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All-things Insulin, Metformin, GLP-1,Sulfonylureas
- Thread starter SHINE
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SHINE
Friends Remembered
- Oct 11, 2010
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Used in the bodybuilding world for insulin insensitivity after or during GH use and insulin use as well.
Diabetes (2002) 51: 2074-81.
Metformin increases AMP-activated protein kinase activity in skeletal muscle of subjects w
N Musi, MF Hirshman, J Nygren, M Svanfeldt, P Bavenholm, O Rooyackers, G Zhou, JM Williamson, O Ljunqvist, S Efendic, DE Moller, A Thorell, LJ Goodyear
Metformin is an effective hypoglycemic drug that lowers blood glucose concentrations by decreasing hepatic glucose production and increasing glucose disposal in skeletal muscle; however, the molecular site of metformin action is not well understood. AMP-activated protein kinase (AMPK) activity increases in response to depletion of cellular energy stores, and this enzyme has been implicated in the stimulation of glucose uptake into skeletal muscle and the inhibition of liver gluconeogenesis. We recently reported that AMPK is activated by metformin in cultured rat hepatocytes, mediating the inhibitory effects of the drug on hepatic glucose production. In the present study, we evaluated whether therapeutic doses of metformin increase AMPK activity in vivo in subjects with type 2 diabetes. Metformin treatment for 10 weeks significantly increased AMPK alpha2 activity in the skeletal muscle, and this was associated with increased phosphorylation of AMPK on Thr172 and decreased acetyl-CoA carboxylase-2 activity. The increase in AMPK alpha2 activity was likely due to a change in muscle energy status because ATP and phosphocreatine concentrations were lower after metformin treatment. Metformin-induced increases in AMPK activity were associated with higher rates of glucose disposal and muscle glycogen concentrations. These findings suggest that the metabolic effects of metformin in subjects with type 2 diabetes may be mediated by the activation of AMPK alpha2
Diabetes (2002) 51: 2074-81.
Metformin increases AMP-activated protein kinase activity in skeletal muscle of subjects w
N Musi, MF Hirshman, J Nygren, M Svanfeldt, P Bavenholm, O Rooyackers, G Zhou, JM Williamson, O Ljunqvist, S Efendic, DE Moller, A Thorell, LJ Goodyear
Metformin is an effective hypoglycemic drug that lowers blood glucose concentrations by decreasing hepatic glucose production and increasing glucose disposal in skeletal muscle; however, the molecular site of metformin action is not well understood. AMP-activated protein kinase (AMPK) activity increases in response to depletion of cellular energy stores, and this enzyme has been implicated in the stimulation of glucose uptake into skeletal muscle and the inhibition of liver gluconeogenesis. We recently reported that AMPK is activated by metformin in cultured rat hepatocytes, mediating the inhibitory effects of the drug on hepatic glucose production. In the present study, we evaluated whether therapeutic doses of metformin increase AMPK activity in vivo in subjects with type 2 diabetes. Metformin treatment for 10 weeks significantly increased AMPK alpha2 activity in the skeletal muscle, and this was associated with increased phosphorylation of AMPK on Thr172 and decreased acetyl-CoA carboxylase-2 activity. The increase in AMPK alpha2 activity was likely due to a change in muscle energy status because ATP and phosphocreatine concentrations were lower after metformin treatment. Metformin-induced increases in AMPK activity were associated with higher rates of glucose disposal and muscle glycogen concentrations. These findings suggest that the metabolic effects of metformin in subjects with type 2 diabetes may be mediated by the activation of AMPK alpha2
SHINE
Friends Remembered
- Oct 11, 2010
- 5,047
- 601
Insulin Causes Vasodilation in Muscle
Insulin Causes Vasodilation in Muscle
by Robbie Durand, M.A., C.S.C.S.
Bio/Chem insulin
Nothing beats a good pump in the gym. Getting a good pump is determined by nitric oxide production in the body, but in addition to taking a nitric oxide precursor; a good insulin spike will also lead to better pumps.
