calpain and Glucose-Intolerance

The receptor for parathyroid hormone (PTH) and PTH-related peptide (PTH1R) belongs to the class II G protein-coupled receptor superfamily. The calpain small subunit encoded by the gene Capns1 is the second protein and the first enzyme identified by a yeast two-hybrid screen using the intracellular C-terminal tail of the rat PTH1R. The calpain regulatory small subunit forms a heterodimer with the calpain large catalytic subunit and modulates various cellular functions as a cysteine protease. To investigate a physiological role of the calpain small subunit in cells of the osteoblast lineage, we generated osteoblast-specific Capns1 knockout mouse models and characterized their bone phenotype. Molecular mechanisms by which calpain modulates cell proliferation of the osteoblast lineage were further examined in vitro. Moreover, we utilized the mutant mice as a disease model of osteoporosis accompanied with impaired bone resorptive function and suggested a possible clinical translation of our basic research finding.

Topics: Animals; Bone and Bones; Bone Resorption; Calpain; Cell Lineage; Cell Proliferation; Cyclin-Dependent Kinase Inhibitor p27; Diet, High-Fat; Gene Expression Regulation; Glucose Intolerance; Mice; Mice, Knockout; Osteoblasts; Osteocalcin; Osteoporosis; Promoter Regions, Genetic; Receptor, Parathyroid Hormone, Type 1; Signal Transduction; Sp7 Transcription Factor; Transcription Factors; Weight Gain

We present data from a genome-wide scan identifying genetic factors conferring susceptibility to type 2 diabetes. The linkage analysis was based on 59 families from northern Sweden, consisting of a total of 129 cases of type 2 diabetes and 19 individuals with impaired glucose tolerance. Model-free linkage analysis revealed a maximum multipoint logarithm of odds score of 3.19 for D2S2987 at 267.7 cM (P=0.00058), suggesting that a gene conferring susceptibility to type 2 diabetes in the northern Swedish population resides in the 2q37 region. These data replicate, in a European population, previously identified linkage of marker loci in this region to type 2 diabetes in Mexican Americans. In contrast, no evidence in support of association to the previously identified single nucleotide polymorphisms in the calpain-10 gene was observed in a case-control cohort derived from the same population.

Topics: Adult; Alleles; Calpain; Diabetes Mellitus, Type 2; Gene Frequency; Genetic Linkage; Genetic Predisposition to Disease; Genome, Human; Genotype; Glucose Intolerance; Haplotypes; Humans; Lod Score; Logistic Models; Middle Aged; Polymorphism, Single Nucleotide; Sweden; White People

The gene encoding calpain-10 (CAPN10) has been identified as a candidate gene for type 2 diabetes. Our aim was to study the impact of genetic (heritability and polymorphisms) and nongenetic (insulin, free fatty acids, and age) factors on CAPN10 mRNA expression in skeletal muscle using two different study designs. Muscle biopsies were obtained before and after hyperinsulinemic-euglycemic clamps from 166 young and elderly monozygotic and dizygotic twins as well as from 15 subjects with normal (NGT) or impaired glucose tolerance (IGT) exposed to an Intralipid infusion. We found hereditary effects on both basal and insulin-exposed CAPN10 mRNA expression. Carriers of the type 2 diabetes-associated single nucleotide polymorphism (SNP)-43 G/G genotype had reduced CAPN10 mRNA levels compared with subjects carrying the SNP-43 A-allele. Age had no significant influence on CAPN10 mRNA levels. Insulin had no significant effect on CAPN10 mRNA levels, neither in the twins nor in the basal state of the Intralipid study. However, after a 24-h infusion of Intralipid, we noted a significant increase in CAPN10 mRNA in response to insulin in subjects with NGT but not in subjects with IGT. In conclusion, we provide evidence that mRNA expression of CAPN10 in skeletal muscle is under genetic control. Glucose-tolerant but not glucose-intolerant individuals upregulate their CAPN10 mRNA levels in response to prolonged exposure to fat.

