 and 11 was determined directly from genomic DNA that had been amplified using the polymerase chain reaction catalyzed by Taq DNA polymerase. Other investigators have reported defects in insulin binding and insulin receptor tyrosine kinase activity in diabetic Pima Indians. However, we did not detect any mutations in this patient's insulin receptor gene. Thus, these observations are consistent with the interpretation that the defects in insulin receptor function are acquired rather than derived from defects in the primary structure of the receptor.     

Association of the C825T polymorphism of the G-protein beta3 subunit gene with hypertension, obesity, hyperlipidemia, insulin resistance, diabetes, diabetic complications, and diabetic therapies among Japanese

A C825T polymorphism of the gene encoding the G-protein beta3 subunit (GNB3) is associated with increased intracellular signal transduction. We know that this C825T polymorphism may influence hypertension and obesity. In whites, the C825T polymorphism has been reported to induce hypertension, obesity, and diabetic nephropathy. Thus, we investigated how genetic variation in the GNB3 gene is associated with hypertension, obesity, insulin resistance, diabetes, diabetic complications, and diabetic therapies in 427 Japanese subjects with type 2 diabetes mellitus and in 368 Japanese subjects who underwent general health examinations. The frequency of the GNB3 gene polymorphism was 0.48 and 0.47 in subjects with diabetes and in those who had general health examinations, respectively. The amount of hyperlipidemia of the CT allele was significantly lower than the amount in the CC allele in the Japanese subjects with diabetes. Our results suggest that the C825T polymorphism influences lipid metabolism and is not associated with hypertension, obesity, insulin resistance, diabetes, diabetic complications, or diabetic therapies.     

The 5′ insulin gene polymorphism and the genetics of vascular complications in Type 1 (insulin-dependent) diabetes mellitus

Summary Recent data suggest genetic contributions to the microvascular complications of Type 1 (insulin-dependent) diabetes mellitus. Most research has focused on the HLA region, and the potential role of other genetic loci has not been adequately explored. We examined the possible relationship between DNA polymorphisms in the region 5 to the insulin gene on chromosome 11 and diabetic nephropathy. This was done by comparison of those diabetic patients homozygous for class 1 alleles at the 5 insulin gene polymorphism locus to 1/3 heterozygotes in a well-characterized series of 324 insulin-requiring diabetic patients from the Wisconsin Epidemiologic Study of Diabetic Retinopathy. Proteinuria (defined as 0.3 g protein/l urine), was used as suggestive evidence for diabetic nephropathy. Hypertension, a frequent associated finding in diabetic patients with nephropathy, was defined as a blood pressure greater than 140/90 or a history of previous treatment of hypertension. The two genotypically defined groups did not differ from each other in regard to sex ratio, age at diagnosis, age at examination, duration of diabetes, body mass, HbA_lc or C-peptide. The 1/1 group had a higher prevalence of proteinuria, 29% as compared to 16.2 % in other genotypes (p<0.05). There was no significant difference in the frequency of hypertension between the two genotypic groups. This finding suggests that the 5 insulin gene polymorphism may be associated with risk for nephropathy, but the pathophysiologic mechanism remains unclear.     

Skin fibroblasts as a tool for identifying the risk of nephropathy in the type 1 diabetic population

Human fibroblasts in culture have been employed as an in vitro system to investigate some pathophysiological mechanisms of diabetes mellitus also associated with the development of diabetic nephropathy. In fact, there is increasing evidence that genetic factors either convey the risk of, or protect from, diabetic nephropathy and that the expression profiles and/or the behaviour of the cultured skin fibroblasts from type 1 diabetic patients could reflect these genetic influences. On the other hand, alterations could be attributable not only to changes in DNA sequence, but also to epigenetic factors. Our aim is to make a critical overview of the studies involving primary cultures of skin fibroblasts as tools to investigate the pathophysiology of diabetic nephropathy performed until now in this area. Cultured skin fibroblasts could be useful not only for the identification of patients at risk of developing diabetic renal disease, but also for a better understanding of the complex multifactorial mechanisms leading to the long-term complications in diabetes.     

