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Biomedical subjects

A Handberg

Publications and source records attributed to A Handberg.

At least 19 recordsLinked to original sources
PubMed1999

Intracellular skeletal muscle glucose metabolism is differentially altered by dexamethasone treatment of normoglycemic relatives of type 2 diabetic patients.

Young first-degree relatives of type 2 diabetic patients are insulin-resistant, with the insulin resistance mainly located in skeletal muscle due to decreased insulin-induced nonoxidative glucose metabolism and muscle glycogen synthase activation. We investigated whether the mechanism differs for dexamethasone (dex)-induced insulin resistance in first-degree relatives of type 2 diabetics versus healthy control subjects by quantifying intracellular glucose processing in muscle biopsies taken before and after 5 days of dex treatment (4 mg/d) in 20 normal glucose-tolerant relatives of type 2 diabetic patients and 20 matched controls (age, 29.4 +/- 1.7 v 29.4 +/- 1.6 years; body mass index, 25.1 +/- 1.0 v 25.1 +/- 0.9 kg/m2). In addition, an intravenous glucose tolerance test (IVGTT) combined with continuous indirect calorimetry was performed. Following 5 days of dex treatment, glucose tolerance deteriorated in both the relatives and the control subjects. Fasting dry-weight muscle glucose and fasting intracellular muscle glucose concentrations increased in response to dex only in the relatives (2.43 +/- 0.21 v 2.97 +/- 0.26 mmol/kg dry weight, P < .05; 0.28 +/- 0.07 v 0.45 +/- 0.08 mmol/L intracellular water, P < .05); no increases were observed in the control subjects. Fasting dry-weight muscle lactate also increased post-dex only in the relatives (7.37 +/- 0.40 v 10.77 +/- 1.22 mmol/kg dry weight, P < .001). Both basal muscle glucose and lactate concentrations from the IVGTT study correlated with the 2-hour post-dex glucose value obtained during the OGTT study in the relatives (R = .76 and R = .74, respectively, both P < .0001) but not in the control subjects. Basal intramuscular glycogen synthase activity decreased approximately 25% in both the relatives and control subjects post-dex; the decrement was significant (P < .01) only in control subjects. Indirect calorimetry during the post-dex IVGTT demonstrated increased glucose oxidation (P < .03) and reduced lipid oxidation (P < .03) in the relatives only. We postulate that the insulin resistance induced by dex in first-degree relatives of type 2 diabetic patients is associated with a preferential channeling of glucose into the glycolytic pathway (increased glucose oxidation and lactate production), probably associated with a preexisting downregulation of the glycosen synthase pathway.

Adult↗
PubMed1998

Diurnal variation of the serum leptin concentration in patients with anorexia nervosa.

OBJECTIVE: In rodents, leptin is involved in regulating eating behaviour, fat storage, and reproductive function. In humans, the serum leptin concentration in obese and normal weight subjects correlates with body mass index, reflecting the body fat store. The serum leptin exhibit diurnal variation, however, this has been reported to be absent in normal weighted amenorrheic athletes. Anorexia nervosa is associated with multiple endocrine abnormalities. Hypothalamic amenorrhoea often precedes the weight loss and may persist after weight recovery. We hypothesized that leptin could be involved in the regulation of eating behaviour and gonadal function in anorexia nervosa. DESIGN: We measured the concentration of leptin in serum samples taken after an overnight fast in 18 female anorexia nervosa patients and 11 controls. To study diurnal variation, eight patients and 11 controls were hospitalized for 24 h and had a standardized diet at regular times. Seven blood samples were obtained at 4 h intervals from each subject. PATIENTS: The patients fulfilled the DSM-IV criteria for anorexia nervosa. The mean body mass index for the patients was 14.2 +/- 2.3 kg/m2 and for controls 20.3 +/- 1.7 kg/m2. RESULTS: The mean fasting leptin concentration as well as the 24 h mean concentration were significantly lower in the anorectic group than in the control group (2.5 +/- 0.9 vs 10.1 +/- 6.1 micrograms/l, P < 0.01 and 2.7 +/- 1.5 vs 10.6 +/- 7.1 micrograms/l, P < 0.01 respectively). In the whole group of subjects (n = 28) a significant positive correlation between the leptin level and body mass index was found (r = 0.63, P < 0.001). In the anorectic group it was found that the leptin level correlated better with body fat percentage than with body mass index. In normalized data the time course of the mean leptin levels showed a monophasic variation with nadir and zenith at about 0900 and 0100 h respectively. However, the individual coefficients of variance were significantly lower in the anorectic group compared to the group of healthy women. CONCLUSION: In patients with anorexia nervosa the leptin level is low, reflecting the low body fat mass, and the relative diurnal variation is strikingly reduced. The similarity to that of normal weighted women with hypothalamic amenorrhoea suggest that altered leptin oscillations may be of particular significance in the hypothalamic regulation of reproductive function.

