Biomedical subjects

H Vestergaard

Publications and source records attributed to H Vestergaard.

At least 19 recordsLinked to original sources

PubMed2006

Partial rescue of in vivo insulin signalling in skeletal muscle by impaired insulin clearance in heterozygous carriers of a mutation in the insulin receptor gene.

AIMS/HYPOTHESIS: Recently we reported the coexistence of postprandial hypoglycaemia and moderate insulin resistance in heterozygous carriers of the Arg1174Gln mutation in the insulin receptor gene (INSR). Controlled studies of in vivo insulin signalling in humans with mutant INSR are unavailable, and therefore the cellular mechanisms underlying insulin resistance in Arg1174Gln carriers remain to be clarified. SUBJECTS, MATERIALS AND METHODS: We studied glucose metabolism and insulin signalling in skeletal muscle from six Arg1174Gln carriers and matched control subjects during a euglycaemic-hyperinsulinaemic clamp. RESULTS: Impaired clearance of exogenous insulin caused four-fold higher clamp insulin levels in Arg1174Gln carriers compared with control subjects (p<0.05). In Arg1174Gln carriers insulin increased glucose disposal and non-oxidative glucose metabolism (p<0.05), but to a lower extent than in controls (p<0.05). Insulin increased Akt phosphorylation at Ser473 and Thr308, inhibited glycogen synthase kinase-3alpha activity, reduced phosphorylation of glycogen synthase at sites 3a+3b, and increased glycogen synthase activity in Arg1174Gln carriers (all p<0.05). In the insulin-stimulated state, Akt phosphorylation at Thr308 and glycogen synthase activity were reduced in Arg1174Gln carriers compared with controls (p<0.05), whereas glycogen synthase kinase-3alpha activity and phosphorylation of glycogen synthase at sites 3a+3b were similar in the two groups. CONCLUSIONS/INTERPRETATION: In vivo insulin signalling in skeletal muscle of patients harbouring the Arg1174Gln mutation is surprisingly intact, with modest impairments in insulin-stimulated activity of Akt and glycogen synthase explaining the moderate degree of insulin resistance. Our data suggest that impaired insulin clearance in part rescues in vivo insulin signalling in muscle in these carriers of a mutant INSR, probably by increasing insulin action on the non-mutated insulin receptors.

Adult↗

PubMed2006

YKL-40, a biomarker of inflammation, is elevated in patients with type 2 diabetes and is related to insulin resistance.

OBJECTIVE AND DESIGN: YKL-40 participates in inflammatory states and vascular processes, which implies that comparison can be made with other inflammatory markers associated with insulin resistance and type 2 diabetes (T2D). In the present study levels of plasma YKL-40 and serum hsCRP were evaluated in patients with T2D. MATERIALS AND METHODS: Patients with T2D and age-matched healthy controls participated in the study. Insulin resistance was estimated using HOMA-IR model. Biochemical parameters were measured in venous blood after a 10 h fast. RESULTS: Patients with T2D were insulin resistant (p<0.001) and had raised levels of plasma YKL-40 (p<0.001) and serum hsCRP (p<0.001). YKL-40 was correlated with HOMA-IR (r=0.23, p<0.01), NEFA (r=0.32, p<0.001) and triglycerides (r=0.24, p<0.05). YKL-40 and hsCRP were not correlated (r=0.17, p=NS). All participants with hsCRP<1 mg/l had higher insulin sensitivity (p<0.05 and p<0.01, respectively). HsCRP were predicted by HOMA-IR and BMI (r2=0.48, p<0.01). Plasma YKL-40 was predicted by HOMA-IR and triglycerides (r2=0.27, p<0.01). CONCLUSIONS: YKL-40 and hsCRP are elevated in patients with T2D and are related to insulin resistance. No correlation was found between YKL-40 and hsCRP indicating that increased levels of YKL-40 occur independently from elevated plasma hsCRP.

Adipokines↗

PubMed2006

YKL-40, a new inflammatory marker with relation to insulin resistance and with a role in endothelial dysfunction and atherosclerosis.