Patients with lipodystrophic diabetes mellitus of the Seip-Berardinelli type,express normal insulin receptors

Summary Lipodystrophic diabetes mellitus of the Seip-Berardinelli type is a syndrome associated with insulin resistance and recessive inheritance. We have examined whether mutations in the insulin receptor are pathogenetic factors in this syndrome. Fibroblasts from three different patients with Seip-Berardinelli's lipodystrophy were tested for insulin binding, and insulin-stimulated receptor autophosphorylation. In addition, the coding region of both alleles of the insulin receptor gene was sequenced. No abnormalities in the number of high affinity insulin binding sites, and in-sulinstimulated receptor autophosphorylation were detected. The insulin receptor related insulin-like growth factor I receptor also showed no functional changes. DNA sequence analysis of the amplified exons of the insulin receptor gene showed a silent mutation in patient 1 at codon Ser³³⁹, changing AGT to AGC. In patient 2 a heterozygous Met for Val substitution at position 985 was detected, which is a rare polymorphism. In patient 3 no mutations, other than described polymorphisms, were observed. These findings demonstrate that the primary genetic lesion in Seip-Berardinelli's lipodystrophy is outside the insulin receptor gene and that an involvement of the insulin-like growth factor I receptor is also unlikely.     

Association of the angiotensinogen M235T and angiotensin-converting enzyme insertion/deletion gene polymorphisms in Turkish type 2 diabetic patients with and without nephropathy

OBJECTIVE: Recent studies have suggested an association between a deletion variant of the angiotensin-converting enzyme (ACE) gene and diabetic nephropathy. However, this finding has not been confirmed by all investigators. Furthermore, an M235T variant of the angiotensinogen (AGT) gene has been associated with hypertension, an important risk factor for the development and progression of diabetic nephropathy. RESEARCH DESIGN AND METHODS: We investigated the relationship of the ACE insertion/deletion (I/D) and AGT M235T gene polymorphisms in Turkish patients with type 2 diabetes mellitus (DM) with and without diabetic nephropathy. A total of 102 individuals were screened for the presence of the ACE I/D and AGT M235T polymorphism: 46 individuals who had type 2 DM with diabetic nephropathy and, as controls, 56 individuals who had type 2 DM without diabetic nephropathy. Gene polymorphisms were determined by the specific melting temperature (T(m)) values of the resulting amplicons after real-time online polymerase chain reaction and melting curve analysis. RESULTS: The frequencies of the ACE DD, ID, and II genotypes were 34.8%, 37.0%, and 28.3%, respectively, among type 2 diabetic patients with nephropathy, and 33.9%, 42.9%, 23.2%, respectively (P=.788), in the control subjects without diabetic nephropathy. On the other hand, the frequencies of the AGT MM, MT, and TT genotypes among the same groups were 26.1%, 52.2%, 21.7% and 26.8%, 57.1%, 16.1%, respectively (P=.758). CONCLUSIONS: There were no differences in the frequencies of the AGT M235T and ACE I/D genotypes between Turkish patients with type 2 DM with and without nephropathy.     

The C825T polymorphism in the human G-protein β3 subunit gene is not associated with diabetic nephropathy in Type I diabetes mellitus

Summary In Type I (insulin-dependent) diabetes mellitus a genetic predisposition exists to nephropathy and is related to parental hypertension. Enhanced G-protein activation, a cellular phenotype observed in cultured cells from patients with essential hypertension, was recently documented in Type I diabetic subjects with nephropathy. This enhanced G-protein activation has been associated with a genetic variant in the G-protein β3 subunit, GNB3. A C→T polymorphism at position 825 in exon 10 is associated with G-protein activation, the T allele associated with enhanced activity. Furthermore the T allele was observed more frequently in a group with essential hypertension. In this report we have analysed the role of the C825T polymorphism in the predisposition to diabetic nephropathy in Type I diabetes. We have investigated the frequency of this polymorphism in a large case-control study and found no association of the T allele with diabetic nephropathy. Specifically carriage of the T allele as CT or TT was observed in 49 % of 200 Type I diabetic control subjects with normoalbuminuria (diabetes duration 24 years) compared with 53 % of 216 Type I diabetic subjects with nephropathy (overt proteinuria or end-stage renal failure). Within this group we have also examined the inheritance of C825T alleles in a family study and found no evidence for excess transmission of the T allele to Type I diabetic offspring with nephropathy (T allele transmitted to 51 % of nephropathy offspring, C allele transmitted to 49 % of nephropathy offspring, p = 0.79). In none of the Type I diabetic datasets examined was there any effect of genotype on variation in systolic or diastolic blood pressure. In conclusion we can find no evidence for the C825T polymorphism of the β3 G-protein subunit as a major gene in the susceptibility to diabetic nephropathy in Type I diabetes. [Diabetologia (1998) 41: 1304–1308] Received: 27 April 1998 and in revised form: 9 July 1998     

