Insulin and Muscle Growth

Human Studies Finally Show Insulin to Be Extremely Anabolic in Human Muscle Tissue -- In Vivo

by Hypertrophy

Extreme hyperinsulinemia unmasks insulin's effect to stimulate protein synthesis in human forearm.

Researchers: Teresa A. Hillier, David A. Fryburg, Linda A. Jahn, and Eugene J. Barrett Division of Endocrinology and Metabolism, Department of Internal Medicine, and General Clinical Research Center, University of Virginia Health Sciences Center, Charlottesville, Virginia 22908

Source: Am. J. Physiol. 274 (Endocrinol. Metab. 37): E1067-E1074, 1998

Summary: In 14 healthy volunteers, forearm insulin concentrations were raised 1,000-fold above basal levels while maintaining euglycemia for 4 h. Amino acids (AA) were given to either maintain basal arterial (n = 4) or venous plasma (n = 6) AA or increment arterial plasma AA by 100% (n = 4) in the forearm. Measurements were taken of forearm muscle glucose, lactate, oxygen, phenylalanine balance, and [3H]phenylalanine kinetics at baseline and at 4 h of insulin infusion.

Results: Extreme hyperinsulinemia strongly reversed postabsorptive (fasting) muscle's phenylalanine balance from a net release to an uptake. This marked anabolic effect resulted from a dramatic stimulation of protein synthesis and a modest decline in protein degradation. Furthermore, this effect was seen even when basal arterial or venous aminoacidemia was maintained. With marked hyperinsulinemia, protein synthesis increased further when plasma AA concentrations were also increased. Forearm blood flow rose at least two fold with the combined insulin and AA infusion, and this was consistent in all groups. These results demonstrate an effect of high concentrations of insulin to markedly stimulate muscle protein synthesis in vivo in adults, even when AA concentrations are not increased. This is similar to prior in vitro reports but distinct from physiological hyperinsulinemia in vivo where stimulation of protein synthesis does not occur. Therefore, the current findings suggest that the differences in insulin concentrations used in prior studies may largely explain the previously reported discrepancy between insulin action on protein synthesis in adult muscle in vivo vs. in vitro.

Discussion: Insulin is an obvious topic of interest among the largest physiques in the culture of bodybuilding. In my search for definitive answers as to the anabolic potential of exogenous insulin administration, I have been sorely disappointed in the lack of human studies showing the anabolic properties of insulin in adults. Many studies show insulin to slow protein break down but data showing insulin to be truly anabolic in muscle tissue was virtually non-existent. Despite this lack of clinical evidence, insulin use still pervades in bodybuilding.

There are a few things that need to be addressed when considering this study. First, the amount of insulin used in this study is extemely high. The quantities of insulin used are far above what should ever be attempted by bodybuilders. Second, the anabolic properties of extreme hyperinsulinemia are likely do to insulin's interaction with IGF-1 receptors, not traditional insulin receptors. Finally, the anabolic effects of extreme hyperinsulinemia were only seen with concomitant amino acid infusion. This means that if there are no amino acids floating around, you will not build muscle no matter how much insulin you are using.

The high levels of insulin used in this study are not practical for bodybuilders to consider using. The subjects blood glucose was kept constant through artificial means to prevent hypoglycemic coma. In other words kiddies, DON'T TRY THIS AT HOME! Besides the danger involved with raising insulin levels 1,000 times above normal without a controlled infusion of glucose, it isn't really necessary if you want to get an anabolic response. Think of what was done in this study like flooding the basement in order to water the lawn. The anabolic effects produced in this study were most likely due to excess insulin binding to hybrid IGF-1 receptors. The same effect through can be achieved without all the insulin by simply adding a little IGF-1. After all, you should always use the right tool for the job. I will admit that further research is necessary to further support my (and the authors of this study) assertions that the anabolic effect of insulin seen in this study was caused by interaction of insulin with IGF-1 receptors. Nevertheless, it would be nice to see bodybuilders use less insulin and perhaps begin to incorporate a mixture of compounds that more closely resembles the complex interaction of hormones which exist naturally in the body.

J Clin Invest. 1995 Feb;95(2):811-9.Click here to read Click here to read Links
Physiologic hyperinsulinemia stimulates protein synthesis and enhances transport of selected amino acids in human skeletal muscle.
Biolo G, Declan Fleming RY, Wolfe RR.

Department of Internal Medicine, University of Texas Medical Branch, Galveston.

