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Query: UMLS:C0011860 (type 2 diabetes)
 57,723 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Members of three families with maturity onset diabetes of youth (MODY) and seven with "common" type 2 diabetes were typed for six DNA markers (H-RAS, INS, HBBC, PTH, CALC1, CAT) on the short arm of chromosome 11. Using conventional pairwise linkage analysis, close linkage in the MODY families was excluded for all six markers. By multipoint analysis and a genetic map of the short arm of chromosome 11, MODY was excluded from a region of at least 35 and up to 60 centiMorgans (cM) on the short arm of chromosome 11. Multipoint analysis in the type 2 families also excludes linkage to the INS, H-RAS region of at least 3 and up to 30 cM. This study using multipoint linkage analysis in non-insulin dependent diabetes provides strong evidence against a role for mutations in or around the insulin gene in the causation of MODY or type 2 diabetes in the families studied.
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PMID:Multipoint linkage analysis of the short arm of chromosome 11 in non-insulin dependent diabetes including maturity onset diabetes of youth. 158 33

As a result of advances in technology, genome searches have been carried out for susceptibility genes for type 1 diabetes in humans and in the NOD mouse. These have shown that, in the NOD mouse, diabetes susceptibility is under the control of at least ten separate chromosomal loci. In the human, in addition to HLA and INS, two new susceptibility genes have been localized, IDDM4 on chromosome 11q and IDDM5 on 6q, demonstrating the polygenic nature of type 1 diabetes and the role of HLA as the major locus. Candidate genes at these loci are the subject of current investigation. Genetic and immunological markers of disease may be of value in screening the general population for individuals at risk of developing type 1 diabetes. The predictive power of different screening strategies should be tested in order to work out the potential value to the general population of preventive therapies that are now undergoing clinical trials in high risk 'pre-diabetics'. Type 2 diabetes is genetically heterogeneous, and, since 1992, two distinct genetic subtypes have been identified. The first is defined by mutations in the GCK gene, which cause up to 60% of cases of MODY. The second, designated MIDD (maternally inherited diabetes and deafness), is defined by mutation in the mitochondrial gene for tRNA(Leu(UUR)). MIDD patients are less obese than is usual for typical type 2 diabetes, may present in early adult life or occasionally in childhood and may have been diagnosed as having autoimmune type 1 diabetes, type 2 diabetes or MODY. Typically, patients with MIDD require insulin earlier than do type 2 diabetics without mitochondrial mutations. Genetically complex diseases, such as diabetes, hypertension, cancer and coronary heart disease, are common in most populations. The approaches to the genetic analysis of diabetes outlined in this review are likely to be useful to the genetic analysis of many of these disorders. Progress in this area will have important implications for public health strategies in the next decade and beyond.
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PMID:Molecular genetics of diabetes mellitus. 757 35

We review the strategy used to identify a susceptibility locus (IDDM2) for type 1 (insulin dependent) diabetes mellitus. As type 1 diabetes is becoming the paradigm for dissecting multifactorial disease genetics, the approach described provides important general guidelines for positional cloning of human disease polygenes. Main topics include: (a) historical conspectus of the mapping and identification of IDDM2--a critical survey of the work leading up to the conclusion that IDDM2 most likely corresponds to allelic variation at the insulin gene minisatellite (VNTR) locus; (b) the nature of allelic (length and sequence) variation at the VNTR locus; (c) gene interactions and disease pathogenesis; (d) mechanism of action of the INS VNTR in type 1 diabetes--insulin gene expression, parent-of-origin effects (genomic imprinting); and (e) summary and future prospects--alleles of the insulin VNTR that are protective for type 1 diabetes appear to encode susceptibility to type 2 diabetes.
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PMID:Human type 1 diabetes and the insulin gene: principles of mapping polygenes. 898 58

