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Biomedical subjects

A Fritsche

Publications and source records attributed to A Fritsche.

At least 19 recordsLinked to original sources
PubMed2006

Tissue selectivity of insulin detemir action in vivo.

AIMS/HYPOTHESIS: Recombinant DNA technology is a useful tool that can be used to create insulin analogues with modified absorption kinetics to improve glycaemic control in patients with type 1 and type 2 diabetes. Among conventional insulin analogues, which are usually created by amino acid exchange, insulin detemir is the first analogue to be acylated with a fatty acid to enable reversible albumin binding. In this study we determined activation of the insulin receptor (IR)-signalling cascade by insulin detemir at the level of IR and IR substrate (Irs) phosphorylation, as well as downstream signalling elements such as phosphatidylinositol 3-kinase and Akt, and performed epidural EEG in vivo. METHODS: C57Bl/6 mice were injected i.v. with either insulin detemir or human insulin and Western blot analysis was performed on liver, muscle, hypothalamic and cerebrocortical tissues. Moreover, cerebrocortical activity was detected by EEG in awake mice and cerebral insulin concentrations were measured following human insulin and insulin detemir injection. RESULTS: The time course and extent of IR phosphorylation in peripheral tissues were similar following insulin detemir treatment compared with human insulin, but insulin signalling in hypothalamic and cerebrocortical tissue determined by tyrosine-phosphorylation of the IR and Irs2 proteins occurred faster and was enhanced due to a higher insulin detemir concentration in the brain. Moreover, epidural EEG in mice displayed increased cortical activity using insulin detemir. CONCLUSIONS/INTERPRETATION: Taken together, these data suggest that insulin detemir has a tissue-selective action, with a relative preference for brain compared with peripheral tissues.

Animals↗
PubMed2006

Association of serum phosphate levels with glucose tolerance, insulin sensitivity and insulin secretion in non-diabetic subjects.

BACKGROUND: Hypophosphatemia is associated with impaired glucose tolerance and insulin resistance in primary hyperparathyroidism. However, little is known about the association between serum phosphate and glucose metabolism in healthy subjects. METHODS: We measured fasting serum phosphate levels (SP, normal range 2.6-4.5 mg/dl) and serum calcium (S-Ca, normal range 2.1-2.6 mmol/l) in 881 non-diabetic subjects (341 male/540 female, age: 38+/-1 years, body mass index 25.9+/-0.2 kg/m(2) (mean+/-standard error of the mean). An oral glucose tolerance test (OGTT) with determination of glucose and insulin every 30 min was performed in all subjects. Insulin secretion and insulin sensitivity (IS) were estimated from the OGTT using validated indices. Furthermore, we tested whether serum phosphate predicts glucose tolerance in 115 subjects during a lifestyle intervention program (LIP). RESULTS: Serum phosphate was negatively correlated with 2-h blood glucose levels independent of age, gender and percent body fat (r=-0.13, P<0.0001). This association remained significant after additional adjustment for S-Ca, creatinine and parathyroid hormone. Serum phosphate was positively correlated with IS (r=0.10, P=0.0006), but not with insulin secretion. This was independent of age, gender, percent body fat, S-Ca and serum creatinine. In the subjects taking part in the LIP low serum phosphate levels at baseline were associated with higher postprandial glucose levels. CONCLUSIONS: In non-diabetic subjects, low serum phosphate levels are associated with high 2-h blood glucose levels and reduced IS. Whether low serum phosphate levels are a cause or a consequence of low IS and impairment of glucose tolerance needs to be tested in further studies.

Adult↗
PubMed2006

[Obesity--an interdisciplinary task].

In industrial nations, over the last five decades conditions concerning nutrition and physical exercise as well as socio-economic circumstances have changed radically. One of the consequences following from this development has been a rapid increase in the prevalence of obesity. Studies have shown that currently 20 percent of the German adult population suffer from obesity. Investigations into the etiology of obesity have to address complex interactions between genetic, socio-economic and psychosocial factors. A year ago, at the University Hospital Tübingen different departments joined to set up the "Plattform Adipositas". Endocrinologists, obesity surgeons, professionals in sports medicine and psychosomatic medicine as well as dieticians are collaborating to develop scientifically based therapy programs and treatment pathways for obese patients. The following article gives an account of this exemplary interdisciplinary cooperation.