We have investigated the mechanisms of the anabolic effect of insulin on muscle protein metabolism in healthy volunteers, using stable isotopic tracers of amino acids. Calculations of muscle protein synthesis, breakdown, and amino acid transport were based on data obtained with the leg arteriovenous catheterization and muscle biopsy. Insulin was infused (0.15 mU/min per 100 ml leg) into the femoral artery to increase femoral venous insulin concentration (from 10 +/- 2 to 77 +/- 9 microU/ml) with minimal systemic perturbations. Tissue concentrations of free essential amino acids decreased (P < 0.05) after insulin. The fractional synthesis rate of muscle protein (precursor-product approach) increased (P < 0.01) after insulin from 0.0401 +/- 0.0072 to 0.0677 +/- 0.0101%/h. Consistent with this observation, rates of utilization for protein synthesis of intracellular phenylalanine and lysine (arteriovenous balance approach) also increased from 40 +/- 8 to 59 +/- 8 (P < 0.05) and from 219 +/- 21 to 298 +/- 37 (P < 0.08) nmol/min per 100 ml leg, respectively. Release from protein breakdown of phenylalanine, leucine, and lysine was not significantly modified by insulin. Local hyperinsulinemia increased (P < 0.05) the rates of inward transport of leucine, lysine, and alanine, from 164 +/- 22 to 200 +/- 25, from 126 +/- 11 to 221 +/- 30, and from 403 +/- 64 to 595 +/- 106 nmol/min per 100 ml leg, respectively. Transport of phenylalanine did not change significantly. We conclude that insulin promoted muscle anabolism, primarily by stimulating protein synthesis independently of any effect on transmembrane transport.

Impaired anabolic response of muscle protein synthesis is associated with S6K1 dysregulation in elderly humans.
Guillet C, Prod'homme M, Balage M, Gachon P, Giraudet C, Morin L, Grizard J, Boirie Y.

Unité du Métabolisme Protéino-Energétique, UMR Université d'Auvergne/INRA, CRNH, Centre Hospitalier Universitaire, Clermont-Ferrand, France.

Age-related loss of muscle protein may involve a decreased response to anabolic factors of muscle protein synthesis through dysregulation of translation factors. To verify this hypothesis, we simultaneously investigated muscle protein synthesis and expression of some factors implicated in insulin signal transduction during hyperinsulinemia and hyperaminoacidemia in 6 young (25+/-1 year; mean+/-sem) and 8 elderly subjects (72+/-2 year). Incorporation of L-[1-13C] leucine in muscle proteins (fractional synthesis rate, FSR) was measured in vastus lateralis, before and during a euglycemic hyperinsulinemic hyperaminoacidemic clamp, together with Western blot analysis of protein kinase B (PKB), mTOR, 4E-BP1, and S6K1 phosphorylation. In basal state, muscle protein FSR was reduced in elderly in comparison with young subjects (0.061+/-0.004% per hour) vs 0.082+/-0.010% per hour, elderly vs. young, P<0.05). During clamp, muscle protein FSR was stimulated in young (0.119+/-0.006% per hour; P<0.05), but this response was significantly lower in elderly subjects (0.084+/-0.005% per hour, P<0.05 vs young subjects). Phosphorylation of PKB, mTOR, and 4E-BP1 were similarly increased by insulin and amino acid in both groups, except for S6K1 phosphorylation, which was not stimulated in elderly subjects. In conclusion, 1) response of muscle protein synthesis to insulin and amino acid is impaired in elderly humans; 2) a defect in S6K1 pathway activation may be responsible for this alteration. This modification is a mechanistic basis of sarcopenia development during aging.

J Pediatr Surg. 2004 Jun;39(6):839-44; discussion 839-44.Click here to read Links
Intravenous insulin decreases protein breakdown in infants on extracorporeal membrane oxygenation.
Agus MS, Javid PJ, Ryan DP, Jaksic T.

Department of Medicine, Children's Hospital Boston, Harvard Medical School, Boston, MA 02115, USA.

BACKGROUND/PURPOSE: Infants requiring extracorporeal membrane oxygenation (ECMO) have the highest rates of protein catabolism ever reported. Recent investigations have found that such extreme protein breakdown is refractory to conventional nutritional management. In this pilot study, the authors sought to use the anabolic hormone insulin to reduce the profound protein degradation in this cohort. METHODS: Four parenterally fed infants on ECMO were enrolled in a prospective, randomized, crossover trial. Subjects were administered an insulin infusion using a 4-hour hyperinsulinemic euglycemic clamp followed by a control saline infusion on consecutive days in random order. Whole-body protein flux and breakdown were quantified using a primed continuous infusion of the stable isotope L-[1-13C]leucine. Statistical analyses were performed using paired t tests. RESULTS: Serum insulin levels were increased 15-fold during the insulin clamp compared with the saline control (407 +/- 103 v 26 +/- 12 microU/mL; P <.05). During the insulin infusion, infants had decreased rates of total leucine flux (214 +/- 25 v 298 +/- 38 micromol/kg/h; P <.05) and leucine flux derived from protein breakdown (156 +/- 40 v 227 +/- 54 micromol/kg/h; P <.05) when compared with saline control. Overall, insulin administration produced a 32% reduction in protein breakdown (P <.05). CONCLUSIONS: In this pilot study, the anabolic hormone insulin markedly reduced protein breakdown in critically ill infants on ECMO. Because elevated protein breakdown correlates with mortality and morbidity, the administration of intravenous insulin may ultimately have broad applicability to the metabolic management of critically ill infants.