Polymorphisms of human paraoxonase 1 gene (PON1) and susceptibility to diabetic nephropathy in Type I diabetes mellitus

Aims/hypothesis. Oxidative stress is a putative mechanism in the development of diabetic nephropathy. Paraoxonase gene 1 is an HDL-bound enzyme that protects tissues against oxidative damage. Three common polymorphisms of paraoxonase gene 1, T-107C in the promoter, Leu54Met and Gln192Arg, that modify paraoxonase activity have been associated with cardiovascular disease. This study aimed to find whether these polymorphisms also contribute to the development of diabetic nephropathy. Methods. The association between diabetic nephropathy and these three polymorphisms was examined in a case-control study. For this purpose, genomic DNA was collected from 188 patients with Type I (insulin-dependent) diabetes mellitus and diabetic nephropathy and from 179 unrelated patients with Type I diabetes but without diabetic nephropathy despite the duration of diabetes of 15 or more years. Results. The genotype and allele frequencies for each of the three polymorphisms (T-107C, Leu54Met and Gln192Arg) were similar in cases and control subjects. Conclusion/interpretation. The three polymorphisms in paraoxonase gene 1 that have been associated with serum levels of paraoxonase are not associated with diabetic nephropathy. We show that this genetically determined component of the antioxidant capacity of HDL does not play a critical part in the development of diabetic nephropathy. [Diabetologia (2000) 43: 1540–1543] Received: 14 July 2000 and in revised form: 21 August 2000     

In vivo proliferation of rat vascular smooth muscle in relation to diabetes mellitus insulin-like growth factor I and insulin

Summary The roles of diabetes mellitus, insulin-like growth factor I and insulin in vascular smooth muscle proliferation in vivo were studied. Proliferation was induced by endothelial injury (balloon catheterization) of rat aorta, and was measured as ³H-thymidine incorporation into DNA. Levels of insulin-like growth factor I mRNA and insulin-like growth factor I receptor mRNA were measured with a solution hybridization assay. The increase in DNA synthesis was most pronounced 2 days after injury in both normal and diabetic rats and declined thereafter, but DNA synthesis in aortas from diabetic rats was lower throughout the time period studied. Levels of insulin-like growth factor I mRNA and the receptor mRNA were both increased in balloon catheterized aortas, and time-course studies showed an increase in receptor mRNA prior to the increase in insulin-like growth factor I mRNA. Diabetic rats were treated with equimolar concentrations of insulin (35 nmol/day) or insulin-like growth factor I (31 nmol/day) for 5 days. Insulin-like growth factor I increased DNA synthesis in injured aortas 2 days after injury without improving blood glucose, whereas the effect of insulin was associated with a decrease in blood glucose levels. In conclusion, vascular smooth muscle proliferation is impaired by diabetes and stimulated by insulin treatment. Insulin-like growth factor I infusion stimulates vascular smooth muscle proliferation without affecting bloo glucose, and gene expressions of insulin-like growth factor I and its receptor are increased in proliferating vascular smooth muscle, indicating that insulin-like growth factor I is involved in vascular smooth muscle proliferation in vivo.     

Linkage analysis of the human insulin receptor gene in Type 2 (non-insulin-dependent) diabetic families and a family with maturity onset diabetes of the young

Summary The possibility of linkage between the human insulin receptor gene locus and diabetes was examined in three Type 2 (non-insulin-dependent) diabetic families and one family with maturity onset diabetes of the young. Insulin receptor gene haplotypes were established using BglII, Rsal and Sstl restriction enzyme digests of genomic DNA from all available family members. The digested DNA was subjected to agarose gel electrophoresis, Southern blotted, and hybridised to ³²P-labelled human insulin receptor gene cDNA. In the pedigree with maturity onset diabetes of the young, formal linkage analysis allowed exclusion of close linkage between the insulin receptor locus and diabetes (logarithm of the odds for linkage versus non-linkage was –5.35 at recombination fraction of 0.01). This confirms the absence of linkage between insulin receptor and diabetes which has been reported in two similar pedigrees. In the three Type 2 diabetic families there were a minimum of 4 recombinants between the insulin receptor locus and diabetes, which makes a direct role for insulin receptor defects unlikely. The importance of using realistic estimates of penetrance when performing linkage analysis in a disease with a late age of onset is emphasised. In contrast to the one previous linkage analysis study of the insulin receptor gene, no specific association of diabetes with the rare Sstl Sl(-) allele was observed in either the maturity onset diabetes of the young or the Type 2 diabetic families.     