The aim of the present study was to evaluate the effects of complementary insulin therapy, consisting of a single dose of 1 to 8 units of shortacting insulin before each meal (4-6x daily) and sometimes at 02.30 h, on concentrations of serum lipids, lipoproteins and apoproteins in type 2 (non-insulin-dependent) diabetic patients, unsatisfactorily controlled either by oral hypoglycemic agents (OHA) or by longacting insulin 1-2x daily (INS 1-2). Compared means +/- SD. Patients on INS 1-2 (n = 82) had better baseline glycemic control than patients on OHA (n = 68) (HbAlc: 9.33 +/- 1.76% vs. 10.59 +/- 1.83%, p < 0.001 and fructosamine: 3.34 +/- 0.74 mmol/l vs. 3.85 +/- 0.84 mmol/l, p < 0.001) and serum triglyceride concentrations (3.03 +/- 2.05 mmol/l vs. 4.95 +/- 4.48 mmol/l, p < 0.001), in spite of longer duration of diabetes (13.35 +/- 8.07 years vs. 10.1 +/- 6.9 years, p < 0.001). After 8-10 weeks of complementary insulin therapy, OHA patients (n = 33) improved both the glycemic control (HbA1c: 10.5 +/- 1.78% vs. 9.0 +/- 1.75%, p < 0.001) and fructosamine: 4.0 +/- 0.85 mmol/l vs. 3.5 +/- 0.76 mmol/l, p < 0.001) and most of the lipid parameters (decreased serum triglyceride: 5.8 +/- 5.64 mmol/l vs. 3.6 +/- 4.69 mmol/l, p < 0.001, total cholesterol/HDL-cholesterol: 6.8 +/- 3.13 vs. 5.6 +/- 2.23, p < 0.01 and increased HDL-cholesterol: 1.0 +/- 0.30 mmol/l vs. 1.2 +/- 0.30 mmol/l, p < 0.001, apo AI: 1.6 +/- 0.26 g/l vs. 1.8 +/- 0.28 g/l, p < 0.001, LpAI particles: 0.6 +/- 0.1 g/l vs. 0.7 +/- 0.12 g/l, p < 0.001 and LDL-cholesterol/apo B: 2.1 +/- 0.67 vs. 2.7 +/- 0.67, p < 0.001). In patients previously on INS 1-2x (n = 34), complementary insulin therapy with reduced dose of insulin per day (49.6 +/- 22.5 U/d vs. 36.6 +/- 13.3 U/d, p < 0.001) did not further improve glycemic control but improved the number of proatherogenic and antiatherogenic lipoprotein particles (decreased apo B: 1.7 +/- 0.52 g/l vs. 1.5 +/- 0.94 g/l, p < 0.01, apo AI/Lp AI: 2.9 +/- 1.01 vs. 2.3 +/- 0.98, p < 0.01 and increased Lp AI particles: 0.6 +/- 0.10 g/l vs. 0.7 +/- 0.12 g/l, p < 0.0001); BMI also decreased (29.4 +/- 4.28 kg/m2 vs. 28.9 +/- 4.24 kg/m2, p < 0.05). These results demonstrate that complementary insulin therapy probably induces antiatherogenic lipoprotein changes in NIDDM patients previously treated by either OHA or INS 1-2x. Thus, this type of therapy should be used more often and start earlier, and should be preferred to longacting insulins.
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PMID:Complementary insulin therapy improves blood glucose and serum lipid parameters in type 2 (non-insulin-dependent) diabetic patients. II. Effects on serum lipids, lipoproteins and apoproteins. 928 51

