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Biomedical subjects

A A Vaag

Publications and source records attributed to A A Vaag.

15 recordsLinked to original sources
PubMed2006

Decreased protein levels of key insulin signalling molecules in adipose tissue from young men with a low birthweight: potential link to increased risk of diabetes?

AIMS/HYPOTHESIS: Individuals with low birthweight are at increased risk of type 2 diabetes mellitus. However, the underlying molecular mechanisms are unknown. Previously we have shown that low birthweight is associated with changes in muscle insulin signalling proteins. Here we determined whether low birthweight is associated with changes in insulin signalling proteins in adipose tissue. METHODS: Men (age 23 years) with either a low (bottom 10th percentile) (n = 17) or a normal (50th-90th percentile) (n = 17) birthweight were recruited from the Danish Medical Birth Registry and subcutaneous adipose biopsies were taken. RESULTS: Between the two groups there was no difference in protein level of the insulin receptor, protein kinase C zeta, glycogen synthase kinase-3 (GSK3) alpha, GSK3 beta, protein kinase B alpha and beta, peroxisome proliferative activated receptor gamma coactivator 1 or Src-homology-2-containing protein. However, the levels of GLUT4 (also known as solute carrier family 2 [facilitated glucose transporter], member 4 [SLC2A4]) (52 +/- 10.9% reduction, p < 0.01), p85alpha subunit of phosphoinositide 3-kinase (PI3K) (45 +/- 9% reduction, p < 0.01), p110ss subunit of PI3K (48 +/- 17% reduction, p = 0.06) and IRS1 (59 +/- 24% reduction, p < 0.05) were reduced in men of low birthweight. CONCLUSIONS/INTERPRETATION: These findings show that low birthweight is associated with reduced levels of adipose insulin signalling proteins, thus providing a potential molecular framework to explain why people with low birthweight are at increased risk of developing type 2 diabetes. These differences precede the development of diabetes and thus may help predict disease risk.

Adipose Tissue↗
PubMed2006

Consequences of low birthweight on urinary excretion of DNA markers of oxidative stress in young men.

OBJECTIVE: Low birthweight (LBW) has been associated with an increased risk of development of type 2 diabetes in adult life. Both type 1 and type 2 diabetes mellitus are characterized by increased oxidative stress. The purpose of this study was to investigate whether young healthy adults born with LBW showed differences in oxidative stress under normal conditions and during the added challenge of a physiological Intralipid infusion. MATERIAL AND METHODS: Urinary excretion of DNA markers of oxidative stress were analyzed by LC-MS/MS in 19 men (aged 19 years) with LBW and in 19 age matched, normal birthweight (NBW) controls pre- and post a 3-fold increase of plasma free fatty acids. RESULTS: Mean excretion rates of 8-oxo-guanine (8oxoGua), 8-oxo-guanosine (8oxoGuo), 8-oxo-2'deoxyguanosine (8oxodG), and 1,N6-ethenodeoxyadenosine (epsilon dA) did not statistically differ between subjects with LBW and NBW (66.9 versus 73.9 nmol/15 h, 17.8 versus 18.5 nmol/15 h, 11.9 versus 14.4 nmol/15 h and 44.0 versus 43.2 pmol/15 h, respectively). Furthermore, Intralipid infusion did not affect excretion of DNA adducts in LBW or NBW subjects. Statistically significant correlations were found between body mass index and urinary excretion of 8oxoGua (r = 0.64, p = 0.003) and 8oxoGuo (r = 0.64, p = 0.003) in the LBW group only. CONCLUSIONS: These findings suggest that oxidative stress may be a consequence of diabetes and is not, or at least only partly, involved in the early pathogenesis of type 2 diabetes.

Adult↗
PubMed2005

Low birthweight is associated with specific changes in muscle insulin-signalling protein expression.