Restriction fragment length polymorphism of the insulin receptor gene, type 2 diabetes and insulin binding.

In searching for a genetic marker of type 2 diabetes we estimated the frequency of alleles of the Bgl II restriction fragment length polymorphism (RFLP) of the insulin receptor gene in a group of type II diabetic patients (n = 50), characterized by OGTT (glucose, insulin, C-peptide) and insulin receptor binding parameters. Leucocyte DNA was incubated with restriction endonuclease Bgl II and specific fragments were determined by Southern blot technique, using radioactive plasmid pINSR 13.1 as insulin receptor gene probe for hybridization. Insulin receptor numbers and receptor affinity were estimated by 125I-(Tyr-A-14)- insulin binding to red blood cells. Among control subjects the 20 kb fragment (allele Bgl II+) had a frequency of 0.21. In our group of diabetic patients this allele had a frequency of 0.10 (n.s., p greater than 0.05). In our study the insulin receptor genotype had no influence on body mass index, insulin and C-peptide during OGTT as well as insulin receptor binding data. So far, etiopathogenetic linkage between diabetes and insulin receptor variants (mutants) could unambiguously be proved in patients with extreme insulin resistance only. In our opinion, the estimation of the role of the gene as the reason underlying the disease inevitably requires the investigation of large families with multiple occurrence of type 2 diabetes.     

The role of ecto-nucleotide pyrophosphatase/phosphodiesterase 1 in diabetic nephropathy

The increased prevalence of diabetes mellitus has caused a rise in the occurrence of its chronic complications, such as diabetic nephropathy (DN), which is associated with elevated morbidity and mortality. Familial aggregation studies have demonstrated that besides the known environmental risk factors, DN has a major genetic component. Therefore, it is necessary to identify genes associated with risk for or protection against DN. Ecto-nucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) is expressed in several tissues, including the kidneys. Increased levels of ENPP1 expression inhibit tyrosine-kinase activity of the insulin receptor in several cell types, leading to insulin resistance. K121Q polymorphism of the ENPP1 gene seems to be associated with insulin resistance and DN development. The elucidation of genetic factors and their associations will provide better understanding of the pathogenesis of DN and, may consequently, lead to a more effective approach to prevention and treatment.     

Angiotensin I-converting enzyme: a pathogenetic role in diabetic renal damage?

The renin-angiotensin aldosterone system (RAAS) is well-established to be involved in diabetic nephropathy. Several abnormalities in the RAAS have been described in diabetes mellitus, including an abnormal aldosterone to renin ratio, elevated angiotensin I-converting enzyme (ACE) levels, and altered angiotensin II sensitivity. Whereas the renoprotective properties of ACE-inhibition in diabetic nephropathy have been demonstrated more than a decade ago, somewhat surprisingly, the role of ACE-activity in the pathogenesis of diabetic nephropathy is not well established. This paper addresses the possible functional impact of genetic and environmental increased in ACE activity in the pathogenesis of diabetic renal damage, in the context of the various other abnormalities in the RAAS in diabetes. Human and experimental data on circulating and tissue ACE in diabetes are reviewed, as well as the associations of ACE with angiotensin I conversion, with pathophysiological responses, and with renal end organ damage. New data from our laboratory provide evidence for interaction between genetical regulation of ACE activity by the ACE (I/D) genotype and diabetes as an environmental factor. Moreover, for functional effects of the elevated ACE activity in terms of increased conversion of angiotensin I to angiotensin II. The effects of enhanced generation of angiotensin II are modulated by the angiotensin II-subtype I receptor (AT1R). Altered AT1R sensitivity has been reported in diabetes that may further modu-late the eventual effects of elevated ACE. Epidemiological data on the association of genetically elevated ACE activity with diabetic nephropathy provide support for a pathogenetic role of elevated ACE activity in diabetic nephropathy. Together, the data suggest that differences in ACE expression and activity, resulting from both genetic and environmental factors and their interaction can modulate the pathogenesis of diabetic nephropathy. Unravelling the nature of this interaction, with focus on modifiable environmental factors, may help to ameliorate the risk for nephropathy in diabetes.