Germany↗
PubMed2006

Plasma homocysteine concentrations in young individuals at increased risk of type 2 diabetes are associated with subtle differences in glomerular filtration rate but not with insulin resistance.

Plasma homocysteine levels are elevated in individuals with type 2 diabetes contributing to the increased cardiovascular risk of these patients. As insulin resistance is a key feature in type 2 diabetic patients, hyperhomocysteinemia might be a consequence of insulin resistance. We studied this hypothesis in 839 individuals(male: 302, female: 537, mean age: 37.5 years) with a higher prevalence of insulin resistance (positive family history of type 2 diabetes, history of gestational diabetes, overweight). Subjects with overt type 2 diabetes or known kidney disease were excluded from the study. Mean plasma homocysteine concentration was 8.9 micromol/l (95% RCI 4.8-14.9). Adjusted for age and sex we could not find a significant correlation between homocysteine levels and BMI, insulin levels, or the insulin sensitivity-index (r = 0.35; p = 0.48). Furthermore, after a successful lifestyle intervention resulting in a significant decrease in BMI, body fat content and improved insulin sensitivity (p < 0.0001 each) no differences in homocysteine concentrations could be achieved. However,in the cross-sectional analysis we found a significant and independent, negative correlation between glomerular filtration rate (GFR) and homocysteine levels (r = -0.37; p < 0.0001). In conclusion, our study did not reveal a significant association between levels of homocysteine and insulin resistance in a population with an increased risk for type 2 diabetes. However, plasma homocysteine levels were related to subtle differences in kidney function at this early stage.

Adult↗
PubMed2006

Beta cell function, insulin resistance and plasma adiponectin concentrations are predictors for the change of postprandial glucose in non-diabetic subjects at risk for type 2 diabetes.

Insulin resistance, impaired insulin secretion, and low adiponectin levels have been shown to be predictors for type 2 diabetes. However, it is not yet clear whether these associations (1) are independent of changes in body weight, or (2) are valid for changes in glucose tolerance in the prediabetic state. Sixty-two non-diabetics (50 with normal glucose tolerance) aged 41 +/- 11 years, BMI 30.5 +/- 5.3 kg/m2 (mean +/- SD) were studied twice with a standard oral glucose tolerance test (oGTT, mean follow-up time 3.0 +/- 1.8 years (mean +/- SD) [range 0.5-6.5 years]). Insulin sensitivity and insulin secretion were estimated from oGTT using validated indices. Two-hour blood glucose during oGTT deteriorated over time (baseline 2 h glucose 6.32 +/- 0.21 VS. follow-up 2 h glucose 7.14 +/- 0.22 mM, p < 0.001) while the percentage body fat did not change (32.7 +/- 1.2 VS. 32.6 +/- 1.2%, p = 0.46). Follow-up 2 h blood glucose was predicted by adiponectin (p = 0.01), baseline insulin sensitivity (p = 0.02) and baseline insulin secretion relative to insulin sensitivity (p = 0.03) independent of sex, age, baseline 2 h blood glucose or change in percentage body fat. Our results suggest that low adiponectin levels, insulin resistance and low beta cell function predict the continuous deterioration of glucose tolerance in early prediabetic states, independent of changes in adiposity. Therefore, the early influence of these parameters should be the subject of future prevention programs to prevent deterioration of glucose tolerance.

Adiponectin↗
PubMed2005

Polymorphisms in the gene encoding adiponectin receptor 1 are associated with insulin resistance and high liver fat.