Substantial evidence supports a role of chronic subclinical inflammation and activation of the innate immune system in the pathogenesis of insulin resistance and endothelial dysfunction and the development of type 2 diabetes (T2D) and atherosclerosis. Several proinflammatory cytokines, acute phase-reactants and cell adhesion molecules play a pivotal role in this chronic subclinical inflammation but a comprehensive understanding of the interrelations of these molecules is still needed. YKL-40 is a new inflammatory marker with relation to acute and chronic inflammation as well as cancer. It is secreted in vitro from a variety of human cells, including vascular smooth muscle cells (VSMCs), activated macrophages and macrophages during late stages of differentiation and is found in vivo in subpopulations of macrophages in tissues with inflammation and extracellular tissue remodelling, such as macrophages in atherosclerotic plaques. YKL-40 promotes chemotaxis, cell attachment and migration of VSMCs and the formation of branching tubules suggesting that YKL-40 plays a role in angiogenesis. Latest studies reveal that YKL-40 is elevated in patients with T2D and is related to insulin resistance. This article reviews the studies of YKL-40 with focus on a possible role of YKL-40 in insulin resistance, endothelial dysfunction and atherosclerosis.

Adipokines↗

PubMed2004

Studies of the Ala/Val98 polymorphism of the hepatocyte nuclear factor-1alpha gene and the relationship to beta-cell function during an OGTT in glucose-tolerant women with and without previous gestational diabetes mellitus.

AIMS: In pregnancies complicated by gestational diabetes mellitus (GDM) an increased demand for insulin is not met due to beta-cell dysfunction. An Ala/Val polymorphism at codon 98 of the hepatocyte nuclear factor-1alpha (HNF-1alpha) gene has been associated with decreased serum insulin and C-peptide responses during an oral glucose tolerance test (OGTT) in glucose-tolerant subjects. The aims of the present study were to evaluate the influence of the polymorphism on the serum insulin and C-peptide responses to an OGTT in glucose-tolerant women with and without previous GDM and to investigate if this polymorphism is associated with GDM. METHODS: The Ala/Val98 polymorphism was measured in 376 women of Danish origin with previous GDM, and in 724 age-matched and 310 middle-aged glucose tolerant women using polymerase chain reaction-restriction fragment length polymorphism. RESULTS: The allelic frequency of the Ala/Val98 polymorphism was 0.043 [95% confidence interval (CI) 0.028, 0.057] in women with previous GDM vs. 0.037 (95% CI 0.028, 0.047) in age-matched and 0.039 (95% CI 0.024, 0.054) in middle-age women. Among 117 glucose-tolerant women with previous GDM, 10 carriers of the Ala/Val98 polymorphism had a non-significant 27% and 22% reduction in serum C-peptide and insulin levels, respectively, at 30 min during an OGTT. Seventy-eight control subjects carrying the Ala/Val98 polymorphism had a 10% (P = 0.001) and 16% (P = 0.004) reduction in serum C-peptide and insulin levels, respectively, compared with 956 Ala/Ala control subjects. CONCLUSIONS: The Ala/Val polymorphism at codon98 of HNF-1alpha is not associated with GDM in Danish women. However, the codon 98 variant is associated with a significant impairment of serum insulin and C-peptide responses during an OGTT in glucose-tolerant women without previous GDM.

Adult↗

PubMed2001

Seasonal variation in food allergy to apple.

The aim of the study was to investigate the possibility of a seasonal variation in reactivity to apples in 27 birch pollen allergic patients. Before and during the birch pollen season 1998, the patients were subjected to double-blind, placebo-controlled food challenges (DBPCFCs) with grated fresh Golden Delicious apple followed by an open food challenge with whole fresh apple. The clinical reactions elicited during the challenges were evaluated both by the patients and the investigators. Moreover, the skin reactivity and the in vitro reactivity to apple were evaluated by skin prick test (SPT), leukocyte histamine release (HR), measurement of specific IgE, and immunoblotting experiments. The sensitivity of the DBPCFC, when compared with the result of the open challenge, was 0.74 (14/19) before the season and 0.80 (16/20) during the season. None of the patients reacted to the blinded challenge without a subsequent reaction to the open challenge. One placebo reaction was registered both before and in season, but not in the same patient. The patient scores of the first positive challenges, and the maximal scores of each combined blinded and open challenge session, were significantly increased during the pollen season (P<0.05). The scores of the open challenge were significantly higher than the scores of the DBPCFC both before the season and during the in-season challenges (P<0.05). Specific IgE against Golden Delicious increased during season (P<0.05), while neither SPT, HR, nor immunoblotting experiments could confirm an increase in reactivity. In conclusion, the results of the oral challenge tests indicated an increase in clinical reactivity to apples during the birch pollen season in birch pollen allergic individuals.