It is well known that insulin is needed for glucose transport into the cells. Insulin can also redirect nutrient blood flow to capillary beds in skeletal muscle leading to enhance blood flow. It has been demonstrated that, within minutes, insulin significantly increases vasodilation in resting skeletal muscle (1). That’s right, if you just drink water during your workouts you may be missing out on insulin’s vasodilating effects on muscle. Insulin enhances both skeletal muscle glucose uptake and total leg blood flow in a dose-dependent fashion (2, 3) (the more insulin is increased, the greater the increase in blood flow.) Studies have shown that insulin-induced increases in total muscle blood flow temporally lag behind the stimulation of muscle glucose uptake (2).
The exact mechanisms by which insulin increases blood flow is unknown but it is speculated to be the result from either a direct vasodilator action of insulin (via receptors on the vascular cells) or indirectly from a signal generated from the stimulation of metabolism within skeletal muscle cells. Insulin could act similar to exercise-induced hyperemia, (Hyperemia describes the increase of blood flow in response to exercise), where muscle blood flow increases to provide sufficient oxygen and nutrients to support muscle contraction. NO is one of many vasodilators found in the vascular system; there is evidence for the involvement of adenosine, potassium, and lactate (6). It is conceivable that any one of these could mediate the increased flow in response to insulin.
Insulin has an effect on increasing NO production, which may be the partial reason for its effects on vasodilation (12). The observation that inhibition of nitric oxide (NO) synthase by the nitric oxide inhibitor (L-NMMA) abolishes insulin-induced increases of leg blood flow in humans and diminishes (~25%) glucose uptake4 supports a physiological role for insulin action on muscle vasodilation4.
High Intensity Exercise is Key for Nitric Oxide Production
During resistance exercise when skeletal muscle contracts, the number of capillaries that control blood flow open up several-fold - this depends on the exercise intensity. To get a good pump, exercise needs to be performed with high intensity. Higher-intensity exercise both enhances vasodilation and increases total blood flow. Studies have shown that low-intensity forearm exercise increases vasodilation without changing total forearm blood flow, whereas higher-intensity exercise increases both forearm blood flow and vasodilation (5). So to get the most of a muscle pump, use high intensity exercise with large muscle groups, and with short rest periods. Training harder causes physiological adaptations which leads to better pumps and more blood flow.
Trained athletes have elevated basal blood flow to muscle during exercise compared with untrained individuals8. Insulin may be part of the answer to this, as Hardin et al.9 demonstrated that insulin-stimulated blood flow was 31% higher in athletes than in controls.
Being a Porker with Insulin Resistance Causes Reduced Blood Flow
If you have a lot of fat on you, you won’t get the same kind of increase in muscle blood flow as someone who is leaner. Insulin, it has been well documented, increases forearm blood flow, but in obese patients there is impaired forearm blood flow compared to lean individuals. The overweight subjects were also more insulin resistant than their leaner controls. In summary, the reduced increase in muscle blood flow in obese subjects was associated with a decline in skeletal muscle insulin-mediated glucose uptake; this suggests insulin resistance.
Furthermore, Dela et al. (10) found that insulin-stimulated blood flow increased after 10 weeks of one-legged training in both healthy subjects and type 2 diabetic patients. The increase in insulin stimulated blood flow was thought to increase in both healthy and diabetic individuals due to increased insulin sensitivity in muscle. So is it glucose or insulin that causes the vasodilation in muscle endothelium? Both need to be present for optimal vasodilation. Intra-arterial infusion of insulin in physiological doses causes forearm vasodilation, which is increased by co-infusion of glucose, leading researchers to speculate that local insulin-mediated vasodilation may depend on insulin-mediated glucose uptake in muscle (14).
Studies by Vollenweider et al (7). have suggested that increased muscle cell glucose metabolism, needed to generate a metabolic vasodilator response, fails to cause vasodilation in the absence of insulin. Whereas combined insulin and glucose infusion significantly increased calf blood flow, there was no such increase during fructose infusion in which insulin levels remained low, but a similar rise in carbohydrate oxidation was achieved.
NSAIDS and High Fat Diets: Pump Killers
As discussed previously, insulin is needed for a good vasodilatory response in blood vessels. If you want to get a better pump during your workouts you need to spike your glucose levels before exercise to get a good insulin response. Now let’s look at some of the pump killers... NO and cyclooxygenase (COX) produce important mediators of vasodilation. The regulation of these enzymes and their capacity to participate in molecular cross-talk is important for vasodilation. COX-2 is mediated in the pain and inflammation response, with many NSAIDS and prescription drugs targeting the COX-2 enzyme for pain relief.
By taking NSAIDS (which blocks all COX enzymes) muscle vasodilation is reduced. Insulin induces an endothelium-dependent vasodilation in normal arteries; however, it has been demonstrated that the mechanism is primarily COX enzyme dependent (11). Another big mistake is to eat a high fat meal before a workout; a high fat meal before exercise can antagonize insulin-mediated glucose uptake. Additionally, the infusion of fatty acids has been shown to reduce insulin mediated glucose uptake in skeletal muscle (13).
It makes sense to get a better pump in the gym and load up on your nitric oxide supplement; but be sure to wash it down with a high carbohydrate/ amino acid beverage to increase vasodilation.
References
1. Rattigan S, Bradley EA, Richards SM, Clark MG. Muscle metabolism and control of capillary blood flow: insulin and exercise. Essays Biochem. 2006;42:133-44. Review.
2. Baron A: Hemodynamic actions of insulin. Am J Physiol267 :E187 –E202,1994.
3. Yki-Jarvinen H, Utriainen T: Insulin-induced vasodilatation: physiology or pharmacology? Diabetologia 41 :369 –379,1998.
4. Steinberg HO, Brechtel G, Johnson A, Fineberg F, Baron AD: Insulin-mediated skeletal muscle vasodilation is nitric oxide dependent: a novel action of insulin to increase nitric oxide release. J Clin Invest 94 :1172 –1179,1994.
5. Jahn L, Vincent MA, Lindner JR, Barrett EJ: Modest exercise enhances human skeletal muscle perfusion by capillary recruitment in the absence of changes in total blood flow. Diabetes51 (Suppl. 2) :A59 ,2002.
6. Segal, SS. Convection, diffusion and mitochondrial utilization of oxygen during exercise. In: Perspectives in Exercise Science and Sports Medicine Vol 5: Energy Metabolism in Exercise and Sport, edited by Lamb DR, and Gisolfi CV.. Dubuque, Iowa, XX: Brown & Benchmark, 1992, p. 269-344.
7. Vollenweider, P, Tappy L, Randin D, Schneiter P, Jequier E, Nicod P, and Scherrer U. Differential effects of hyperinsulinemia and carbohydrate metabolism on sympathetic nerve activity and muscle blood flow in humans. J Clin Invest 92: 147-154, 1993.
8. Ebeling, P, Bourey R, Koranyi L, Tuominen JA, Groop LC, Henriksson J, Mueckler M, Sovijarvi A, and Koivisto VA. Mechanism of enhanced insulin sensitivity in athletes. Increased blood flow, muscle glucose transport protein (GLUT-4) concentration, and glycogen synthase activity. J Clin Invest 92: 1623-1631, 1993.
9. Hardin, DS, Azzarelli B, Edwards J, Wigglesworth J, Maianu L, Brechtel G, Johnson A, Baron A, and Garvey WT. Mechanisms of enhanced insulin sensitivity in endurance-trained athletes: effects on blood flow and differential expression of GLUT 4 in skeletal muscles. J Clin Endocrinol Metab 80: 2437-2446, 1995.
10. Dela, F, Larsen JJ, Mikines KJ, Ploug T, Petersen LN, and Galbo H. Insulin-stimulated muscle glucose clearance in patients with NIDDM. Effects of one-legged physical training. Diabetes 44: 1010-1020, 1995.
11. Miller AW, Tulbert C, Puskar M, Busija DW. Enhanced endothelin activity prevents vasodilation to insulin in insulin resistance. Hypertension. 2002 Jul;40(1):78-82.
12. Scherrer U, Randin D, Vollenweider P, Vollenweider L, Nicod P. Nitric oxide release accounts for insulin's vascular effects in humans. J Clin Invest. 1994;94:2511–2515.
13. Clerk LH, Rattigan S, Clark MG: Lipid infusion impairs physiologic insulin-mediated capillary recruitment and muscle glucose uptake in vivo. Diabetes51 :1138 –1145,2002.
14. Ueda S, Petrie JR, Cleland SJ, Elliott HL, Connell JM. Vasodilator response to local hyperinsulinemia. Hypertension. 1999 Dec;34(6):e12-3.
Insulin Causes Vasodilation in Muscle
by Robbie Durand, M.A., C.S.C.S.
Bio/Chem insulin
Nothing beats a good pump in the gym. Getting a good pump is determined by nitric oxide production in the body, but in addition to taking a nitric oxide precursor; a good insulin spike will also lead to better pumps.
It is well known that insulin is needed for glucose transport into the cells. Insulin can also redirect nutrient blood flow to capillary beds in skeletal muscle leading to enhance blood flow. It has been demonstrated that, within minutes, insulin significantly increases vasodilation in resting skeletal muscle (1). That’s right, if you just drink water during your workouts you may be missing out on insulin’s vasodilating effects on muscle. Insulin enhances both skeletal muscle glucose uptake and total leg blood flow in a dose-dependent fashion (2, 3) (the more insulin is increased, the greater the increase in blood flow.) Studies have shown that insulin-induced increases in total muscle blood flow temporally lag behind the stimulation of muscle glucose uptake (2).
The exact mechanisms by which insulin increases blood flow is unknown but it is speculated to be the result from either a direct vasodilator action of insulin (via receptors on the vascular cells) or indirectly from a signal generated from the stimulation of metabolism within skeletal muscle cells. Insulin could act similar to exercise-induced hyperemia, (Hyperemia describes the increase of blood flow in response to exercise), where muscle blood flow increases to provide sufficient oxygen and nutrients to support muscle contraction. NO is one of many vasodilators found in the vascular system; there is evidence for the involvement of adenosine, potassium, and lactate (6). It is conceivable that any one of these could mediate the increased flow in response to insulin.
Insulin has an effect on increasing NO production, which may be the partial reason for its effects on vasodilation (12). The observation that inhibition of nitric oxide (NO) synthase by the nitric oxide inhibitor (L-NMMA) abolishes insulin-induced increases of leg blood flow in humans and diminishes (~25%) glucose uptake4 supports a physiological role for insulin action on muscle vasodilation4.
High Intensity Exercise is Key for Nitric Oxide Production
During resistance exercise when skeletal muscle contracts, the number of capillaries that control blood flow open up several-fold - this depends on the exercise intensity. To get a good pump, exercise needs to be performed with high intensity. Higher-intensity exercise both enhances vasodilation and increases total blood flow. Studies have shown that low-intensity forearm exercise increases vasodilation without changing total forearm blood flow, whereas higher-intensity exercise increases both forearm blood flow and vasodilation (5). So to get the most of a muscle pump, use high intensity exercise with large muscle groups, and with short rest periods. Training harder causes physiological adaptations which leads to better pumps and more blood flow.
Trained athletes have elevated basal blood flow to muscle during exercise compared with untrained individuals8. Insulin may be part of the answer to this, as Hardin et al.9 demonstrated that insulin-stimulated blood flow was 31% higher in athletes than in controls.
Being a Porker with Insulin Resistance Causes Reduced Blood Flow
If you have a lot of fat on you, you won’t get the same kind of increase in muscle blood flow as someone who is leaner. Insulin, it has been well documented, increases forearm blood flow, but in obese patients there is impaired forearm blood flow compared to lean individuals. The overweight subjects were also more insulin resistant than their leaner controls. In summary, the reduced increase in muscle blood flow in obese subjects was associated with a decline in skeletal muscle insulin-mediated glucose uptake; this suggests insulin resistance.
Furthermore, Dela et al. (10) found that insulin-stimulated blood flow increased after 10 weeks of one-legged training in both healthy subjects and type 2 diabetic patients. The increase in insulin stimulated blood flow was thought to increase in both healthy and diabetic individuals due to increased insulin sensitivity in muscle. So is it glucose or insulin that causes the vasodilation in muscle endothelium? Both need to be present for optimal vasodilation. Intra-arterial infusion of insulin in physiological doses causes forearm vasodilation, which is increased by co-infusion of glucose, leading researchers to speculate that local insulin-mediated vasodilation may depend on insulin-mediated glucose uptake in muscle (14).
Studies by Vollenweider et al (7). have suggested that increased muscle cell glucose metabolism, needed to generate a metabolic vasodilator response, fails to cause vasodilation in the absence of insulin. Whereas combined insulin and glucose infusion significantly increased calf blood flow, there was no such increase during fructose infusion in which insulin levels remained low, but a similar rise in carbohydrate oxidation was achieved.
NSAIDS and High Fat Diets: Pump Killers
As discussed previously, insulin is needed for a good vasodilatory response in blood vessels. If you want to get a better pump during your workouts you need to spike your glucose levels before exercise to get a good insulin response. Now let’s look at some of the pump killers... NO and cyclooxygenase (COX) produce important mediators of vasodilation. The regulation of these enzymes and their capacity to participate in molecular cross-talk is important for vasodilation. COX-2 is mediated in the pain and inflammation response, with many NSAIDS and prescription drugs targeting the COX-2 enzyme for pain relief.
By taking NSAIDS (which blocks all COX enzymes) muscle vasodilation is reduced. Insulin induces an endothelium-dependent vasodilation in normal arteries; however, it has been demonstrated that the mechanism is primarily COX enzyme dependent (11). Another big mistake is to eat a high fat meal before a workout; a high fat meal before exercise can antagonize insulin-mediated glucose uptake. Additionally, the infusion of fatty acids has been shown to reduce insulin mediated glucose uptake in skeletal muscle (13).
It makes sense to get a better pump in the gym and load up on your nitric oxide supplement; but be sure to wash it down with a high carbohydrate/ amino acid beverage to increase vasodilation.
References
1. Rattigan S, Bradley EA, Richards SM, Clark MG. Muscle metabolism and control of capillary blood flow: insulin and exercise. Essays Biochem. 2006;42:133-44. Review.
2. Baron A: Hemodynamic actions of insulin. Am J Physiol267 :E187 –E202,1994.
3. Yki-Jarvinen H, Utriainen T: Insulin-induced vasodilatation: physiology or pharmacology? Diabetologia 41 :369 –379,1998.
4. Steinberg HO, Brechtel G, Johnson A, Fineberg F, Baron AD: Insulin-mediated skeletal muscle vasodilation is nitric oxide dependent: a novel action of insulin to increase nitric oxide release. J Clin Invest 94 :1172 –1179,1994.
5. Jahn L, Vincent MA, Lindner JR, Barrett EJ: Modest exercise enhances human skeletal muscle perfusion by capillary recruitment in the absence of changes in total blood flow. Diabetes51 (Suppl. 2) :A59 ,2002.
6. Segal, SS. Convection, diffusion and mitochondrial utilization of oxygen during exercise. In: Perspectives in Exercise Science and Sports Medicine Vol 5: Energy Metabolism in Exercise and Sport, edited by Lamb DR, and Gisolfi CV.. Dubuque, Iowa, XX: Brown & Benchmark, 1992, p. 269-344.
7. Vollenweider, P, Tappy L, Randin D, Schneiter P, Jequier E, Nicod P, and Scherrer U. Differential effects of hyperinsulinemia and carbohydrate metabolism on sympathetic nerve activity and muscle blood flow in humans. J Clin Invest 92: 147-154, 1993.
8. Ebeling, P, Bourey R, Koranyi L, Tuominen JA, Groop LC, Henriksson J, Mueckler M, Sovijarvi A, and Koivisto VA. Mechanism of enhanced insulin sensitivity in athletes. Increased blood flow, muscle glucose transport protein (GLUT-4) concentration, and glycogen synthase activity. J Clin Invest 92: 1623-1631, 1993.
9. Hardin, DS, Azzarelli B, Edwards J, Wigglesworth J, Maianu L, Brechtel G, Johnson A, Baron A, and Garvey WT. Mechanisms of enhanced insulin sensitivity in endurance-trained athletes: effects on blood flow and differential expression of GLUT 4 in skeletal muscles. J Clin Endocrinol Metab 80: 2437-2446, 1995.
10. Dela, F, Larsen JJ, Mikines KJ, Ploug T, Petersen LN, and Galbo H. Insulin-stimulated muscle glucose clearance in patients with NIDDM. Effects of one-legged physical training. Diabetes 44: 1010-1020, 1995.
11. Miller AW, Tulbert C, Puskar M, Busija DW. Enhanced endothelin activity prevents vasodilation to insulin in insulin resistance. Hypertension. 2002 Jul;40(1):78-82.
12. Scherrer U, Randin D, Vollenweider P, Vollenweider L, Nicod P. Nitric oxide release accounts for insulin's vascular effects in humans. J Clin Invest. 1994;94:2511–2515.
13. Clerk LH, Rattigan S, Clark MG: Lipid infusion impairs physiologic insulin-mediated capillary recruitment and muscle glucose uptake in vivo. Diabetes51 :1138 –1145,2002.
14. Ueda S, Petrie JR, Cleland SJ, Elliott HL, Connell JM. Vasodilator response to local hyperinsulinemia. Hypertension. 1999 Dec;34(6):e12-3.
SHINE
Friends Remembered
- Oct 11, 2010
- 5,047
- 601
Metformin Restores Leptin Sensitivity in High-Fat–Fed Obese Rats With Leptin Resistance
Metformin, an oral biguanide insulin-sensitizing agent, inhibits hepatic glucose production, enhances the effects of insulin on glucose uptake in skeletal muscles and adipocytes, and decreases intestinal absorption of glucose (4–7). It is also well known that metformin administration reduces body weight (8,9). Moreover, metformin decreases leptin concentration in morbidly obese subjects (9,10) and in normal-weight healthy men (11). Although leptin concentration is closely related to body fat mass, the leptin-reducing effect of metformin cannot be fully explained by body weight reduction because metformin reduces leptin level even without changing body weight in normal-weight healthy men (11). However, the mechanisms by which metformin reduces body weight and leptin concentration are poorly understood. In addition, it has been recently reported that metformin targets AMP-activated protein kinase (AMPK), which is also activated by leptin (12–14). The above findings imply that a more delicate interaction takes place between metformin and leptin. We hypothesized that metformin increases leptin sensitivity and that the anorexic and leptin-reducing effects of metformin are a result of increased leptin sensitivity....................... http://diabetes.diabetesjournals.org/content/55/3/716.full
Metformin, an oral biguanide insulin-sensitizing agent, inhibits hepatic glucose production, enhances the effects of insulin on glucose uptake in skeletal muscles and adipocytes, and decreases intestinal absorption of glucose (4–7). It is also well known that metformin administration reduces body weight (8,9). Moreover, metformin decreases leptin concentration in morbidly obese subjects (9,10) and in normal-weight healthy men (11). Although leptin concentration is closely related to body fat mass, the leptin-reducing effect of metformin cannot be fully explained by body weight reduction because metformin reduces leptin level even without changing body weight in normal-weight healthy men (11). However, the mechanisms by which metformin reduces body weight and leptin concentration are poorly understood. In addition, it has been recently reported that metformin targets AMP-activated protein kinase (AMPK), which is also activated by leptin (12–14). The above findings imply that a more delicate interaction takes place between metformin and leptin. We hypothesized that metformin increases leptin sensitivity and that the anorexic and leptin-reducing effects of metformin are a result of increased leptin sensitivity....................... http://diabetes.diabetesjournals.org/content/55/3/716.full
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