Biomedical subjects

G L Dohm

Publications and source records attributed to G L Dohm.

At least 19 recordsLinked to original sources

PubMed1992

Surgical treatment of obesity and its effect on diabetes: 10-y follow-up.

Since 1980 we have performed the identical Greenville gastric bypass (GGB) procedure on 479 morbidly obese patients with an acceptable morbidity and a mortality rate of 1.2%. The weight loss in the series was well maintained over the follow-up period of 10 y. The GGB can control non-insulin-dependent diabetes mellitus (NIDDM) in most patients. The group of 479 patients included 101 (21%) with NIDDM and another 62 (13%) who were glucose impaired. Of these 163 individuals, 141 reverted to normal and only 22 (5%) remained with inadequate control of their carbohydrate metabolism. Those patients who were older or whose diabetes was of longer duration were less likely to revert to normal values. The gastric bypass operation is an effective approach for the treatment of morbid obesity. Along with its control of weight, the operation also controls the hyperglycemia, hyperinsulinemia, and insulin resistance of the majority of patients with either glucose impairment or frank NIDDM.

Adult↗

PubMed1992

Is type II diabetes mellitus (NIDDM) a surgical disease?

Since February 1, 1980, 515 morbidly obese patients have undergone the Greenville gastric bypass (GGB) operation. Of these, 212 (41.2%) were euglycemic, 288 (55.9%) were either diabetic or had glucose intolerance, and 15 (2.9%) were unable to complete the evaluation. After the operation, only 30 (5.8%) patients remained diabetic (and 20 of these improved), 457 (88.7%) became and have remained euglycemic, and inadequate data prevented classification of the other 28 (5.4%). The patients who failed to return to normal glucose values were older and their diabetes was of longer duration than those who did. The effect of the GGB was not only limited to the correction of abnormal glucose levels. The GGB also corrected the abnormal levels of fasting insulin and glycosylated hemoglobin in a cohort of 52 consecutive severely obese patients with non-insulin-dependent diabetes. The GGB effectively controls weight. If morbid obesity is defined as 100 pounds over ideal body weight, 89% of the patients are no longer "morbidly" obese within 2 years. In most patients, the control of the weight has been well maintained during the 11 years of follow-up; most of the upward creep in weight of 20.8% between 24 and 132 months was from the 49 (9.5%) patients who had staple line breakdowns between the large and small gastric pouches. Non-insulin-dependent diabetes, previously considered a chronic unrelenting disease, can be controlled in the severely obese by the gastric bypass. Whether the correction of glucose metabolism affects the complications of diabetes is unknown. Whether the gastric bypass should be considered for patients with advanced non-insulin-dependent diabetes but who are not severely obese deserves consideration. The GGB has an unacceptably high rate of staple line failure. Accordingly, the authors have recently changed their procedure to one that divides the stomach rather than partitions it with staples.

Adolescent↗

PubMed1992

Effect of training and detraining on skeletal muscle glucose transporter (GLUT4) content in rats.

The aim of the present study was to examine the effects of treadmill exercise training and detraining on the skeletal muscle fiber type specific expression of the insulin-regulated glucose transporter protein (GLUT4) in rats. GLUT4 protein content was determined by Western and dot-blot analysis, using a polyclonal antibody raised against the carboxy-terminal peptide. Rats were sacrificed 24 h after the last training session. There were no significant changes in muscle GLUT4 after 1 day or 1 week of training. Six weeks of training increased GLUT4 protein content 1.4- to 1.7-fold (p < 0.05) over controls in the soleus and red vastus lateralis, whereas no significant change was evident in the white vastus lateralis muscle. GLUT4 protein content in both soleus and red vastus lateralis muscle returned to near control values after 7 days of detraining. Similar to GLUT4, citrate synthase activity showed no change after 1 day or 1 week of training, increased 1.8-fold over controls after 6 weeks of training, but returned to control values after 7 days detraining. These findings demonstrate that muscle GLUT4 protein is increased in rats with as little as 6 weeks of treadmill exercise training but that the adaptation is lost within 1 week of detraining. It is suggested that expression of the GLUT4 protein is coordinated with the well-documented adaptations in oxidative enzyme activity with endurance training and detraining.

Animals↗

PubMed1992

Effect of aging and exercise on GLUT-4 glucose transporters in muscle.

This study was conducted to investigate whether changes in muscle glucose transporter GLUT-4 protein might be associated with a previously reported deterioration in glucose tolerance with aging, and, furthermore, to determine whether exercise training could increase GLUT-4 protein levels in older animals. GLUT-4 protein concentration was measured in soleus, gastrocnemius, and extensor digitorum longus muscles of trained (10 or 15 wk treadmill running) and untrained young (6-8 mo), middle-aged (15-17 mo), and old (27-29 mo) Fischer 344 rats. All GLUT-4 protein values were expressed as a percent of the mean for the young untrained group. Two-way analysis of variance demonstrated significant main effects of both training and aging in the gastrocnemius and soleus muscles. Exercise training produced significant increases in GLUT-4 protein in the soleus muscle of young (273 +/- 32.9 vs. 100 +/- 38.5%) and middle-aged rats (215 +/- 19.9 vs. 108 +/- 33.2%) compared with sedentary controls. Similar significant increases were also found in the gastrocnemius muscle of young (169 +/- 20.1 vs. 100 +/- 5.8%) and middle-aged rats (167 +/- 46.7 vs. 60 +/- 7.9%) with training. In the oldest rats, GLUT-4 was not significantly increased with training, but the trend toward an increase was apparent in all three muscle types. The main effect of aging was primarily due to a statistically significant difference between the old trained and young trained rats. A trend toward decreased GLUT-4 with aging was apparent in the untrained animals, but this was not statistically significant.

Aging↗

PubMed1992

Restoration of insulin responsiveness in skeletal muscle of morbidly obese patients after weight loss. Effect on muscle glucose transport and glucose transporter GLUT4.

A major defect contributing to impaired insulin action in human obesity is reduced glucose transport activity in skeletal muscle. This study was designed to determine whether the improvement in whole body glucose disposal associated with weight reduction is related to a change in skeletal muscle glucose transport activity and levels of the glucose transporter protein GLUT4. Seven morbidly obese (body mass index = 45.8 +/- 2.5, mean +/- SE) patients, including four with non-insulin-dependent diabetes mellitus (NIDDM), underwent gastric bypass surgery for treatment of their obesity. In vivo glucose disposal during a euglycemic clamp at an insulin infusion rate of 40 mU/m2 per min was reduced to 27% of nonobese controls (P less than 0.01) and improved to 78% of normal after weight loss of 43.1 +/- 3.1 kg (P less than 0.01). Maximal insulin-stimulated glucose transport activity in incubated muscle fibers was reduced by approximately 50% in obese patients at the time of gastric bypass surgery but increased twofold (P less than 0.01) to 88% of normal in five separate patients after similar weight reduction. Muscle biopsies obtained from vastus lateralis before and after weight loss revealed no significant change in levels of GLUT4 glucose transporter protein. These data demonstrate conclusively that insulin resistance in skeletal muscle of mobidly obese patients with and without NIDDM cannot be causally related to the cellular content of GLUT4 protein. The results further suggest that morbid obesity contributes to whole body insulin resistance through a reversible defect in skeletal muscle glucose transport activity. The mechanism for this improvement may involve enhanced transporter translocation and/or activation.

Adult↗

PubMed1991

Mitochondrial biogenesis in striated muscles: rapid induction of citrate synthase mRNA by nerve stimulation.

Tonic contractile activity induces mitochondrial biogenesis in mammalian skeletal muscles, necessitating regulation of both nuclear and mitochondrial genes encoding mitochondrial proteins. In this study we compared the time course of induction of citrate synthase (CS) mRNA, a nuclear gene product, to that of genes encoded by mitochondrial DNA during the adaptive response to indirect nerve stimulation in tibialis anterior muscles of adult rabbits. A CS cDNA probe was prepared from a rabbit heart cDNA library by the polymerase chain reaction using synthetic oligonucleotide primers based on the published sequence of the porcine gene. This cDNA probe hybridized to a single band on Northern blots of total or polyadenylated RNA from adult rabbit tissues. Nerve stimulation for 3 days increased the abundance of CS mRNA relative to total cellular RNA by 2.3 +/- 0.2-fold (mean +/- SE, n = 8; P less than 0.01). In contrast, CS enzyme activity and mitochondrial RNA transcripts were not significantly increased at this time point. However, when nerve stimulation was continued for 21 days, the increases in CS mRNA and mitochondrial RNAs were similar. These results support the hypothesis that genetic signaling mechanisms triggered by neural input are sensed initially within the nucleus and that expression of mitochondrial genes is regulated as a secondary event.

Animals↗

PubMed1991

Decreased expression of glucose transporter in muscle from insulin-resistant patients.

We have observed that in vitro incubated human muscle fiber strips from obese patients with or without non-insulin-dependent diabetes mellitus (NIDDM) have reduced insulin-stimulated glucose transport rates compared with nonobese control patients. To investigate if the decrease in glucose transport is associated with a depletion of glucose transport protein, we performed Western blot analysis of muscle samples from nonobese control, obese nondiabetic, and obese NIDDM patients to measure the levels of the muscle-adipose tissue glucose transporter (GLUT-4) protein. Glucose transporter protein was depressed by 23% in the obese nondiabetic and 18% in the obese NIDDM group. The results were essentially the same in the rectus abdominus and vastus lateralis muscles. These data suggest that the decreased glucose transport rate observed in muscle of these obese patients with or without NIDDM may be due, at least in part, to a decreased expression of the "insulin-sensitive" (GLUT-4) glucose transporter. This alteration may play a role in the insulin resistance seen in obesity and diabetes.

Diabetes Mellitus↗

PubMed1991

Muscle insulin resistance in uremic humans: glucose transport, glucose transporters, and insulin receptors.

To determine the cellular basis for insulin resistance observed in patients with uremia, we investigated insulin action in vivo and in vitro using skeletal muscle obtained from patients with chronic renal failure. Uremic subjects had significantly reduced rates of insulin-stimulated glucose disposal, as determined by a 3-h intravenous glucose tolerance test and using the hyperinsulinemic euglycemic clamp technique. Hepatic glucose production was similar before (control, 76.2 +/- 6.3 vs. uremic, 74.2 +/- 6.9 mg.kg-1.min-1) and during insulin infusion at 40 mU.m-2.min-1 (control, -60.9 +/- 6.6 vs. uremic, -53.9 +/- 6.3 mg.kg-1.min-1). In incubated human skeletal muscle fiber strips, basal 2-deoxy-D-glucose transport was unchanged in uremic subjects compared with controls. However, the increase in insulin-stimulated glucose transport was significantly reduced by 50% in muscles from uremic patients (P = 0.012). In partially purified insulin receptors prepared from skeletal muscle, 125I-labeled insulin binding, beta-subunit receptor autophosphorylation, and tyrosine kinase activity were all unchanged in uremic subjects. The abundance of insulin-sensitive (muscle/fat, GLUT-4) glucose transporter protein measured by Western blot using Mab 1F8 or polyclonal antisera was similar in muscles of control and uremic patients. These findings suggest that the insulin resistance observed in skeletal muscle of uremic patients cannot be attributed to defects in insulin receptor function or depletion of the GLUT-4 glucose transporter protein. An alternative step in insulin-dependent activation of the glucose transport process may be involved.

Adult↗

PubMed1991

Elevated skeletal muscle glucose transporter levels in exercise-trained middle-aged men.

Exercise training has been proposed to improve whole body insulin sensitivity through a postreceptor adaptation in skeletal muscle. This study examined if levels of the insulin-responsive muscle glucose transporter protein (GLUT-4) were associated with improved insulin sensitivity in trained vs. sedentary middle-aged individuals. Muscle GLUT-4 levels and oral glucose tolerance test (OGTT) responses were obtained in age-matched trained and sedentary men (n = 11). Plasma insulin levels during the OGTT were significantly lower (P less than 0.01) in the trained men, whereas no differences were seen in plasma glucose responses. GLUT-4 protein content was approximately twofold higher in the trained men (2.41 +/- 0.17 vs. 1.36 +/- 0.11 micrograms standard, P less than 0.001). OGTT responses and GLUT-4 levels were not altered 15-18 h after a standard exercise bout in six representative sedentary subjects. These data suggest that GLUT-4 levels are increased in conjunction with insulin sensitivity in chronically exercise-trained middle-aged men. This finding suggests a possible mechanism for the improved insulin sensitivity observed with exercise training in humans.

Adult↗

PubMed1991

Altered expression of muscle glucose transporter GLUT-4 in diabetic fatty Zucker rats (ZDF/Drt-fa).

We examined GLUT-4 glucose transporter protein and mRNA in muscle tissue from a new rodent model of non-insulin-dependent diabetes mellitus (NIDDM), the male obese Zucker diabetic fatty (ZDF) rat [ZDF/Drt-fa(F10)]. We also determined whether prevention of hyperglycemia might affect GLUT-4 expression by feeding the intestinal alpha-glucosidase inhibitor acarbose (40 mg/100 g diet) in the diet of male ZDF rats for 19 wk, starting at least 1 wk before the onset of diabetes. Fasting glucose was four- to sixfold greater in diabetic ZDF rats (24.1 +/- 6.7 mM) compared with lean or obese nondiabetic rats. Fasting insulin in diabetic ZDF rats (0.5 +/- 0.1 ng/ml) was similar to lean rats (0.4 +/- 0.1) but greatly reduced compared with obese nondiabetic rats (18.7 +/- 4.0 ng/ml). Acarbose treatment significantly reduced fasting glucose levels to 13.4 +/- 1.4 mM, while insulin levels increased to 1.6 +/- 0.3 ng/ml. GLUT-4 protein levels in diabetic ZDF rats were reduced approximately 40% in red quadriceps and mixed gastrocnemius muscles but were unchanged in white quadriceps muscle. Acarbose treatment was associated with a twofold increase in GLUT-4 protein and mRNA in mixed gastrocnemius muscle. These data indicate that, in this obese model of NIDDM without hyperinsulinemia, there is reduced muscle GLUT-4 protein in red but not white muscle fiber types. The decrease in muscle GLUT-4 expression in this model of NIDDM can be prevented by acarbose treatment, which reduces hyperglycemia and increases beta-cell responsiveness.

Acarbose↗

PubMed1991

Regulation of glycogen resynthesis following exercise. Dietary considerations.

With the cessation of exercise, glycogen repletion begins to take place rapidly in skeletal muscle and can result in glycogen levels higher than those present before exercise. Understanding the rate-limiting steps that regulate glycogen synthesis will provide us with strategies to increase the resynthesis of glycogen during recovery from exercise, and thus improve performance. Given the importance of muscle glycogen to endurance performance, various factors which may optimise glycogen resynthesis rate and insure complete restoration have been of interest to both the scientist and athlete. The time required for complete muscle glycogen resynthesis after prolonged moderate intensity exercise is generally considered to be 24 hours provided approximately 500 to 700g of carbohydrate is ingested. Muscle glycogen synthesis rate is highest during the first 2 hours after exercise. Ingestion of 0.70g glucose/kg bodyweight every 2 hours appears to maximise glycogen resynthesis rate at approximately 5 to 6 mumol/g wet weight/h during the first 4 to 6 hours after exhaustive exercise. Further enhancement of glycogen resynthesis rate with ingestion of greater than 0.70g glucose/kg bodyweight appears to be limited by the constraints imposed by gastric emptying. Ingestion of glucose or sucrose results in similar muscle glycogen resynthesis rates while glycogen synthesis in liver is better served with the ingestion of fructose. Also, increases in muscle glycogen content during the first 4 to 6 hours after exercise are greater with ingestion of simple as compared with complex carbohydrate. Glycogen synthase activity is a key component in the regulation of glycogen resynthesis. Glycogen synthase enzyme exists in 2 states: the less active, more phosphorylated (D) form which is under allosteric control of glucose-6-phosphate, and the more active, less phosphorylated (I) form which is independent of glucose-6-phosphate. There is generally an inverse relationship between glycogen content in muscle and the percentage synthase in the activated (I) form. Exercise and insulin by themselves activate glycogen synthase by conversion to glycogen synthase I. Although small changes in the activity ratio (% I form) can lead to large changes in the rate of glycogen synthesis, glycogen synthase I appears to increase very little (approximately 25%) in response to glycogen depletion and returns to pre-exercise levels as glycogen levels return to normal. Thus glycogen resynthesis, which may increase 3- to 5-fold, may also be influenced by glucose-6-phosphate, which can activate glycogen synthase in the D form.(ABSTRACT TRUNCATED AT 400 WORDS)

Biological Transport↗

PubMed1991

Immunolocalization of glucose transporter GLUT4 within human skeletal muscle.

To investigate the cellular and subcellular distribution of glucose transporters in skeletal muscle, the glucose transporter isoform GLUT4 was localized in human muscle by electron microscopy via immunogold labeling with monoclonal (1F8) or COOH-terminal peptide polyclonal (ECU4) antibody and in isolated rat membranes by Western blot. There was no labeling of GLUT4 in endothelial cells of the capillaries. There also was no labeling of GLUT4 on the surface plasma membrane (sarcolemma) under either basal or insulin-stimulated conditions. Specific labeling for GLUT4 was clearly observed in two compartments: within the triad (on terminal cisternae and transverse tubules) and on an intracellular compartment, possibly sarcoplasmic tubules. Isolated triad membranes from rat muscle also contained substantial quantities of GLUT4 transporter, but there was no detectable GLUT4 protein in isolated sarcolemmal membranes. These data suggest a possible mechanism that involves glucose transport across the muscle cell at the transverse tubule membrane, not the sarcolemma.

Animals↗

PubMed1990

Insulin responsiveness in skeletal muscle is determined by glucose transporter (Glut4) protein level.

Glucose transport in skeletal muscle is mediated by two distinct transporter isoforms, designated muscle/adipose glucose transporter (Glut4) and erythrocyte/HepG2/brain glucose transporter (Glut1), which differ in both abundance and membrane distribution. The present study was designed to investigate whether differences in insulin responsiveness of red and white muscle might be due to differential expression of the glucose transporter isoforms. Glucose transport, as well as Glut1 and Glut4 protein and mRNA levels, were determined in red and white portions of the quadriceps and gastrocnemius muscles of male Sprague-Dawley rats (body wt. approx. 250 g). Maximal glucose transport (in response to 100 nM-insulin) in the perfused hindlimb was 3.6 times greater in red than in white muscle. Red muscle contained approx. 5 times more total Glut4 protein and 2 times more Glut4 mRNA than white muscle, but there were no differences in the Glut1 protein or mRNA levels between the fibre types. Our data indicate that differences in responsiveness of glucose transport in specific skeletal muscle fibre types may be dependent upon the amount of Glut4 protein. Because this protein plays such an integral part in glucose transport in skeletal muscle, any impairment in its expression may play a role in insulin resistance.

Animals↗

PubMed1990

Increased glucose transporter (GLUT4) protein expression in hyperthyroidism.

We have studied skeletal muscle glucose uptake by perfused hindquarter preparations from rats treated with thyroxine. Basal glucose uptake (in the absence of insulin) was approximately 2 fold higher in muscle of hyperthyroid rats compared to controls. Insulin (10(-7) M) stimulated glucose uptake 4.0 and 6.8 fold in the 10 day and 30 day controls rats, respectively. Maximal glucose uptake (10(-7) M insulin) was not different in control and hyperthyroid rats and thus insulin responsiveness in the hyperthyroid animals was reduced to 2.5 fold stimulation. The abundance of the insulin-sensitive glucose transporter protein (muscle/fat, GLUT-4), measured by Western blot analysis using polyclonal antisera, was higher in skeletal muscle from both groups of hyperthyroid rats. These studies indicate that thyroid hormones increase basal glucose uptake in skeletal muscle and this is due, at least in part, to an increment of GLUT-4 isoform. Increased expression of muscle glucose transporter proteins may be responsible for the increased peripheral glucose utilization seen in hyperthyroidism.

Animals↗

PubMed1990

Exercise training increases glucose transporter protein GLUT-4 in skeletal muscle of obese Zucker (fa/fa) rats.

The present study examined the level of GLUT-4 glucose transporter protein in gastrocnemius muscles of 36 week old genetically obese Zucker (fa/fa) rats and their lean (Fa/-) littermates, and in obese Zucker rats following 18 or 30 weeks of treadmill exercise training. Despite skeletal muscle insulin resistance, the level of GLUT-4 glucose transporter protein was similar in lean and obese Zucker rats. In contrast, exercise training increased GLUT-4 protein levels by 1.7 and 2.3 fold above sedentary obese rats. These findings suggest endurance training stimulates expression of skeletal muscle GLUT-4 protein which may be responsible for the previously observed increase in insulin sensitivity with training.

Animals↗

PubMed1990

The effect of fasting on the activation in vivo of the insulin receptor kinase.

Fasting causes insulin resistance in liver and fat, and increases insulin sensitivity in muscle. We studied the response in vitro and in vivo to insulin of the insulin receptor tyrosine kinase in muscle and liver from 72 h fasted and control rats. Insulin was injected intraperitoneally together with glucose, and blood and tissue samples were obtained 0, 5, 15 and 30 min later. Basal serum glucose and insulin levels were significantly higher in control than in fasting rats. Serum glucose rose to approximately 300 mg/dl at 5 min and then progressively declined without hypoglycaemia. Receptors were prepared from whole tissue by wheat germ lectin affinity chromatography. 125I-insulin binding to purified receptors was increased by fasting in both muscle (18%) and liver (50%). In untreated fasting and control animals, muscle and liver insulin receptor tyrosine kinase activity was stimulated to similar levels by insulin added in vitro. With only insulin treatment in vivo, muscle receptor tyrosine kinase behaved similarly in fasting and control animals with maximal activation at 15 min post injection. In liver, insulin in vivo stimulated receptor tyrosine kinase activity maximally at 5 min post injection in both fasting and control, but in fasting animals the treatment in vivo caused a significantly larger and more prolonged activation of the enzymic activity, possibly due to a decrease in the rate of dephosphorylation and deactivation of the beta subunits.

Animals↗

PubMed1990

Insulin resistance induced by high-fat feeding is only partially reversed by exercise training.

Diets high in saturated fat and simple carbohydrate result in an insulin-resistant state, while training increases insulin sensitivity. Insulin resistance was induced by feeding a high-fat, high-sucrose (HFS) diet to 4-week-old female Sprague-Dawley rats. A control diet (low-fat, complex-carbohydrate) was fed to another group for comparison. During the 4-week dietary treatment, half of each group was trained by treadmill running (2 h day-1, 6 days week-1m 30 m min-1, 0% grade). At the end of this 4-week experimental period, hindquarter perfusions were performed at either basal (0) or maximal (100 nM) insulin concentrations to determine glucose uptake, glycogen synthesis, total glycogen content and the activity of several enzymes. Insulin (100 nM) significantly increased glucose uptake and glycogen synthesis in all four groups (CON-UN, CON-TR, HFS-UN, HFS-TR, where CON, UN and TR refer to control, untrained and trained respectively). HFS feeding significantly decreased (P less than 0.002) glucose uptake (mumol g-1 h-1) with maximal insulin stimulation, while training significantly increased uptake (P less than 0.01) at both insulin concentrations. Glycogen synthesis was also increased by training (P less than 0.05) at both insulin concentrations, but accounted for only 25-28% of the glucose uptake. Although training improved the insulin resistance caused by the HFS diet, glucose uptake in the HFS-TR group was still significantly lower than the CON-TR group. Changes in glycogen synthesis are not great enough to account for the decrease or increase in glucose uptake found in the HFS-fed or trained animals.

Animals↗

PubMed1990

Differences in glucose transport rates between perfused and in vitro incubated muscles.

In vitro incubated muscles are a convenient preparation for glucose transport studies, but it is not known how closely they reflect the in vivo condition. Perfused muscle preparations more closely resemble the in vivo condition, and thus to validate the use of in vitro incubated muscles, we have compared glucose transport rates in the two preparations. 3-O-Methylglucose transport rates in incubated soleus (SOL) and extensor digitorum longus (EDL) muscle strips were compared to transport rates obtained in SOL and EDL muscles removed from perfused hindquarters. Male Sprague-Dawley rats (250 g) were used for both procedures. SOL muscles showed an average 25% higher transport rate than EDL muscles at all insulin concentrations examined (0-100 nM) in the perfused system. This difference was diminished in the incubated muscles, SOL being 15% greater than EDL, but the relationship between the two muscles was maintained. Basal transport was lower and maximal transport was higher in the perfused muscles compared to the incubated muscles. This resulted in significantly higher fold stimulation in the perfused vs. incubated muscles (15 vs. 2.5 in the SOL, and 9.8 vs. 2.3 in the EDL). We conclude that in vitro muscle preparations may be convenient for showing relative differences between experimental treatments, but absolute transport rates and insulin stimulation must be interpreted with caution.

Animals↗