AIMS/HYPOTHESIS: People with low birthweight have an increased risk of developing type 2 diabetes mellitus in adulthood. The mechanistic basis of this phenomenon is not known. Here we investigate the effect of early growth restriction on the expression of insulin-signalling proteins in skeletal muscle in a human cohort and a rat model. METHODS: We recruited 20 young men with low birthweight (mean birthweight 2702+/-202 g) and 20 age-matched control subjects (mean birthweight 3801+/-99 g). Biopsies were obtained from the vastus lateralis muscle and protein expression of selected insulin-signalling proteins was determined. Rats used for this study were male offspring born to dams fed a standard (20%) protein diet or a low (8%) protein diet during pregnancy and lactation. Protein expression was determined in soleus muscle from adult offspring. RESULTS: Low-birthweight subjects showed reduced muscle expression of protein kinase C (PKC)zeta, p85alpha, p110beta and GLUT4. PKCzeta, GLUT4 and p85 were also reduced in the muscle of rats fed a low-protein diet. Other proteins studied were unchanged in low-birthweight humans and in rats fed a low-protein diet when compared with control groups. CONCLUSIONS/INTERPRETATION: We found decreased expression of specific insulin-signalling proteins in low-birthweight subjects compared to controls. These changes precede the onset of impaired glucose tolerance. The similarity of protein expression profile in the men with low birthweight compared to that of the offspring of rats fed a low-protein diet suggests that the rodent model is an accurate representation of the human situation. It also provides a potential mechanistic explanation as to why the fetal environment plays an important role in determining risk of developing type 2 diabetes.

Adult↗
PubMed2003

Normal insulin-stimulated endothelial function and impaired insulin-stimulated muscle glucose uptake in young adults with low birth weight.

Low birth weight has been linked to insulin resistance and cardiovascular disease. We hypothesized that insulin sensitivity of both muscle and vascular tissues were impaired in young men with low birth weight. Blood flow was measured by venous occlusion plethysmography during dose-response studies of acetylcholine and sodium nitroprusside in the forearm of fourteen 21-yr-old men with low birth weight and 16 controls of normal birth weight. Glucose uptake was measured during intraarterial insulin infusion. Dose-response studies were repeated during insulin infusion. The maximal blood flow during acetylcholine infusion was 14.1 +/- 2.7 and 14.4 +/- 2.1 [ml x (100 ml forearm)(-1) x min(-1)] in low and normal birth weight subjects, respectively. Insulin coinfusion increased acetylcholine-stimulated flow in both groups: 18.0 +/- 3.1 vs. 17.9 +/- 3.1 [ml x (100 ml forearm)(-1) x min(-1)], NS. Insulin infusion increased glucose uptake significantly in the normal birth weight group, compared with the low birth weight group: 0.40 +/- 0.09 to 1.00 +/- 0.16 vs. 0.44 +/- 0.09 to 0.59 +/- 0.1 [ micro mol glucose x (100 ml forearm)(-1) x min(-1)], P = 0.04. Young men with low birth weight have normal insulin-stimulated endothelial function and impaired insulin-stimulated forearm glucose uptake. Thus, endothelial dysfunction does not necessarily coexist with metabolic alterations in subjects with low birth weight.

Adipose Tissue↗
PubMed1998

[Is low birth weight a risk factor for development of non-insulin-dependent diabetes mellitus?].

Different lines of evidence indicate that low birth weight and insufficient intrauterine nutrition may represent significant risk factors for the development of late onset non-insulin dependent diabetes mellitus (NIDDM). The evidence includes epidemiological studies, animal studies and metabolic studies of non-diabetic subjects with low birth weight. Insufficient intrauterine nutrition may induce a variety of abnormalities of metabolism in different tissues including muscle, liver, pancreas and adipose tissue; which can all in turn be related to known defects of glucose metabolism involved in the development of hyperglycaemia in NIDDM. Future studies should address the important question as to which roles genetics versus intrauterine and postnatal factors play in the etiology of late onset NIDDM in the general population. This may have important implications for which initiatives that should be applied to prevent NIDDM.

Diabetes Mellitus, Type 2↗
PubMed1998

[Low birth weight is associated with non-insulin-dependent diabetes mellitus in discordant monozygotic and dizygotic twins].

