Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0011860 (type 2 diabetes)
 57,723 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Vagally-mediated hyperinsulinemia is a common abnormality in various rodent models of genetic and hypothalamic obesity that have a high propensity for type 2 diabetes. We hypothesized that Pima Indians, a population with a high prevalence of hyperinsulinemia, obesity, and type 2 diabetes also have an increased parasympathetic drive to the pancreas. To test this, we measured plasma concentrations of insulin and pancreatic polypeptide (PP), a surrogate marker of pancreatic vagal tone, in lean and obese Pima Indian and Caucasian children (n = 43, 26P/17C, 7 +/- 1 y) and adults (n = 92, 61P/31C, 31 +/- 5 y). Pima Indian children had approximately 2-fold higher fasting insulin and 57% higher fasting PP concentrations than age- and sex-matched Caucasian children (P < .05). Although there was no difference in fasting PP concentration between Pima Indian and Caucasian adults, in response to a mixed meal, Pima Indians had a 51% higher early (30 minutes) PP concentration and 2-fold higher early insulin concentration than Caucasians (P < .05). PP concentrations at 60 minutes and 120 minutes after the meal were also markedly higher in both lean and obese Pima Indians compared with lean and obese Caucasians. These results suggest that Pima Indians may have an increased parasympathetic drive to the pancreas, which could lead to a primary hypersecretion of insulin and contribute to their high propensity for obesity and diabetes, as is the case in various rodent models of obesity.
 ...
PMID:Exaggerated pancreatic polypeptide secretion in Pima Indians: can an increased parasympathetic drive to the pancreas contribute to hyperinsulinemia, obesity, and diabetes in humans? 1122 33

Large subcutaneous abdominal adipocyte size (s.c. abd. AS) is associated with insulin resistance and predicts type 2 diabetes in Pima Indians. Because type 2 diabetes is familial, we aimed to determine whether mean s.c. abd. AS is also familial and if so, to identify chromosomal regions linked to this measure. Body composition (hydrodensitometry) and mean s.c. abd. AS (fat biopsy) were measured in 295 Pima Indians (179 with normal, 80 with impaired, and 36 with diabetic glucose tolerance) representing 164 nuclear families. Mean s.c. abd. AS, adjusted for age, sex, and percentage body fat was a familial trait (heritability h(2) = 0.48, P < 0.0001). A genome-wide autosomal scan revealed suggestive evidence for linkage (LOD 1.73) of adjusted mean s.c. abd. AS to chromosome 1q21--q23, a region containing LMNA, the gene encoding for the nuclear envelope proteins lamin A/C. Rare mutations in LMNA were recently shown to underlie familial partial lipodystrophy (FPLD), a syndrome characterized by regional loss of adipose tissue, insulin resistance, and glucose intolerance. A common (allelic frequency 0.43) single nucleotide polymorphism (silent 1908C --> T substitution) in exon 10 of LMNA (GenBank X03444) was associated with reduced age-, sex- and percentage body fat-adjusted mean s.c. abd. AS [0.80 +/- 0.17 (CC), 0.76 +/- 0.15 (CT), 0.73 +/- 0.16 (TT) microg lipid/cell, P < 0.05 for CC vs TT]. These findings indicate that approximately half of the variance in mean s.c. abd. AS can be attributed to familial factors and that genetic variation in LMNA might not only underlie rare cases of FPLD, but may also contribute to variation in adipocyte size in the general population.
 ...
PMID:Subcutaneous abdominal adipocyte size, a predictor of type 2 diabetes, is linked to chromosome 1q21--q23 and is associated with a common polymorphism in LMNA in Pima Indians. 1124 29