Am J Physiol Endocrinol Metab. 2004 Apr;286(4):E529-34. Epub 2003 Dec 9.Click here to read Links
Extremity hyperinsulinemia stimulates muscle protein synthesis in severely injured patients.
Gore DC, Wolf SE, Sanford AP, Herndon DN, Wolfe RR.

The University of Texas Medical Branch, 301 University Boulevard, Galveston, TX 77555-1172, USA. dcgore@utmb.edu

Insulin has a well-recognized anabolic effect on muscle protein, yet critically ill, severely injured patients are often considered "resistant" to the action of insulin. The purpose of this study was to assess the in vivo effects of hyperinsulinemia on human skeletal muscle in severely injured patients. To accomplish this goal, 14 patients with burns encompassing >40% of their body surface area underwent metabolic evaluation utilizing isotopic dilution of phenylalanine, femoral artery and vein blood sampling, and sequential muscle biopsies of the leg. After baseline metabolic measurements were taken, insulin was infused into the femoral artery at 0.45 mIU.min(-1).100 ml leg volume(-1) to create a local hyperinsulinemia but with minimal systemic perturbations. Insulin administration increased femoral venous concentration of insulin (P < 0.01) but with only a 4% (insignificant) decrease in the arterial glucose concentration and a 7% (insignificant) decrease in the arterial concentration of phenylalanine. Extremity hyperinsulinemia significantly increased leg blood flow (P < 0.05) and the rate of muscle protein synthesis (P < 0.05). Neither the rate of muscle protein breakdown nor the rate of transmembrane transport of phenylalanine was significantly altered with extremity hyperinsulinemia. In conclusion, this study demonstrates that insulin directly stimulates muscle protein synthesis in severely injured patients.

Diabetes. 1996 Sep;45(9):1245-52.Links
Contribution of amino acids and insulin to protein anabolism during meal absorption.
Volpi E, Lucidi P, Cruciani G, Monacchia F, Reboldi G, Brunetti P, Bolli GB, De Feo P.

Department of Internal Medicine, Endocrine and Metabolic Sciences, University of Perugia, Italy.

The contribution of dietary amino acids and endogenous hyperinsulinemia to prandial protein anabolism still has not been established. To this end, leucine estimates ([1-14C]leucine infusion, plasma alpha-ketoisocaproic acid [KIC] specific activity [SA] as precursor pool SA) of whole-body protein kinetics and fractional secretory rates (FSRs) of albumin, fibrinogen, antithrombin III, and immunoglobulin G (IgG) were measured in three groups of healthy volunteers during intragastric infusion of water (controls, n = 5), liquid glucose-lipid-amino acid (AA) meal (meal+AA, n = 7), or isocaloric glucose-lipid meal (meal-AA, n = 7) that induced the same insulin response as the meal+AA. The results of this study demonstrate that 1) by increasing (P < 0.01) whole-body protein synthesis and decreasing (P < 0.01) proteolysis, dietary amino acids account for the largest part (approximately 90%) of postprandial protein anabolism; 2) the ingestion of an isocaloric meal deprived of amino acids exerts a modest protein anabolic effect (10% of postprandial protein anabolism) by decreasing amino acid oxidation and increasing (P < 0.01) albumin synthesis; 3) albumin FSR is increased (approximately 20%) by postprandial hyperinsulinemia (meal-AA) and additionally increased (approximately 50%) by amino acid intake (meal+AA); 4) IgG FSR is stimulated (approximately 40%) by amino acids, not by insulin; and 5) fibrinogen and antithrombin III FSR are not regulated by amino acids or insulin.

J Clin Invest. 1995 Feb;95(2):811-9.Click here to read Click here to read Links
Physiologic hyperinsulinemia stimulates protein synthesis and enhances transport of selected amino acids in human skeletal muscle.
Biolo G, Declan Fleming RY, Wolfe RR.

Department of Internal Medicine, University of Texas Medical Branch, Galveston.

We have investigated the mechanisms of the anabolic effect of insulin on muscle protein metabolism in healthy volunteers, using stable isotopic tracers of amino acids. Calculations of muscle protein synthesis, breakdown, and amino acid transport were based on data obtained with the leg arteriovenous catheterization and muscle biopsy. Insulin was infused (0.15 mU/min per 100 ml leg) into the femoral artery to increase femoral venous insulin concentration (from 10 +/- 2 to 77 +/- 9 microU/ml) with minimal systemic perturbations. Tissue concentrations of free essential amino acids decreased (P < 0.05) after insulin. The fractional synthesis rate of muscle protein (precursor-product approach) increased (P < 0.01) after insulin from 0.0401 +/- 0.0072 to 0.0677 +/- 0.0101%/h. Consistent with this observation, rates of utilization for protein synthesis of intracellular phenylalanine and lysine (arteriovenous balance approach) also increased from 40 +/- 8 to 59 +/- 8 (P < 0.05) and from 219 +/- 21 to 298 +/- 37 (P < 0.08) nmol/min per 100 ml leg, respectively. Release from protein breakdown of phenylalanine, leucine, and lysine was not significantly modified by insulin. Local hyperinsulinemia increased (P < 0.05) the rates of inward transport of leucine, lysine, and alanine, from 164 +/- 22 to 200 +/- 25, from 126 +/- 11 to 221 +/- 30, and from 403 +/- 64 to 595 +/- 106 nmol/min per 100 ml leg, respectively. Transport of phenylalanine did not change significantly. We conclude that insulin promoted muscle anabolism, primarily by stimulating protein synthesis independently of any effect on transmembrane transport.

Baillieres Clin Endocrinol Metab. 1993 Oct;7(4):989-1005.Links
Insulin action on protein metabolism.
Biolo G, Wolfe RR.

Shriners Burns Institute, Galveston, TX 77550.

On the basis of the preceding observations, the following sequence of events can be postulated during insulin deficiency or excess. The main feature of insulin deficiency is the disruption of protein balance in muscle that rapidly leads to emaciation and wasting. Muscle protein degradation is greatly enhanced while increased amino acid availability maintains protein synthesis. In splanchnic tissues, both degradation and synthesis are increased but with an altered pattern, so that the levels of some proteins are increased (e.g. proteins of the acute-phase response), while those of others are decreased (e.g. albumin). As a result, intracellular protein content in liver is maintained but secretion of plasma proteins is abnormal. In healthy subjects, an acute increase in insulin concentration, as occurs after a meal, leads to a rapid suppression of protein breakdown in the splanchnic area. If hyperinsulinaemia is not supported by an exogenous amino acid supply, as might occur during a protein-free meal or experimentally during euglycaemic hyperinsulinaemic clamping, the plasma as well as muscle free amino acid concentration drops, owing to reduced splanchnic release. With reduced amino acid availability, insulin is not anabolic in muscle. If amino acid concentrations are maintained at normal or high levels, e.g. following a mixed meal, a net protein deposition in muscle may occur, primarily because of a stimulation of synthesis and possibly owing to inhibition of breakdown.

Novartis Found Symp. 2004;262:56-77; discussion 77-83, 265-8.Links
IGF-1 and insulin as growth hormones.
Laron Z.

Endocrinology and Diabetes Research Unit, Schneider Children's Medical Center, WHO Collaborating Center for the Study of Diabetes in Youth, Petah Tikva and Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.

IGF-1 generated in the liver is the anabolic effector and linear growth promoting hormone of the pituitary growth hormone (GH). This is evidenced by dwarfism in states of congenital IGF-1 deficiency, Igf1 gene mutation/deletions or knockouts, and in Laron syndrome (LS), due to GH receptor gene mutations/deletions or IGF-1 receptor blocking. In a positive way, daily IGF-1 administration to stunted patients with LS or hGH gene deletion accelerates linear growth velocity. IGF-1 acts on the proliferative cells of the epiphyseal cartilage. IGF-1 also induces organ and tissue growth; its absence causing organomicria. Insulin shares a common ancestry with IGF-1 and with 45% amino acid homology, as well as very close relationships in the structure of its receptors and post-receptor cascade, also acts as a growth hormone. It has protein anabolic activity and stimulates IGF-1 synthesis. Pancreas agenesis causes short babies, and obese children with hyperinsulinism, with or without pituitary GH, have an accelerated growth rate and skeletal maturation; so do babies with macrosomia. Whether the insulin growth effect is direct, or mediated by IGF-1 or leptin is controversial.