AIMS/HYPOTHESIS: The adipokine adiponectin has insulin-sensitising, anti-atherogenic and anti-inflammatory properties. Recently, the genes for mouse and human adiponectin receptor-1 (ADIPOR1) and -2 (ADIPOR2) have been cloned. The aim of this study was to investigate whether genetic variants of the genes encoding ADIPOR1 and ADIPOR2 play a role in human metabolism. MATERIALS AND METHODS: We screened ADIPOR1 and ADIPOR2 for polymorphisms and determined their association with glucose metabolism, lipid metabolism, an atherogenic lipid profile and inflammatory markers in 502 non-diabetic subjects. A subgroup participated in a longitudinal study; these subjects received diet counselling and increased their physical activity. RESULTS: We identified six variants of ADIPOR1 and seven variants of ADIPOR2. A single-nucleotide polymorphism (SNP) in the putative promoter region 8503 bp upstream of the translational start codon (-8503 G/A) of ADIPOR1 (frequency of allele A=0.31) was in almost complete linkage disequilibrium with another SNP (-1927 T/C) in intron 1. Subjects carrying the -8503 A and -1927 C alleles had lower insulin sensitivity, as estimated from a 75 g OGTT (p=0.04) and determined during a euglycaemic clamp (n=295, p=0.04); they also had higher HbA(1)c levels (p=0.02) and, although the difference was not statistically significant, higher liver fat (n=85, determined by proton magnetic resonance spectroscopy, p=0.056) (all p values are adjusted for age, sex and percentage of body fat). In the longitudinal study (n=45), the -8503 A and -1927 C alleles were associated with lower insulin sensitivity (p=0.03) and higher liver fat (p=0.02) at follow-up compared with the -8503 G and -1927 T alleles, independently of basal measurements, sex and baseline and follow-up percentage of body fat. CONCLUSIONS/INTERPRETATION: The present findings suggest that the -8503 G/A SNP in the promoter or the -1927 T/C SNP in intron 1 of ADIPOR1 may affect insulin sensitivity and liver fat in humans.

Adipose Tissue↗
PubMed2005

Adiponectin is functionally active in human islets but does not affect insulin secretory function or beta-cell lipoapoptosis.

CONTEXT: The adipokine adiponectin has insulin-sensitizing, antiatherogenic, and antiinflammatory properties. Mouse and human adiponectin receptor-1 and -2 have been cloned, both of which are expressed in various tissues and mediate effects of globular and full-length adiponectin. Whether adiponectin affects insulin secretion and beta-cell apoptosis and whether plasma adiponectin is associated with beta-cell function in humans is under investigation. DESIGN AND METHODS: In human islets from multiorgan donors, we investigated expression of adiponectin receptor-1 and -2. Furthermore, glucose-stimulated insulin secretion was determined by RIA. In addition, we investigated fatty acid-induced beta-cell apoptosis by terminal dUTP nick end labeling and flow-cytometric cell cycle analysis (sub-G1 formation). In humans in vivo, insulin secretory function was measured during hyperglycemic clamps in 65 normal glucose-tolerant subjects. We determined first and second phase of glucose-stimulated, glucagon-like peptide-1-stimulated, and arginine-stimulated insulin secretion. RESULTS: Adiponectin receptor-1 and -2 are expressed in human islets at the mRNA and protein level. Moreover, full-length adiponectin induces phosphorylation of acetyl coenzyme A carboxylase. However, adiponectin did not affect basal or glucose-stimulated insulin secretion or basal or fatty acid-induced beta-cell apoptosis. In vivo, fasting plasma adiponectin concentrations were not associated with glucose-stimulated first- and second-phase insulin secretion or with glucagon-like peptide-1- or arginine-stimulated insulin secretion (all P > 0.42). CONCLUSIONS: These data support a regulatory role of adiponectin in human islets; however, adiponectin does not seem to affect insulin secretion or basal/fatty acid-induced beta-cell apoptosis in humans.

Adiponectin↗
PubMed2005

Age and gender related effects on adipose tissue compartments of subjects with increased risk for type 2 diabetes: a whole body MRI/MRS study.

Quantitative measurement of adipose tissue (AT) compartments in the entire body and of lipids in muscle and liver cells by means of MRI and MRS. Assessment of age and gender related differences in AT compartments and determination of cross-correlations between AT compartments in a heterogeneous cohort at increased risk for metabolic diseases. One hundred and fifty healthy volunteers with increased risk to type 2 diabetes were examined. T1-weighted MRI was applied for whole-body adipose tissue quantification. Adipose tissue compartments were subdivided in lower extremities, trunk (abdominal subcutaneous (SCAT) and visceral (VAT) adipose tissue), and upper extremities. Intrahepatocellular lipids (IHCL) and intramyocellular lipids (IMCL) in tibialis anterior and soleus muscle were determined by volume selective MRS. Females are characterized by lower %VAT (2.8+/-1.3% vs. 4.6+/-1.4%, p<0.001) and higher %SCAT (14.7+/-3.9% vs. 9.3+/-2.9%, p<0.001). There is a strong correlation between %VAT and age (r=0.64/0.60 for females/males), whereas %SCAT remained virtually unchanged in males (r=-0.09) and was only slightly increaseding in females (r =0.30, p<0.01). For IHCL, age related differences were observed in females with significantly increased IHCL in the older women, but not in males. IMCL contents in both muscles were found almost independent of age in both, males and females. Furthermore, VAT and IHCL show significant correlations in both groups. Assessed age and gender related differences, especially the age related significant increase of VAT and IHCL, as well as cross-correlations between different lipid compartments might contribute to a better understanding of the lipid metabolism under normal and pathologic metabolic conditions in humans.