In humans, the Met326Ile missense variant of the p85alpha regulatory subunit of the phosphoinositide 3-kinase (PI3K) has been associated with either significant reductions in glucose effectiveness and intravenous glucose tolerance in Caucasians or a significantly higher insulin secretory response in Pima Indians. In the present study, we genotyped 1,190 Caucasian males to evaluate the impact in vivo of the Met326Ile variant of the p85alpha subunit of PI3K on the acute insulin response, intravenous glucose tolerance, insulin-mediated glucose uptake, and the prevalence of type 2 diabetes after 20 years of follow-up. We also expressed the variant in vitro to evaluate the impact on insulin-stimulated activation of protein kinase B (PKB). The Met326Ile variant of p85alpha was not associated with type 2 diabetes or with alterations in insulin secretion, insulin sensitivity, or intravenous glucose tolerance in vivo. Expressed in vitro, the Ile326 and the Met326 variant acted equally as a dominant-negative and prevented (60-70% inhibition) insulin-mediated activation of PKB by inhibiting the phosphorylation of PKB at Thr308. We conclude that the Met326Ile variant of the p85alpha regulatory subunit of PI3K is likely to be as functionally normal in vivo as in vitro.
 ...
PMID:In vitro and in vivo studies of a naturally occurring variant of the human p85alpha regulatory subunit of the phosphoinositide 3-kinase: inhibition of protein kinase B and relationships with type 2 diabetes, insulin secretion, glucose disappearance constant, and insulin sensitivity. 1124 93

The human proto-oncogene PBX1 codes for a homeodomain containing protein that modulates expression of several genes, including those contributing to regulation of insulin action and glucose metabolism. PBX1 is located on chromosome 1q22, a region linked with type 2 diabetes in Pima Indians, Caucasians, and an Old Order Amish population. We have investigated the PBX1 genomic sequence to identify polymorphisms that may contribute to diabetes susceptibility in the Pimas. PBX1 is composed of nine exons spanning approx. 117 kb and is located within 300 kb of microsatellite D1S1677, which marks the peak of linkage to diabetes susceptibility in the Pima Indians. We detected 16 single nucleotide polymorphisms in PBX1 including one causing a glycine to serine substitution at residue 21. Comparison of the frequencies of the polymorphisms between affected and unaffected Pima Indians did not detect any significant differences, indicating that mutations in PBX1 do not explain the linkage of 1q with type 2 diabetes in this population. The genomic structure of PBX1 provides a basis for similar systematic examinations of this candidate locus in other populations in relation to both type 2 diabetes and other metabolic disorders.
 ...
PMID:Analysis of PBX1 as a candidate gene for type 2 diabetes mellitus in Pima Indians. 1126 83

Mutations in the SLC19A2 gene cause thiamine-responsive megaloblastic anemia (TRMA) frequently combined with diabetes mellitus and deafness. Type 2 diabetes mellitus is heritable and a region on 1q21-q23 encompassing SLC19A2 was linked with the disease in Pima Indians and Caucasians. We therefore investigated this candidate gene in selected diabetic and nondiabetic Pimas and found no variants. We conclude that mutations in SLC19A2 do not contribute to type 2 diabetes in this population.
 ...
PMID:Analysis of slc19a2, on 1q23.3 encoding a thiamine transporter as a candidate gene for type 2 diabetes mellitus in pima indians. 1128 12

Although insulin resistance has been shown to be a primary defect causing type 2 (non insulin-dependent) diabetes mellitus in Pima Indians and Caucasians, insulin secretory defect has also been known to be an important factor in the development of type 2 diabetes. We undertook a study to investigate the initial abnormality of glucose intolerance in Koreans. A total of 370 Korean subjects were classified into 5 groups according to their degree of glucose intolerance (normal fasting glucose [NFG]/normal glucose tolerance [NGT], n = 95; impaired fasting glucose [IFG]/NGT, n = 29; NFG/impaired glucose tolerance [IGT], n = 60; IFG/IGT, n = 68; diabetes, n = 118). Insulinogenic index was used as an index of early-phase insulin secretion. Insulin resistance was assessed by the R value of the homeostasis model assessment [HOMA(R)]. Insulinogenic index significantly decreased in subjects with IFG/NGT and NFG/IGT compared with those with NFG/NGT. However, there was no significant difference in HOMA(R) between subjects with NFG/NGT and those with IFG/NGT or NFG/IGT. Insulinogenic index decreased significantly with the increase of plasma glucose 120-minute value at the earlier stage of glucose intolerance compared with HOMA(R). These results suggest that early-phase insulin secretory defect may be the initial abnormality in the development of type 2 diabetes in Korean subjects.
 ...
PMID:Insulin secretory dysfunction and insulin resistance in the pathogenesis of korean type 2 diabetes mellitus. 1131 22