Type 2 diabetes is a polygenic and genetically heterogeneous disease . The age of onset of the disease is usually late and environmental factors may be required to induce the complete diabetic phenotype. Susceptibility genes for diabetes have not yet been identified. Islet-brain-1 (IB1, encoded by MAPK8IP1), a novel DNA-binding transactivator of the glucose transporter GLUT2 (encoded by SLC2A2), is the homologue of the c-Jun amino-terminal kinase-interacting protein-1 (JIP-1; refs 2-5). We evaluated the role of IBi in beta-cells by expression of a MAPK8IP1 antisense RNA in a stable insulinoma beta-cell line. A 38% decrease in IB1 protein content resulted in a 49% and a 41% reduction in SLC2A2 and INS (encoding insulin) mRNA expression, respectively. In addition, we detected MAPK8IP1 transcripts and IBi protein in human pancreatic islets. These data establish MAPK8IP1 as a candidate gene for human diabetes. Sibpair analyses performed on i49 multiplex French families with type 2 diabetes excluded MAPK8IP1 as a major diabetogenic locus. We did, however, identify in one family a missense mutation located in the coding region of MAPK8IP1 (559N) that segregated with diabetes. In vitro, this mutation was associated with an inability of IB1 to prevent apoptosis induced by MAPK/ERK kinase kinase 1 (MEKK1) and a reduced ability to counteract the inhibitory action of the activated c-JUN amino-terminal kinase (JNK) pathway on INS transcriptional activity. Identification of this novel non-maturity onset diabetes of the young (MODY) form of diabetes demonstrates that IB1 is a key regulator of 3-cell function.
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PMID:The gene MAPK8IP1, encoding islet-brain-1, is a candidate for type 2 diabetes. 1070 Jan 86

A high association between type 2 diabetes mellitus and depressive illness has been reported. Insulin resistance during depressive illness might contribute to the linkage between depression and type 2 diabetes. To determine whether the genetic polymorphisms of the tyrosine hydroxylase ([TH] HUMTH01) and insulin (INS-VNTR) genes contribute to insulin resistance in depressive illness, we analyzed the association between the polymorphisms and insulin resistance in 41 Japanese patients with depressive disorder, 204 normal control subjects, 161 cohort subjects with normal glucose tolerance (NGT) and without depressive symptomatology, and 59 NGT subjects with depressive symptomatology. The depressive patients had a significantly lower insulin sensitivity index (SI) than the control subjects (P= .016). Depressive NGT subjects had a significantly higher homeostasis model assessment (HOMA) insulin resistance index [HOMA(R)] than the nondepressive NGT subjects (P < .0001). The depressive patients and NGT subjects had more HUMTH01 allele 7 (TH7) than the controls and nondepressive NGT subjects. SI was significantly lower in patients with the TH7/7 homozygote versus patients with the other genotypes and the controls. TH7 was associated with higher HOMA(R) as compared with the other alleles in the NGT subjects. Insulin resistance was associated with depressive disorders. The HUMTH01 and INS-VNTR were associated with insulin resistance and depressive symptoms.
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PMID:Tyrosine hydroxylase gene microsatellite polymorphism associated with insulin resistance in depressive disorder. 1101 95

Polycystic ovary syndrome (PCOS) is a common endocrine disorder in women of reproductive age. The disorder is characterized by clinical features of hyperandrogenism, menstrual irregularities and often central obesity and hyperinsulinaemia. PCOS may increase the risk for infertility, type 2 diabetes mellitus, dyslipidaemia, cardiovascular disease and endometrial cancer, emphasizing the need for early diagnosis of the syndrome. The genetic basis of PCOS is unknown. There is a strong familial component but the mode of inheritance is uncertain and several candidate genes have been proposed to contribute to susceptibility. Not only genes involved in steroid hormone biosynthesis have been studied but also genes associated with the regulation of insulin secretion and action since hyperinsulinaemia is a characteristic of PCOS. So far there is evidence that INS VNTR (insulin variable number of tandem repeats) or CYP11alpha (cholesterol side chain cleavage) genes are associated with this syndrome. PCOS appears, however, to be an oligogenic disorder and more studies are necessary to define the genetic basis.
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PMID:The genetic basis of polycystic ovary syndrome. 1245 45