Adolescent↗
PubMed1997

Eccentric contractions decrease glucose transporter transcription rate, mRNA, and protein in skeletal muscle.

We have recently shown that eccentric contractions (ECs; forced lengthening of active muscle) elicit a delayed decrease in glucose transporter (GLUT-4) protein content in rat skeletal muscle and a decrease in subsequent contraction-stimulated glucose transport. Here, we investigate whether this decrease in total GLUT-4 protein after prior ECs is due to changes in GLUT-4 gene transcription rate and GLUT-4 mRNA level. Furthermore, the effect of prior ECs on sarcolemmal GLUT-4 protein content in plasma membrane (PM) vesicles isolated from contraction-stimulated muscle was determined. Rat gastrocnemius muscle was electrically stimulated for ECs, and the contralateral muscle served, as unstimulated control (UC). Two days later, the total GLUT-4 protein content was decreased by 50% (P < 0.05) and 32% (P < 0.05) in the white and red gastrocnemius muscle, respectively. Furthermore, the GLUT-4 mRNA concentration was decreased by 41% (P < 0.05) in both the white and red gastrocnemius muscle. Moreover, the GLUT-4 transcription rate, determined by nuclear run-on analysis, was decreased by 75% (P < 0.05) in mixed EC gastrocnemius muscle compared with UC muscle. PM vesicles were isolated from EC and UC muscle after 15 min of isometric contractions. The PM GLUT-4 protein content was reduced by 51% (P < 0.05) in EC muscle compared with UC muscle. In conclusion, 2 days after ECs, the GLUT-4 transcription rate, GLUT-4 mRNA, and GLUT-4 protein content were decreased in rat skeletal muscle. Moreover, the PM GLUT-4 protein content in contraction-stimulated muscle was decreased. We suggest that eccentric muscle contractions decrease muscle GLUT-4 transcription rate, resulting in a lower GLUT-4 protein content, which in turn decreases the number of GLUT-4 transporters translocated to the sarcolemma, ultimately leading to decreased contraction-induced muscle glucose transport.

Animals↗
PubMed1996

Decreased skeletal muscle phosphotyrosine phosphatase (PTPase) activity towards insulin receptors in insulin-resistant Zucker rats measured by delayed Europium fluorescence.

In order to measure the phosphotyrosine phosphatase (PTPase) activity in small muscle biopsies, a sandwich-immunofluorescence assay was developed using the phosphorylated human insulin receptor as a substrate, a C-terminal insulin receptor antibody as catching antibody and Europium-labelled anti-phosphotyrosine as detecting antibody. Soluble and particulate muscle fractions were prepared from soleus muscle of obese, diabetic (fa/fa) Zucker rats and their lean littermates (Fa/-). In the soluble muscle fractions of the obese (fa/fa) rats PTPase activity was significantly reduced compared to control (Fa/-) rats (45.2 +/- 2.6% vs 61.3 +/- 4.7%, p < 0.02). This reduction was completely prevented by 24 days of metformin treatment which decreased plasma glucose and plasma insulin levels. In particulate muscle fractions, however, no difference in PTPase activity was found among any groups of rats examined. These results show that the alterations in soluble PTPase activity in the insulin-resistant, diabetic Zucker rat vary with the abnormality in glucose homeostasis.

