Increased Insulin Action Research Articles

Enhanced insulin action on glucose transport and insulin signaling in 7-day unweighted rat soleus muscle

Hindlimb suspension (HS), a model of simulated weightlessness, enhances insulin action on glucose transport in unweighted rat soleus muscle. In the present study, we tested the hypothesis that these changes in glucose transport in 3- and 7-day HS soleus of juvenile, female Sprague-Dawley rats were due to increased functionality of insulin signaling factors, including insulin receptor (IR), IR substrate-1 (IRS-1), phosphatidylinositol 3-kinase (PI3-kinase), and Akt. Insulin-stimulated (2 mU/ml) glucose transport was significantly (P < 0.05) enhanced in 3- and 7-day HS soleus by 59 and 113%, respectively, compared with weight-bearing controls. Insulin-stimulated tyrosine phosphorylation of IR and Ser(473) phosphorylation of Akt was not altered by unweighting. Despite decreased (34 and 64%) IRS-1 protein in 3- and 7-day HS soleus, absolute insulin-stimulated tyrosine phosphorylation of IRS-1 was not diminished, indicating relative increases in IRS-1 phosphorylation of 62 and 184%, respectively. In the 7-day HS soleus, this was accompanied by increased (47%) insulin-stimulated IRS-1 associated with the p85 subunit of PI3-kinase. Interestingly, the enhanced insulin-stimulated glucose transport in the unweighted soleus was not completely inhibited (89-92%) by wortmannin, a PI3-kinase inhibitor. Finally, protein expression and activation of p38 MAPK, a stress-activated serine/threonine kinase associated with insulin resistance, was decreased by 32 and 18% in 7-day HS soleus. These results indicate that the increased insulin action on glucose transport in the 7-day unweighted soleus is associated with increased insulin signaling through IRS-1 and PI3-kinase and decreased p38 MAPK protein expression. However, PI3-kinase-independent mechanisms must also play a small role in this adaptive response to HS.

Resistance training enhances insulin-mediated glucose disposal with minimal effect on the tumor necrosis factor-alpha system in older hypertensives

The purpose of the present study was to determine if the improvement in insulin sensitivity after resistance training (RT) is associated with a decline in plasma levels of tumor necrosis factor-alpha (TNF-α), soluble TNF-α receptor 1 (sTNF R1), and soluble TNF receptor 2 (sTNF R2). Eleven older hypertensives (5 men/6 women, 67 ± 2 years) participated in a 4-month RT program. Following RT there was a significant increase in upper body ( P = .029) and lower body strength ( P = .001), assessed by the bench press 1-repetition maximum (1RM) and leg press 1RM, respectively. The RT program produced a significant increase in lean body mass (LBM) ( P = .029), a trend for a decline in percent body fat ( P = .083), and no change in total body mass ( P = .958). Insulin-mediated glucose disposal, assessed by the hyperinsulinemic euglycemic clamp procedure, significantly increased following RT ( P = .026). Despite the increase in insulin action, plasma levels of TNF-α, sTNF R1, and sTNF R2 were not significantly altered by RT (TNF-α: P = .118, sTNF R1: P = .184, sTNF R2: P = .168). In conclusion, a 4-month RT program significantly increased insulin-mediated glucose disposal and LBM without a significant reduction in plasma levels of TNF-α, sTNF R1, and sTNF R2 in older hypertensive subjects.

Physical exercise improves glucose metabolism in lifestyle-related diseases.

The beneficial effects of physical exercise on the decreased insulin sensitivity caused by detrimental lifestyle were reviewed based on experimental evidences. In epidemiological studies, disease prevention has been considered at three levels: primary (avoiding the occurrence of disease), secondary (early detection and reversal), and tertiary (prevention or delay of complications). The major purpose of physical exercise for primary prevention and treatment of lifestyle-related diseases is to improve insulin sensitivity. It is known that, during physical exercise, glucose uptake by the working muscles rises 7 to 20 times over the basal level, depending on the intensity of the work performed. However, intense exercise provokes the release of insulin-counter regulatory hormones such as glucagons and catecholamines, which ultimately cause a reduction in the insulin action. Continued physical training improves the reduced peripheral tissue sensitivity to insulin in impaired glucose tolerance and Type II diabetes, along with regularization of abnormal lipid metabolism. Furthermore, combination of salt intake restriction and physical training ameliorates hypertension. In practical terms, before diabetic patients undertake any program of physical exercise, various medical examinations are needed to determine whether they have good glycemic control and are without progressive complications. Because the effect of exercise that is manifested in improved insulin sensitivity decreases within 3 days after exercise and is no longer apparent after 1 week, a continued program is needed. For a safety practice, moderate- or low-intensity exercise is preferable. In conclusion, we have found sufficient evidences that support the theory that, combined with other forms of therapy, mild exercise training increases insulin action despite no influence on body mass index or maximal oxygen uptake. Along with evident benefits in health promotion, moderate-intensity exercise might play an important role in facilitating treatment of various diseases.

Resistance training and insulin action in humans: effects of de-training

Aerobic endurance training increases insulin action in skeletal muscle, but the effect of resistance training has not been well described. Controversy exists about whether the effect of resistance training is merely due to an increase in muscle mass. We studied the effect of cessation of resistance training in young, healthy subjects by taking muscle biopsies and measuring insulin-mediated whole body and leg glucose uptake rates after 90 days of heavy resistance training (T) and again after 90 days of de-training (dT). Data on leg glucose uptake were expressed relative to accurate measures of leg muscle mass by MRI scanning. Muscle strength (239 ± 43 vs. 208 ± 33 N m), quadriceps area (8463 ± 453 vs. 7763 ± 329 mm2) and glycogen content (458 ± 22 vs. 400 ± 26 mmol (kg dry weight muscle)−1) decreased, while myosin heavy chain isoform IIX increased 4-fold in dT vs. T, respectively (all P < 0.05). GLUT4 mRNA levels and enzyme activities and mRNA levels of glycolytic, lipolytic and glyconeogenic enzymes did not change with de-training. Likewise, capillary density did not change. Whole body glucose uptake decreased 11 % and leg glucose uptake decreased from 75 ± 11 (T) to 50 ± 6 (dT) nmol min−1 (mm muscle)−2 (P < 0.05) at maximal insulin, the latter decrease being due to decreased arterio-femoral venous glucose extraction. The decrease was mainly due to reduced non-oxidative glucose disposal. We have thus shown that 90 days after the termination of heavy resistance training, insulin-mediated glucose uptake rates per unit of skeletal muscle have decreased significantly.

Interaction of insulin and prior exercise in control of hepatic metabolism of a glucose load.

To determine if prior exercise enhances insulin-stimulated extraction of glucose by the liver, chronically catheterized dogs were submitted to 150 min of treadmill exercise or rest. After exercise or rest, dogs received portal glucose (18 micro mol x kg(-1) x min(-1)), peripheral somatostatin, and basal portal glucagon infusions from t = 0 to 150 min. A peripheral glucose infusion was used to clamp arterial blood glucose at 8.3 mmol/l. Insulin was infused into the portal vein to create either basal levels or mild hyperinsulinemia. Prior exercise did not increase whole-body glucose disposal in the presence of basal insulin (25.5 +/- 1.5 vs. 20.3 +/- 1.7 micro mol x kg(-1) x min(-1)), but resulted in a marked enhancement in the presence of elevated insulin (97.2 +/- 15.1 vs. 64.4 +/- 7.4 micro mol x kg(-1) x min(-1)). Prior exercise also increased net hepatic glucose uptake in the presence of both basal insulin (7.5 +/- 1.2 vs. 2.9 +/- 2.4 micro mol x kg(-1) x min(-1)) and elevated insulin (22.0 +/- 3.5 vs. 11.5 +/- 1.8 micro mol x kg(-1) x min(-1)). Likewise, net hepatic glucose fractional extraction was increased by prior exercise with both basal insulin (0.04 +/- 0.01 vs. 0.01 +/- 0.01 micro mol x kg(-1) x min(-1)) and elevated insulin (0.10 +/- 0.01 vs. 0.05 +/- 0.01). Hepatic glycogen synthesis was increased by elevated insulin, but was not enhanced by prior exercise. Although the increase in glucose extraction after exercise could be ascribed to increased insulin action, the increase in hepatic glycogen synthesis was independent of it.

Changes in aerobic capacity and visceral fat but not myocyte lipid levels predict increased insulin action after exercise in overweight and obese men.

To examine the effect of moderate intensity physical activity on the interactions between central abdominal adiposity, myocyte lipid content, and insulin action in overweight and obese, sedentary men. Myocyte lipid (biochemical triglyceride and long-chain acyl CoA [LCAC] from vastus lateralis biopsy and soleus and tibialis anterior intramyocellular lipid by (1)H-magnetic resonance spectroscopy), regional body and abdominal fat (dual-energy X-ray absorptiometry and magnetic resonance imaging), serum lipids, insulin action (hyperinsulinemic-euglycemic clamp), and substrate oxidation were measured in 18 nondiabetic, sedentary, and overweight to obese men (aged 37.4 +/- 1.3 years and BMI 30.9 +/- 0.7 kg/m(2), range 26.4-37.6) at baseline, after the first two to four bouts of aerobic exercise (55-70% of VO(2max) for 40 min/session), and at completion of 4.1 +/- 0.2 exercise sessions/week for 9.7 +/- 0.5 weeks (postexercise measurements performed 24-36 h after the last exercise bout). Mean whole body insulin-stimulated glucose uptake and basal fat oxidation rate increased 16 and 41%, respectively, after two to four bouts of exercise, without further increase at program end. Mean aerobic capacity increased 11%, and central abdominal fat decreased 5% at program end, but myocyte lipid levels were not significantly changed. Posttraining increases in insulin-stimulated glucose uptake were predicted by increase in aerobic capacity (r = 0.726, P = 0.001) and magnitude of reduction in visceral fat (r = -0.544, P = 0.02) and not by changes in myocyte lipid or LCAC levels. These results suggest that in overweight and obese sedentary men, increase in insulin sensitivity with moderate intensity exercise is predicted by improvement in aerobic capacity and reduction in visceral fat but is independent of myocyte triglyceride or LCAC levels.

Effects of aerobic and resistance exercise training on insulin action in the elderly

Background: Aging is associated with a declining glucose tolerance, which is primarily caused by peripheral insulin resistance, and with a decline in physical activity. The aim of this study was to assess the effect of aerobic and resistance exercise training on insulin action in the elderly.Methods: Fourteen healthy male subjects (age: 65–73 years) were enrolled and divided into two exercise groups: resistance training (RT) or a combined aerobic and resistance training (CT). Subjects participated in each training program three times a week for 12 weeks. Before and after the training program, insulin action was determined using the euglycemic clamp technique at insulin infusion rates of 40 (low) or 400 (high) mU/m2 per min. Body composition was measured by dual‐energy X‐ray absorptiometry (DXA).Results: Percent fat decreased significantly in both groups. Fat‐free mass (FFM) tended to increase in the RT group (P = 0.054), but not in the CT group. In the CT group, the glucose infusion rate (GIR) increased 16.6% (P &lt; 0.05) at the low insulin infusion rate and 21.7% (P &lt; 0.01) at the high rate. In the RT group, GIR tended to increase at the low insulin infusion rate, but was not statistically significant (P = 0.052) and increased 9.9% (P &lt; 0.05) at the high rate. When calculated per FFM, the increased insulin action persisted in the CT group (P &lt; 0.01), but not in the RT group.Conclusion: The combination of aerobic and resistance training is more effective for improving the decreased insulin action in the elderly than resistance training alone.

Effects of AICAR and exercise on insulin-stimulated glucose uptake, signaling, and GLUT-4 content in rat muscles.

Physical activity is known to increase insulin action in skeletal muscle, and data have indicated that 5'-AMP-activated protein kinase (AMPK) is involved in the molecular mechanisms behind this beneficial effect. 5-Aminoimidazole-4-carboxamide-1-beta-d-ribofuranoside (AICAR) can be used as a pharmacological tool to repetitively activate AMPK, and the objective of this study was to explore whether the increase in insulin-stimulated glucose uptake after either long-term exercise or chronic AICAR administration was followed by fiber-type-specific changes in insulin signaling and/or changes in GLUT-4 expression. Wistar rats were allocated into three groups: an exercise group trained on treadmill for 5 days, an AICAR group exposed to daily subcutaneous injections of AICAR, and a sedentary control group. AMPK activity, insulin-stimulated glucose transport, insulin signaling, and GLUT-4 expression were determined in muscles characterized by different fiber type compositions. Both exercised and AICAR-injected animals displayed a fiber-type-specific increase in glucose transport with the most marked increase in muscles with a high content of type IIb fibers. This increase was accompanied by a concomitant increase in GLUT-4 expression. Insulin signaling as assessed by phosphatidylinositol 3-kinase and PKB/Akt activity was enhanced only after AICAR administration and in a non-fiber-type-specific manner. In conclusion, chronic AICAR administration and long-term exercise both improve insulin-stimulated glucose transport in skeletal muscle in a fiber-type-specific way, and this is associated with an increase in GLUT-4 content.

Role of chromium supplementation in Indians with type 2 diabetes mellitus

Type 2 diabetes mellitus is a complex metabolic disorder with adverse cardiovascular risk. The role of micronutrients has not yet been well clarified in this condition, especially in India. The objectives of this study were to: (1) evaluate chromium status in Indian subjects with type 2 diabetes mellitus, (2) assess the effect of chromium picolinate (200 μg trivalent chromium twice daily) administration on glycaemic control and lipid profile in these subjects and (3) comment on the possible mechanism of any beneficial effect noted above. Fifty subjects were studied in a double blind, placebo-controlled, crossover fashion, with each treatment arm (chromium/placebo) lasting 12 weeks and 4 weeks’ wash-off period in between. 50 healthy age- and sex-matched volunteers served as controls. Serum chromium level appeared to be higher in the general population in our country compared to western countries (36.5–59.5 nmol/L as compared to 2.3–40.3 nmol/L) However, the local diabetics were found to have a lower serum chromium level than the healthy controls (32.3 nmol/L against 44.7 nmol/L; p < 0.0001) and a mean increase of 3.5 nmol/L was noted after 12 weeks of chromium supplementation that was, expectedly, not seen in the placebo phase ( p < 0.0001). Significant improvement in glycaemic control was noted in the chromium-treated group (ΔFasting serum glucose = 0.44 mmol/L, p < 0.001; ΔPost-prandial serum glucose = 1.97 mmol/L, p < 0.001; Δglycated hemoglobin = 0.01; p = 0.04, in comparison to placebo) This was accompanied by a significant greater fall in fasting serum insulin in the chromium-treated group, p < 0.05. The change in lipid parameters (total serum cholesterol, high density lipoprotein cholesterol, low density lipoprotein cholesterol and triglycerides) did not show significant difference between the chromium and placebo groups. Clinically significant hematological, renal or hepatic toxicity were excluded by routine hemogram, serum urea, creatinine, alanine amino transferase (ALT) and alkaline phosphatase estimations. In conclusion, chromium supplementation seems to improve glycaemic control in type 2 diabetic patients, which appears to be due to an increase in insulin action rather than stimulation of insulin secretion.

Impairment of insulin signaling in human skeletal muscle cells by co-culture with human adipocytes.

Adipocyte factors play a major role in the induction of insulin resistance in skeletal muscle. To analyze this cross-talk, we established a system of co-culture of human fat and skeletal muscle cells. Cells of three muscle donors were kept in co-culture with cells of various fat cell donors, and insulin signaling was subsequently analyzed in myocytes. Insulin-induced tyrosine phosphorylation of insulin receptor substrate (IRS)-1 was completely blocked, with unaltered expression of IRS-1. Troglitazone increased insulin action on IRS-1 phosphorylation, in both the absence and presence of co-culture. Insulin-regulated activation of Akt kinase in the myocytes was significantly reduced after co-culture, with troglitazone restoring insulin action. Addition of tumor necrosis factor (TNF)-alpha (2.5 nmol/l) to myocytes for 48 h reduced IRS-1 expression and inhibited IRS-1 and Akt phosphorylation comparable to the effect of co-culture. Lower doses of TNF-alpha were ineffective. After co-culture, TNF-alpha in the culture medium was below the detection limit of 0.3 pmol/l. A very low level of resistin was detected in the supernatant of myocytes, but not of adipocytes. In conclusion, the release of fat cell factors induces insulin resistance in human skeletal muscle cells; however, TNF-alpha and resistin appear not to be involved in this process.

Invited review: effect of acute exercise on insulin signaling and action in humans.

After a single bout of exercise, insulin action is increased in the muscles that were active during exercise. The increased insulin action has been shown to involve glucose transport, glycogen synthesis, and glycogen synthase (GS) activation as well as amino acid transport. A major mechanism involved in increased insulin stimulation of glucose uptake after exercise seems to be the exercise-associated decrease in muscle glycogen content. Muscle glycogen content also plays a pivotal role for the activity of GS and for the ability of insulin to increase GS activity. Insulin signaling in human skeletal muscle is activated by physiological insulin concentrations, but the increase in insulin action after exercise does not seem to be related to increased insulin signaling [insulin receptor tyrosine kinase activity, insulin receptor substrate-1 (IRS-1) tyrosine phosphorylation (RS1), IRS-1-associated phosphatidylinositol 3-kinase activity, Akt phosphorylation (Ser(473)), glycogen synthase kinase 3 (GSK3) phosphorylation (Ser(21)), and GSK3alpha activity], as measured in muscle lysates. Furthermore, insulin signaling is also largely unaffected by exercise itself. This, however, does not preclude that exercise influences insulin signaling through changes in the spatial arrangement of the signaling compounds or by affecting unidentified signaling intermediates. Finally, 5'-AMP-activated protein kinase has recently entered the stage as a promising player in explaining at least a part of the mechanism by which exercise enhances insulin action.

Prior exercise and the response to insulin-induced hypoglycemia in the dog.

To test whether hepatic insulin action and the response to an insulin-induced decrement in blood glucose are enhanced in the immediate postexercise state as they are during exercise, dogs had sampling (artery, portal vein, and hepatic vein) catheters and flow probes (portal vein and hepatic artery) implanted 16 days before a study. After 150 min of moderate treadmill exercise or rest, dogs were studied during a 150-min hyperinsulinemic (1 mU.kg(-1).min(-1)) euglycemic (n = 5 exercised and n = 9 sedentary) or hypoglycemic (65 mg/dl; n = 8 exercised and n = 9 sedentary) clamp. Net hepatic glucose output (NHGO) and endogenous glucose appearance (R(a)) and utilization (R(d)) were assessed with arteriovenous and isotopic ([3-(3)H]glucose) methods. Results show that, immediately after prolonged, moderate exercise, in relation to sedentary controls: 1) the glucose infusion rate required to maintain euglycemia, but not hypoglycemia, was higher; 2) R(d) was greater under euglycemic, but not hypoglycemic conditions; 3) NHGO, but not R(a), was suppressed more by a hyperinsulinemic euglycemic clamp, suggesting that hepatic glucose uptake was increased; 4) a decrement in glucose completely reversed the enhanced suppression of NHGO by insulin that followed exercise; and 5) arterial glucagon and cortisol were transiently higher in the presence of a decrement in glucose. In summary, an increase in insulin action that was readily evident under euglycemic conditions after exercise was abolished by moderate hypoglycemia. The means by which the glucoregulatory system is able to overcome the increase in insulin action during moderate hypoglycemia is related not to an increase in R(a) but to a reduction in insulin-stimulated R(d). The primary site of this reduction is the liver.

Insulin signal transduction in skeletal muscle from glucose-intolerant relatives of type 2 diabetic patients [corrected

To determine whether defects in the insulin signal transduction cascade are present in skeletal muscle from prediabetic individuals, we excised biopsies from eight glucose-intolerant male first-degree relatives of patients with type 2 diabetes (IGT relatives) and nine matched control subjects before and during a euglycemic-hyperinsulinemic clamp. IGT relatives were insulin-resistant in oxidative and nonoxidative pathways for glucose metabolism. In vivo insulin infusion increased skeletal muscle insulin receptor substrate-1 (IRS-1) tyrosine phosphorylation (P = 0.01) and phosphatidylinositide 3-kinase (PI 3-kinase) activity (phosphotyrosine and IRS-1 associated) in control subjects (P < 0.02) but not in IGT relatives (NS). The incremental increase in insulin action on IRS-1 tyrosine phosphorylation was lower in IGT relatives versus control subjects (P < 0.05). The incremental defects in signal transduction noted for IRS-1 and PI 3-kinase may be attributed to elevated basal phosphorylation/activity of these parameters, because absolute phosphorylation/activity under insulin-stimulated conditions was similar between IGT relatives and control subjects. Insulin increased Akt serine phosphorylation in control subjects and IGT relatives, with a tendency for reduced phosphorylation in IGT relatives (P = 0.12). In conclusion, aberrant phosphorylation/activity of IRS-1, PI 3-kinase, and Akt is observed in skeletal muscle from relatives of patients with type 2 diabetes with IGT. However, the elevated basal activity of these signaling intermediates and the lack of a strong correlation between these parameters to glucose metabolism suggests that other defects of insulin signal transduction and/or downstream components of glucose metabolism may play a greater role in the development of insulin resistance in skeletal muscle from relatives of patients with type 2 diabetes.

Selective angiotensin II receptor antagonism reduces insulin resistance in obese Zucker rats.

Effects of oral administration of the angiotensin II receptor antagonist (selective AT(1)-subtype) irbesartan on glucose tolerance and insulin action on skeletal-muscle glucose transport were assessed in the insulin-resistant obese Zucker rat. In the acute study, obese rats received either vehicle (water) or irbesartan 1 hour before the experiment. Although irbesartan had no effect on glucose transport (2-deoxyglucose uptake) in the epitrochlearis muscle, which consists mainly of type IIb fibers, acute angiotensin II receptor antagonism led to a dose-dependent increase in insulin action in the predominantly type I soleus muscle. Irbesartan at 25 and 50 mg/kg induced significant increases (41% and 50%, respectively; P<0.05) in insulin-mediated glucose transport. Moreover, these acute irbesartan-induced improvements in soleus-muscle glucose transport were associated with enhancements in whole-body insulin sensitivity (r=-0.732; P<0.05), as assessed during an oral glucose tolerance test. After chronic administration of irbesartan (21 days at 50 mg. kg(-1). d(-1)), glucose tolerance was enhanced further, and insulin-mediated glucose transport was significantly elevated in both epitrochlearis (32%) and soleus (73%) muscle. Chronic angiotensin II receptor antagonism was associated with significant increases in glucose transporter-4 (GLUT-4) protein expression in soleus (22%) and plantaris (20%) muscle and myocardium (15%). Chronic irbesartan-induced increases in whole-body insulin sensitivity were associated with increased insulin-mediated glucose transport in both epitrochlearis (r=-0.677; P<0.05) and soleus (r=-0.892; P<0.05) muscle. In summary, angiotensin II receptor (AT(1)-subtype) antagonism, either acutely or chronically, improves glucose tolerance, at least in part because of an enhancement in skeletal-muscle glucose transport, and the effect of chronic angiotensin II receptor antagonism on type I skeletal-muscle glucose uptake is associated with an increase in GLUT-4 protein expression.

Interactions of exercise training and lipoic acid on skeletal muscle glucose transport in obese Zucker rats.

Exercise training (ET) or the antioxidant R(+)-alpha-lipoic acid (R-ALA) individually increases insulin action in the insulin-resistant obese Zucker rat. The purpose of the present study was to determine the interactions of ET and R-ALA on insulin action and oxidative stress in skeletal muscle of the obese Zucker rat. Animals either remained sedentary, received R-ALA (30 mg x kg body wt(-1) x day(-1)), performed ET (treadmill running), or underwent both R-ALA treatment and ET for 6 wk. During an oral glucose tolerance test, ET alone or in combination with R-ALA resulted in a significant lowering of the glucose (26-32%) and insulin (29-30%) responses compared with sedentary controls. R-ALA alone decreased (19%) the glucose-insulin index (indicative of increased insulin sensitivity), and this parameter was reduced (48-52%) to the greatest extent in the ET and combined treatment groups. ET or R-ALA individually increased insulin-mediated glucose transport activity in isolated epitrochlearis (44-48%) and soleus (37-57%) muscles. The greatest increases in insulin action in these muscles (80 and 99%, respectively) were observed in the combined treatment group. Whereas the improvement in insulin-mediated glucose transport in soleus due to R-ALA was associated with decreased protein carbonyl levels (an index of oxidative stress), improvement because of ET was associated with decreased protein carbonyls as well as enhanced GLUT-4 protein. However, there was no interactive effect of ET and R-ALA on GLUT-4 protein or protein carbonyl levels. These results indicate that ET and R-ALA interact in an additive fashion to improve insulin action in insulin-resistant skeletal muscle. Because the further improvement in muscle glucose transport in the combined group was not associated with additional upregulation of GLUT-4 protein or a further reduction in oxidative stress, the mechanism for this interaction must be due to additional, as yet unidentified, factors.

Exercise training increases ERK2 activity in skeletal muscle of obese Zucker rats.

Acute exercise and training increase insulin action in skeletal muscle, but the mechanism responsible for this effect is unknown. Activation of the insulin receptor initiates signaling through both the phosphatidylinositol (PI) 3-kinase and the mitogen-activated protein kinase [MAPK, also referred to as extracellular signal-regulated kinases (ERK1/2)] pathways. Acute exercise has no effect on the PI3-kinase pathway signaling elements but does activate the MAPK pathway, which may play a role in the adaptation of muscle to exercise. It is unknown whether training produces a chronic effect on basal activity or insulin response of the MAPK pathway. The present study was undertaken to determine whether exercise training improves the activity of the MAPK pathway or its response to insulin in obese Zucker rats, a well-characterized model of insulin resistance. To accomplish this, obese Zucker rats were studied by using the hindlimb perfusion method with or without 7 wk of treadmill training. Activation of the MAPK pathway was determined in gastrocnemius muscles exposed in situ to insulin. Compared with lean Zucker rats, untrained obese Zucker rats had reduced basal and insulin-stimulated activities of ERK2 and its downstream target p90 ribosomal S6 kinase (RSK2). Seven weeks of training significantly increased basal and insulin-stimulated ERK2 and RSK2 activities, as well as insulin stimulation of MAPK kinase activity. This effect was maintained for at least 96 h in the case of ERK2. The training-induced increase in basal ERK2 activity was correlated with the increase in citrate synthase activity. Therefore, 7 wk of training increases basal and insulin-stimulated ERK2 activity. The increase in basal ERK2 activity may be related to the response of muscle to training.

Diabetes and life-styles: role of physical exercise for primary prevention.

Regular physical exercise has been known to be beneficial in the treatment of type 2 diabetes. Epidemiological studies of physical exercise: previous non-randomized studies suggested that a life-style intervention program involving diet and/or exercise reduced the progression of impaired glucose tolerance (IGT) to type 2 diabetes. Recent randomized controlled intervention trials also showed that diet and/or exercise intervention led to a significant decrease in the incidence of diabetes among those with IGT. Endocrinological and metabolic effects of exercise: in well controlled diabetic patients, physical exercise promotes utilization of blood glucose and lowers blood glucose levels. On the other hand, in poorly controlled diabetic patients with ketosis, physical exercise results in further rises in blood glucose, free fatty acids and ketone body concentrations. Long-term gentle regular jogging increases insulin action in respect of both carbohydrate and lipid metabolism despite no influence on body mass index or maximal oxygen uptake. A significant correlation was observed between deltaMCR (insulin sensitivity) and average daily steps Our recent data suggested that the improvement of insulin action by physical exercise was attributed, at least in part, to the increase in insulin-sensitive GLUT4 (glucose transporter 4) on the plasma membrane in skeletal muscle. In conclusion, as an adjunct to other forms of therapy, mild regular physical exercise will play an important role in primarily preventing type 2 diabetes.

Changes in plasma leptin and insulin action with resistive training in postmenopausal women.

To determine the effects of 16 weeks of resistive training alone (RT) and with weight loss (RT+WL) on insulin action, plasma leptin concentrations and leptin's relationship to beta-cell sensitivity to glucose, resting metabolic rate (RMR), and plasma catecholamines in older women. Fifteen obese postmenopausal women aged 50-69 y. Body composition (by dual-energy X-ray absorptiometry), RMR (by indirect calorimetry), insulin action (by 2 h hyperglycemic clamps; 7.9 mmol/l above basal plasma glucose levels), plasma leptin and insulin (by RIA), and plasma catecholamines (by enzymatic methods). RT and RT+WL resulted in significant improvements in muscular strength (P<0.01) with no changes in maximal oxygen consumption. Body weight, fat mass and percent body fat did not change with RT, but decreased with RT+WL (P<0.001). Fat-free mass and RMR increased after training when both groups were combined (P<0.05). The insulin response during the last 20 min of the 2 h hyperglycemic clamps decreased 16% after RT (P=0.05), 43% after RT+WL (P<0.05), and 29% in the entire group (P<0. 01) without any changes in glucose utilization. Plasma leptin levels did not change after RT, but decreased by 36% after RT+WL (P<0.05). Baseline leptin levels correlated with body weight (r=0.68, P<0.01), body fat mass (r=0.77, P<0.001), and RMR (kcal/d; (r=0.69, P<0.005), but not with baseline norepinephrine or epinephrine levels. Plasma leptin levels correlated with basal insulin (r=0.73, P<0.005), and approached significance with the 0-10 min and 100-120 min insulin response to hyperglycemia before training (both r=0.51, P=0.07). In the entire group, the change in insulin response from 100-120 min during the clamp correlated with the change in leptin levels (r=0.60, P<0.05), but this was not independent of changes in fat mass. Although changes in leptin levels were not related to changes in RMR or plasma catecholamines after RT with and without weight loss, the increase in insulin action after training and weight loss may be related to the decrease in leptin levels that were mediated by the loss of body fat in the obese, postmenopausal women. International Journal of Obesity (2000)24, 27-32

Androgen Effect on Insulin Action and Glucose Metabolism

Our understanding of the effect of androgens on insulin action and glucose metabolism is incomplete. Data derive from several different models and methods, and the limitations of each must be considered. Results suggest that in humans, low-dose testosterone (replacement dosages) may increase insulin action; high-dose testosterone (supplemental or pharmacologic dosages) decreases insulin action; and dehydroepiandrosterone appears to have no effect.

ACE inhibition and glucose transport in insulinresistant muscle: roles of bradykinin and nitric oxide.

Acute administration of the angiotensin-converting enzyme (ACE) inhibitor captopril enhances insulin-stimulated glucose transport activity in skeletal muscle of the insulin-resistant obese Zucker rat. The present study was designed to assess whether this effect is mediated by an increase in the nonapeptide bradykinin (BK), by a decrease in action of ANG II, or both. Obese Zucker rats (8-9 wk old) were treated for 2 h with either captopril (50 mg/kg orally), bradykinin (200 micrograms/kg ip), or the ANG II receptor (AT(1) subtype) antagonist eprosartan (20 mg/kg orally). Captopril treatment enhanced in vitro insulin-stimulated (2 mU/ml) 2-deoxyglucose uptake in the epitrochlearis muscle by 22% (251 +/- 7 vs. 205 +/- 9 pmol. mg(-1). 20 min(-1); P < 0.05), whereas BK treatment enhanced this variable by 18% (249 +/- 15 vs. 215 +/- 7 pmol. mg(-1). 20 min(-1); P < 0.05). Eprosartan did not significantly modify insulin action. The BK-mediated increase in insulin action was completely abolished by pretreatment with either the specific BK-B(2) receptor antagonist HOE 140 (200 micrograms/kg ip) or the nitric oxide synthase inhibitor N(omega)-nitro-L-arginine methyl ester (50 mg/kg ip). Collectively, these results indicate that the modulation of insulin action by BK likely underlies the metabolic effects of ACE inhibitors in the insulin-resistant obese Zucker rat. Moreover, this modulation of insulin action by BK is likely mediated through B(2) receptors and by an increase in nitric oxide production and/or action in skeletal muscle tissue.