Blotting, Western↗

PubMed2001

Studies of variability in the PTEN gene among Danish caucasian patients with Type II diabetes mellitus.

AIM/HYPOTHESIS: Phosphatase and tensin homologue deleted from chromosome ten (PTEN) has recently been characterized as a novel member in the expanding network of proteins regulating the intracellular effects of insulin. By dephosphorylation of phosphatidyl-inositol-(3, 4, 5)-trisphosphate (PIP3) the PTEN protein regulates the insulin-dependent phosphoinositide 3-kinase (PI3K) signalling cassette and accordingly might function as a regulator of insulin sensitivity in skeletal muscle and adipose tissue. In this study we tested PTEN as a candidate gene for insulin resistance and late-onset Type II (non-insulin-dependent) diabetes mellitus in a Danish Caucasian population. METHODS: The nine exons of the PTEN, including intronic flanking regions were analysed by PCR-SSCP and heteroduplex analysis in 62 patients with insulin-resistant Type II diabetes. RESULTS: No mutations predicted to influence the expression or biological function of the PTEN protein but four intronic polymorphisms were identified: IVS1-96 A-->G (allelic frequency 0.22, 95 % CI: 0.12-0.32), IVS3 + 99 C-->T (0.01, CI: 0-0.03), IVS7-3 TT-->T (0.10, CI: 0.03-0.18) and IVS8 + 32 G-->T (0.35, CI: 0.23-0.47). The IVS8 + 32 G-->T polymorphism was used as a bi-allelic marker for the PTEN locus and examined in 379 patients with Type II diabetes and in 224 control subjects with normal glucose tolerance. The IVS8 + 32 G-->T polymorphism in the PTEN was not associated with Type II diabetes and it did not have any effect on body-mass index, blood pressure, HOMA insulin resistance index, or concentrations of plasma glucose, serum insulin or serum C peptide obtained during an oral glucose tolerance test (OGTT). CONCLUSION/INTERPRETATION: Variability in the PTEN is not a common cause of Type II diabetes in the Danish Caucasian population.

Adipose Tissue↗

PubMed2001

Allergens from fish and egg.

Allergens from fish and egg belong to some of the most frequent causes of food allergic reactions reported in the literature. Egg allergens have been described in both white and yolk, and the egg white proteins ovomucoid, ovalbumin, ovotransferrin and lysozyme have been adopted in the allergen nomenclature as Gal d1-d4. The most reported allergen from egg yolk seems to be alpha-livitin. In fish, the dominating allergen is the homologues of Gad c1 from cod, formerly described as protein M. A close cross-reactivity exists within different species of fish between this calcium-binding protein family, denominated the parvalbumins. This cross-reactivity has been indicated to be of clinical relevance for several species, since patients with a positive double-blind, placebo-controlled food challenge to cod will also react with other fish species, such as herring, plaice and mackerel. In spite of the importance of these two allergen systems, only a few studies have been performed, and the scarcity of cloned allergens from both of the systems is emphasized.

Allergens↗

PubMed2001

Double-blind, placebo-controlled food challenge with apple.

The aim of the study was to develop and evaluate different methods of double-blind, placebo-controlled food challenge (DBPCFC) with apple. Three different DBPCFC models were evaluated: fresh apple juice, freshly grated apple, and freeze-dried apple powder. All challenges were performed outside the pollen season and took place from 1997 to 1999. The freeze-dried apple material was characterized by means of leukocyte histamine release (HR), skin prick test (SPT), and immunoblotting experiments. The study population consisted of birch pollen-allergic patients with a history of rhinitis in the birch-pollen season and positive specific IgE to birch. For comparison of the DBPCFC models, 65 patients with a positive open oral challenge with apple were selected. In the characterization of the freeze-dried apple material, 46 birch pollen-allergic patients were included. The IgE reactivity to apple was evaluated by measurement of specific IgE, HR, and SPT. Golden Delicious apples were used in all experiments. The results of this study showed that it was possible to perform DBPCFC with apple in birch pollen-allergic individuals. The model with freshly squeezed apple juice had a low sensitivity and displayed a high frequency of reactions to placebo, probably due to the ingredients used for blinding. The sensitivity of the models with freshly grated apple and freeze-dried apple powder was 0.74/0.60. An increase in sensitivity is desirable. The freeze-dried apple powder proved to be useful for SPT, HR, and oral challenges, but further investigation of the stability and the allergenic profile of the material is needed.

Cross Reactions↗

PubMed2001

Increments in insulin sensitivity during intensive treatment are closely correlated with decrements in glucocorticoid receptor mRNA in skeletal muscle from patients with Type II diabetes.

To test the hypothesis that changes in the expression of the glucocorticoid receptor (GCR) and the beta(2)-adrenoceptor (beta(2)-AR) contribute significantly to the abnormal glucose metabolism in skeletal muscle from patients with Type II diabetes, we have examined (1) the levels of total GCR (alpha+beta isoforms), the alpha/alpha 2 isoform of GCR and beta(2)-AR mRNAs in skeletal muscle from insulin-resistant patients with Type II diabetes (n=10) and healthy controls (n=15), and (2) the effects of 8 weeks of intensive treatment on the whole-body glucose disposal rate and on total GCR, alpha/alpha 2 GCR and beta(2)-AR mRNA levels in diabetic patients. The total glucose disposal rate was measured by the euglycaemic hyperinsulinaemic (2 m-units x min(-1) x kg(-1)) clamp technique, and mRNA levels were assessed by reverse transcriptase-PCR and HPLC for separation of standard and unknown and quantification. Mean levels of total GCR and alpha/alpha 2 GCR mRNAs were increased in patients with Type II diabetes when compared with control subjects [total GCR, 2.06+/-0.30 and 1.47+/-0.10 amol/microg of total RNA respectively (P=0.09); alpha/alpha 2 GCR mRNA, 1.69+/-0.31 and 0.92+/-0.09 amol/microg of total RNA respectively (P=0.02)], whereas mRNA levels of the beta isoform of GCR (total GCR minus alpha/alpha 2 GCR) were decreased (P=0.006). beta(2)-AR mRNA levels were comparable in diabetic patients and control subjects (0.53+/-0.05 and 0.45+/-0.02 amol/microg of total RNA respectively; P=0.2). Intensive treatment for 8 weeks was associated with improved glycaemic control (P=0.019), and during the clamp a 75% (P=0.001) increase in the whole-body insulin-stimulated glucose disposal rate was demonstrated. Total GCR (P=0.005), alpha/alpha 2 GCR (P=0.005) and beta(2)-AR (P=0.03) mRNA levels all decreased significantly after intensive insulin treatment. A close correlation was found between increments in glucose uptake during intensive treatment and decrements in skeletal muscle total GCR mRNA (r=0.95, P<0.001; multiple regression analysis), and between glucose uptake and alpha/alpha 2 GCR m RNA levels (r=0.88, P<0.001; simple correlation). In conclusion, the abnormal regulation of GCR mRNA is likely to play a significant role in the insulin resistance observed in obese patients with Type II diabetes.

Adult↗

PubMed2001

Rosiglitazone treatment of patients with extreme insulin resistance and diabetes mellitus due to insulin receptor mutations has no effects on glucose and lipid metabolism.