Previous studies have demonstrated an association between low weight at birth and risk of later development of non-insulin dependent diabetes mellitus (NIDDM). It is unknown whether this association may be due to an impact of intrauterine malnutrition per se, or whether it may be due to a coincidence between the putative "NIDDM susceptibility genotype" and a genetically determined low weight at birth. We traced original midwife birthweight record determinations in a group of monozygotic (n = 14 pairs) and dizygotic (n = 14 pairs) twins who phenotypically appeared discordant for NIDDM at a mean age of 67 and 64 years respectively. Birthweights were lower in the NIDDM twins compared with both their identical and non-identical non-diabetic co-twins respectively (p < 0.02 both). Using a similar approach in twin pairs discordant for impaired glucose tolerance (IGT) per se, no significantly decreased birthweight was detected in the IGT twins compared with their non-diabetic co-twins. However, when a larger group of twins with different glucose tolerances were considered, birthweights were lower in twins with abnormal glucose tolerance including both NIDDM and IGT. Furthermore, the twins with the lowest birthweights among the two co-twins had the highest plasma glucose concentrations 120 min after the 75 g oral glucose load (n = 86 pairs, p = 0.02). The study supports the hypothesis that low birthweight and a non-genetically determined intrauterine component such af malnutrition may play a role for the development of NIDDM in twins.

Aged↗
PubMed1997

Low birth weight is associated with NIDDM in discordant monozygotic and dizygotic twin pairs.

Previous studies have demonstrated an association between low weight at birth and risk of later development of non-insulin-dependent diabetes mellitus (NIDDM). It is not known whether this association is due to an impact of intrauterine malnutrition per se, or whether it is due to a coincidence between the putative "NIDDM susceptibility genotype" and a genetically determined low weight at birth. It is also unclear whether differences in gestational age, maternal height, birth order and/or sex could explain the association. Twins are born of the same mother and have similar gestational ages. Furthermore, monozygotic (MZ) twins have identical genotypes. Original midwife birth weight record determinations were traced in MZ and dizygotic (DZ) twins discordant for NIDDM. Birth weights were lower in the NIDDM twins (n = 2 x 14) compared with both their identical (MZ; n = 14) and non-identical (DZ; n = 14) non-diabetic co-twins, respectively (MZ: mean +/- SEM 2634 +/- 135 vs 2829 +/- 131 g, p < 0.02; DZ: 2509 +/- 135 vs 2854 +/- 168 g, p < 0.02). Using a similar approach in 39 MZ and DZ twin pairs discordant for impaired glucose tolerance (IGT), no significantly lower birth weights were detected in the IGT twins compared with their normal glucose tolerant co-twins. However, when a larger group of twins with different glucose tolerance were considered, birth weights were lower in the twins with abnormal glucose tolerance (NIDDM + IGT; n = 106; 2622 +/- 45 g) and IGT (n = 62: 2613 +/- 55 g) compared with twins with normal glucose tolerance (n = 112: 2800 +/- 51 g; p = 0.01 and p = 0.03, respectively). Furthermore, the twins with the lowest birth weights among the two co-twins had the highest plasma glucose concentrations 120 min after the 75-g oral glucose load (n = 86 pairs: 9.6 +/- 0.6 vs 8.0 +/- 0.4 mmol/l, p = 0.03). In conclusion, the association between low birth weight and NIDDM in twins is at least partly independent of genotype and may be due to intrauterine malnutrition. IGT was also associated with low birth weight in twins. However, the possibility cannot be excluded that the association between low birth weight and IGT could be due to a coincidence with a certain genotype causing both low birth weight and IGT in some subjects.

Aged↗
PubMed1996

Gut incretin hormones in identical twins discordant for non-insulin-dependent diabetes mellitus (NIDDM)--evidence for decreased glucagon-like peptide 1 secretion during oral glucose ingestion in NIDDM twins.

The incremental glucagon-like peptide 1 (GLP-1) and gastric inhibitory polypeptide (GIP) responses (areas under curves; AUCs) were determined during a standard 180-min 75-g oral glucose tolerance test in a group of 12 identical twin pairs discordant for non-insulin-dependent diabetes mellitus (NIDDM) and 13 matched controls without family history of diabetes using highly sensitive and specific radioimmunoassay hormone assays. Data were analysed using multifactor analysis of variance (ANOVA) to identify and correct for possible covariates and to correct for multiple comparisons. Fasting plasma GLP-1 and GIP concentrations were similar in all groups. The twins with frank NIDDM had a decreased incremental GLP-1 response during oral glucose ingestion compared with controls without family history of diabetes (AUC +/- SEM: 0.55 +/- 0.14 vs 1.17 +/- 0.25 (mmol/l) x min, p < 0.05). The incremental GLP-1 secretion in the non-diabetic twins was not significantly different from neither their NIDDM co-twins nor the controls without family history of diabetes. The incremental GIP responses were similar in all study groups. Gender was identified as the major independent covariate for incremental glucose, insulin, GIP and GLP-1 responses, with higher values of all parameters in females. Waist-to-hip ratio and body mass index (BMI) were identified as independent but oppositely directed covariates for the incremental GLP-1 responses (waist-to-hip ratio: r = 0.43, p < 0.02; BMI: r = -0.34, p = 0.06). Incremental GLP-1 responses correlated with incremental insulin responses in the combined study population (N = 37; R = 0.42, p = 0.01). In conclusion, a decreased intestinal GLP-1 secretion may contribute to the abnormal insulin secretion during oral glucose ingestion in NIDDM twins. However, decreased secretion of gut incretin hormones (GLP-1 or GIP) does not explain all of the defects of pancreatic insulin secretion in NIDDM patients/twins or in non-diabetic individuals (identical twins) with a genetic predisposition to NIDDM.

Administration, Oral↗
PubMed1994

[Injection site for quick-acting insulin. Significance for glycemic control in basal bolus insulin regimen].

The impact on glycaemic control of soluble insulin injected either intramuscularly into the thigh (IMT), subcutaneously into the abdominal wall (SCA) or subcutaneously into the thigh (SCT) was evaluated in 49 Type 1 diabetic outpatients following a randomised three-month intervention study. Insulin doses were adjusted based on patients' self-monitored blood glucose values and reported hypoglycaemic episodes. More patients in the SCA and IMT groups than in the SCT group had serum fructosamine values within normal limits following intervention. Blood glucose at 03.00 was lower in the SCT group than in the SCA and IMT groups, due to a higher number of low nocturnal blood glucose values (less than 4 mmol/l) in the SCT group. In conclusion, s.c. injection of soluble insulin into the abdominal wall or intramuscularly into the thigh is preferable compared to s.c. injection into the thigh in the basal bolus insulin delivery regimen. Soluble insulin injection s.c. into the thigh during daytime is a risk factor for nocturnal hypoglycaemia.

Abdominal Muscles↗
PubMed1994

Glucose-fatty acid cycle operates in humans at the levels of both whole body and skeletal muscle during low and high physiological plasma insulin concentrations.

Plasma non-esterified fatty acid concentrations were elevated acutely (Intralipid+heparin infusion) in 14 normal humans in order to study the effects of fatty acids on whole-body basal and insulin-stimulated glucose metabolism, and on activities of skeletal muscle key enzymes. Whole-body glucose metabolism was assessed using [3-3H]glucose and indirect calorimetry. Biopsies were taken from the vastus lateralis muscle during basal and insulin-stimulated (3 h, 40 mU.m-2.min-1) steady-state periods. Total peripheral glucose uptake was unaffected by Intralipid infusion in the basal state, whereas it decreased during Intralipid infusion in the hyperinsulinemic state (10.7 +/- 0.7 vs 8.7 +/- 0.8 mg.kg-1 fat-free mass.min-1, p < 0.02). Intralipid infusion decreased whole-body glucose oxidation in the basal state (1.3 +/- 0.2 vs 0.8 +/- 0.1 mg.kg-1 fat-free mass.min-1, p < 0.001) and during hyperinsulinemia (3.6 +/- 0.2 vs 1.7 +/- 0.2 mg.kg-1 fat-free mass.min-1 p < 0.001). Whole-body nonoxidative glucose uptake increased during Intralipid infusion in the basal state and was unaffected in the hyperinsulinemic state. The skeletal muscle pyruvate dehydrogenase activity ratio decreased in the basal state during Intralipid infusion (55 +/- 6 vs 43 +/- 5%, p < 0.05), whereas no statistical significant decrease in the pyruvate dehydrogenase activity ratio was observed during insulin infusion (57 +/- 8 vs 47 +/- 5%, NS). Insulin increased the activity of the active form of pyruvate dehydrogenase on the control day, but not during Intralipid infusion. Activities of phosphofructokinase and glycogen synthase were unaffected by Intralipid infusion. Plasma glucose concentrations were similar during Intralipid infusion and on the control day, whereas Intralipid infusion increased the muscle glucose content in the basal state (1.36 +/- 0.09 vs 1.77 +/- 0.12 mmol/kg dry wt, p < 0.05) and in the hyperinsulinemic state (1.23 +/- 0.09 vs 1.82 +/- 0.16 mmol/kg dry wt, p < 0.05). Insulin increased the muscle lactate content on the control day (6.50 +/- 0.95 vs 8.65 +/- 0.77 mmol/kg dry wt, p < 0.05), but not during Intralipid infusion. In conclusion, the glucose-fatty acid cycle operates in humans in vivo at the levels of both whole body and skeletal muscle during both low and high physiological insulin concentrations.

Adult↗
PubMed1993

Local skin-fold thickness as a clinical predictor of depot size during basal rate infusion of insulin.

OBJECTIVE: To determine the influence of local adiposity on insulin depot size during CSII at basal rate. RESEARCH DESIGN AND METHODS: In 27 diabetic patients, a constant infusion of 125I-labeled Actrapid insulin was given, with U-40 insulin at a rate of 1.12 IU/h in 20 patients, and U-100 at a rate of 1 IU/h in 7 patients. After 16 h of infusion, the steady-state depot size was measured by external counting, and the local skin fold was measured with a Harpenden skin-fold caliper. RESULTS: U-40 insulin infusion resulted in a steady-state depot size of 5.1 U (2.1-10.9 U), and a corresponding skin-fold thickness of 17.8 mm (5-34 mm). A positive correlation was found between depot size and skin-fold thickness. A similar correlation was observed with U-100 insulin. CONCLUSIONS: During basal rate CSII, large variations in local skin-fold thickness create large variations in the steady-state depot size, which is partly predictable just by lifting the skin fold.

Adipose Tissue↗
PubMed1992

Effects of prolonged Acipimox treatment on glucose and lipid metabolism and on in vivo insulin sensitivity in patients with non-insulin dependent diabetes mellitus.

The effect of prolonged treatment with Acipimox on in vivo peripheral insulin sensitivity, and on glucose and lipid metabolism, was investigated in patients with NIDDM in a double-blind study. Twelve NIDDM patients were randomized to treatment with either placebo or Acipimox in pharmacological doses (250 mg x 3) for three months. Fasting plasma glucose, insulin, C-peptide and HbA1c concentrations were unaffected after three months of acipimox treatment. However, fasting plasma non-esterified fatty acid (NEFA) concentrations were twofold elevated after Acipimox treatment (1.34 +/- 0.09 vs 0.66 +/- 0.09 mmol/l; p < 0.05). Despite this, repeated acute Acipimox administration after the three months' treatment period enhanced total insulin-stimulated glucose disposal to the same extent as acute Acipimox administration before the treatment period (367 +/- 59 vs 392 +/- 66 mg.m-2.min-1, NS; both p < 0.05 vs placebo glucose disposal) (267 +/- 44 mg.m-2.min-1). In conclusion, insulin resistance or tachyphylaxis towards the effects of Acipimox on insulin stimulated glucose disposal was not induced during prolonged Acipimox treatment. The lack of improvement of blood glucose control in the patients with NIDDM may be due to the demonstrated rebound effect of lipolysis.

Diabetes Mellitus, Type 2↗