Adipose Tissue↗
PubMed2005

A novel functional polymorphism (-336A/G) in the promoter of the partitioning-defective protein-6alpha gene is associated with increased glucose tolerance and lower concentrations of serum non-esterified fatty acids.

AIMS/HYPOTHESIS: Partitioning-defective protein-6alpha (Par6alpha) has recently been demonstrated to negatively regulate insulin signalling in murine myoblasts. To address whether Par6alpha plays a role in human physiology, the present study investigated whether mutations exist in the Par6alpha gene and whether these mutations, if present, are associated with pre-diabetic phenotypes in non-diabetic subjects. METHODS: The complete gene (part of the promoter [2.1 kb], all exons/introns and the 3' untranslated region) encoding Par6alpha was analysed in 664 non-diabetic subjects. We investigated possible associations between single nucleotide polymorphisms and percentage of body fat, glucose tolerance (as determined by OGTT), serum NEFA concentrations and whole-body insulin sensitivity (estimated during the OGTT, and for a subgroup of 242 subjects determined by the euglycaemic-hyperinsulinaemic clamp). RESULTS: A rare A/G polymorphism was found 336-bp upstream of the translational start codon (allele frequency 0.03). The data for subjects homozygous and heterozygous for -336G (R/G, n=43) were combined and compared with those for subjects homozygous for -336A (A/A, n=621). Subjects with the R/G genotype had lower fasting (4.84+/-0.09 mmol/l, means+/-SEM, p=0.049) and 2-h (5.50+/-0.02 mmol/l, p=0.050) plasma glucose concentrations than subjects with the A/A genotype (5.02+/-0.02 and 5.94+/-0.06 mmol/l, respectively). Subjects with the R/G genotype also had lower fasting (448+/-31 micromol/l, p=0.018) and 2-h serum NEFA concentrations (61+/-7 micromol/l, p=0.015) than subjects with the A/A genotype (529+/-9 and 75+/-2 micromol/l, respectively), adjusted for age, sex and percentage of body fat. There were no differences in adiposity or whole-body insulin sensitivity between the two genotype groups (all p>0.36). A luciferase reporter gene assay revealed that the -336G promoter variant had a significantly lower (-22.8%, p=0.006) transcriptional activity in transfected C2C12 murine myoblasts than the -336A promoter variant. CONCLUSIONS/INTERPRETATION: A novel functional variant in the promoter of the Par6alpha gene is associated with reduced fasting glycaemia, increased glucose tolerance and reduced serum NEFA concentrations.

Adult↗
PubMed2005

Genetic determinants of insulin action in polycystic ovary syndrome.

INTRODUCTION: Insulin resistance is associated with both type 2 diabetes (T2 D) and polycystic ovary syndrome (PCOS). There is an association of T2 D with several polymorphisms in candidate genes related to insulin resistance. However, there is limited information about the association of these polymorphisms with PCOS. METHODS: 57 non-diabetic women with PCOS and a control group of 567 healthy non-diabetic women underwent an oral glucose tolerance test (OGTT). They were genotyped for the polymorphisms Gly972Arg in IRS-1, Gly1057Asp in IRS-2, SNP 43, 44, and 45 in CAPN10, Pro12Ala in PPAR(gamma)2, C-512 T in FOXC2, and T45 G in adiponectin. RESULTS: Women with PCOS had higher 2-h blood glucose levels (6.5 +/- 0.2 vs. 6.0 +/- 0.06 mmol/l, p = 0.03) compared to control women, higher fasting insulin (79 +/- 7 vs. 53 +/- 2 pmol/l, p = 0.02), and a lower insulin sensitivity estimated from the OGTT (12.4 +/- 1.1 vs. 19.1 +/- 0.5 U, p = 0.0001). More homozygous G allele carriers of the T45 G polymorphism in the adiponectin gene were found in women with PCOS compared to controls (13.2 % vs. 2.6 %, p = 0.008). In women with PCOS, G-allele carriers had lower fasting insulin levels than TT carriers (61 +/- 9 vs. 88 +/- 10, p = 0.02) in contrast to controls (p = 0.03 for interaction genotype x PCOS). The other polymorphisms were distributed equally among women with PCOS and controls (all p > 0.5). SUMMARY: We found a higher prevalence of the T45 G polymorphism in the adiponectin gene in women with PCOS compared to controls. This was not associated with a more insulin resistant phenotype in PCOS, however. Other frequent polymorphisms in genes related to insulin resistance and type 2 diabetes showed no association with PCOS.

Adiponectin↗
PubMed2005

Elevated serum GGT concentrations predict reduced insulin sensitivity and increased intrahepatic lipids.

Elevated serum gamma-glutamyltransferase (GGT) concentrations have been related to features of the metabolic syndrome as well as increased risk of cardiovascular and liver disease. More recently, elevated GGT levels were shown to predict development of type 2 diabetes in a longitudinal study from Korea. The aim of the present study was to test the hypothesis that serum GGT is associated with glucose tolerance, insulin sensitivity and beta-cell function in a healthy, non-diabetic Caucasian population from the Tübingen family study. Insulin sensitivity was estimated by oGTT (n = 850) or measured by hyperinsulinemic euglycemic clamp (n = 245), respectively. A subgroup (n = 70) underwent additional determination of intrahepatic lipid content using 1H magnetic resonance spectroscopy. Serum GGT was positively correlated with two-hour glucose during oGTT (r = 0.15, p < 0.0001) and negatively correlated with insulin sensitivity from oGTT (r = -0.31, p < 0.0001) and clamp (r = -0.27, p < 0.0001). The relationship between GGT and insulin sensitivity remained significant after adjusting for sex, age, BMI, and AST using multivariate regression analysis. Inclusion of serum triglyceride levels as a parameter of lipid metabolism kept the relationship significant in the oGTT group (p < 0.0001), but not in the smaller clamp group (p = 0.11). Additionally, serum GGT was positively correlated with hepatic lipid content (r = 0.49, p < 0.001) independent of sex, age, BMI, AST or serum triglycerides. There was no significant correlation between GGT and the index for beta-cell function after adjusting for age, sex, BMI and insulin sensitivity (p = 0.74). In conclusion, elevated serum GGT levels predict glucose intolerance probably via insulin resistance rather than beta-cell dysfunction. This may be primarily related to hepatic insulin resistance and increased intrahepatic lipids. The association observed between elevated hepatic lipids and reduced insulin sensitivity might explain the increased diabetes risk observed in subjects with elevated serum GGT concentrations. In the absence of overt liver disease, elevated serum GGT concentrations may point the clinician to incipient disturbances in the glucose metabolism.

Adolescent↗
PubMed2004

Serum adiponectin levels predict the effect of short-term dietary interventions on insulin sensitivity in humans.

AIMS/HYPOTHESIS: Fat-rich diets can acutely induce insulin resistance. Data from adiponectin knock-out mice suggest that this effect might be increased in the absence of adiponectin. In the present study we tested whether plasma adiponectin concentrations influence changes in insulin sensitivity induced by a short-term dietary intervention in humans. METHODS: We analysed data from 27 healthy, non-obese men with normal glucose tolerance. These men ate a diet high in fat and a diet high in carbohydrates for three days each. RESULTS: The high-fat diet induced a significant drop in insulin sensitivity (determined by euglycaemic-hyperinsulinaemic clamp) compared to baseline (0.100+/-0.009 vs 0.083+/-0.007 micro mol.kg(-1).min(-1).(pmol.l(-1)), p=0.01). The drop in insulin sensitivity was more pronounced in subjects with low serum adiponectin (0.094+/-0.011 vs 0.077+/-0.010 micro mol.kg(-1).min(-1).(pmol.l(-1)), p=0.02) than in subjects with high serum adiponectin (0.103+/-0.011 vs 0.090+/-0.040 micro mol.kg(-1).min(-1).(pmol.l(-1)), p=0.16). In the whole group the high-carbohydrate, low-fat diet did not cause an increase in insulin sensitivity (0.095+/-0.007 vs 0.102+/-0.009 micro mol.kg(-1).min(-1).(pmol.l(-1)), p=0.06). However, insulin sensitivity was significantly increased in the subgroup with low serum adiponectin levels (0.084+/-0.013 vs 0.099+/-0.018 micro mol.kg(-1).min(-1).(pmol.l(-1)), p=0.01). In an additional multivariate analysis post-intervention insulin sensitivity was predicted by pre-intervention insulin sensitivity ( p<0.001) and adiponectin concentrations ( p=0.001). CONCLUSIONS/INTERPRETATION: These data indicate that the reduction in insulin sensitivity achieved by a short-term high-fat diet is more pronounced in non-obese subjects with low serum adiponectin. Thus it is possible that the restriction of dietary fat and a diet high in carbohydrates might be particularly effective in subjects with low adiponectin such as obese or Type 2 diabetic individuals.

Adiponectin↗
PubMed2004

[Reduced insulin effect in subclinical fatty liver].

BACKGROUND AND OBJECTIVE: Steatosis of the liver is known to be associated with impaired insulin action and is considered to be a feature of the metabolic syndrome. In the present study we addressed the question whether liver fat content, as measured by proton MR spectroscopy ( (1)H MRS), in healthy subjects without clinical signs (hepatomegaly, elevation of transaminases) of relevant liver disease correlates with whole-body insulin sensitivity. METHODS: 21 (18 males and 3 females, age 35 +/- 11 years) non-diabetic subjects underwent the euglycemic-hyperinsulinemic clamp test for determination of whole body insulin action. Liver fat content was measured by means of proton MR spectroscopy ( (1)H MRS). Lipid content was calculated as percentage share of the lipid signal in relation to the entire signal of the spectrum (water and lipid signals). Clinically relevant steatosis of the liver was ruled out by standard magnetic resonance imaging (MRI). Subjects with a history of alcohol intake of more than 40 g/d were excluded from analysis. RESULTS: In a single correlation analysis percentage liver fat strongly correlated with insulin sensitivity index (ISI) (r = 0.7, p = 0.001). After adjusting for the effects of percentage body fat (PFAT) percentage liver fat remained an independent determinant of ISI (p = 0.01). CONCLUSION: Our results suggest that liver fat content is an important predictor of whole-body insulin sensitivity in healthy subjects. The correlation of liver fat content with insulin sensitivity was found in the absence of clinical steatosis and was independent of body fat content.

Adult↗
PubMed2004

[White blood cell count as a predictor of glucose tolerance and insulin sensitivity. The role of inflammation in the pathogenesis of type 2 diabetes mellitus].

BACKGROUND AND OBJECTIVE: Chronic subclinical activation of the immune system is probably involved in the pathogenesis of type 2 diabetes. In the present study we examined whether an association exists between a non-specific inflammatory marker such as white blood count (WBC) and factors relevant to the pathogenesis of type 2 diabetes. PATIENTS AND METHODS: The statistical association between WBC and glucose tolerance, insulin secretion and insulin sensitivity estimated in an oral glucose tolerance test (OGTT, n = 607) or measured during an euglycemic clamp (N = 280) was determined in non-diabetic individuals. RESULTS: WBC was positively correlated with body weight (r = 0.32, p < 0.001) and postprandial (2-hour) blood glucose during the OGTT (r = 0.22, p < 0.001) independent of sex, age and percentage body fat. WBC negatively correlated with insulin sensitivity both measured by the euglycemic clamp (r = -0.23, p < 0.001) and estimated from the OGTT (r = -0.34, p < 0.001). This relationship remained significant upon adjusting for sex, age and percentage body fat. No relationship between WBC and insulin secretion independent of percentage body fat and insulin sensitivity was found (p = 0.95). CONCLUSION: An increase in WBC is associated with deterioration of glucose tolerance. This is mostly explained by reduced insulin sensitivity. These results are compatible with the hypothesis that chronic subclinical inflammation is involved in the pathogenesis of type 2 diabetes.

Adolescent↗