BACKGROUND: Rosiglitazone, a thiazolidinedione (TZD), increases insulin sensitivity by reducing levels of plasma NEFA, triglycerides (TG), glucose and serum insulin. Rosiglitazone treatment decreases insulin resistance in type 2 diabetic patients, but no data exist concerning rosiglitazone treatment of patients with syndromes of extreme insulin resistance. OBJECTIVES: To evaluate whether hyperglycaemia in two lean patients with primary severe insulin resistance due to insulin receptor (IR) mutations and diabetes mellitus could be reduced by supplement of rosiglitazone for 180 days and secondary, to evaluate the effects on plasma NEFA, TG, Apo B, PAI-1 and serum insulin. SUBJECTS: Both patients (brothers) have known mutations in the IR gene localized to the tyrosine kinase domain and a deletion of exon 17 in part of their IR mRNA. Prior to the study the HbA1c values were higher than 10% in both patients for more than 12 months during treatment with insulin and metformin. RESULTS: After 180 days of rosiglitazone supplement (8 mg day(-1)), no changes were observed in fasting plasma glucose and HbA1c. Incremental plasma glucose areas under the curves during a 75-g oral glucose tolerance test (OGTT) were unchanged. Likewise, no improvements were seen in either first or second phase insulin secretion during a 0.3 g kg(-1) intravenous glucose tolerance test (IVGTT). Fasting plasma VLDL and HDL cholesterol, TG and Apo B levels were unchanged, whereas a small increase was seen in total and LDL cholesterol levels. Fasting plasma NEFA increased by 51% in KC after 90 days of treatment, and after 180 days plasma NEFA was still 26% higher, when compared with pretreatment levels. In BC an initial 16% decrease was seen in plasma NEFA after 90 days of treatment. Plasma NEFA was increased 14% after 180 days of treatment, when compared with pretreatment levels, but 35% when compared with day 90. Plasma PAI-1 decreased in both patients after 45 and 90 days of treatment but the decrease was only maintained in KC (47%). CONCLUSIONS: Rosiglitazone treatment, in combination with insulin and metformin, of patients with severe primary insulin resistance due to IR mutations and diabetes mellitus, had no impact on the measured estimates of glucose and lipid metabolism. These findings may suggest that the effect of rosiglitazone on glucose and lipid metabolism are dependent on the presence of intact IR protein.

Adolescent↗

PubMed2001

Serum leptin levels in pregnant women with type 1 diabetes mellitus.

BACKGROUND: Leptin is an important weight regulator and during pregnancy leptin is not only synthesized in adipose tissue but also in the placenta. AIM: To examine changes in serum leptin levels in women with type 1 diabetes mellitus during pregnancy and post delivery in relation to concomitant changes in maternal body weight, birth weight, glycemic control, and blood pressure. METHODS: Non-fasting serum leptin from 45 women with type 1 diabetes mellitus were studied consecutively throughout pregnancy and 3 months post partum. RESULTS: Serum leptin was positively associated with HbA1c in week 18, 22 and 30 (r=0.38, 0.41, and 0.54, respectively, p<0.05, adjusted for body weight). Moreover, serum leptin correlated positively with maternal body weight and BMI (0.45 25 kg/m2), the changes during pregnancy and the level of serum leptin were significantly greater compared to lean women (p<0.05). The women with low ambulatory blood pressure (lower tertile, mean arterial blood pressure <83.4 mmHg) showed the lowest level of serum leptin throughout pregnancy and it changed significantly differently from the women with higher blood pressure (p<0.05). CONCLUSION: Changes in serum leptin levels of pregnant women with type 1 diabetes mellitus were associated with parallel changes in maternal body weight and glycemic control. Women with low blood pressure had the lowest serum leptin levels throughout pregnancy.

Adult↗

PubMed2000

[Interaction between warfarin and oral miconazole gel].

We report a case of a 76 year-old woman who had been taking warfarin for seven years because of relapsing deep venous thrombosis. Her daily maintenance dose was 5 mg. Monthly measurements of international normalised ratio (INR) were stable between 2-3. She developed oral candidiasis and miconazole gel was prescribed. One week later she developed bleeding gums. Eight days later she was admitted to the hospital with haematuria. INR was > 10. Warfarin and the miconazole gel were withdrawn. She was treated with phytonadione. INR normalised after four days and she continued warfarin treatment. Caution should be exercised whenever the combination of warfarin and miconazole gel are prescribed.

Aged↗

PubMed2000

Physicians' use of plasma methylmalonic acid as a diagnostic tool.

OBJECTIVES: To investigate physicians' reasons for requesting plasma methylmalonic acid and their reactions to an increased concentration of plasma methylmalonic acid. DESIGN: Study of medical records. SETTING: Three somatic district hospitals in Denmark. SUBJECTS: Medical records of 198 patients with a plasma methylmalonic acid measurement above the reference interval. Information on diagnostic decisions was available for 177 patients. MAIN OUTCOME MEASURES: Reasons for requesting plasma methylmalonic acid and the reactions to the finding of elevated plasma methylmalonic acid. RESULTS: An explicit reason for requesting plasma methylmalonic acid was stated in 57% of 198 examined medical records, known or suspected anaemia being the most frequent reason. No further action was taken in 109 (62%) of the 177 cases available for follow-up. Amongst the remaining 68 patients, the finding of an increased plasma methylmalonic acid led to diagnosis of cobalamin deficiency in 46 patients. Six patients with a markedly increased plasma methylmalonic acid (above 0.99 micromol L-1) and clearly decreased plasma cobalamins (below 200 pmol L-1) were not recognized as having cobalamin deficiency. CONCLUSIONS: This lack of response to an increased plasma methylmalonic acid raises an important question. Is the clinical response inadequate, or is the connection between an increased level of plasma methylmalonic acid and signs of clinical significant cobalamin deficiency less clear?

Adult↗

PubMed1999

Implications of compound heterozygous insulin receptor mutations in congenital muscle fibre type disproportion myopathy for the receptor kinase activation.

We studied insulin receptor kinase activation in two brothers with congenital muscle fibre type disproportion myopathy and compound heterozygous mutations of the insulin receptor gene, their parents, and their unaffected brother. In the father who has a heterozygote Arg1174-->Gln mutation, in situ activation of the receptor kinase in skeletal muscle was reduced about 70%. Selection of only those receptors that bound to anti-phosphotyrosine antibody showed that these receptors had normal kinase activity and that the reduction in overall kinase activity was due to the inability of about 70% of the receptors to become insulin-dependently activated. The mother carries a point mutation at the last base pair in exon 17 which, due to abnormal alternative splicing, could lead to normally transcribed receptor or truncated receptor lacking the kinase region. Kinase activation was normal in the mother's skeletal muscle, suggesting that virtually no truncated receptor was expressed. Receptor kinase activity was, however, reduced by 95 and 91% in the compound heterozygous brothers. This suggests that the mother's mutated allele contributes little to the generation of functional receptor protein and that the receptors in the mother's skeletal muscle are transcribed almost exclusively from the non-mutated allele. The mutation in exon 17 could lead to reduced transcription or rapid degradation of a predominantly transcribed truncated gene product or both.

Adult↗

PubMed1999

Low incidence rate of overt hypothyroidism compared with hyperthyroidism in an area with moderately low iodine intake.

In areas with relatively high iodine intake, the incidence rate of hypothyroidism is several-fold higher than that of hyperthyroidism. Recently, we found a similarly high prevalence rate of subclinical hypothyroidism compared with hyperthyroidism in a high iodine intake area, while a relatively low prevalence of subclinical hypothyroidism was observed in a low iodine intake area. In the present study we compared the incidence rate (newly diagnosed in primary care and at hospital) of overt hypothyroidism with that of hyperthyroidism in a well-defined geographical area in Jutland, Denmark, with an iodine intake around 60 microg/day. The number of personsxyears studied was 569,108. Data on hyperthyroidism have been published previously. The overall incidence of hypothyroidism was 13.5/100,000 per year (F/M 22.9/3.6), hyperthyroidism 38.7/100.000 per year (F/M 63.0/13.0). The incidence of hypothyroidism was steadily increasing with age up to 80/100,000 per year in subjects older than 70 years of age, but apart from congenital hypothyroidism it was lower than that of hyperthyroidism at all ages. The majority of patients (79%) was diagnosed to have spontaneous autoimmune hypothyroidism (16% with goiter, 84% with no thyroid visible or palpable). In conclusion, in an area with moderately low iodine intake, hypothyroidism was considerably less common than hyperthyroidism. This is in contrast to findings in high iodine intake areas. The iodine intake of an area seems to be of major importance for the pattern of thyroid disorders observed.

Adolescent↗

PubMed1999

Insulin resistance, exercise capacity and body composition in subjects with two hypertensive parents.

OBJECTIVE: To study insulin resistance in subjects with strong genetic predisposition to essential hypertension, compared with non-disposed subjects. SUBJECTS: Thirty normotensive subjects aged 18-35 years whose parents both had essential hypertension, and 30 age- and sex matched subjects whose parents were both normotensive, were studied. Subjects or parents with diabetes and morbid obesity were excluded. METHODS: The study comprised (1) a frequent sampling oral glucose tolerance test; (2) an isoglycemic hyperinsulinemic clamp study; (3) an analysis of body composition by dual-energy X-ray absorptiometry; (4) an exercise test with gas exchange analysis; and (5) investigation of composition of usual diet by diet registration for 5 days. RESULTS: The 24-h diastolic blood pressure was higher in subjects predisposed to hypertension compared with the controls: 78.1 versus 74.0 mmHg (confidence interval for the difference between the means; -0.5; -7.9), but the insulin sensitivity index was similar: 312 versus 362 I(2) min(-1) pmol(-1) kg(-1) (28; -129). The two groups were similar in terms of body composition, exercise capacity and composition of usual diet. Resting and 24-h diastolic blood pressures were correlated to abdominal fat mass but not to insulin sensitivity. CONCLUSION: Subjects with a strong genetic predisposition to essential hypertension had increased diastolic blood pressure compared with subjects with normotensive parents, but they were not insulin resistant. This may be due to the subjects being highly selected as to confounding factors. The increased blood pressure in the hypertension prone subjects could not be attributed to differences in body composition, exercise capacity or dietary habits.

Absorptiometry, Photon↗

PubMed1999

Alternative splicing of exon 17 and a missense mutation in exon 20 of the insulin receptor gene in two brothers with a novel syndrome of insulin resistance (congenital fiber-type disproportion myopathy).

The insulin receptor (IR) in two brothers with a rare syndrome of congenital muscle fiber type disproportion myopathy (CFTDM) associated with diabetes and severe insulin resistance was studied. By direct sequencing of Epstein-Barr virus-transformed lymphocytes both patients were found to be compound heterozygotes for mutations in the IR gene. The maternal allele was alternatively spliced in exon 17 due to a point mutation in the -1 donor splice site of the exon. The abnormal skipping of exon 17 shifts the amino acid reading frame and leads to a truncated IR, missing the entire tyrosine kinase domain. In the correct spliced variant, the point mutation is silent and results in a normally translated IR. The paternal allele carries a missense mutation in the tyrosine kinase domain. All three cDNA variants were present in the lymphocytes of the patients. Purified IR from 293 cells overexpressing either of the two mutated receptors lacked basal or stimulated IR beta-subunit autophosphorylation. A third brother who inherited both normal alleles has an normal muscle phenotype and insulin sensitivity, suggesting a direct linkage of these IR mutations with the CFTDM phenotype.

Adolescent↗

PubMed1999

Mutational analysis of the coding regions of the genes encoding protein kinase B-alpha and -beta, phosphoinositide-dependent protein kinase-1, phosphatase targeting to glycogen, protein phosphatase inhibitor-1, and glycogenin: lessons from a search for genetic variability of the insulin-stimulated glycogen synthesis pathway of skeletal muscle in NIDDM patients.

The finding of a reduced insulin-stimulated glucose uptake and glycogen synthesis in the skeletal muscle of glucose-tolerant first-degree relatives of patients with NIDDM, as well as in cultured fibroblasts and skeletal muscle cells isolated from NIDDM patients, has been interpreted as evidence for a genetic involvement in the disease. The mode of inheritance of the common forms of NIDDM is as yet unclear, but the prevailing hypothesis supports a polygenic model. In the present study, we tested the hypothesis that the putative inheritable defects of insulin-stimulated muscle glycogen synthesis might be caused by genetic variability in the genes encoding proteins shown by biochemical evidence to be involved in insulin-stimulated glycogen synthesis in skeletal muscle. In 70 insulin-resistant Danish NIDDM patients, mutational analysis by reverse transcription-polymerase chain reaction-single strand conformation polymorphism-heteroduplex analysis was performed on genomic DNA or skeletal muscle-derived cDNAs encoding glycogenin, protein phosphatase inhibitor-1, phophatase targeting to glycogen, protein kinase B-alpha and -beta, and the phosphoinositide-dependent protein kinase-1. Although a number of silent variants were identified in some of the examined genes, we found no evidence for the hypothesis that the defective insulin-stimulated glycogen synthesis in skeletal muscle in NIDDM is caused by structural changes in the genes encoding the known components of the insulin-sensitive glycogen synthesis pathway of skeletal muscle.

3-Phosphoinositide-Dependent Protein Kinases↗