Plasma concentrations of adiponectin, a novel adipose-specific protein with putative antiatherogenic and antiinflammatory effects, were found to be decreased in Japanese individuals with obesity, type 2 diabetes, and cardiovascular disease, conditions commonly associated with insulin resistance and hyperinsulinemia. To further characterize the relationship between adiponectinemia and adiposity, insulin sensitivity, insulinemia, and glucose tolerance, we measured plasma adiponectin concentrations, body composition (dual-energy x-ray absorptiometry), insulin sensitivity (M, hyperinsulinemic clamp), and glucose tolerance (75-g oral glucose tolerance test) in 23 Caucasians and 121 Pima Indians, a population with a high propensity for obesity and type 2 diabetes. Plasma adiponectin concentration was negatively correlated with percent body fat (r = -0.43), waist-to-thigh ratio (r = -0.46), fasting plasma insulin concentration (r = -0.63), and 2-h glucose concentration (r = -0.38), and positively correlated with M (r = 0.59) (all P < 0.001); all relations were evident in both ethnic groups. In a multivariate analysis, fasting plasma insulin concentration, M, and waist-to-thigh ratio, but not percent body fat or 2-h glucose concentration, were significant independent determinates of adiponectinemia, explaining 47% of the variance (r(2) = 0.47). Differences in adiponectinemia between Pima Indians and Caucasians (7.2 +/- 2.6 vs. 10.2 +/- 4.3 microg/ml, P < 0.0001) and between Pima Indians with normal, impaired, and diabetic glucose tolerance (7.5 +/- 2.7, 6.1 +/- 2.0, 5.5 +/- 1.6 microg/ml, P < 0.0001) remained significant after adjustment for adiposity, but not after additional adjustment for M or fasting insulin concentration. These results confirm that obesity and type 2 diabetes are associated with low plasma adiponectin concentrations in different ethnic groups and indicate that the degree of hypoadiponectinemia is more closely related to the degree of insulin resistance and hyperinsulinemia than to the degree of adiposity and glucose intolerance.
 ...
PMID:Hypoadiponectinemia in obesity and type 2 diabetes: close association with insulin resistance and hyperinsulinemia. 1134 87

The KCNJ9 gene encodes a G-protein-coupled inwardly rectifying potassium channel and is located within a region on human chromosome 1 that has been linked with type 2 diabetes mellitus in Pima Indians and Caucasians. To assess the potential contribution of genetic alterations within KCNJ9 to diabetes susceptibility in the Pimas, we have genotyped 11 single nucleotide polymorphisms (SNPs) in 50 Pimas with diabetes and 50 Pimas over the age of 45 without diabetes and in 51 sib pairs, discordant for the disease, who were characterized by decreased allele sharing at the chromosomal location of the maximum LOD score. We detected three SNP clusters exhibiting distinct linkage disequilibria. Polymorphisms in intron 2, exon 3, and the 3'-UTR were in statistically significant linkage disequilibrium with diabetes in the case-control group (P = 0.006), but not the sibling pairs (P = 0.097). A weak association with diabetes was also found in the original linkage set comprising 1150 Pimas (odds ratio = 0.64/P = 0.079 for a dominant model and OR = 0.67/P = 0.005 for a recessive model). However, no effect on linkage was detected following adjustment for one of the most strongly associated SNPs in the entire original linkage set. Our results indicate that variants in KCNJ9 are associated with diabetes in Pimas but do not account for the linkage of 1q with diabetes in this population.
 ...
PMID:Analysis of linkage disequilibrium between polymorphisms in the KCNJ9 gene with type 2 diabetes mellitus in Pima Indians. 1135 Jan 89

