calpain and Diabetes-Mellitus

Diabetes mellitus (DM) is associated with acute and chronic complications that cause major morbidity and significant mortality. Calpains, a family of Ca(2+)-dependent cytosolic cysteine proteases, can modulate their substrates' structure and function through limited proteolytic activity. Calpain is a ubiquitous calcium-sensitive protease that is essential for normal physiologic function. However, alterations in calcium homeostasis lead to pathologic activation of calpain in diabetes mellitus. Since not much is known on the relationship between calpain and diabetes mellitus, this review outlines the contribution of calpain to chronic complications of diabetes mellitus, such as diabetic cardiomyopathy, diabetic nephropathy and diabetic retinopathy.

Topics: Animals; Calcium; Calpain; Chronic Disease; Diabetes Complications; Diabetes Mellitus; Humans

Diabetes mellitus is a major risk factor for vascular diseases and is associated with accelerated atherosclerosis and a high rate of arterial thrombotic complications. A number of studies support the concept that platelets contribute to the pathogenesis and progression of the vascular complications of diabetes. µ-Calpain, a non-lysosomal, Ca(2+)-dependent cysteine protease, is expressed in platelets and is involved in physiological platelet activation. However, the inappropriate activation of calpain alters platelet function, partially degrades a spectrum of proteins and results in hyperaggregability. Changes in the activity of calpain in different cells involved in diabetes-related pathways, or the polymorphism of calpain genes have been associated with the development of type 2 diabetes but their relevance to the diabetes-related vascular complications is not really clear. This review will give an overview of the role of calpain in diabetes and analyze the role of calpain in platelet activation and the changes occurring during the onset of diabetes. Finally, we will discuss future therapeutic possibilities for the improvement of diabetes-associated vascular diseases.

Topics: Animals; Blood Platelets; Calpain; Diabetes Mellitus; Diabetic Angiopathies; Humans; Hypoglycemic Agents; Platelet Activation; Platelet Aggregation; Platelet Aggregation Inhibitors

Several genes are implicated to be the cause for diabetes, such as genes of PPAR gamma (peroxisome proliferator-activated receptor-gamma), adiponectin, beta 3-adrenergic receptor, etc., and their polymorphisms may have significant impact on the treatment and prevention of diabetes. Detection and analysis of such susceptibility genes will provide an enormous benefit for the future tailor-made medicine of diabetes, which include choosing the most effective treatment policy for each individual and developing novel drugs based on the genetic information that are applicable for corresponding individuals. Tailor-made medicine will be an efficient tool for treatment and prevention of lifestyle diseases, especially type 2 diabetes, along with further identification of its disease-causing genes.

Topics: Acetates; Adiponectin; Benzoates; Biphenyl Compounds; Calpain; Diabetes Mellitus; Drug Design; Genetic Predisposition to Disease; Genome, Human; Humans; Indoles; Intercellular Signaling Peptides and Proteins; Polymorphism, Genetic; Proteins; Receptors, Adrenergic, beta-3; Receptors, Cytoplasmic and Nuclear; Transcription Factors

Several topics in diabetes research and practice in the coming 'post-genomic era' are described. 1) Insulin-producing pancreatic beta cells are a plausible target of gene therapy for type 1 diabetes mellitus. Functional genomics will reveal the mechanism of beta cell growth and regeneration. Attempts are being made to differentiate non-beta cells(including ES cells) into insulin-producing cells in vitro or in vivo. 2) Very recently, an intron variation in calpain 10 gene was found to be associated with type 2 diabetes, which confirmed the importance of SNPs in common diseases. More and more SNPs related to type 2 diabetes will be discovered and, in combination with pharmacogenomics, 'personalized medicine' based on SNP information of the individuals will hopefully be achieved.

Topics: Animals; Calpain; Cell Differentiation; Diabetes Mellitus; Genetic Therapy; Genomics; Human Genome Project; Humans; Islets of Langerhans; Polymorphism, Single Nucleotide; Regeneration

Rosuvastatin contributes to the improvement of vascular complications in diabetes, but the protective mechanisms remain unclear. The aim of the present study was to investigate the effect and mechanism of rosuvastatin on endothelial dysfunction induced by diabetes.. Calpain-1 knockout (Capn1 EK684-/-) and C57BL/6 mice were intraperitoneally injected with STZ to induce type 1 diabetes. Human umbilical vein endothelial cells (HUVECs) were incubated with high glucose in this study. The function of isolated vascular rings, apoptosis, and endoplasmic reticulum stress (ERS) indicators were measured in this experiment.. The results showed that rosuvastatin (5 mg/kg/d) and calpain-1 knockout improved impaired vasodilation in an endothelial-dependent manner, and this effect was abolished by an ERS inducer. Rosuvastatin administration inhibited calpain-1 activation and ERS induced by high glucose, as well as apoptosis and oxidative stress both in vivo and in vitro. In addition, an ERS inducer (tunicamycin) offset the beneficial effect of rosuvastatin on endothelial dysfunction and ERS, which was accompanied by increased calpain-1 expression. The ERS inhibitor showed a similar improvement in endothelial dysfunction with rosuvastatin but could not increase the improvement in endothelial function of rosuvastatin.. These results suggested that rosuvastatin improves endothelial dysfunction by suppressing calpain- 1 and normalizing ERS, subsequently decreasing apoptosis and oxidative stress.

Topics: Animals; Apoptosis; Calpain; Diabetes Mellitus; Endoplasmic Reticulum Stress; Glucose; Human Umbilical Vein Endothelial Cells; Humans; Mice; Mice, Inbred C57BL; Oxidative Stress; Rosuvastatin Calcium; Vascular Diseases

Diabetes mellitus (DM) has been considered an accelerator of Alzheimer's disease (AD), but the cellular and molecular mechanisms underlying this effect are not fully understood. Here, we attempted to determine the role and regulatory mechanism of calpain in the AD-like cognitive decline and pathological changes in rats caused by DM. In the initial stages, our results verified that DM model rats showed cognitive impairment, as well as a loss of neurons, decreased pericyte marker (PDGFR-β and α-SMA), and calpain-2 expression and amyloid-β (Aβ) deposition in the hippocampal tissues. In high glucose-induced primary pericytes, the cell apoptotic rate was increased, and cell proliferation was inhibited in a time-dependent manner. The protein level of calpain-2 was also upregulated by HG induction, but the level of calpain-1 did not change with HG treatment, which was also observed in DM model rats. Subsequently, some DM model rats were administered calpeptin, an inhibitor of calpain. Our data revealed that calpeptin treatment significantly suppressed calpain-1 and calpain-2 expression in the hippocampal tissues and effectively improved the cognitive impairments of DM model rats. Neuronal loss, Aβ accumulation, pericyte loss, inflammation, and oxidative stress injury in the hippocampal tissues of DM model rats were also partly rescued by calpeptin administration. Our work demonstrated that the calpain inhibitor calpeptin could alleviate DM-induced AD-like cognitive impairments and pathological changes in rats, and this effect may be associated with pericytes. Calpeptin may become a promising drug to treat the AD-like complications of DM.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Calpain; Cognitive Dysfunction; Diabetes Mellitus; Dipeptides; Glucose; Glycoproteins; Rats

The relationship between diabetes and endothelial dysfunction remains unclear, particularly the association with pathological activation of calpain, an intracellular cysteine protease. Here, we used human induced pluripotent stem cells-derived endothelial cells (iPSC-ECs) to investigate the effects of diabetes on vascular health. Our results indicate that iPSC-ECs exposed to hyperglycemia had impaired autophagy, increased mitochondria fragmentation, and was associated with increased calpain activity. In addition, hyperglycemic iPSC-ECs had increased susceptibility to cell death when subjected to a secondary insult-simulated ischemia-reperfusion injury (sIRI). Importantly, calpain inhibition restored autophagy and reduced mitochondrial fragmentation, concurrent with maintenance of ATP production, normalized reactive oxygen species levels and reduced susceptibility to sIRI. Using a human iPSC model of diabetic endotheliopathy, we demonstrated that restoration of autophagy and prevention of mitochondrial fragmentation via calpain inhibition improves vascular integrity. Our human iPSC-EC model thus represents a valuable platform to explore biological mechanisms and new treatments for diabetes-induced endothelial dysfunction.

Topics: Autophagy; Calpain; Cells, Cultured; Diabetes Complications; Diabetes Mellitus; Endothelial Cells; Endothelium, Vascular; Glycoproteins; Humans; Hyperglycemia; Induced Pluripotent Stem Cells; Mitochondria; Reactive Oxygen Species; Vascular Diseases

Topics: Animals; Aorta; Calcium; Calpain; Caveolin 1; Diabetes Mellitus; Endothelial Cells; HSP90 Heat-Shock Proteins; Humans; Membrane Microdomains; Nitric Oxide; Nitric Oxide Synthase Type I; Nitric Oxide Synthase Type III; Oligopeptides; Proteolysis; Rats

Expression of klotho, the renoprotective anti-aging gene, is decreased in diabetic model kidneys. We hypothesized that klotho protein attenuates renal hypertrophy and glomerular injury in a mouse model of diabetic nephropathy.. Klotho transgenic (KLTG) mice were crossed with spontaneously diabetic Ins2Akita (AKITA) mice. Glomerular morphology, macrophage infiltration, urinary albumin excretion and urinary 8-hydroxy-2-deoxy guanosine excretion were examined. In vitro, human glomerular endothelial cells were stimulated with high glucose with or without recombinant klotho, and calpain activity and proinflammatory cytokine expressions were measured.. We found that klotho protein overexpression attenuates renal hypertrophy and glomerular injury in this mouse model of diabetic nephropathy. Klotho overexpression attenuated renal hypertrophy, albuminuria, glomerular mesangial expansion, and endothelial glycocalyx loss in the AKITA mice. AKITA mice exhibit high levels of urinary 8-hydroxy-2-deoxy guanosine excretion. In the presence of klotho overexpression, this effect was reversed. In addition, the glomerular macrophage infiltration characteristic of AKITA mice was attenuated in KLTG-AKITA mice. In human glomerular endothelial cells, high glucose induced calpain activity. This effect was suppressed by expression of recombinant klotho, which also suppressed the induction of proinflammatory cytokines.. Our data suggest klotho protein protects against diabetic nephropathy through multiple pathways.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Albuminuria; Animals; Biomarkers; Calpain; Cells, Cultured; Deoxyguanosine; Diabetes Mellitus; Diabetic Nephropathies; Disease Models, Animal; Genotype; Glucose; Glucuronidase; Humans; Hypertrophy; Inflammation Mediators; Kidney Glomerulus; Klotho Proteins; Macrophages; Mice, Inbred C57BL; Mice, Transgenic; Phenotype; Transfection

To compare the expression of calpain and caspase-12 in human lens epithelial cells (LECs) of cataract patients with or without diabetic retinopathy (DR).. Prospective, comparative case series.. Patients were divided into 4 groups: patients without diabetes mellitus (DM) (Group 1), patients with DM and without diabetic retinopathy (DR) (Group 2), diabetic patients with nonprolifeative DR (NPDR) (Group 3), and diabetic patients with proliferative DR (PDR) (Group 4). Data on DM duration and glycated hemoglobin (HbA1c) level were collected. The LECs were obtained during cataract surgery and immunohistochemical staining was performed for calpain and caspase-12. The reactivity score of each specimen was determined using confocal microscopy.. A total of 40 patients (40 eyes) were evaluated, and each group was composed of 10 patients. The expression of calpain and caspase-12 was highest in Group 4, followed by Group 3, Group 2, and Group 1 (P < .001). The expressions were significantly higher with a longer duration of DM, increased HbA1c level, or advanced DR.. Endoplasmic reticulum stress may be associated with apoptosis of LECs, resulting in cataract formation in diabetic patients.

Topics: Aged; Aged, 80 and over; Calpain; Caspase 12; Cataract; Diabetes Mellitus; Diabetic Retinopathy; Epithelial Cells; Fluorescent Antibody Technique, Indirect; Glycated Hemoglobin; Humans; Lens, Crystalline; Microscopy, Confocal; Middle Aged; Prospective Studies

We aimed to selectively breed a spontaneous diabetic gerbil when a sub-line of inbred gerbil showed increased blood glucose levels was found recently. Then we investigated the characteristics including the serum insulin, triglyceride, cholesterol, leptin, adiponectin and explored the underlying molecular mechanism for the diabetic phenotype.. The spontaneous diabetic line of gerbils was selectively inbreed the sub-line of gerbil by monitoring blood glucose of each animal. The serum insulin, adiponectin, and leptin levels were tested using an ELISA kit. The expression levels of GLUT4, Akt, leptin, adiponectin, and calpain 10 (CAPN10) were tested by western blot and Quantitative Real-time PCR (qPCR) in liver, skeletal muscle, and white adipose.. Our results show that the percentages of animals with FPG≥5.2 (mmol/l), PG2h≥6.8 (mmol/l) and both FPG≥5.2 and PG2h≥6.8 (mmol/l) were increased with the number of breeding generations from F0 (21.33%) to F6 (38.46%). These diabetic gerbils exhibited insulin resistance and leptin resistance as well as decreased adiponectin level in the serum. We also observed decreased expression of adiponectin and increased expression of leptin in the skeletal muscle, respectively.. These results indicate that we have primarily established a spontaneous diabetic gerbil line, and the diabetic phenotypes may have been accounted for by altered expression of leptin and adiponectin.

Topics: Adiponectin; Adipose Tissue, White; Animals; Blood Glucose; Breeding; Calpain; Cholesterol; Diabetes Mellitus; Female; Founder Effect; Gene Expression Regulation; Gerbillinae; Glucose Transporter Type 4; Insulin; Insulin Resistance; Leptin; Liver; Male; Muscle, Skeletal; Phenotype; Proto-Oncogene Proteins c-akt; Triglycerides

The present study was to investigate the role of calpain in reactive oxygen species (ROS) production in endothelial cells and endothelium-dependent vascular dysfunction under experimental conditions of diabetes.. Exposure to high glucose activated calpain, induced apoptosis and reduced nitric oxide (NO) production without changing eNOS protein expression, its phosphorylation and dimers formation in primary human umbilical vein endothelial cells (HUVECs). These effects of high glucose correlated with intracellular ROS production and mitochondrial superoxide generation. Selectively scavenging mitochondrial superoxide increased NO production in high glucose-stimulated HUVECs. Inhibition of calpain using over-expression of calpastatin or pharmacological calpain inhibitor prevented high glucose-induced ROS production, mitochondrial superoxide generation and apoptosis, which were concurrent with an elevation of NO production in HUVECs. In mouse models of streptozotocin-induced type-1 diabetes and OVE26 type-1 diabetic mice, calpain activation correlated with an increase in ROS production and peroxynitrite formation in aortas. Transgenic over-expression of calpastatin reduced ROS production and peroxynitrite formation in diabetic mice. In parallel, diabetes-induced reduction of endothelium-dependent relaxation in aortic ring was reversed by over-expression of calpastatin in mouse models of diabetes. However, the protective effect of calpastatin on endothelium-dependent relaxation was abrogated by eNOS deletion in diabetic mice.. This study suggests that calpain may play a role in vascular endothelial cell ROS production and endothelium-dependent dysfunction in diabetes. Thus, calpain may be an important therapeutic target to overcome diabetes-induced vascular dysfunction.

Topics: Animals; Calpain; Diabetes Mellitus; Endothelium, Vascular; Glycoproteins; Human Umbilical Vein Endothelial Cells; Humans; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Organ Culture Techniques; Oxidative Stress; Reactive Oxygen Species

Whereas most calpains are cytosolic proteases, calpain 10 is resident in mitochondria and is important in mitochondrial homeostasis. Because calpain 10 has been implicated in type 2 diabetes, we studied its possible role in diabetes-induced renal dysfunction. We treated renal proximal tubular cells with high glucose (17 mmol/l) and found decreased mitochondrial calpain 10 mRNA and protein at 96 h compared with cells incubated with 0 or 5 mmol/l glucose or 17 mmol/l D-mannitol. High glucose increased mitochondrial calpain 10 substrates (NDUFB8 and ATP synthase β), decreased basal and uncoupled respiration, and initiated cell apoptosis as indicated by cleaved caspase 3 and nuclear condensation. Renal calpain 10 protein and mRNA were specifically decreased in streptozotocin-induced diabetic rats with kidney dysfunction, and in diabetic ob/ob mice. In agreement with our in vitro data, the kidneys of streptozotocin-induced diabetic rats had elevated calpain 10 substrates and cleaved caspase 3. Finally, specific siRNA-induced knockdown of calpain 10 in the proximal tubules of control rats resulted in decreased renal function as evidenced by increased serum creatinine, and increased caspase 3 cleavage compared with rats receiving scrambled siRNA. Thus, the glucose-induced loss of calpain 10 in vivo results in renal cell apoptosis and organ failure through accumulation of mitochondrial calpain 10 substrates and mitochondrial dysfunction. Whether this is a major cause of the decreased renal function in diabetic nephropathy will require further studies.

Topics: Animals; Apoptosis; Calpain; Caspase 3; Cells, Cultured; Diabetes Mellitus; Diabetic Nephropathies; Down-Regulation; Female; Glucose; Kidney Tubules, Proximal; Male; Mice; Mice, Obese; Mitochondria; Mitochondrial Proton-Translocating ATPases; Rabbits; Rats; Rats, Sprague-Dawley; RNA, Messenger; RNA, Small Interfering; Streptozocin

Glucocorticoids (GCs), such as prednisolone (PRED), are widely prescribed anti-inflammatory drugs, but their use may induce glucose intolerance and diabetes. GC-induced beta cell dysfunction contributes to these diabetogenic effects through mechanisms that remain to be elucidated. In this study, we hypothesized that activation of the unfolded protein response (UPR) following endoplasmic reticulum (ER) stress could be one of the underlying mechanisms involved in GC-induced beta cell dysfunction. We report here that PRED did not affect basal insulin release but time-dependently inhibited glucose-stimulated insulin secretion in INS-1E cells. PRED treatment also decreased both PDX1 and insulin expression, leading to a marked reduction in cellular insulin content. These PRED-induced detrimental effects were found to be prevented by prior treatment with the glucocorticoid receptor (GR) antagonist RU486 and associated with activation of two of the three branches of the UPR. Indeed, PRED induced a GR-mediated activation of both ATF6 and IRE1/XBP1 pathways but was found to reduce the phosphorylation of PERK and its downstream substrate eIF2α. These modulations of ER stress pathways were accompanied by upregulation of calpain 10 and increased cleaved caspase 3, indicating that long term exposure to PRED ultimately promotes apoptosis. Taken together, our data suggest that the inhibition of insulin biosynthesis by PRED in the insulin-secreting INS-1E cells results, at least in part, from a GR-mediated impairment in ER homeostasis which may lead to apoptotic cell death.

Topics: Activating Transcription Factor 6; Animals; Apoptosis; Calpain; Cell Line; Diabetes Mellitus; eIF-2 Kinase; Endoplasmic Reticulum; Eukaryotic Initiation Factor-2; Gene Expression Regulation; Glucose; Homeodomain Proteins; Homeostasis; Humans; Insulin; Insulin Secretion; Insulin-Secreting Cells; Membrane Proteins; Mifepristone; Phosphorylation; Prednisolone; Protein Serine-Threonine Kinases; Rats; Receptors, Glucocorticoid; Signal Transduction; Trans-Activators; Unfolded Protein Response

Diabetes and atherosclerosis may share common genetic determinants. A prior study in Hispanics found association of haplotypes in the diabetes gene calpain-10 (CAPN10) with carotid artery intima-media thickness (CIMT). This study sought to replicate this association in an independent cohort.. Four CAPN10 SNPs were genotyped and haplotypes determined in 487 Hispanic Americans from 143 families ascertained via an index case with hypertension. CIMT was measured from B-mode ultrasound, and glycemic traits quantified from euglycemic clamps. Association of SNPs and haplotypes with CIMT was determined.. The minor alleles of SNP-56 and SNP-63 were associated with increased CIMT in dominant and additive models. The association of haplotype 1112 with increased CIMT was replicated. No associations with fasting insulin, insulin secretion, or insulin sensitivity were observed.. CAPN10 association with CIMT was replicated, further supporting its role as a common genetic determinant of diabetes and atherosclerosis in Hispanics.

Topics: Adult; Calpain; Carotid Arteries; Cohort Studies; Diabetes Mellitus; Female; Genotype; Haplotypes; Hispanic or Latino; Humans; Hypertension; Insulin; Male; Tunica Intima; Tunica Media; Ultrasonography

Calpain-10 was first identified through a genome scan seeking to identify diabetes predisposition genes. Both genetic and functional data has since indicated that calpain-10 has an important role in insulin resistance and intermediate phenotypes, including those associated with adipocytes and skeletal muscle. Evidence presented in this issue by Brown, Yeaman, and Walker utilizes siRNA technology to specifically knock down calpain-10 expression, and suggests that calpain-10 facilitates GLUT4 translocation through effects on the distal secretory pathway. Calpain-10 is also an important molecule in the pancreatic beta-cell, where it has been shown to regulate exocytosis through partial proteolysis of a member of the secretory granule fusion machinery. In addition, calpain-10 has also been implicated in reorganization of the actin cytoskeleton that accompanies both GLUT4 vesicle translocation and insulin secretion. Taken together, these findings provide fresh hope for the development of novel diabetic treatments, utilizing either pharmacological activators that specifically target calpain-10, or through targeted calpain-10 gene therapy. Therapeutic intervention in this way could simultaneously enhance both insulin secretion and insulin action.

Topics: Calpain; Cytoskeleton; Diabetes Mellitus; Exocytosis; Genetic Therapy; Humans; Insulin; Insulin Secretion; RNA, Messenger

Diabetes mellitus (DM) and abnormal glucose tolerance (IGT) are common in cystic fibrosis (CF). The loss of pancreatic beta-cells due to pancreatic fibrosis is thought to be one of the principal causes of diabetes in CF, but the aetiology of DM remains somewhat puzzling. Genetic factors may contribute to the development of CF related diabetes (CFRD). The purpose of this study was to investigate the role of polymorphisms in six genes on IGT or DM incidence. PCR and dHPLC were used to screen DNA samples for polymorphisms. Using 2-h oral glucose tolerance tests, 163 adult pancreatic insufficient CF patients have been subdivided in 3 groups: 54 NGT (normal glucose tolerance), 33 IGT and 76 CFRD. We found the first evidence for the association between CFRD and UCSNP-19 polymorphism in the CAPN10 gene. The UCSNP-19 genotype distribution differed significantly between NGT, IGT and CFRD groups. The difference reflected an increase in the 22 genotype (3 copies of 32-bp sequence) in IGT and CFRD patients (p=0.05). Odds ratio for the homozygote 22 versus homozygote 11 was 3.4 (p=0.02). All allele and genotype distributions for the other polymorphisms were similar in the three groups. In conclusion, our observations suggest that UCSNP-19 of CAPN10 may be involved in the pathogenesis of diabetes in CF.

Topics: Adult; Alleles; Blood Glucose; Calpain; Chromatography, High Pressure Liquid; Cystic Fibrosis; Diabetes Mellitus; DNA; Female; Genotype; Humans; Male; Polymerase Chain Reaction; Polymorphism, Genetic

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