Adenosine Triphosphate↗
PubMed1996

C-peptide stimulates glucose transport in isolated human skeletal muscle independent of insulin receptor and tyrosine kinase activation.

We have previously demonstrated that C-peptide stimulates glucose transport in skeletal muscle from non-diabetic subjects in a dose-dependent manner. To further elucidate the mechanism by which C-peptide activates glucose transport, we investigated the influence of human recombinant C-peptide on receptor and post-receptor events involved in the glucose transport process. Human skeletal muscle specimens were obtained from the vastus lateralis by means of an open biopsy procedure. Stimulation of isolated muscle strips from healthy control subjects with supra-physiological concentrations of insulin (6,000 pmol/l) and C-peptide (2,500 pmol/l), did not further augment the twofold increase in the rate of 3-o-methylglucose transport induced by either stimulus alone. C-peptide did not displace 125I-insulin binding from partially purified receptors, nor did it activate receptor tyrosine kinase activity. Tyrosine-labelled 125I-C-peptide did not bind specifically to crude membranes prepared from skeletal muscle, or to any serum protein other than albumin. The beta-adrenergic receptor stimulation with isoproterenol inhibited insulin- but not C-peptide-mediated 3-o-methylglucose transport by 63 +/- 18% (p < 0.01), whereas the cyclic AMP analogue, Bt2cAMP, abolished the insulin- and C-peptide-stimulated 3-o-methylglucose transport. C-peptide (600 pmol/l) increased 3-o-methylglucose transport 1.8 +/- 0.2-fold in skeletal muscle specimens from patients with insulin-dependent diabetes mellitus. In conclusion, C-peptide stimulates glucose transport by a mechanism independent of insulin receptor and tyrosine kinase activation. In contrast to the effect on insulin-stimulated glucose transport, catecholamines do not appear to have a counter regulatory action on C-peptide-mediated glucose transport.

3-O-Methylglucose↗
PubMed1996

Altered basal and insulin-stimulated phosphotyrosine phosphatase (PTPase) activity in skeletal muscle from NIDDM patients compared with control subjects.

To measure possible changes in basal and insulin-stimulated phosphotyrosine phosphatase (PTPase) activity in skeletal muscle from insulin-resistant individuals, soluble and particulate muscle fractions were prepared from biopsies taken before and after a 3-h hyperinsulinaemic euglycaemic clamp in eight non-insulin-dependent diabetic (NIDDM) patients and nine control subjects. We used a sensitive sandwich-immunofluorescence assay and the human insulin receptor as the substrate. PTPase activity was expressed as percentage of dephosphorylation of phosphotyrosyl-residues in immobilized insulin receptors per 2 h incubation time per 83 micrograms and 19 micrograms muscle fraction protein (soluble and particulate fraction, respectively). In the diabetic soluble muscle fractions, the basal PTPase activity was decreased compared with that of control subjects (11.5 +/- 5.5 vs 27.5 +/- 3.3, p < 0.04, mean +/- SEM). In the particulate muscle fractions from the control subjects, PTPase activity was increased after 3 h hyperinsulinaemia (20.0 +/- 3.2 vs 30.2 +/- 3.6, p < 0.03) and in the corresponding soluble fractions PTPase activity seemed decreased (27.5 +/- 3.3 vs 19.9 +/- 5.9, NS). No effect of insulin on PTPase activity was found in NIDDM patients (25.1 +/- 4.1 vs 27.2 +/- 5.2, 11.5 +/- 5.5 vs 15.1 +/- 4.5 [particulate and soluble fractions], NS). In conclusion, we found that the basal PTPase activity in soluble muscle fractions was decreased in NIDDM patients; furthermore, insulin stimulation was unable to increase PTPase activities in the particulate fractions, as opposed to the effect of insulin in control subjects.

Biopsy↗
PubMed1996

Glucose processing during the intravenous glucose tolerance test.

The impact of the dynamic changes in plasma glucose and insulin levels observed during a frequently sampled intravenous (IV) glucose tolerance test (FSIGT) on whole-body glucose processing and muscle glycogen metabolism is not known. Paired randomized FSIGTs were performed in eight healthy subjects (age, 31 years; range, 28 to 35; BMI, 25.4 kg/m2; range, 22.3 to 32.1), one with muscle biopsy samples and one without. The mean time average (0- to 40- and 0- to 120-minute) insulin levels during the test were 26.6 and 11.4 mU/1, respectively. Glucose oxidation increased following the IV glucose bolus (basal 1.34 +/- 0.21 v mean value at 0 to 120 minutes 2.09 +/- 0.22 mg/kg fat-free mass [FFM]/min, P < .02). In contrast, fractional glucose-6-phosphate [G-6-P]) (0.1/10 mmol/L) skeletal muscle glycogen synthase activity in muscle biopsies obtained before and following the IV glucose bolus (-30, 30,60, and 120 minutes, respectively) were unchanged (38.1% +/- 2.3%, 38.3% +/- 2.9%, 38.1% +/- 2.3%, 35.4% +/- 2.3%, NS). Skeletal muscle glycogen concentration decreased slightly (449 +/- 54, 439 +/- 55, and 383 +/- 29, and 438 +/- 48 mmol/kg dry weight, P =.05), indicating no net storage of glucose into glycogen during the FSIGT. G-6-P decreased (0.77 +/- 0.08, 0.64 +/- 0.07, 0.66 +/- 0.07, and 0.54 +/- 0.04 mmol/kg dry weight, P < .05). Levels of the insulin-regulatable glucose transporter, GLUT-4, were unchanged. Insulin sensitivity (Si), glucose effectiveness, and insulin secretion parameters (01 and 02) were not affected by the muscle biopsy procedure. In conclusion, the FSIGT is associated predominantly with increased whole-body glucose oxidation with no apparent activation of muscle glucose storage as glycogen. Thus, the Si measured by the FSIGT, although similar in magnitude to the clamp-derived parameter, represents primarily glucose oxidation, in contrast to the euglycemic clamp, which involves glucose oxidation and storage.

Adult↗
PubMed1996

Reciprocal GLUT-1 and GLUT-4 expression and glucose transport in denervated muscles.

We investigated in 3-day-denervated muscles 1) the expression of GLUT-1 in perineurial sheaths (PNS) and muscle, 2) the muscle fiber-specific changes in GLUT-1 and GLUT-4, and 3) changes in basal and insulin-stimulated 3-O-methylglucose transport. GLUT-1 was increased in both the PNS (P < 0.05) and in the muscle membranes (P < 0.05). GLUT-1 and GLUT-4 concentrations were changed reciprocally, in a fiber-dependent fashion [GLUT-1: red gastrocnemius (RG), +31%; white gastrocnemius (WG), +10%; GLUT-4: RG, -53%; WG, -16%]. Basal glucose transport was increased (P < 0.05), and this increase was correlated with the oxidative nature of the muscles (r = 0.97). Insulin-stimulated glucose transport was decreased in denervated muscles (P < 0.05). This was also related to the oxidative nature of the muscles (r = -0.88). The increase in basal glucose transport was correlated with the loss of insulin-stimulated transport (r = 0.95). Thus the increase in GLUT-1 compensates for the loss of GLUT-4, resulting in a 56% regain of the reduced insulin-stimulated glucose transport.

3-O-Methylglucose↗
PubMed1995

Effect of immobilization on glucose transport and glucose transporter expression in rat skeletal muscle.

The effect of 42-48 h of immobilization by casting on maximal velocity of 3-O-methylglucose (3-MG) transport in skeletal muscle was studied in the perfused rat hindquarter. Immobilization resulted in a decrease of approximately 42% for maximum insulin-stimulated 3-MG transport in fast-twitch red fibers and a decrease of approximately 42% for contraction-stimulated transport in slow-twitch red fibers compared with nonimmobilized control muscle. No effect of immobilization on 3-MG transport was found in fast-twitch white muscle. Combination of insulin and muscle contractions always resulted in glucose transport that was identical in immobilized and control muscle. Western blot did not detect a decrease in GLUT-1 or GLUT-4 protein with immobilization. Furthermore, in fast-twitch red fibers, insulin receptor number and receptor kinase activity did not differ between immobilized and control muscle. It is concluded that during short-term immobilization a resistance of muscle glucose transport to stimulation develops that is fiber type specific and selective for insulin or contractions. The resistance can be overcome by the combined action of insulin and contractions and reflect factors other than glucose transporter number and insulin receptor binding and receptor kinase activity.

3-O-Methylglucose↗
PubMed1995

Stability of GLUT-1 and GLUT-4 expression in perfused rat muscle stimulated by insulin and exercise.

In vivo exercise and insulin may change the concentrations of GLUT-4 protein and mRNA in muscle. We studied in vitro whether adaptations in glucose transporter expression are initiated during a single prolonged period of contractions or during insulin stimulation. Rat hindquarters were perfused at 7 mM glucose for 2 h with or without insulin (> 20,000 microU/ml) while the sciatic nerve of one leg was stimulated to produce repeated tetanic contractions. During electrical stimulation, contraction force decreased 93 +/- 1% (SE; n = 26) and muscle glycogen was markedly diminished (P < 0.05). Both contractions and insulin markedly increased glucose transport and uptake (P < 0.05). At the end of contractions, glycogen was higher in the presence of than in the absence of insulin (24 +/- 4 vs. 14 +/- 3 mumol/g for the soleus and 13 +/- 2 vs. 8 +/- 1 mumol/g for the red gastrocnemius, respectively; P < 0.05). In nonstimulated muscle, glucose transporter mRNA and protein concentrations were higher in the soleus than in the white gastrocnemius (GLUT-4 mRNA 184 +/- 18 vs. 131 +/- 36 arbitrary units; GLUT-1 mRNA 173 +/- 29 vs. 114 +/- 26 arbitrary units; GLUT-4 protein 0.96 +/- 0.09 vs. 0.46 +/- 0.03 arbitrary units; GLUT-1 protein 0.41 +/- 0.08 vs. 0.19 +/- 0.05 arbitrary units, respectively; P < 0.05). These concentrations were not changed by contractions or insulin. In conclusion, GLUT-1 and GLUT-4 mRNA and protein levels are higher in slow-twitch oxidative than in fast-twitch glycolytic fibers.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

Quantity of Na/K-ATPase and glucose transporters in the plasma membrane of rat adipocytes is reduced by in vivo triiodothyronine.

The expression of sodium-potassium pumps and glucose transporters in pure adipocyte plasma membranes from a hyperthyroid animal model was studied. Hyperthyroidism was induced by enteral administration of five doses of 90 micrograms of triiodothyronine every second day to 8-week-old rats. Following isolation of epididymal adipocytes, 3-O-methylglucose transport was measured and the number of Na/K-ATPase-(alpha 1- and alpha 2-isoforms) and glucose transporter (GLUT1 and GLUT4) molecules in sheets of adipocyte plasma membrane were determined by quantitative immunoelectron microscopy, using gold labelling. Maximal in vitro insulin stimulation of adipocytes increased the glucose transport rate and the amount of GLUT4 in the plasma membrane 15-fold, whereas the amount of alpha 2 was unaffected. In adipocytes from hyperthyroid rats, mean adipocyte volume was decreased by 18% and the quantities of GLUT4 per unit area of plasma membrane (maximal insulin stimulation) and of alpha 2 were decreased by 19% and 15%, respectively. Thus, hypotrophia of fat tissue in the hyperthyroid state is associated with a decreased expression in the plasma membrane of the glucose transporter GLUT4 and the alpha 2-isoform of Na/K-ATPase.

3-O-Methylglucose↗
PubMed1994

Elevated GLUT 1 level in crude muscle membranes from diabetic Zucker rats despite a normal GLUT 1 level in perineurial sheaths.

Recently, we demonstrated that approximately 60% of GLUT 1 in a crude membrane fraction of rat skeletal muscle originates from perineurial sheaths. To study the in vivo regulation of GLUT 1 expression in different tissues in muscles, we measured the level of GLUT 1 in crude muscle membranes and in perineurial sheaths in diabetic (fa/fa) Zucker rats and lean controls, with and without metformin treatment. The GLUT 1 concentration in perineurial sheaths was identical in all four groups of rats, both when measured by quantitative immunofluorescence and by immunoblotting and densitometry. In a fraction of crude membranes of soleus muscles GLUT 1 expression was more than two-fold higher in (fa/fa) rats than in lean controls (p < 0.005). Metformin treatment significantly elevated GLUT 1 in control rats (p < 0.05) and tended to decrease GLUT 1 in diabetic rats (p < 0.075). The expressions of GLUT 1 and GLUT 4 in crude muscle membranes were inversely correlated (p < 0.01), and GLUT 1 expression correlated positively with fasting glucose (p < 0.05). In conclusion, GLUT 1 expression in perineurial sheaths is unaffected by alterations in glucose homeostasis and by the genes responsible for obesity and diabetes in the Zucker rat. GLUT 1 expression in a crude membrane fraction of soleus muscle is increased in the diabetic animals, likely due to an increased expression in muscle cells proper.

Animals↗
PubMed1994

Increased glucose effectiveness in normoglycemic but insulin-resistant relatives of patients with non-insulin-dependent diabetes mellitus. A novel compensatory mechanism.

20 normoglycemic first degree relatives of non-insulin-dependent diabetes mellitus (NIDDM) patients were compared with 20 matched subjects without any family history of diabetes using the intravenous glucose tolerance test with minimal model analysis of glucose disappearance and insulin kinetics. Intravenous glucose tolerance index (Kg) was similar in both groups (1.60 +/- 0.14 vs 1.59 +/- 0.18, x 10(-2) min-1, NS). However, insulin sensitivity (Si) was reduced (3.49 +/- 0.43 vs 4.80 +/- 0.61, x 10(-4) min-1 per mU/liter, P = 0.05), whereas glucose effectiveness (Sg) was increased (1.93 +/- 0.14 vs 1.52 +/- 0.16, x 10(-2) min-1, P < 0.05) in the relatives. Despite insulin resistance neither fasting plasma insulin concentration (7.63 +/- 0.48 vs 6.88 +/- 0.45, mU/liter, NS) nor first phase insulin responsiveness (Phi1) (3.56 +/- 0.53 vs 4.13 +/- 0.62, mU/liter min-1 per mg/dl, NS) were increased in the relatives. Phi1 was reduced for the degree of insulin resistance in the relatives so that the Phi1 x Si index was lower in the relatives (11.5 +/- 2.2 vs 16.7 +/- 2.0, x 10(-4) min-2 per mg/dl, P < 0.05). Importantly, glucose effectiveness correlated with Kg and with basal glucose oxidation but not with total glucose transporter 4 (GLUT4) content in a basal muscle biopsy. In conclusion we confirm the presence of insulin resistance in first degree relatives of NIDDM patients. However, insulin secretion was altered and reduced for the degree of insulin resistance in the relatives, whereas glucose effectiveness was increased. We hypothesize that increased glucose effectiveness maintains glucose tolerance within normal limits in these "normoinsulinemic" relatives of NIDDM patients.

Adult↗
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↗
PubMed1994

Physical training increases muscle GLUT4 protein and mRNA in patients with NIDDM.

Patients with non-insulin-dependent diabetes mellitus (NIDDM) exhibit insulin resistance and decreased glucose transport in skeletal muscle. Total content of muscle GLUT4 protein is not affected by NIDDM, whereas GLUT4 mRNA content is reported, variously, to be unaffected or increased. Physical training is recommended in the treatment of NIDDM, but the effect of training on muscle GLUT4 protein and mRNA content is unknown. To clarify the effect of training in NIDDM, seven men with NIDDM (58 +/- 2 years of age [mean +/- SE]) and eight healthy men (59 +/- 1 years of age) (control group) performed one-legged ergometer bicycle training for 9 weeks, 6 days/week, 30 min/day. Biopsies were obtained from the vastus lateralis leg muscle before and after training. GLUT4 protein analyses was performed along with analyses of muscle biopsies from five young (23 +/- 1 years of age) (young group), healthy subjects who participated in a previously published identical study. In response to training, maximal oxygen uptake increased (delta 3.3 +/- 1.8 in NIDDM subjects and 4.5 +/- 1.2 ml.min-1.kg-1 in control subjects [both P < 0.05]). Before training, GLUT4 protein content was similar in NIDDM, control, and young subjects (0.35 +/- 0.02, 0.34 +/- 0.03, and 0.41 +/- 0.03 arbitrary units, respectively), and it increased (P < 0.05) in all groups during training (to 0.43 +/- 0.03, 0.40 +/- 0.03, and 0.57 +/- 0.08 arbitrary units, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1993

Decreased tyrosine kinase activity in partially purified insulin receptors from muscle of young, non-obese first degree relatives of patients with type 2 (non-insulin-dependent) diabetes mellitus.

Recently, we demonstrated insulin resistance due to reduced glucose storage in young relatives of Type 2 diabetic patients. To investigate whether this was associated with a defective insulin receptor kinase, we studied ten of these young (27 +/- 1 years old) non-obese glucose tolerant first degree relatives of patients with Type 2 diabetes and eight matched control subjects with no family history of diabetes. Insulin sensitivity was assessed by a hyperinsulinaemic, euglycaemic clamp. Insulin receptors were partially purified from muscle biopsies obtained in the basal and the insulin-stimulated state during the clamp. Insulin binding capacity was decreased by 28% in the relatives (p < 0.05) in the basal biopsy. Tyrosine kinase activity in the receptor preparation was decreased by 50% in both basal and insulin-stimulated biopsies from the relatives. After stimulation with insulin "in vitro", kinase activity was reduced in the relatives in basal (p < 0.005) and insulin-stimulated (p < 0.01) biopsies and also when expressed per insulin binding capacity (p approximately 0.05). Insulin stimulation of non-oxidative glucose metabolism correlated with "in vitro" insulin-stimulated tyrosine kinase activity (r = 0.61, p < 0.01) and also when expressed per binding capacity (r = 0.53, p < 0.025). We suggest that the marked defect in tyrosine kinase activity in partially purified insulin receptors from skeletal muscle is an early event in the development of insulin resistance and contributes to the pathophysiology of Type 2 diabetes.

Adult↗
PubMed1993

Metformin ameliorates diabetes but does not normalize the decreased GLUT 4 content in skeletal muscle of obese (fa/fa) Zucker rats.

We studied the expression of the glucose transporter GLUT 4 in the soleus and red gastrocnemius muscles from obese, diabetic (fa/fa) Zucker rats compared to their lean littermates (Fa/-), with and without treatment with the antidiabetic drug metformin. In the untreated groups of rats, the GLUT 4 content in a crude membrane fraction of both the soleus and the red gastrocnemius muscles were significantly lower in the obese (fa/fa) rats (3.46 +/- 0.28 vs. 6.04 +/- 0.41, p < 0.001 and 6.0 +/- 0.24 vs. 9.1 +/- 0.48, p < 0.0001, respectively). Differences in GLUT 4 expression in soleus muscle from the same rats were confirmed by quantitative immunofluorescence microscopy, and the results were significantly correlated with the results obtained from quantitative immunoblotting (rho = 0.70, p < 0.0005). The decreased expression of GLUT 4 in fa/fa rats could contribute to the well-established insulin resistance in skeletal muscle of these animals. After 4 weeks of treatment with metformin, weight gain was not affected in either the diabetic (fa/fa) rats or the lean (Fa/-) rats. Improvement of glucose homeostasis by metformin was not associated with normalization of the GLUT 4 expression in the skeletal muscles studied, indicating (1) that the decreased GLUT 4 expression is not directly related to hyperinsulinaemia and diabetes mellitus and (2) that metformin does not normalize the expression of GLUT 4 in skeletal muscle of the diabetic (fa/fa) Zucker rats.

Animals↗