Glucose-dependent insulinotropic polypeptide (GIP) is secreted postprandially and acts in concert with glucose to stimulate insulin secretion from the pancreas. Here, we describe a novel pathway for the regulation of GIP receptor (GIPR) expression within clonal beta-cell lines, pancreatic islets, and in vivo. High (25 mM) glucose was able to significantly reduce GIPR mRNA levels in INS(832/13) cells after only 6 h. In contrast, palmitic acid (2 mM) and WY 14643 (100 microM) stimulated approximate doublings of GIPR expression in INS(832/13) cells under low (5.5 mM), but not high (25 mM), glucose conditions, suggesting that fat can regulate GIPR expression via PPARalpha in a glucose-dependent manner. Both MK-886, an antagonist of PPARalpha, and a dominant negative form of PPARalpha transfected into INS(832/13) cells caused a significant reduction in GIPR expression in low, but not high, glucose conditions. Finally, in hyperglycemic clamped rats, there was a 70% reduction in GIPR expression in the islets and a 71% reduction in GIP-stimulated insulin secretion from the perfused pancreas. Thus, evidence is presented that the GIPR is controlled at normoglycemia by the fatty acid load on the islet; however, when exposed to hyperglycemic conditions, the GIPR is down-regulated, which may contribute to the decreased responsiveness to GIP that is observed in type 2 diabetes.
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PMID:A novel pathway for regulation of glucose-dependent insulinotropic polypeptide (GIP) receptor expression in beta cells. 1247 13

The insulin gene variable number tandem repeat (INS-VNTR) is proposed to exert pleiotropic genetic effects on birth weight and diabetes susceptibility. In our study, we examined the influence of a polymorphism in tight linkage disequilibrium with INS-VNTR (-23Hph1) on birth weight and type 2 diabetes in the Pima population. A parent-offspring "trio" design was used to assess parent-of-origin effects and population stratification. The presence of the -23Hph1 T-allele was associated with lower birth weight (n = 192; -140 g per copy of the T-allele; P = 0.04), even after adjustment for effects of population stratification (P = 0.03). The effects of paternally transmitted T-alleles were greater than those of maternally transmitted alleles (paternally transmitted: -250 g, P = 0.05; maternally transmitted: -111 g, P = 0.43), but this difference was not statistically significant (P = 0.50). The -23Hph1 T-allele was associated with an increased prevalence of type 2 diabetes (P = 0.009), which family-based association analysis suggested was attributable to population structure (P = 0.04) without significant evidence of linkage disequilibrium between diabetes prevalence and genotype (P = 0.86). Thus allelic variation of the INS gene is associated with lower birth weight and increased prevalence of type 2 diabetes. Significant linkage disequilibrium was found between -23Hph1 and birth weight but not type 2 diabetes, an observation that supports a potential functional role of INS polymorphisms in the regulation of birth weight.
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PMID:The insulin gene variable number tandem repeat class I/III polymorphism is in linkage disequilibrium with birth weight but not Type 2 diabetes in the Pima population. 1250 11

The insulin gene variable number of tandem repeats minisatellite (INS-VNTR) class III allele is associated with altered fetal growth, type 2 diabetes risk (especially when paternally inherited), and insulin and IGF2 gene expression. Further studies are needed to establish the role of the INS-VNTR in fetal growth and assess whether its effects depend on the parent of origin. We analyzed the INS-VNTR-linked -23 Hph1 polymorphism in 2283 subjects, comprising 1184 children and 1099 parents. There were no differences (P < 0.05) in birth weight between offspring of the three genotypes: III/III (n = 108) vs. I/I (n = 558), effect size, -8 g (P = 0.87); and I/III (n = 464) vs. I/I, effect size, -19 g (P = 0.54). We observed no differences in head circumference [III/III (n = 95) vs. I/I (n = 470), effect size, -0.14 cm; P = 0.31] or birth length. No differences were observed when stratifying by postnatal growth realignments [nonchangers III/III (n = 37) vs. I/I (n = 170), effect size, -43 g; P = 1.00] or by parent of origin of the class III allele (presence of paternal III allele effect size, -15 g; P = 0.74). INS-VNTR was nominally associated (P < 0.05) with body mass index and insulin resistance, but not with beta-cell function, in young adults. In the largest study to date, we found a lack of support for a role for INS-VNTR in fetal growth and nominal association with type 2 diabetes-related intermediate traits.
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PMID:Lack of support for a role of the insulin gene variable number of tandem repeats minisatellite (INS-VNTR) locus in fetal growth or type 2 diabetes-related intermediate traits in United Kingdom populations. 1471 66


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