It has been proposed that inflammation or infection may contribute to the development of type 2 diabetes. We examined whether serum gamma globulin, a nonspecific measure of the humoral immune system, predicted changes in glucose tolerance in 2,530 members of the Pima Indian population, a group with a marked predisposition to type 2 diabetes. Cross-sectionally, gamma globulin was positively related to age (r = 0.08, P < 0.0005), BMI (r = 0.09; P < 0.0001), and female sex (P < 0.0001). Gamma globulin concentrations were familial, being positively correlated among siblings (r = 0.23; P < 0.0001) and between parents and their children (mother/child: r = 0.17, P < 0.0001; father/child: r = 0.25, P < 0.0001). Gamma globulin concentrations were higher with greater degrees of American Indian heritage (P < 0.004, with adjustment for age, sex, and BMI) and in the presence of a family history of type 2 diabetes (P < 0.04). Higher gamma globulin levels predicted risk of diabetes. In univariate analysis, a 1 SD difference in gamma globulin was associated with a 20% higher incidence of diabetes in those who were normal glucose tolerant at baseline (hazard rate ratio 1.20 [CI 1.11-1.30]; P < 0.0001) and remained as a significant predictor of diabetes, even when controlled for effects of sex, BMI, and 2-h glucose as additional predictors (hazard rate ratio for 1 SD difference in gamma globulin, 1.14 [1.05-1.24]; P = 0.002). Gamma globulin was also associated in univariate analysis with later development of impaired glucose tolerance (IGT) (hazard rate ratio 1.15 [1.07-1.23]; P < 0.0001), but not with the transition from IGT to diabetes (hazard rate ratio 1.04 [0.90-1.20]; P = 0.6). Thus, gamma globulin levels predict increased risk of diabetes in the Pima population. We suggest that immune function or activation may play a role in the development of type 2 diabetes.
 ...
PMID:Gamma globulin levels predict type 2 diabetes in the Pima Indian population. 1142 81

The offspring of Pima Indians with early onset type 2 diabetes are at high risk for developing diabetes at an early age. This risk is greater among those whose mothers were diabetic during pregnancy. To define the metabolic abnormalities predisposing individuals in these high-risk groups to diabetes, we conducted a series of studies to measure insulin secretion and insulin action in healthy adult Pima Indians. In 104 normal glucose-tolerant subjects, acute insulin secretory response (AIR) to a 25-g intravenous glucose challenge correlated with the age at onset of diabetes in the mother (r = 0.23, P = 0.03) and, in multiple regression analyses, the age at onset of diabetes in the father (P = 0.02), after adjusting for maternal age at onset and after allowing for an interaction between these terms. In contrast, insulin action (hyperinsulinemic glucose clamp) did not correlate with the age at onset of diabetes in the parents. To determine whether early onset diabetes in the parents affected insulin secretion in the offspring across a range of glucose concentrations, responses to a stepped glucose infusion were measured in 23 subjects. Insulin secretion rates were lower in individuals whose mothers had developed diabetes before 35 years of age (n = 8) compared with those whose parents remained nondiabetic until at least 49 years of age (n = 15) (average insulin secretory rates: geometric mean [95% CI] 369 [209-652] vs. 571 [418-780] pmol/min, P = 0.007). Finally, the AIR was lower in individuals whose mothers were diabetic during pregnancy (n = 8) than in those whose mothers developed diabetes at an early age but after the birth of the subject (n = 41) (740 [510-1,310] vs. 1,255 [1,045-1,505] pmol/l, P < 0.02). Thus, insulin secretion is lower in normal glucose tolerant offspring of people with early onset type 2 diabetes. This impairment may be worsened by exposure to a diabetic environment in utero.
 ...
PMID:Low acute insulin secretory responses in adult offspring of people with early onset type 2 diabetes. 1147 45


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>