Insulin signaling in the whole spectrum of GH deficiency

Heraldo Mendes Garmes Alejandro Rosell Castillo About the authors

ABSTRACT

GH is one of the insulin counterregulatory hormones which acts in the opposite way to insulin, increasing the glucose production by the liver and kidneys and decreasing glucose uptake from peripheral tissues, thus being a hyperglycemic hormone. When in excess, as in acromegaly, it induces glucose intolerance and diabetes. As expected, patients with GH deficiency (GHD) have hypoglycemia, especially in early childhood, but as GH is also a lipolytic hormone, these patients are becoming obese with higher percentages of body fat. Although obesity in general is directly related to insulin resistance, in patients with GH secretion disorders this relationship may be altered. In acromegaly there is a decrease in fat mass with worsening insulin sensitivity and mice with isolated GHD are characterized by greater insulin sensitivity despite excess fat mass. In humans with GHD, body composition shows increased body fat and decreased free fat mass, but the results regarding insulin sensitivity are still controversial in these patients. These discrepant results regarding insulin sensitivity in patients with GHD suggest the existence of other variables influencing these results. In the present review, we will try to follow the path of the different researches conducted on this subject, both in animal and human models, with the goal of understanding the current knowledge of insulin sensitivity across the spectrum of GHD. Arch Endocrinol Metab. 2019;63(6):582-91

GH deficiency; insulin sensitivity; euglicemic hyperinsulinemic clamp

INTRODUCTION

GH deficiency (GHD) is characterized by signs and symptoms resulting from decreased serum GH levels that vary according to the age of patient. Adult GHD syndrome was first described in 1992 (11. Cuneo RC, Salomon F, McGauley GA, Sonksen PH. The growth hormone deficiency syndrome in adults. Clin Endocrinol. 1992;37:387-97.), as a consequence of diseases that compromise the anatomy and secretory function of pituitary somatotrophic cells or interfere with peripheral GH action. They have varied etiologies, from inherited genetic factors to acquired lesions, such as tumors, inflammatory processes and vascular lesions. The etiology or therapy of these varied etiologies can directly influence insulin sensitivity regardless of the decrease in serum GH levels. Adults with GHD may be classified according to stage of disease onset; when it begins in childhood, congenital diseases are the most common etiologies, being secondary to pituitary structural lesions in most cases who have onset in adulthood (22. Molitch ME, Clemmons DR, Malozowski S, Merriam GR, Vance ML; Endocrine Society. Evaluation and Treatment of Adult Growth Hormone Deficiency: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2011;96:1587-609.).

From a clinical standpoint in childhood GHD usually produces severe hypoglycemia, sometimes associated with seizures, prolonged hyperbilirubinemia and hypothermia. Height at birth is usually normal. After 12 months of age, there is usually short stature, with decreased growth velocity and delayed bone maturation (33. Toogood AA, Stewart PM. Hypopituitarism: Clinical features, diagnosis, and management. Endocrinol Metab Clin North Am. 2008;37:235-61.). GHD in adults is not associated with a single symptom or pathognomonic sign, usually adults have nonspecific symptoms such as weakness, social isolation and difficulty concentrating. The most specific and striking changes are those of body composition with increased fat mass of 7% to 10% higher than expected for age, sex and height and decreased muscle mass, total body water and bone mineral density (44. Rosen T, Wiren L, Wilhelmsen L, Wiklund I, Bengtsson BA. Decreased psychological well-being in adult patients with growth hormone deficiency. Clin Endocrinol (Oxf). 1994;40:111-6.

5. De Boer H, Blok GJ, Voerman HJ, De Vries PM, van der Veen EA. Body composition in adult growth hormone-deficient men, assessed by anthropometry and bioimpedance analysis. J Clin Endocrinol Metab. 1992;75:833-7.
-66. Rosen T, Wilhelmsen L, Landin-Wilhelmsen K, Lappas G, Bengtsson BA. Increased fracture frequency in adult patients with hypopituitarism and GH deficiency. Eur J Endocrinol. 1997;137:240-5.). GHD often overlaps with metabolic syndrome in relation to obesity and hyperlipidemia.

In this sense, we know that the percentage of fat tissue is increased in patients with GHD and that decreased insulin sensitivity (IS) is a characteristic of overweight and metabolic syndrome, but the relationship between IS and GHD is still controversial. In the context of GHD the results of animal studies have shown that there is a greater IS in this condition, while human studies have contradictory results. These discrepant results regarding IS in patients with GHD suggest the existence of other variables influencing these results. In this paper we review the complex physiology that influences glucose metabolism and IS in GHD patients, the results from animal and human studies about IS in GHD and discuss presumed factors that would justify the discrepancy of results in assessing IS in these patients

INSULIN

Human insulin is a protein with a molecular weight of 5.808 Kda and is made up of two amino acid chains, linked via disulfide bonds (77. Patti M-E, Kahn CR. The Insulin Receptor – A Critical Link in Glucose Homeostasis and Insulin Action. J Basic Clin Physiol Pharmacol. 1998;9:2-4.). To exert its effects on target cells, insulin binds and activates a membrane protein receptor, which is formed by four subunits that are held together by disulfide bonds: two alpha subunits, which are located entirely on the outside of the cell membrane and two beta subunits, which penetrate through the membrane, projecting into the cell cytoplasm. Insulin couples to alpha subunits and induces phosphorylation of the intracellular portion of the receptor (77. Patti M-E, Kahn CR. The Insulin Receptor – A Critical Link in Glucose Homeostasis and Insulin Action. J Basic Clin Physiol Pharmacol. 1998;9:2-4.). Autophosphorylation of receptor beta subunits activates a local tyrosine kinase, which in turn causes phosphorylation of several other intracellular enzymes, including the group called insulin receptor substrates (88. Saad MJ, Araki E, Miralpeix M, Rothenberg PL, White MF, Kahn CR. Regulation of insulin receptor substrate-1 in liver and muscle of animal models of insulin resistance. J Clin Invest. 1992;90: 1839-49.). The main effects of insulin stimulation are to promote glucose uptake in muscle and hepatic tissue and its storage in glycogen form, to further promote the conversion of excess glucose into fatty acids for lipogenesis, to inhibit hepatic glucose production and finally to promote protein synthesis and storage in muscle tissue (99. Huang PL. A comprehensive definition for metabolic syndrome. Dis Model Mech. 2009;2:231-7.).

Although several plasma factors play an important role in the control of insulin secretion, serum glucose concentration is the main regulator of its secretion, and increased blood glucose induces insulin release to restore normoglycemia. On the other hand, lowering glycemic levels rapidly induces interruption of insulin secretion and activates various counterregulation mechanisms in order to increase glucose levels. There is increased glucagon secretion by the pancreatic alpha cells, the hypothalamus stimulates the sympathetic nerve system and later both cortisol and GH are secreted in response to hypoglycemia. These hormones decrease glucose uptake by peripheral tissues and increase glucose production in the liver and kidneys, helping to prevent hypoglycemia (1010. Himsworth HP. RBK. Insulin-sensitive and insulin-insensitive types of diabetes mellitus. Clin Sci. 1939;4:119-52.,1111. Taylor SI, Accili D, Imai Y. Insulin resistance or insulin deficiency. Which is the primary cause of NIDDM?. Diabetes. 1994;43:735-40.).

GROWTH HORMONE (GH)

The GH, also known as somatotropic hormone or somatotropin, is a protein that contains 191 single chain amino acids with a molecular weight of 22.005 Kda (1212. Tsai YC, Cooke NE, Liebhaber SA. Long-range looping of a locus control region drives tissue-specific chromatin packing within a multigene cluster. Nucleic Acids Res. 2016;44:4651-64.). It is produced by pituitary somatotrophs, and its secretion occurs in pulses that are controlled by the hypothalamus through GH-releasing hormone (GHRH), somatostatin and ghrelin (1313. Melmed S. Acromegaly pathogenesis and treatment. J Clin Invest. 2009;119:3189-202.,1414. Casanueva FF, Camiña JP, Carreira MC, Pazos Y, Varga JL, Schally AV. Growth hormone-releasing hormone as an agonist of the ghrelin receptor GHS-R1a. Proc Natl Acad Sci U S A. 2008;105:20452-7.). Somatostatin exerts an inhibitory effect, while GHRH and ghrelin stimulate GH secretion through different specific G protein-coupled receptors. GH pulses are greater at night and may not exist during the day, when their serum level may be undetectable, especially in obese and elderly people. Episodic release of GH increases with exercise and fasting. GH secretion is suppressed by increased glucose levels and is stimulated by insulin-induced hypoglycemia (1515. Yamashita S, Melmed S. Insulin-like growth factor I action on rat anterior pituitary cells: suppression of growth hormone secretion and messenger ribonucleic acid levels. Endocrinology. 1986;118:176-82.

16. Roth J, Glick SM, Yalow RS, Berson SA. Hypoglycemia: a potent stimulus to secretion of growth hormone. Science. 1963;140:987-8.

17. Luger A, Watschinger B, Deuster P, Svoboda T, Clodi M, Chrousos GP. Plasma growth hormone and prolactin responses to graded levels of acute exercise and to a lactate infusion. Neuroendocrinology. 1992;56:112-17.

18. Vila G, Maier C, Riedl M, Noworny P, Ludvik B, Luger A, et al. Bacterial endotoxin induces biphasic changes in plasma ghrelin in healthy humans. J Clin Endocrinol Metab. 2007;92:3930-4.

19. Hartman ML, Clayton PE, Johnson ML, Celniker A, Perlman AJ, Alberti KG, et al. A low dose euglycemic infusion of recombinant human insulin-like growth factor I rapidly suppresses fasting-enhanced pulsatile growth hormone secretion in humans. J Clin Invest. 1993;91:2453-62.
-2020. Casanueva F, Villanueva L, Penalva A, Vila T, Cabezas-Cerrato J. Free fatty acid inhibition of exercise-induced growth hormone secretion. Horm Metab Res. 1981;13:348-50.).

Upon secretion, GH binds to its peripheral receptors (GHRs) which belong to specifically class 1 cytokine receptor family. These receptors are expressed in various tissues of the organism especially the liver, cartilage, muscle, fat, pancreas and in the kidneys. Following binding of GH to the receptor, intracellular signal transduction is triggered by activation and phosphorylation of the enzyme janus kinase 2 (JAK2), resulting in the engagement of various intracellular signaling proteins, including signal transducers and activators of transcription (STAT), and mitogen-activated protein kinase (MAP) pathway components that in turn regulate target genes such as hepatic genes for the production of insulin-like growth factor-1 (IGF-1) (2121. Brooks AJ, Dai W, O’Mara ML, Abankwa D, Chhabra Y, Pelekanos RA, et al. Mechanism of activation of protein kinase JAK2 by the growth hormone receptor. Science. 2014;344:1249783.

22. Carter-Su C, Schwartz J, Argetsinger LS. Growth hormone signaling pathways. Growth Horm IGF Res. 2016;28:11-5.

23. Rotwein P. Mapping the growth hormone–Stat5b–IGF-I transcriptional circuit. Trends Endocrinol Metab. 2012;23:186-93.
-2424. Kofoed EM, Hwa V, Little B, Woods KA, Buckway CK, Tsubaki J, et al. Growth hormone insensitivity associated with a STAT5b mutation. N Engl J Med. 2003; 349: 1139-1147.). GH and IGF-1 are known to have independent actions in both growth and metabolism (2525. Yakar S, Liu JL, Stannard B, Butler A, Accili D, Sauer B, et al. Normal growth and development in the absence of hepatic insulin-like growth factor I. Proc Natl Acad Sci U S A. 1999;96:7324-9.).

In addition to its general growth-provoking effect, growth hormone has several specific metabolic effects including increased protein synthesis; increased fatty acid mobilization of adipose tissue inducing increased blood level of fatty acids and increased use of fatty acids as a source of energy. There is also reduced utilization of glucose and increased hepatic and renal glucose production (2626. Kupfer SR, Underwood LE, Baxter RC, Clemmons DR. Enhancement of the anabolic effects of growth hormone and insulin-like growth factor I by use of both agents simultaneously. J Clin Invest. 1993;91:391-6.

27. Chikani V, Ho KK. Action of GH on skeletal muscle function: molecular and metabolic mechanisms. J Mol Endocrinol. 2013;52:R107-23.

28. Vijayakumar A, Yakar S, Leroith D. The intricate role of growth hormone in metabolism. Front Endocrinol (Lausanne). 2011;2:32.

29. Zhao JT, Cowley MJ, Lee P, Birzniece V, Kaplan W, Ho KK. Identification of novel GH-regulated pathway of lipid metabolism in adipose tissue: a gene expression study in hypopituitary men. J Clin Endocrinol Metab. 2011;96:E1188-96.
-3030. Mazziotti G, Frara S, Giustina A. Pituitary diseases and bone. Endocr Rev. 2018;39:440-88.). These changes result in growth hormone-induced insulin resistance that favors increased blood glucose. The ability of GH to promote the catabolic effect on adipose tissues along with the anabolic effect on muscle tissue induces increased lean mass.

The IGF-1 produced in the liver by GH stimulation suppresses GH secretion by negative feedback and negativaly regulates GH receptors through paracrine action (3131. Leung K, Rajkovic IA, Peters E, Markus I, Van Wyk JJ, Ho KK. Insulin-like growth factor I and insulin down-regulate growth hormone (GH) receptors in rat osteoblasts: evidence for a peripheral feedback loop regulating GH action. Endocrinology. 1996;137:2694-702.). IGF-I, also known as somatomedine C, belongs to the IGF system, which consists of different elements: IGF-I and IGF-2, two receptor types: IGFR-1 and IGFR-2 and various binding proteins IGFBP 1 to 6. The IGFs have a high degree of structural homology with insulin, which has an acceptable affinity for IGFR-1 and the IGF-1 also has affinity for insulin receptor (3232. Jones JI, Clemmons DR. Insulin-like growth factors and their binding proteins: biological actions. Endocr Rev. 1995;16:3-34.). IGF-1 has an important effect on carbohydrate metabolism, and studies have shown that IGF-1 can exert insulin-like effects on blood transport and glucose concentrations (3333. Frara S, Maffezzoni F, Mazziotti G, Giustina A. Current and emerging aspects of diabetes mellitus in acromegaly. Trends Endocrinol Metab. 2016;27:470-83.

34. Di Cola G, Cool MH, Accili D. Hypoglycemic effect of insulin-like growth factor-1 in mice lacking insulin receptors. J Clin Invest. 1997;99:2538-544.
-3535. Froesch ER, Schmid C, Schwander J, Zapf J. Actions of insulin like growth factors. Annu Rev Physiol. 1985;47:443-67.). It is noteworthy that it is not yet well understood which effects on carbohydrate metabolism depend on the action of GH or IGF-1.

INSULIN SENSITIVITY

The concept of IS was introduced by Sir Harold Himsworth in 1939 when studying the response of diabetic patients to glycemic and insulin stimulus (99. Huang PL. A comprehensive definition for metabolic syndrome. Dis Model Mech. 2009;2:231-7.). Insulin resistance is defined as a decrease in the sensitivity of peripheral tissues (skeletal muscle, adipose and liver) to insulin actions, it is a metabolic state in which target cells have insufficient response to normal levels of circulating insulin, thus being an important predictor of Diabetes Mellitus type 2 development (99. Huang PL. A comprehensive definition for metabolic syndrome. Dis Model Mech. 2009;2:231-7.

10. Himsworth HP. RBK. Insulin-sensitive and insulin-insensitive types of diabetes mellitus. Clin Sci. 1939;4:119-52.
-1111. Taylor SI, Accili D, Imai Y. Insulin resistance or insulin deficiency. Which is the primary cause of NIDDM?. Diabetes. 1994;43:735-40.).

INSULIN SENSITIVITY ASSESSMENT METHOD

To assess IS many methods have been developed, it can be accessed through direct methods or indirect markers. Direct evaluation can investigate the action of exogenous insulin, as in the euglycemic hyperinsulinemic clamp (EHC) or endogenous insulin released from a stimulus as in the glucose tolerance test (TTG) and Bergman’s minimal model, hyperglycemic clamp, oral glucose tolerance test (OGTT) or with foods such as mixed meal tolerance test (MTT) (3636. Bergman RN, Phillips LS, Cobelli C. Physiologic evaluation of factors controlling glucose tolerance in man: measurement of insulin sensitivity and beta-cell glucose sensitivity from the response to intravenous glucose. J Clin Invest. 1981;68:1456-67.). The EHC is considered the gold standard to investigate IS (3737. Andres R, Swerdloff R, Pozefsky T, Coleman D. Manual feedback technique for the control of blood glucose concentration. In: Skeggs LT Jr (ed.): Automation in analytical chemistry. New York: Mediad. 1966;486-91.), since the other tests are influenced by several factors involved in the glucose metabolism such as pancreatic alpha and beta cell function, incretinic and counterregulators hormones and hepatic glucose production (3636. Bergman RN, Phillips LS, Cobelli C. Physiologic evaluation of factors controlling glucose tolerance in man: measurement of insulin sensitivity and beta-cell glucose sensitivity from the response to intravenous glucose. J Clin Invest. 1981;68:1456-67.,3838. Ferrannini E, Mari A. How to measure insulin sensitivity. J Hypertens. 1998;16:895-906.,3939. Bonadonna RC, Groop L, Kraemer N, Ferrannini E, Del Prato S, DeFronzo RA. Obesity and insulin resistance in humans: a dose-response study. Metabolism. 1990;39:452-9.). However, the cost, technical difficulties and execution time make it difficult to use the EHC in clinical practice and even in clinical research. Thus, several authors seek indirect markers that are more accessible for investigating insulin sensitivity as homeostatic model assessment insulin resistance (HOMA-IR) (3838. Ferrannini E, Mari A. How to measure insulin sensitivity. J Hypertens. 1998;16:895-906.).

Patients with multiple pituitary deficiency have impaired glucose metabolism and cannot increase the production of counter-regulating hormones, such as cortisol and GH, when blood glucose decreases. Because of this, they cannot increase glucose production in the context of hypoglycemia. Therefore, to assess IS in patients with GHD, a method that removes the influence of counterregulatory hormones on glucose production and uptake by the liver and peripheral tissues should be used. As previously explained, EHC is a good method for investigating IS which, due to its hyperinsulinemic state induces suppression of endogenous glucose production, removing the influence of the absence of counterregulatory hormones and does not depend on an insulin secretion which can be impaired in GHD patients (4040. Liu JL, Coschigano KT, Robertson K, Lipsett M, Guo Y, Kopchick JJ, et al. Disruption of growth hormone receptor gene causes diminished pancreatic islet size and increased insulin sensitivity in mice. Am J Physiol Endocrinol Metab. 2004;287:405-13.). It only evaluates insulin-dependent glucose uptake, faithfully representing the sensitivity to insulin action in these patients. In this regard, studies in humans have already demonstrated the lack of correlation between EHC and other methods used to assess IS in patients with GHD (4141. Ciresi A, Guarnotta V, Pizzolanti G, Giordano C. Comparison between euglycemic hyperinsulinemic clamp and surrogate indices of insulin sensitivity in children with growth hormone deficiency. Growth Horm IGF Res. 2018;39:40-4.,4242. Castillo AR, de Souza AL, Alegre SM, Atala YB, Zantut-Wittmann DE, Garmes HM. Insulin Sensitivity Is Not Decreased in Adult Patients With Hypopituitarism Without Growth Hormone Replacement. Front Endocrinol. 2019;10:534.) suggesting that using other methods may induce controversial results. Therefore, in this review we considered only scientific studies that used HEC as a method for assessing IS in patients with GHD.

BMI is known to be inversely related to IS in humans and GHD patients have increased fat mass and decreased free fat mass. In this sense, it is important to compare IS data in patients with GHD with a control group paired by BMI, as well as age and gender that also influence the assessment of IS. Therefore, we only use in this review studies that evaluated IS in GHD patients and compared them to age, sex and BMI matched groups, avoiding controversial results.

INSULIN SENSITIVITY IN ANIMAL MODELS

In the 1990s in order to better understand the physiological effects of growth hormone, a strain of GHR receptor (GHR -/-) disrupted mice was generated in the laboratory. These mice are insensitive to GH and have low levels of IGF-1 and high GH. They are small and the organs are also proportionally small. In addition to these characteristics, GHR -/- mice have low insulin and glucose levels and are sensitive to insulin, although they are glucose intolerant due to pancreatic islet size reduction. One of the most interesting features is that these mice have a longer life expectancy and are resistant to various cancers (4040. Liu JL, Coschigano KT, Robertson K, Lipsett M, Guo Y, Kopchick JJ, et al. Disruption of growth hormone receptor gene causes diminished pancreatic islet size and increased insulin sensitivity in mice. Am J Physiol Endocrinol Metab. 2004;287:405-13.,4343. Coschigano KT, Holland AN, Riders ME, List EO, Flyvbjerg A, Kopchick JJ. Deletion, but not antagonism, of the mouse growth hormone receptor results in severely decreased body weights, insulin, and insulin-like growth factor I levels and increased life span. Endocrinology. 2003;144:3799-810.

44. Lubbers ER, List EO, Jara A, Sackman-Sala L, Cordoba-Chacon J, Gahete MD, et al. Adiponectin in mice with altered GH action: links to insulin sensitivity and longevity? J Endocrinol. 2013;216:363-74.
-4545. Junnila RK, Duran-Ortiz S, Suer O, Sustarsic EG, Berryman DE, List EO, et al. Disruption of the GH Receptor Gene in Adult Mice Increases Maximal Lifespan in Females. Endocrinology. 2016;157:4502-13.). More recently other mouse strains have been developed: an onset isolated GHD (AOiGHD) model with selective acquired destruction of somatotrophic cells in the anterior pituitary and a model that presents a genetic mutation in the gene encoding GH (GH -/-), with both presenting low GH and IGF-1 levels (4646. Luque RM, Lin Q, Córdoba-Chacón J, Subbaiah PV, Buch T, Waisman A, et al. Metabolic impact of adult-onset, isolated, growth hormone deficiency (AOiGHD) due to destruction of pituitary somatotropes. PLoS One. 2011;19:15767.,4747. List EO, Berryman DE, Buchman M, Jensen EA, Funk K, Duran-Ortiz S. GH “knockout” mice have increased subcutaneous adipose tissue with decreased fibrosis and enhanced insulin sensitivity. Endocrinology. 2019;160:1743-56.). These mouse strains, like the GHR -/- strain have low levels of insulin and glycemia, are extremely sensitive to insulin when compared to controls despite having a higher amount of fat, and are also intolerant to glucose due to a decrease in size of the pancreatic islets (4646. Luque RM, Lin Q, Córdoba-Chacón J, Subbaiah PV, Buch T, Waisman A, et al. Metabolic impact of adult-onset, isolated, growth hormone deficiency (AOiGHD) due to destruction of pituitary somatotropes. PLoS One. 2011;19:15767.,4747. List EO, Berryman DE, Buchman M, Jensen EA, Funk K, Duran-Ortiz S. GH “knockout” mice have increased subcutaneous adipose tissue with decreased fibrosis and enhanced insulin sensitivity. Endocrinology. 2019;160:1743-56.). It is noteworthy that in these studies the method used for IS evaluation was the insulin tolerance test (ITT) (4040. Liu JL, Coschigano KT, Robertson K, Lipsett M, Guo Y, Kopchick JJ, et al. Disruption of growth hormone receptor gene causes diminished pancreatic islet size and increased insulin sensitivity in mice. Am J Physiol Endocrinol Metab. 2004;287:405-13.,4343. Coschigano KT, Holland AN, Riders ME, List EO, Flyvbjerg A, Kopchick JJ. Deletion, but not antagonism, of the mouse growth hormone receptor results in severely decreased body weights, insulin, and insulin-like growth factor I levels and increased life span. Endocrinology. 2003;144:3799-810.

44. Lubbers ER, List EO, Jara A, Sackman-Sala L, Cordoba-Chacon J, Gahete MD, et al. Adiponectin in mice with altered GH action: links to insulin sensitivity and longevity? J Endocrinol. 2013;216:363-74.

45. Junnila RK, Duran-Ortiz S, Suer O, Sustarsic EG, Berryman DE, List EO, et al. Disruption of the GH Receptor Gene in Adult Mice Increases Maximal Lifespan in Females. Endocrinology. 2016;157:4502-13.

46. Luque RM, Lin Q, Córdoba-Chacón J, Subbaiah PV, Buch T, Waisman A, et al. Metabolic impact of adult-onset, isolated, growth hormone deficiency (AOiGHD) due to destruction of pituitary somatotropes. PLoS One. 2011;19:15767.
-4747. List EO, Berryman DE, Buchman M, Jensen EA, Funk K, Duran-Ortiz S. GH “knockout” mice have increased subcutaneous adipose tissue with decreased fibrosis and enhanced insulin sensitivity. Endocrinology. 2019;160:1743-56.). On the other hand, other studies in transgenic animals with global antagonism in GH (GHa) and AOiGHD using EHC for IS evaluation showed similar IS in relation to controls (4848. Haluzik M, Yakar S, Gavrilova O, Setser J, Boisclair Y, LeRoith D. Insulin resistance in the liver-specific IGF-1 gene-deleted mouse is abrogated by deletion of the acid-labile subunit of the IGF-binding protein-3 complex: relative roles of growth hormone and IGF-1 in insulin resistance. Diabetes. 2003;52:2483-9.

49. Yakar S, Setser J, Zhao H, Stannard B, Haluzik M, Glatt V, et al. Inhibition of growth hormone action improves insulin sensitivity in liver IGF-1-deficient mice. J Clin Invest. 2004;113:96-105.
-5050. Cordoba-Chacon J, Gahete MD, McGuinness OP, Kineman RD. Differential impact of selective GH deficiency and endogenous GH excess on insulin-mediated actions in muscle and liver of male mice. Am J Physiol Endocrinol Metab. 2014;307:928-34.).

All of these animal models have been very helpful in better understanding the effects and functions of GH aiming to establish a similarity with what happens in humans. GHR -/- animal models have the pattern of Laron Syndrome, AOiGHD would be equivalent to acquired isolated GHD in adults and the newer GH -/- animal model would simulate what happens in isolated GHD syndrome. Finally, the authors of these studies observed that there is a consensus in animal model studies that non-action of GH would lead to decreased insulin and glucose levels, glucose intolerance and increased IS despite having a higher percentage of fat (4747. List EO, Berryman DE, Buchman M, Jensen EA, Funk K, Duran-Ortiz S. GH “knockout” mice have increased subcutaneous adipose tissue with decreased fibrosis and enhanced insulin sensitivity. Endocrinology. 2019;160:1743-56.,5151. Duran-Ortiz S, Noboa V, Kopchick JJ. Disruption of the GH receptor gene in adult mice and in insulin sensitive tissues. Growth Horm IGF Res. 2018;38:3-7.) (Table 1).

Table 1
Insulin sensitivity (IS) in some types of animals without GH signaling

INSULIN SENSITIVITY IN GHD FROM CONGENITAL DISEASES

In a human cohort with a mutation of the GHRH receptor gene, known as isolated GHD (IGHD), GH and IGF-1 levels are significantly decreased from birth. Although these patients have normal size at birth, they evolve with low growth velocity and severe short stature. IGHD patients have a significant increase in visceral fat (5252. Gomes-Santos E, Salvatori R, Ferrão TO, Oliveira CRP, Diniz RDCA, Santana JAM, et al. Increased Visceral Adiposity and Cortisol to Cortisone Ratio in Adults With Congenital Lifetime Isolated GH Deficiency. J Clin Endocrinol Metab. 2014;99:3285-9.), but IS is increased in relation to age, sex and BMI matched control group when evaluated by HOMA-IR and similar to control group when assessed by glucose and insulin curves from GTT, clearly showing that patients with IGHD do not have insulin resistance (5353. Oliveira CR, Salvatori R, Barreto-Filho JA, Rocha IE, Mari A, Pereira RM, et al. Insulin Sensitivity and β-Cell Function in Adults with Lifetime, Untreated Isolated Growth Hormone Deficiency. J Clin Endocrinol Metab. 2012;97:1013-9.). It is noteworthy that, in this same study, the authors also showed that these patients have decreased HOMA-β, indicating lower insulin secretion capacity, justifying a higher percentage of patients with glucose intolerance when compared to the control group.

Regarding patients with GH resistance due to multiple inactivating mutation on the GH receptor gene, Laron Syndrome, some regions of the world concentrate a larger number of patients. In the Israeli cohort, body composition showed excess percentage of body fat associated with low muscle and bone mass (5454. Laron Z, Ginsberg S, Lilos P, Arbiv M, Vaisman N. Body composition in untreated adult patients with Laron syndrome (primary GH insensitivity). Clin Endocrinol (Oxf). 2006;65:114-7.). Patients had frequent hypoglycemia in early childhood and blood glucose levels were lower than in the normal population, with higher serum insulin levels for concomitant glucose level (5555. Laron Z, Avitzur Y, Klinger B. Carbohydrate metabolism in primary growth hormone resistance (Laron syndrome) before and during insulin-like growth factor-I treatment. Metabolism [Internet]. 1995;44:113-8.). In the Ecuadorian cohort, despite obesity, patients had lower blood glucose, insulin and HOMA-IR values, indicating better insulin sensitivity and had a lower incidence of diabetes than their relatives (5656. Guevara-Aguirre J, Procel P, Guevara C, Guevara-Aguirre M, Rosado V, Teran E. Despite higher body fat content, Ecuadorian subjects with Laron syndrome have less insulin resistance and lower incidence of diabetes than their relatives. Growth Horm IGF Res. 2016;28:76-8.). Interestingly, a study comparing these patients with a group of patients with intrauterine growth retardation, severe short stature, decreased pancreatic reserve, but normal GH signaling demonstrated its importance for the presence of insulin resistance, since this group of patients with normal signaling presented insulin resistance and early onset type 2 diabetes (5757. Guevara-Aguirre J, Guevara A, Bahamonde M. Insulin resistance depends on GH counter-regulation in two syndromes of short stature. Growth Horm IGF Res. 2018;38:44-8.).

INSULIN SENSITIVITY IN ACROMEGALY AND AFTER GH REPLACEMENT

The classic counterregulatory effect of insulin exerted by GH justifies the high rates of glucose intolerance and diabetes mellitus found in patients with acromegaly, where excess GH induces insulin resistance (5858. Hansen I, Tsalikian E, Beaufrere B, Gerich J, Haymond M, Rizza R. Insulin resistance in acromegaly: defects in both hepatic and extrahepatic insulin action. Am J Physiol. 1986;250:269-73.

59. Karlander S, Vranić M, Efendić S. Increased glucose turnover and glucose cycling in acromegalic patients with normal glucose tolerance. Diabetologia. 1986;29:778-83.

60. Møller N, Schmitz O, Jøorgensen JO, Astrup J, Bak JF, Christensen SE, et al. Basal- and insulin-stimulated substrate metabolism in patients with active acromegaly before and after adenomectomy. J Clin Endocrinol Metab. 1992;74:1012-19.
-6161. Møller N, Jørgensen JOL. Effects of Growth Hormone on Glucose, Lipid, and Protein Metabolism in Human Subjects. Endocr Rev [Internet]. 2009;30:152-77.). GH has a lipolytic effect, increasing serum FFA levels that could compromise insulin action. The patient with acromegaly is an example of a patient with low fat mass percentage and insulin resistance. Excess circulating FFA and insulin resistance would induce beta cell failure over time, favoring glucose intolerance present in more than 50% of patients with new diagnosis of acromegaly (6262. Alexopoulou O, Bex M, Kamenicky P, Mvoula AB, Chanson P, Maiter D. Prevalence and risk factors of impaired glucose tolerance and diabetes mellitus at diagnosis of acromegaly: a study in 148 patients. Pituitary. 2014;17:81-9.).

In turn, GH replacement treatment in patients with GHD also seems to induce decreased IS. Although some studies have shown increased IS with GH replacement (6363. Roemmler J, Kuenkler M, Schneider HJ, Dieterle C, Schopohl J. Comparison of glucose and lipid metabolism and bone mineralization in patients with growth hormone deficiency with and without long-term growth hormone replacement. Metabolism. 2010;59:350-8.), most studies using HEC as an evaluation method have shown worsening IS with GH therapy in both adults (6464. Fowelin J, Attvall S, Lager I, Bengtsson BA. Effects of treatment with recombinant human growth hormone on insulin sensitivity and glucose metabolism in adults with growth hormone deficiency. Metabolism 1993;42:1443-7.

65. Christopher M, Hew FL, Oakley M, Rantzau C, Alford F. Defects of Insulin Action and Skeletal Muscle Glucose Metabolism in Growth Hormone-Deficient Adults Persist after 24 Months of Recombinant Human Growth Hormone Therapy. J Clin Endocrinol Metab. 1998;83:1668-81.
-6666. Bramnert M, Segerlantz M, Laurila E, Daugaard JR, Manhem P, Groop L. Growth Hormone Replacement Therapy Induces Insulin Resistance by Activating the Glucose-Fatty Acid Cycle. J Clin Endocrinol Metab. 2003;88:1455-63.) and children (6767. Heptulla RA, Boulware SD, Caprio S, Silver D, Sherwin RS, Tamborlane WV. Decreased Insulin Sensitivity and Compensatory Hyperinsulinemia after Hormone Treatment in Children with Short Stature. J Clin Endocrinol Metab. 1997;82:3234-8.,6868. Ciresi A, Amato MC, Giordano C. Reduction in insulin sensitivity and inadequate β-cell capacity to counteract the increase in insulin resistance in children with idiopathic growth hormone deficiency during 12 months of growth hormone treatment. J Endocrinol Invest. 2015;38:351-9.) evidencing the role of GH as a counterregulatory hormone. Also regarding treatment, it is noteworthy that in adults with GHD, low doses of GH appear to exert less insulin counterregulatory effect than classic doses aiming to normalize IGF-1 (6969. Yuen KC, Frystyk J, White DK, Twickler TB, Koppeschaar HP, Harris PE, et al. Improvement in insulin sensitivity without concomitant changes in body composition and cardiovascular risk markers following fixed administration of a very low growth hormone (GH) dose in adults with severe GH deficiency. Clin Endocrinol (Oxf). 2005;63:428-36.), and these contrarregulatory effects are more evident in obese and older (7070. Luger A, Mattsson AF, