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PubMed2007

Cardiac substrate uptake and metabolism in obesity and type-2 diabetes: role of sarcolemmal substrate transporters.

Cardiovascular disease is the primary cause of death in obesity and type-2 diabetes mellitus (T2DM). Alterations in substrate metabolism are believed to be involved in the development of both cardiac dysfunction and insulin resistance in these conditions. Under physiological circumstances the heart utilizes predominantly long-chain fatty acids (LCFAs) (60-70%), with the remainder covered by carbohydrates, i.e., glucose (20%) and lactate (10%). The cellular uptake of both LCFA and glucose is regulated by the sarcolemmal amount of specific transport proteins, i.e., fatty acid translocase (FAT)/CD36 and GLUT4, respectively. These transport proteins are not only present at the sarcolemma, but also in intracellular storage compartments. Both an increased workload and the hormone insulin induce translocation of FAT/CD36 and GLUT4 to the sarcolemma. In this review, recent findings on the insulin and contraction signalling pathways involved in substrate uptake and utilization by cardiac myocytes under physiological conditions are discussed. New insights in alterations in substrate uptake and utilization during insulin resistance and its progression towards T2DM suggest a pivotal role for substrate transporters. During the development of obesity towards T2DM alterations in cardiac lipid homeostasis were found to precede alterations in glucose homeostasis. In the early stages of T2DM, relocation of FAT/CD36 to the sarcolemma is associated with the myocardial accumulation of triacylglycerols (TAGs) eventually leading to an impaired insulin-stimulated GLUT4-translocation. These novel insights may result in new strategies for the prevention of development of cardiac dysfunction and insulin resistance in obesity and T2DM.

Animals↗
PubMedDate not supplied

Genes and type 2 diabetes mellitus.

Type 2 diabetes (T2DM) comprises a group of entities with different genetic causes. In most patients, T2DM results from alterations of various genes, each having a partial and additive effect. The inheritance pattern is thus complex, and environmental factors play an important role in favoring or delaying the expression of the disease. The identification of susceptibility genes and genetic variants requires different methodological approaches. Here we address some of the most important strategies and findings on the genomic basis of T2DM, as well as evidence of genetic heterogeneity among populations. The identification of the underlying genetic causes of T2DM and other related traits such as obesity and hypertension will lead to the development of new therapeutic targets likely to impact the way we treat these diseases. Survival and quality of life for T2DM patients is expected to eventually increase, significantly lessening the socioeconomic burden of the disease.

Alleles↗
PubMed2005

Glycemic control and morbidity in the Canadian primary care setting (results of the diabetes in Canada evaluation study).

The objective of this national, cross-sectional study was to provide insight into the care and treatment of type 2 diabetes (T2DM) in the Canadian primary care setting. Specifically, the study examines glycemic control, management and morbidity load among T2DM patients, and investigates the relationship of glycemic control and morbidity load with duration of diabetes. Participating primary care physicians (PCPs) (N=243) completed a chart audit for the first 10 patients with T2DM attending their clinics (2473 eligible patient records). The mean A1C was 7.3% with 49% of patients not at target (A1C>or=7.0%). Glycemic control eroded significantly with increasing duration of diabetes in spite of increasing therapeutic intervention. T2DM patients experienced a high morbidity load (hypertension 63%; dyslipidemia 59%; macrovascular complications 28%; microvascular complications 38%) each of which increased significantly with duration of diabetes. For 79% of patients not at target, PCPs identified lifestyle intervention as the strategy for achieving glycemic targets while more aggressive treatment plans were identified for only 56%. These results underscore the complexity of primary care management of T2DM and suggest that current treatment approaches are not intensive enough for a large proportion of patients especially those with longer duration of disease.

Blood Glucose↗
PubMed2006

Novel mutations found in mitochondrial diabetes in Chinese Han population.

Mitochondria provide cells with most of the energy in the form of ATP. Mutations in mitochondrial DNA (mtDNA) are associated with type 2 diabetes mellitus (T2DM) because ATP plays a critical role in the production and the release of insulin. To systematically determine mutant loci and to investigate their association with T2DM in Chinese Han population, 17 commonly reported mutant loci were screened in 236 cases of T2DM and 240 normal controls by PCR-RFLP, allele-specific PCR (AS-PCR) and DNA sequencing methods. Biological softwares were used to analyze the secondary structure of DNA, RNA and the corresponding proteins for missense mutations. Sixteen mutant loci were detected in total, of which five were novel, GenBank accession nos. were DQ092356, DQ473644 and DQ473645; they were mainly in16S rRNA, ND1 and ND4 gene. There was significant difference between the two groups for ND1 and ND4 genes mutation frequencies (ND1: P=0.001, OR=3.944, 95% CI 1.671-9.306; ND4: P=0.010, OR=5.818, 95% CI 1.275-26.537). No significant association was observed between the two groups for 5178A/C polymorphisms (P=0.418). Our study suggested that T3394C and A12026G might be associated with T2DM in Chinese Han population, and T2DM with mtDNA variant should be considered mitochondrial diabetes.

Adult↗
PubMed2006

Insulin secretion and insulin resistance in newly diagnosed, drug naive prediabetes and type 2 diabetes patients with/without metabolic syndrome.

The relationships between insulin secretion and resistance in subjects with newly diagnosed prediabetes (preDM) and type 2 DM according to the presence of metabolic syndrome (MS) were controversial. We performed OGTT on 322 drug naive subjects with a history of hyperglycemia of < or =3 months, and divided into three groups, NGT, preDM (IFG and/or IGT), and T2DM. We also diagnosed these subjects with respect to MS according to ATP III criteria modified by Asia-Pacific guidelines and compared IGI and HOMA-IR. When compare groups stratified by the presence of MS, preDM and T2DM groups with MS showed significantly higher mean HOMA-IR and IGI than those without. When compare groups with respect to glucose tolerance, NGT, preDM, and T2DM subgroups in MS group showed significant higher HOMA-IR and lower IGI according to glucose tolerance. However, NGT, preDM, and T2DM subgroups in non-MS group showed a significant decrease in IGI but no significant difference in HOMA-IR as glucose tolerance worsened. In conclusion, deterioration in IGI and aggravation of HOMA-IR are both important in the primary pathogenesis of diabetes in those with MS. However, IGI deterioration may be the only important factor in the primary pathogenesis of T2DM in the absence of MS.

Adult↗
PubMed2005

Thromboxane-dependent CD40 ligand release in type 2 diabetes mellitus.

OBJECTIVES: The goals of this study were to characterize the platelet contribution to soluble CD40 ligand (sCD40L), to correlate its formation with the extent of oxidative stress and platelet activation, and to investigate the effects of improved metabolic control and low-dose aspirin on these processes. BACKGROUND: Inflammation, oxidative stress, and platelet activation are involved in the pathogenesis of type 2 diabetes (T2DM) and its complications. The CD40-CD40L interactions result in inflammatory and pro-thrombotic responses. METHODS: Urinary 8-iso-prostaglandin (PG)F2alpha and 11-dehydro-thromboxane (TX)B2, in vivo markers of oxidative stress and platelet activation, respectively, plasma CD40L, and C-reactive protein (CRP) were measured in 114 T2DM patients and 114 control patients. A randomized, parallel group, 17-day study of aspirin (30, 100, or 325 mg/day) was performed in 18 T2DM patients. A similar study was performed in six healthy volunteers (aspirin, 100 mg/day). Twenty poorly controlled T2DM patients were studied before and after improved metabolic control. RESULTS: Compared with control patients, diabetic patients showed significantly higher levels of 8-iso-PGF2alpha, 11-dehydro-TXB2, sCD40L, and CRP. On multiple regression analysis, 11-dehydro-TXB2 and 8-iso-PGF2alpha excretion rates predicted sCD40L levels. Soluble CD40L linearly correlated with 11-dehydro-TXB2 (rho = 0.67, p < 0.0001), and both were reduced after one week of aspirin (p < 0.0026), with slow recovery over 10 days after aspirin withdrawal. Improved metabolic control was associated with a reduction in sCD40L, 8-iso-PGF2alpha, and 11-dehydro-TXB2. CONCLUSIONS: This study provides several lines of evidence for the dependence of sCD40L release on TXA(2)-dependent platelet activation in T2DM and provides novel mechanistic insight into the amplification loops of persistent platelet activation in this setting.

Aged↗
PubMed2006

Insulin therapy is associated with platelet dysfunction in patients with type 2 diabetes mellitus on dual oral antiplatelet treatment.

OBJECTIVES: This study sought to assess the influence of type 2 diabetes mellitus (T2DM) and the impact of hypoglycemic treatment (insulin vs. noninsulin) on platelet function profiles in patients treated with dual oral antiplatelet therapy. BACKGROUND: Insulin inhibits platelet aggregation by suppressing the P2Y12 pathway. However, T2DM patients have a loss of responsiveness to insulin that leads to upregulation of the P2Y12 pathway, increased platelet reactivity, and reduced responsiveness to antiplatelet agents. Patients with insulin-treated diabetes mellitus (ITDM) have a more advanced disease status and higher atherothrombotic risk compared with non-ITDM (NITDM). However, the impact of insulin therapy on platelet dysfunction in patients treated with P2Y12 antagonists is unknown. METHODS: A total of 201 T2DM and 65 nondiabetic patients with coronary artery disease in a steady phase of aspirin and clopidogrel treatment were studied. Platelet aggregation was assessed using agonists specific (6 and 20 microM adenosine diphosphate [ADP]) and nonspecific (6 microg/ml collagen and 20 microM epinephrine) for the P2Y12 pathway. High shear-induced platelet reactivity was assessed by means of the PFA-100 system (Dade-Behring International, Miami, Florida). RESULTS: The T2DM patients had platelet aggregation and shear-induced platelet function significantly increased compared with nondiabetic patients using all assays. Platelet aggregation was increased in ITDM (n = 68) compared with NITDM (n = 133) patients after P2Y12-specific stimuli. Insulin treatment was the strongest predictor of ADP-induced aggregation. Platelet function profiles were similar between ITDM and NITDM using assays nonspecific to the P2Y12 pathway. Platelet dysfunction was independent of glycemic control and inflammatory status. CONCLUSIONS: The P2Y12-dependent and -independent pathways of platelet reactivity are altered in T2DM compared with nondiabetic patients, and ITDM have greater ADP-induced platelet aggregation compared with NITDM.

Aged↗
PubMed2006

Valsartan improves resting skin blood flow in type 2 diabetic patients and reduces poly(adenosine diphosphate-ribose) polymerase activation.

OBJECTIVE: To examine the effect of a 12-week daily treatment with 160 mg of valsartan, an angiotensin II receptor blocker, on the microcirculation and macrocirculation of type 2 diabetic patients (T2DM) and healthy subjects. METHODS: This was a prospective, randomized, double-blind, placebo-controlled crossover study. Thirteen T2DM with no severe complications and 13 healthy subjects completed the trial. RESULTS: Treatment with valsartan in T2DM improved the resting forearm skin blood flow and increased the resting brachial artery diameter but had no effects on arterial blood pressure, large vessel vascular reactivity, or carotid intima-media thickness. Resting skin blood flow increased by 60% (2%-90%; median and 25th-75th percentiles) during valsartan treatment and by only 2% (-22% to 27%) during placebo treatment (P < .05). No changes were observed in the nondiabetic subjects. Immunostaining studies of forearm skin biopsy samples from T2DM and healthy subjects showed that valsartan reduced poly(adenosine diphosphate-ribose) polymerase (PARP) activity in 50% (6/12) of the subjects. PARP activity remained unchanged in placebo-treated subjects (P < .02). In addition, valsartan treatment increased CD31 staining in 33% (4/12) of the subjects, whereas no change was noted in sequential skin biopsy samples of placebo-treated subjects (P = .057). Valsartan had no effect on the biochemical markers of endothelial cell activation and other cytokines, including CAMs, interleukin 6, tumor necrosis factor alpha, C-reactive protein, adiponectin, and plasma activator inhibitor 1. CONCLUSIONS: Valsartan increases the resting skin blood flow in T2DM, likely through reduction of PARP activity.

Administration, Oral↗
PubMed2005

Vesicle-associated membrane protein 4, a positional candidate gene on 1q24-q25, is not associated with type 2 diabetes in the Old Order Amish.

OBJECTIVE: The vesicle-associated membrane protein-4 (VAMP4) gene is an excellent type 2 diabetes (T2DM) positional candidate gene. It is located on chromosome 1q24-q25, a region of linkage to T2DM in the Amish and several other populations. VAMP4 is expressed in liver and skeletal muscle and participates in intracellular trafficking of secreted and membrane-associated proteins. DESIGN AND METHODS: We sequenced VAMP4 in 20 Amish subjects. Polymorphisms in and around VAMP4 were genotyped in 65 Amish subjects with T2DM, 64 subjects with impaired glucose homeostasis (IGH), and 126 normal glucose tolerant controls, as well as in an expanded set of 749 participants of the Amish Family Diabetes Study for whom glucose and insulin levels during an oral glucose tolerance test (OGTT) and other quantitative traits related to diabetes were available. Case-control and quantitative trait association analyses were performed. RESULTS: We found three common non-coding intragenic polymorphisms: a 23bp insertion/deletion (I/D) in the 5' untranslated region (UTR) in exon 1 at position 73127, and G35319T and C335296T single nucleotide polymorphisms (SNPs) in the 3' UTR (NCBI Accession No. Z98751). The two 3' UTR SNPs were in complete linkage disequilibrium (LD) and both were in strong LD with the exon 1 I/D polymorphism (|D'|=0.82). Similarly, three extragenic flanking SNPs (rs978985, rs203255, and rs1023479) showed moderate LD with the neighboring intragenic SNPs (|D'|=0.23-0.69). None of the SNPs individually nor any of the 2-, 3-, 4-, or 5-polymorphism haplotypes were associated with T2DM or IGH. The exon 1 I/D polymorphism was not associated with significant differences in mean fasting or stimulated glucose or insulin levels during an OGTT or other diabetes-related quantitative traits in the expanded set of 749 subjects. CONCLUSION: Variation in VAMP4 does not significantly influence risk of T2DM or IGH in the Amish.

Adaptor Proteins, Vesicular Transport↗
PubMed2005

Evaluation of sequence variants in the pre-B cell leukemia transcription factor 1 gene: a positional and functional candidate for type 2 diabetes and impaired insulin secretion.

Pre-B cell leukemia transcription factor 1 (PBX1) encodes a homeodomain containing protein that is essential for pancreatic development and interacts with insulin promoter factor 1 to regulate insulin secretion. PBX1 maps to chromosome 1q22, a region with replicated linkage to type 2 diabetes (T2DM). We screened for sequence variation in nine exons, intronic regions flanking the exons, the 3' untranslated region (3' UTR), as well as 1-kb upstream of exon 1 in 16 Caucasians and 16 African American individuals with T2DM. We evaluated 18 variants including the nonsynonymous substitution G21S in exon 1, one 4 bp insertion/deletion, and one 7 bp insertion/deletion. We typed 10 variants on the basis of frequency and linkage disequilibrium patterns unrelated Caucasian subjects with T2DM and controls, and nine common variants in 129 Caucasian individuals for whom we had detailed assessments of insulin action and insulin secretion. We typed four common variants in African Americans individuals and additional SNPs in pooled DNA samples from both populations. No coding variant was associated with diabetes and no association was found among African American subjects. However, three variants in Caucasians (78287, 91227, and 252050 bp) were associated with T2DM (p<0.05), as were four marker haplotypes that included intron 2 variants. Additionally, three variants including G21S (61 bp) and the diabetes associated SNP at 78287 were significant determinants of insulin sensitivity (S(I)) in interaction with body mass index (p<0.02). Sequence variants in different locations of the PBX1 gene may have modest pleiotropic effects on T2DM susceptibility in Caucasians.

Black People↗
PubMed2002

Cloning, expression and genomic structure of human LMX1A, and variant screening in Pima Indians.

LIM-homeodomain containing protein LMX1A activates transcription of the insulin gene. The human LMX1A gene maps to 1q22-q23, a region identified as a putative type 2 diabetes mellitus (T2DM) locus in several different populations. We analyzed LMX1A as a positional and biological candidate gene for T2DM in the Pima Indians, in whom a linkage of T2DM to 1q21-q23 has been previously reported. In the present study, we describe the cloning, expression and genomic organization of the LMX1A gene, which is composed of 11 exons spanning approximately 151 kb. In addition to a transcript encoding the predicted full-length protein of 382 amino acids, we identified two truncated cDNA forms produced via additional transcription start sites and alternative splicing. We identified seven single nucleotide polymorphisms (SNPs) throughout the LMX1A locus and determined allele frequency distributions in 150 diabetic and 150 unaffected Pimas. We did not find evidence for association of any LMX1A SNPs with T2DM and conclude that LMX1A does not contribute significantly to T2DM etiology in Pima Indians.

Alleles↗
PubMedDate not supplied

Rosiglitazone treatment increases nitric oxide production in human peripheral skin: a controlled clinical trial in patients with type 2 diabetes mellitus.

Type 2 diabetes mellitus (T2DM) is associated with an increased risk of micro- and macrovascular complications, causing considerable morbidity and mortality. Endothelial dysfunction and insulin resistance have been strongly associated with reduced vascular reactivity in T2DM. We investigated the effect of the insulin-sensitizing antidiabetic agent rosiglitazone at a dose level of 8 mg/day on in vivo skin nitric oxide (NO) production and blood flow in the foot in a 16-week, randomized, double-blind, placebo-controlled crossover to open-label, single-blind study in patients with T2DM. NO production was assessed using an amperometric meter inserted directly into the skin. Skin perfusion was studied using laser Doppler techniques in response to local warming. Ten patients completed the study. NO production was significantly increased by rosiglitazone compared with baseline after 8-16 weeks of treatment (from 61.6+/-13.5 to 85.3+/-6.4 nM, P<.05 in response to warming). Fasting serum C-peptide levels were significantly reduced (P<.05) compared with baseline following rosiglitazone (4.78+/-1.19 ng/dl at Week 2 compared with 3.63+/-0.72 ng/dl after rosiglitazone treatment at Week 16), correlating inversely (r=-.65, P=.08) with the increase in NO production. Skin perfusion increased after 16 weeks of rosiglitazone treatment (P=ns). This is the first study to show that rosiglitazone attenuates the effects of T2DM on NO production, a marker of endothelial function, in vivo. This provides further evidence for the beneficial effects of rosiglitazone on nontraditional cardiovascular risk factors associated with T2DM.

Adult↗
PubMed2003

A C-reactive protein promoter polymorphism is associated with type 2 diabetes mellitus in Pima Indians.

Linkage analysis has identified a susceptibility locus for type 2 diabetes mellitus (T2DM) on chromosome 1q21-q23 in several populations. Results from recent prospective studies indicate that increased levels of C-reactive protein (CRP), a marker of immune system activation, are predictive of diabetes, independent of adiposity. Because CRP is located on 1q21, we considered it a potential positional candidate gene for T2DM. We therefore evaluated CRP and the nearby serum amyloid P-component, APCS, which is structurally similar to CRP, as candidate diabetes susceptibility genes. Approximately 10.9kb of the CRP-APCS locus was screened for polymorphisms using denaturing high performance liquid chromatography and direct sequencing. We identified 27 informative polymorphisms, including 26 single nucleotide polymorphisms (SNPs) and 1 insertion/deletion, which were divided into 7 linkage disequilibrium clusters. We genotyped representative SNPs in approximately 1300 Pima samples and found a single variant in the CRP promoter (SNP 133552) that was associated with T2DM (P=0.014), as well as a common haplotype (CGCG) that was associated with both T2DM (P=0.029) and corrected insulin response, a surrogate measure of insulin secretion in non-diabetic subjects (P=0.050). Linkage analyses that adjusted for the effect of these polymorphisms indicated that they do not in themselves account for the observed linkage with T2DM on chromosome 1q. However, these findings suggest that variation within the CRP locus may play a role in diabetes susceptibility in Pima Indians.

Base Sequence↗
PubMed2006

Polymorphisms in the gene encoding hepatocyte nuclear factor-4alpha and susceptibility to type 2 diabetes in a Polish population.

Recently, several association studies of type 2 diabetes mellitus (T2DM) and the hepatocyte nuclear factor (HNF)-4alpha gene were reported with conflicting results. Our aim was to search for association between two polymorphisms of HNF-4alpha and T2DM in Polish Caucasians. The study groups comprised of 461 T2DM cases and 366 controls. Genotype-quantitative trait analyses were based on the oral glucose tolerance test (OGTT), glucose and insulin results, and comprised 310 glucose-tolerant subjects. All individuals were genotyped for two HNF-4alpha polymorphisms. The frequencies of the minor alleles were as follows: 19.2% in T2DM vs. 17.6% in controls for rs2144908; and 20.6% vs. 20.1% for rs4810424, respectively. The distributions of alleles, genotypes, and haplotypes of the HNF-4alpha polymorphisms did not differ between the study groups (lowest P = 0.41). None of the examined SNPs showed an association in control subjects with quantitative traits of fasting plasma glucose, fasting insulin, as well as plasma glucose and insulin 2 hours after glucose load in OGTT. We conclude that both examined polymorphisms in HNF-4alpha are not associated with T2DM and prediabetic phenotypes in Polish Caucasian study groups of this size.

Blood Glucose↗
PubMed2003

Nutritional effects of fat on carbohydrate metabolism.

Obesity is commonly associated with elevated plasma levels of free fatty acids (FFAs). High levels of FFA have emerged as a major link between obesity and insulin resistance/type 2 diabetes (T2DM). Thus, acute and chronic elevations of plasma FFAs produce insulin resistance in skeletal muscle and liver. In skeletal muscle, FFA-induced insulin resistance is associated with accumulation of intramyocellular triglyceride and diacylglycerol, and with activation of protein kinase C (the beta and delta isoforms). It is suggested that FFAs interfere with insulin signalling via PKC-induced serine phosphorylation of the insulin receptor substrate-1. In the liver, FFAs cause insulin resistance by interfering with insulin suppression of glycogenolysis. In beta-cells, FFAs potentiate glucose-stimulated insulin secretion acutely and chronically. It is postulated that this prevents the development of T2DM in most (>80%) obese insulin-resistant people who have FFA-mediated insulin resistance. Elevated levels of FFA also seem to activate a pro-inflammatory and pro-atherogenic pathway (the IkappaB/NFkappaB pathway) and may be responsible, at least in part, for the increase in atherosclerotic vascular disease seen in patients with T2DM. As increased plasma levels account for up to 50% of insulin resistance in obese patients with T2DM, lowering of plasma FFAs could be a new and promising approach to the treatment of T2DM.

Animals↗
PubMed2006

Increased levels of tumour necrosis factor-alpha (TNF-alpha) in patients with Type II diabetes mellitus after myocardial infarction are related to endothelial dysfunction.

The pathophysiology of insulin resistance and atherosclerosis may share a common inflammatory basis, maintaining endothelial dysfunction, suggesting why patients with T2DM (Type II diabetes mellitus) have an impaired prognosis after an MI (myocardial infarction), but it remains unclear how these parameters are inter-related. Forty patients with an MI (20 patients with and 20 patients without T2DM) took part in this cross-sectional study. Endothelium-dependent [FMD (flow-mediated dilation)] and -independent [NTG (nitroglycerine)] vasodilatation (determined by ultrasound), S(I) (insulin sensitivity index; determined by isoglycaemic-hyperinsulinaemic clamp) and serum levels of CRP (C-reactive protein), TNF-alpha (tumour necrosis factor-alpha), IL-6 (interleukin 6), resistin and adiponectin (determined by ELISA) were measured. Associations between FMD/NTG and S(I), and CRP, TNF-alpha, IL-6, adiponectin, resistin, lipids, blood pressure, BMI (body mass index) and brachial artery diameter were then assessed. FMD (2.1 compared with 4.7%; P<0.05), NTG (14.9 compared with 21.2%; P<0.05) and S(I) [4.3 compared with 6.6 10(-4) dl.kg(-1) of body weight.min(-1).(mu-units/ml)(-1); P<0.05], and adiponectin levels (3.1 compared with 6.4 microg/ml; P<0.01) were all lower in patients with T2DM. TNF-alpha (6.9 compared with 1.8 pg/ml; P<0.01) and IL-6 (2.3 compared with 1.2 pg/ml; P<0.01) levels were higher in patients with T2DM, whereas differences in CRP and resistin levels did not attain statistical significance between the two groups. TNF-alpha concentrations and brachial artery diameter were negatively, whereas S(I) was positively, correlated with FMD. Adjustment for age weakened the association for S(I), whereas TNF-alpha and brachial artery diameter remained significantly associated with FMD after adjustment for group, age and BMI. Endothelial dysfunction and low-grade inflammation co-exist in T2DM after MI. These results suggest that the endothelium is negatively impacted in multiple ways by the diabetic state after an MI.

Adiponectin↗
PubMed2003

Increased skeletal muscle expression of PKC-theta but not PKC-alpha mRNA in type 2 diabetes: inverse relationship with in-vivo insulin sensitivity.

BACKGROUND: Increases in PKC-theta (the major isoenzymic form of PKC in skeletal muscle) protein and isozyme activity have been reported in skeletal muscle from patients with type 2 diabetes mellitus (T2DM) and dietary-induced rodent models of insulin resistance, but the underlying biochemical mechanism is unclear and muscle PKC-theta mRNA expression has not been previously reported in patients with T2DM or in relation to in-vivo measurements of insulin sensitivity. METHODS: Diet-only treated patients with T2DM (n=7) and healthy nondiabetic controls (n=7) of similar BMI attended the clinical research unit on two occasions, 1 week apart, for a skeletal muscle biopsy 2 h after a 75-g oral glucose load and measurement of whole-body insulin sensitivity using the euglycaemic hyperinsulinaemic clamp. RESULTS: Type 2 DM patients were insulin resistant (M-value 3.0 +/- 0.4 vs. 8.6 +/- 0.8 mg glucose kg(-1) min(-1)) with fasting hyperinsulinaemia (306 +/- 116 vs. 34 +/- 9 pmol L(-1), P<0.001) and hypertriglyceridaemia (3.6 +/- 0.7 vs. 1.3 +/- 0.3 mmol L(-1), P<0.01) relative to controls. Semi-quantitative RT-PCR showed that expression of PKC-theta mRNA (relative to GAPDH mRNA) was 6-fold higher in T2DM subjects (0.63 + 0.25% vs. 0.09 + 0.07%, P<0.001), whereas there was no difference in expression of PKC-alpha mRNA between the two groups. Expression of PKC-theta mRNA was inversely correlated with insulin sensitivity (M) and positively correlated with fasting serum insulin concentration (P<0.02). CONCLUSIONS: This is the first clinical study of PKC-theta mRNA expression in human diabetic skeletal muscle. The results indicate that transcriptional up-regulation of PKC-theta may at least partly contribute to the increased muscle PKC-theta signalling in T2DM, and that PKC-theta mRNA may be inversely related to in-vivo insulin sensitivity.

Adult↗
PubMed2004

Insulin sensitivity in physically fit and unfit children of parents with Type 2 diabetes.

AIMS: First-degree relatives of patients with Type 2 diabetes mellitus (T2DM) are often reported to be insulin resistant. We wanted to identify early metabolic abnormalities in this condition, and determine whether they are altered by regular physical training. METHODS: We measured insulin sensitivity using the euglycaemic glucose clamp technique and insulin response to oral glucose in 10 unfit (did not participate in routine physical exercise) offspring of T2DM parents and 10 unfit control subjects, and compared them with six fit (routinely swam for 3 h/day 5 days/week) offspring of T2DM parents and six fit controls with no family history of T2DM. RESULTS: Unfit offspring had a higher plasma glucose response than the other three groups. The mean area under the glucose curve was also significantly higher in unfit offspring than in the other three groups (12.6 +/- 0.6 vs. 10.4 +/- 0.4, 9.6 +/- 0.5, and 9.5 +/- 0.7 mmol/l per hour for the unfit controls, fit offspring and fit controls, respectively; P < 0.05). The corresponding insulin response of unfit offspring was significantly higher at 60 min in the oral glucose tolerance test (OGTT) that that of fit offspring or fit controls. In addition, the mean area under the insulin curve was significantly greater in unfit offspring than in either fit offspring or fit controls (868 +/- 172 vs. 294 +/- 71, 287 +/- 43 mmol/l per hour, respectively; P < 0.05). Moreover, the glucose disposal rate (GDR), measured using a euglycaemic clamp, was significantly lower in unfit and fit offspring than in unfit and fit controls (5.6 +/- 0.3 vs. 8.6 +/- 0.3 mg/kg per minute; P < 0.01 and 9.3 +/- 0.9 vs. 12.1 +/- 0.8 mg/kg per minute, respectively; P < 0.015), whereas the GDR was similar in unfit controls and fit offspring (8.6 +/- 0.4 vs. 9.3 +/- 0.9 mg/kg per minute; P > 0.05). CONCLUSION: These results support the concept that early metabolic abnormalities, as reflected by a decreased GDR (insulin sensitivity) in the offspring of T2DM patients, may be improved by increased physical fitness.

Administration, Oral↗