Topics: Adult; Aged; Aging; Biopsy; Blood Glucose; Calpain; Fat Emulsions, Intravenous; Fatty Acids, Nonesterified; Gene Expression Regulation; Genotype; Glucose Clamp Technique; Glucose Intolerance; Humans; Insulin; Middle Aged; Muscle, Skeletal; Polymorphism, Genetic; Polymorphism, Single Nucleotide; RNA, Messenger; Twin Studies as Topic; Twins, Dizygotic; Twins, Monozygotic

The aim of the study was to evaluate the relationship between insulin sensitivity, beta cell function and glucose tolerance, and its dependence on variants in the newly identified Type 2 diabetes susceptibility gene, calpain-10 ( CAPN10).. We studied 203 men of the same age but with varying degrees of glucose tolerance. These men participated in (i) an oral glucose tolerance test, (ii) a euglycaemic clamp combined with indirect calorimetry and infusion of [3-(3)H]-glucose and (iii) a stepwise assessment of acute insulin response to arginine (AIR) at three different glucose concentrations (fasting, 14 and 28 mmol/l).. There was a linear increase in NEFA levels ( p<0.0005) and WHR ( p<0.0005) and decrease in glucose uptake due to a reduction in glucose storage over the entire range of glucose tolerance ( r=-0.404; p<0.005). No increase in endogenous glucose production (EGP) was seen until patients had manifest diabetes. However, when EGP was expressed relative to fasting insulin concentrations, there was a linear deterioration of basal hepatic insulin sensitivity ( r=-0.514; p<0.005). The AIR followed a bell-shaped curve with an initial rise and subsequent decrease. However, AIR adjusted for insulin sensitivity (disposition index) showed a linear decrease with increasing glucose concentrations ( r=-0.563; p<0.001) starting already in subjects with normal glucose tolerance. There was an inverse correlation between increase in WHR and NEFA and peripheral as well as hepatic insulin sensitivity. Subjects with the genotype combination of CAPN10 consisting of SNP44 TT and SNP43 GG genotypes had significantly lower insulin-stimulated glucose uptake than carriers of the other genotype combinations (5.3+/-0.4 vs 7.2+/-0.4 mg.ffm kg(-1).min(-1).mU.l(-1); p<0.005).. We conclude that the pre-diabetic state is characterised by a similar linear deterioration of peripheral and hepatic insulin sensitivity as beta cell function and that variants in the CAPN10 gene modify this relationship. These findings are compatible with a common defect in muscle, liver and beta cells in the pathogenesis of Type 2 diabetes.

Topics: Adult; Aged; Blood Glucose; Body Size; Calpain; Diabetes Mellitus; Exercise Test; Fatty Acids, Nonesterified; Genetic Predisposition to Disease; Genotype; Glucose; Glucose Clamp Technique; Glucose Intolerance; Glucose Tolerance Test; Humans; Insulin Resistance; Islets of Langerhans; Oxygen Consumption

A G-to-A (UCSNP-43) polymorphism of the calpain-10 gene was significantly associated with type 2 diabetes (DM) in Mexican-American, and was postulated, together with a T-to-C (UCSNP-44) polymorphism, as a risk factor for DM. We examined the association of these genotypes with DM in Japanese. Eighty-one subjects with DM and 81 non-diabetic subjects (NGT) were recruited. The number of subjects with genotypes UCSNP-43 G/G, G/A and A/A were 76, 5 and 0, respectively, for the DM and NGT groups. The number of subjects with genotypes UCSNP-44 T/T, T/C and C/C were 66, 14 and 1 for the DM group and 64, 17 and 0 for the NGT group. There was no difference between the groups in terms of frequency of any genotype combinations. No association between the genotypes and DM was observed. We next examined the differences between the genotypes or genotype combinations in terms of the traits related to DM, obesity, hypertension and dyslipidemia. No differences were observed between the genotypes UCSNP43 G/G and G/A, between UCSNP-44 T/T and the others, or between the genotype combination UCSNP-43 G/G and UCSNP-44 T/T and the others, except that the individuals with the genotype combination had significantly increased serum cholesterol levels (212.6 +/- 34.3 vs. 198.5 +/- 29.9, P=0.020). The genotype combination might be a risk factor, not for DM, obesity and hypertension, but for increased serum cholesterol.

Topics: Aged; Asian People; Calpain; Cholesterol; Diabetes Mellitus, Type 2; Female; Glucose Intolerance; Humans; Hypercholesterolemia; Japan; Male; Middle Aged; Polymerase Chain Reaction; Polymorphism, Genetic; Polymorphism, Restriction Fragment Length