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Biomedical subjects

M Hawkins

Publications and source records attributed to M Hawkins.

At least 37 records · Page 2Linked to original sources
PubMed1999

Second malignant neoplasms after a first cancer in childhood: temporal pattern of risk according to type of treatment.

The variation in the risk of solid second malignant neoplasms (SMN) with time since first cancer during childhood has been previously reported. However, no study has been performed that controls for the distribution of radiation dose and the aggressiveness of past chemotherapy, which could be responsible for the observed temporal variation of the risk. The purpose of this study was to investigate the influence of the treatment on the long-term pattern of the incidence of solid SMN after a first cancer in childhood. We studied a cohort of 4400 patients from eight centres in France and the UK. Patients had to be alive 3 years or more after a first cancer treated before the age of 17 years and before the end of 1985. For each patient in the cohort, the complete clinical, chemotherapy and radiotherapy history was recorded. For each patient who had received external radiotherapy, the dose of radiation received by 151 sites of the body were estimated. After a mean follow-up of 15 years, 113 children developed a solid SMN, compared to 12.3 expected from general population rates. A similar distribution pattern was observed among the 1045 patients treated with radiotherapy alone and the 2064 patients treated with radiotherapy plus chemotherapy; the relative risk, but not the excess absolute risk, of solid SMN decreased with time after first treatment; the excess absolute risk increased during a period of at least 30 years after the first cancer. This pattern remained after controlling for chemotherapy and for the average dose of radiation to the major sites of SMN. It also remained when excluding patients with a first cancer type or an associated syndrome known to predispose to SMN. When compared with radiotherapy alone, the addition of chemotherapy increases the risk of solid SMN after a first cancer in childhood, but does not significantly modify the variation of this risk during the time after the first cancer.

Age of Onset↗
PubMed1999

Ventricular dilatation in the absence of ACE inhibitors: influence of haemodynamic and neurohormonal variables following myocardial infarction.

OBJECTIVE: To examine the relation between patterns of ventricular remodelling and haemodynamic and neurohormonal variables, at rest and during symptom limited exercise, in the year following acute myocardial infarction in patients not receiving angiotensin converting enzyme (ACE) inhibitors. DESIGN: A prospective observational study. PATIENTS: 65 patients recruited following hospital admission with a transmural anterior myocardial infarction. METHODS: Central haemodynamics and neurohormonal activation at rest and during symptom limited treadmill exercise were measured at baseline before hospital discharge, one month later, and at three monthly intervals thereafter. PATIENTS were classified according to individual patterns of change in left ventricular end diastolic volumes at rest, assessed at each visit using transthoracic echocardiography. RESULTS: In most patients (n = 43, 66%) ventricular volumes were unchanged or reduced. Mean (SEM) treadmill exercise capacity and peak exercise cardiac index increased at month 12 by 200 (24) seconds (p < 0.001 v baseline) and by 0.8 (0.4) l/min/m2 (p<0.05 v baseline), respectively, in this group. In patients with limited ventricular dilatation (n = 11, 17%) exercise capacity increased by 259 (52) seconds (p < 0.001 v baseline) and peak exercise cardiac index improved by 0.8 (0.7) l/min/m2 (NS). In the remaining 11 patients with progressive left ventricular dilatation, exercise capacity increased by 308 (53) seconds (p< 0. 001 v baseline) and peak exercise cardiac index similarly improved by 1.3 (0.7) l/min/m2 (NS). There were trends towards increased atrial natriuretic factor (ANF) secretion at rest and at peak exercise in this group. CONCLUSIONS: Ventricular dilatation after acute myocardial infarction is a heterogeneous process that is progressive in only a minority of patients. Compensatory mechanisms, including ANF release, appear capable of maintaining and improving exercise capacity in most patients for at least 12 months, even in those with a progressive increase in ventricular size.

Adult↗
PubMed1999

High-dose recombinant interleukin 2 therapy for patients with metastatic melanoma: analysis of 270 patients treated between 1985 and 1993.

PURPOSE: To determine the short- and long-term efficacy and toxicity of the high-dose intravenous bolus interleukin 2 (IL-2) regimen in patients with metastatic melanoma. PATIENTS AND METHODS: Two hundred seventy assessable patients were entered onto eight clinical trials conducted between 1985 and 1993. IL-2 (Proleukin [aldesleukin]; Chiron Corp, Emeryville, CA) 600,000 or 720,000 IU/kg was administered by 15-minute intravenous infusion every 8 hours for up to 14 consecutive doses over 5 days as clinically tolerated with maximum support, including pressors. A second identical treatment cycle was scheduled after 6 to 9 days of rest, and courses could be repeated every 6 to 12 weeks in stable or responding patients. Data were analyzed through fall 1996. RESULTS: The overall objective response rate was 16% (95% confidence interval, 12% to 21%); there were 17 complete responses (CRs) (6%) and 26 partial responses (PRs) (10%). Responses occurred with all sites of disease and in patients with large tumor burdens. The median response duration for patients who achieved a CR has not been reached and was 5.9 months for those who achieved a PR. Twelve (28%) of the responding patients, including 10 (59%) of the patients who achieved a CR, remain progression-free. Disease did not progress in any patient responding for more than 30 months. Baseline performance status and whether patients had received prior systemic therapy were the only predictive prognostic factors for response to IL-2 therapy. Toxicities, although severe, generally reversed rapidly after therapy was completed. Six patients (2%) died from adverse events, all related to sepsis. CONCLUSION: High-dose IL-2 treatment seems to benefit some patients with metastatic melanoma by producing durable CRs or PRs and should be considered for appropriately selected melanoma patients.

Adult↗
PubMed1998

Intracerebroventricular leptin regulates hepatic but not peripheral glucose fluxes.

Acute intravenous infusions of leptin markedly alter hepatic glucose fluxes (Rossetti, L., Massillon, D., Barzilai, N., Vuguin, P., Chen, W., Hawkins, M., Wu, J., and Wang, J. (1997) J. Biol. Chem. 272, 27758-22763). Here we examine whether intracerebroventricular (ICV) leptin administration regulates peripheral and hepatic insulin action. Recombinant mouse leptin (n = 14; 0.02 or 1 microgram/kg.h) or vehicle (n = 9) were administered ICV for 6 h to conscious rats, and insulin action was determined by insulin (3 milliunits/kg.min) clamp and tracer dilution techniques. During physiologic hyperinsulinemia (approximately 65 microunits/ml), the rates of glucose uptake (Rd, 20.1 +/- 0.6 and 23.1 +/- 0.7 versus 21.7 +/- 0.6 mg/kg.min; p = NS), glycolysis and glycogen synthesis were similar in rats receiving low- and high-dose leptin versus vehicle. ICV leptin resulted in a 2-3-fold increase in hepatic phosphoenolpyruvate carboxykinase mRNA levels. Glycogenolysis and PEP-gluconeogenesis (2.1 +/- 0.3 mg/kg. min) contributed similarly to endogenous glucose production (GP) in the vehicle-infused group. However, gluconeogenesis accounted for approximately 80% of GP in both groups receiving ICV leptin, while hepatic glycogenolysis was markedly suppressed (0.7 +/- 0.3 and 1.2 +/- 0.3 versus 2.2 +/- 0.4 mg/kg.min, in rats receiving low- and high-dose leptin versus vehicle, respectively; p < 0.01). In summary, short-term ICV leptin administration: 1) failed to affect peripheral insulin action, but 2) induced a striking re-distribution of intrahepatic glucose fluxes. The latter effect largely reproduced that of leptin given systemically at much higher doses. Thus, the regulation of hepatic glucose fluxes by leptin is largely mediated via its central receptors.

Animals↗
PubMed1998

Regulation of endogenous glucose production by glucose per se is impaired in type 2 diabetes mellitus.

We examined the ability of an equivalent increase in circulating glucose concentrations to inhibit endogenous glucose production (EGP) and to stimulate glucose metabolism in patients with Type 2 diabetes mellitus (DM2). Somatostatin was infused in the presence of basal replacements of glucoregulatory hormones and plasma glucose was maintained either at 90 or 180 mg/dl. Overnight low-dose insulin was used to normalize the plasma glucose levels in DM2 before initiation of the study protocol. In the presence of identical and constant plasma insulin, glucagon, and growth hormone concentrations, a doubling of the plasma glucose levels inhibited EGP by 42% and stimulated peripheral glucose uptake by 69% in nondiabetic subjects. However, the same increment in the plasma glucose concentrations failed to lower EGP, and stimulated glucose uptake by only 49% in patients with DM2. The rate of glucose infusion required to maintain the same hyperglycemic plateau was 58% lower in DM2 than in nondiabetic individuals. Despite diminished rates of total glucose uptake during hyperglycemia, the ability of glucose per se (at basal insulin) to stimulate whole body glycogen synthesis (glucose uptake minus glycolysis) was comparable in DM2 and in nondiabetic subjects. To examine the mechanisms responsible for the lack of inhibition of EGP by hyperglycemia in DM2 we also assessed the rates of total glucose output (TGO), i.e., flux through glucose-6-phosphatase, and the rate of glucose cycling in a subgroup of the study subjects. In the nondiabetic group, hyperglycemia inhibited TGO by 35%, while glucose cycling did not change significantly. In DM2, neither TGO or glucose cycling was affected by hyperglycemia. The lack of increase in glucose cycling in the face of a doubling in circulating glucose concentrations suggested that hyperglycemia at basal insulin inhibits glucose-6-phosphatase activity in vivo. Conversely, the lack of increase in glucose cycling in the presence of hyperglycemia and unchanged TGO suggest that the increase in the plasma glucose concentration failed to enhance the flux through glucokinase in DM2. In summary, both lack of inhibition of EGP and diminished stimulation of glucose uptake contribute to impaired glucose effectiveness in DM2. The abilities of glucose at basal insulin to both increase the flux through glucokinase and to inhibit the flux through glucose-6-phosphatase are impaired in DM2. Conversely, glycogen synthesis is exquisitely sensitive to changes in plasma glucose in patients with DM2.

Adult↗
PubMed1998

A nutrient-sensing pathway regulates leptin gene expression in muscle and fat.

Leptin, the protein encoded by the obese (ob) gene, is synthesized and released in response to increased energy storage in adipose tissue. However, it is still not known how incoming energy is sensed and transduced into increased expression of the ob gene. The hexosamine biosynthetic pathway is a cellular 'sensor' of energy availability and mediates the effects of glucose on the expression of several gene products. Here we provide evidence for rapid activation of ob gene expression in skeletal muscle by glucosamine. Increased tissue concentrations of the end product of the hexosamine biosynthetic pathway, UDP-N-acetylglucosamine (UDP-GlcNAc), result in rapid and marked increases in leptin messenger RNA and protein levels (although these levels were much lower than those in fat). Plasma leptin levels and leptin mRNA and protein levels in adipose tissue also increase. Most important, stimulation of leptin synthesis is reproduced by either hyperglycaemia or hyperlipidaemia, which also increase tissue levels of UDP-N-acetylglucosamine in conscious rodents. Finally, incubation of 3T3-L1 pre-adipocytes and L6 myocytes with glucosamine rapidly induces ob gene expression. Our findings are the first evidence of inducible leptin expression in skeletal muscle and unveil an important biochemical link between increased availability of nutrients and leptin expression.

3T3 Cells↗
PubMed1998

Caloric restriction reverses hepatic insulin resistance in aging rats by decreasing visceral fat.

Hyperinsulinemia and increased visceral/abdominal fat (VF) are common features of human aging. To examine the relationships among VF, peripheral, and hepatic insulin sensitivity, we studied 4- and 18-mo-old male Sprague-Dawley rats (n = 42) fed ad libitum (4 AL and 18 AL) or moderately calorie restricted (18 CR) up to 18 mo of age. Total fat mass (FM) and VF were decreased in 18 CR to approximately one-third of that of 18 AL (P < 0.001), while lean body mass (LBM) was unchanged. Most important, 18 CR had more FM (65+/-6 vs. 45+/-6 g) but less VF (7.8+/-0.6 vs. 12.3+/-3.3 g) compared with 4 AL (P < 0.01 for both). Thus, the effects of variable VF on HIS could be assessed, independent of FM and age. Marked hepatic insulin resistance ensued with aging (18 AL) and CR restored hepatic insulin sensitivity to the levels of young rats, while peripheral insulin sensitivity remained unchanged (by insulin clamp of 18 mU/kg/min). In fact, the rates of insulin infusion required to maintain basal hepatic glucose production in the presence of pancreatic clamp were 0.75+/-0.10, 1.41+/-0.13, and 0.51+/-0.12 mU/kg . min, in 4 AL, 18 AL, and 18 CR, respectively (P < 0.01 between all groups), and in 18 CR rats infused with insulin at similar rates as in the 18 AL (1.4 mU/kg/min) hepatic glucose production was decreased by 32% (P < 0. 005). Furthermore, when 18 CR rats were fed AL for 14 d, VF rapidly and selectively increased and severe hepatic insulin resistance was induced. We propose that in this animal model the age-associated decrease in hepatic (rather than peripheral) insulin action is the major determinant of fasting hyperinsulinemia and that increased visceral adiposity plays the major role in inducing hepatic insulin resistance. Thus, interventions designed to prevent the accumulation of VF are likely to represent an effective mean to improve carbohydrate metabolism in aging.

Adipose Tissue↗
PubMed1998

Carbon flux via the pentose phosphate pathway regulates the hepatic expression of the glucose-6-phosphatase and phosphoenolpyruvate carboxykinase genes in conscious rats.

Hepatic gene expression of P-enolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (Glc-6-Pase) is regulated in response to changes in the availability of substrates, in particular glucose (Glc; Massillon, D., Barzilai, N., Chen, W., Hu, M., and Rossetti, L. (1996) J. Biol. Chem. 271, 9871-9874). We investigated the mechanism(s) in conscious rats. Hyperglycemia per se caused a rapid and marked increase in Glc-6-Pase mRNA abundance and protein levels. By contrast, hyperglycemia decreased the abundance of PEPCK mRNA. Importantly, inhibition of glucokinase activity by glucosamine infusion blunted both the stimulation of Glc-6-Pase and the inhibition of PEPCK gene expression by Glc, suggesting that an intrahepatic signal (metabolite) generated by the metabolism of glucose at or beyond Glc-6-P was responsible for the regulatory effect of Glc. The effect of Glc on the L-type pyruvate kinase gene is mediated by xylulose-5-P (Doiron, B., Cuif, M., Chen, R., and Kahn, A. (1996) J. Biol. Chem. 271, 5321-5324). Thus, we next investigated whether an isolated increase in the hepatic concentration of this metabolite can also reproduce the effects of Glc on Glc-6-Pase and PEPCK gene expression in vivo. Xylitol, which is directly converted to xylulose-5-P in the liver, was infused to raise the hepatic concentration of xylulose-5-P by approximately 3-fold. Xylitol infusion did not alter the levels of Glc-6-P and of fructose-2,6-biphosphate. However, it replicated the effects of hyperglycemia on Glc-6-Pase and PEPCK gene expression and resulted in a 75% increase in the in vivo flux through Glc-6-Pase (total glucose output).

Animals↗
PubMed1998

Fibreoptic intubation using the cuffed oropharyngeal airway and Aintree intubation catheter.

A cuffed oropharyngeal airway has recently been introduced which has larger internal dimensions than a comparable Guedel airway. This allows a ventilation/exchange bougie, the Aintree Intubation Catheter, mounted on a fibreoptic laryngoscope to pass through it. Its 15-mm connector and pharyngeal cuff suggested the possibility of using a Rüsch sealed-port angle piece to allow ventilation through the oropharyngeal airway during fibreoptic laryngoscopy. This study investigated using this equipment to intubate the trachea through the cuffed oropharyngeal airway in paralysed patients, whilst maintaining ventilation manually with a Bain system. In 20 patients, airway control was satisfactory throughout and tracheal intubation was accomplished without complications. The cuffed oropharyngeal airway was easy to manipulate to improve a suboptimal fibreoptic view of the larynx. This may give it an advantage over the laryngeal mask airway when used as a ventilation/intubation conduit.

Adolescent↗
PubMed1998

The effect of age-dependent increase in fat mass on peripheral insulin action is saturable.

Insulin resistance and increased fat mass (FM) are common in human aging. We aimed to investigate the relationship between the age-dependent increase in FM and insulin resistance (by euglycemic hyperinsulinemic clamp technique), in a homogenous rodent model. The decline in insulin responsiveness was linear until late adulthood when body weight, FM, and epididymal fat reached a critical amount (r > .750, for all). Above this critical point, there was no further decline in insulin responsiveness with aging and with increased BW (p < .00001 for all spline curve analyses). This decline in insulin-mediated glucose uptake was accounted for by a decrease in whole body glycolytic rate with no change in the rate of glycogen synthesis. Thus, in this homogenous model, an early increase in FM is associated with impairment in insulin action until a critical FM is achieved, after which there is no additional insulin resistance with aging. We suggest that decreasing insulin responsiveness, in a heterogeneous group such as humans, will only occur within a specific accretion of visceral or total FM.

Adipose Tissue↗
PubMed1998

Nicotine-induced limbic cortical activation in the human brain: a functional MRI study.

OBJECTIVE: Nicotine is a highly addictive substance, and cigarette smoking is a major cause of premature death among humans. Little is known about the neuropharmacology and sites of action of nicotine in the human brain. Such knowledge might help in the development of new behavioral and pharmacological therapies to aid in treating nicotine dependence and to improve smoking cessation success rates. METHOD: Functional magnetic resonance imaging, a real-time imaging technique, was used to determine the acute CNS effects of intravenous nicotine in 16 active cigarette smokers. An injection of saline followed by injections of three doses of nicotine (0.75, 1.50, and 2.25 mg/70 kg of weight) were each administered intravenously over 1-minute periods in an ascending, cumulative-dosing paradigm while whole brain gradient-echo, echo-planar images were acquired every 6 seconds during consecutive 20-minute trials. RESULTS: Nicotine induced a dose-dependent increase in several behavioral parameters, including feelings of "rush" and "high" and drug liking. Nicotine also induced a dose-dependent increase in neuronal activity in a distributed system of brain regions, including the nucleus accumbens, amygdala, cingulate, and frontal lobes. Activation in these structures is consistent with nicotine's behavior-arousing and behavior-reinforcing properties in humans. CONCLUSIONS: The identified brain regions have been previously shown to participate in the reinforcing, mood-elevating, and cognitive properties of other abused drugs such as cocaine, amphetamine, and opiates, suggesting that nicotine acts similarly in the human brain to produce its reinforcing and dependence properties.

Adolescent↗
PubMed1997

Leptin selectively decreases visceral adiposity and enhances insulin action.

Intraabdominal adiposity and insulin resistance are risk factors for diabetes mellitus, dyslipidemia, arteriosclerosis, and mortality. Leptin, a fat-derived protein encoded by the ob gene, has been postulated to be a sensor of energy storage in adipose tissue capable of mediating a feedback signal to sites involved in the regulation of energy homeostasis. Here, we provide evidence for specific effects of leptin on fat distribution and in vivo insulin action. Leptin (LEP) or vehicle (CON) was administered by osmotic minipumps for 8 d to pair-fed adult rats. During the 8 d of the study, body weight and total fat mass decreased similarly in LEP and in CON. However, while moderate calorie restriction (CON) resulted in similar decreases in whole body (by 20%) and visceral (by 21%) fat, leptin administration led to a specific and marked decrease (by 62%) in visceral adiposity. During physiologic hyperinsulinemia (insulin clamp), leptin markedly enhanced insulin action on both inhibition of hepatic glucose production and stimulation of glucose uptake. Finally, leptin exerted complex effects on the hepatic gene expression of key metabolic enzymes and on the intrahepatic partitioning of metabolic fluxes, which are likely to represent a defense against excessive storage of energy in adipose depots. These studies demonstrate novel actions of circulating leptin in the regulation of fat distribution, insulin action, and hepatic gene expression and suggest that it may play a role in the pathophysiology of abdominal obesity and insulin resistance.

Adipose Tissue↗
PubMed1997

Short term effects of leptin on hepatic gluconeogenesis and in vivo insulin action.

Long term administration of leptin decreases caloric intake and fat mass and improves glucose tolerance. Here we examine whether leptin acutely regulates peripheral and hepatic insulin action. Recombinant mouse leptin (0.3 mg/kg.h, Leptin +) or vehicle (Leptin -) were administered for 6 h to 4-month-old rats (n = 20), and insulin (3 milliunits/kg.min) clamp studies were performed. During physiologic hyperinsulinemia (plasma insulin approximately 65 microunits/ml), the rates of whole body glucose uptake, glycolysis, and glycogen synthesis and the rates of 2-deoxyglucose uptake in individual tissues were similar in Leptin - and Leptin +. Post-absorptive hepatic glucose production (HGP) was similar in the two groups. However, leptin enhanced insulin's inhibition of HGP (4.1 +/- 0.7 and 6.2 +/- 0.7 mg/kg.min; p < 0.05). The decreased HGP in the Leptin + group was due to a marked suppression of hepatic glycogenolysis (0.7 +/- 0.1 versus 4.1 +/- 0.6 mg/kg.min, in Leptin + versus Leptin -, respectively; p < 0.001), whereas the % contribution of gluconeogenesis to HGP was markedly increased (82 +/- 3% versus 36 +/- 4% in Leptin + and Leptin -, respectively; p < 0.001). At the end of the 6-h leptin infusion, the hepatic abundance of glucokinase mRNA was decreased, whereas that of phosphoenolpyruvate carboxykinase mRNA was increased compared with Leptin -. We conclude that an acute increase in plasma leptin 1) enhances insulin's ability to inhibit HGP, 2) does not affect peripheral insulin action, and 3) induces a redistribution of intrahepatic glucose fluxes and changes in the gene expression of hepatic enzymes that closely resemble those of fasting.

Animals↗
PubMed1997

Relation of daily activity levels in patients with chronic heart failure to long-term prognosis.

Symptom-limited, laboratory-based exercise tests are often used to define prognosis in patients with chronic heart failure, but they do not relate to measures of normal daily activity. Invasive measures of central hemodynamics similarly relate poorly to outcome. Pedometer scores of weekly walking are markedly reduced in patients with heart failure, but whether this less artificial measure of exercise capacity is important in predicting prognosis is not known. Eighty-four patients with chronic heart failure were followed for a mean of 710 days during which 44 died and 3 underwent cardiac transplantation. Symptom-limited treadmill exercise capacity using 2 different protocols did not predict survival, whereas reduced weekly pedometer scores were strong predictors of death (p < 0.001). Other variables that predicted death included resting cardiac output, arterial blood pressure, diuretic requirements, New York Heart Association class, increased bilirubin, and hyponatremia (all p < 0.01). Reduced levels of daily activity are strong predictors of death in chronic heart failure and appear more powerful than laboratory-based exercise tests. This type of assessment is valuable in identifying patients at high risk and provides an objective measure of incapacity during normal daily life. The exercise capacity of patients unable to exercise in the laboratory could also be assessed using this technique. This may prove invaluable in clinical and mortality trials.

Activities of Daily Living↗
PubMed1997

Role of the glucosamine pathway in fat-induced insulin resistance.

To examine whether the hexosamine biosynthetic pathway might play a role in fat-induced insulin resistance, we monitored the effects of prolonged elevations in FFA availability both on skeletal muscle levels of UDP-N-acetyl-hexosamines and on peripheral glucose disposal during 7-h euglycemic-hyperinsulinemic (approximately 500 microU/ml) clamp studies. When the insulin-induced decrease in the plasma FFA levels (to approximately 0.3 mM) was prevented by infusion of a lipid emulsion in 15 conscious rats (plasma FFA approximately 1.4 mM), glucose uptake (5-7 h = 32.5+/-1.7 vs 0-2 h = 45.2+/-2.8 mg/kg per min; P < 0.01) and glycogen synthesis (P < 0.01) were markedly decreased. During lipid infusion, muscle UDP-N-acetyl-glucosamine (UDP-GlcNAc) increased by twofold (to 53.4+/-1.1 at 3 h and to 55.5+/-1.1 nmol/gram at 7 h vs 20.4+/-1.7 at 0 h, P < 0.01) while glucose-6-phosphate (Glc-6-P) levels were increased at 3 h (475+/-49 nmol/gram) and decreased at 7 h (133+/-7 vs 337+/-28 nmol/gram at 0 h, P < 0.01). To discern whether such an increase in the skeletal muscle UDP-GlcNAc concentration could account for the development of insulin resistance, we generated similar increases in muscle UDP-GlcNAc using three alternate experimental approaches. Euglycemic clamps were performed after prolonged hyperglycemia (18 mM, n = 10), or increased availability of either glucosamine (3 micromol/kg per min; n = 10) or uridine (30 micromol/kg per min; n = 4). These conditions all resulted in very similar increases in the skeletal muscle UDP-GlcNAc (to approximately 55 nmol/gram) and markedly impaired glucose uptake and glycogen synthesis. Thus, fat-induced insulin resistance is associated with: (a) decreased skeletal muscle Glc-6-P levels indicating defective transport/phosphorylation of glucose; (b) marked accumulation of the endproducts of the hexosamine biosynthetic pathway preceding the onset of insulin resistance. Most important, the same degree of insulin resistance can be reproduced in the absence of increased FFA availability by a similar increase in skeletal muscle UDP-N-acetyl-hexosamines. In conclusion, our results support the hypothesis that increased FFA availability induces skeletal muscle insulin resistance by increasing the flux of fructose-6-phosphate into the hexosamine pathway.

Animals↗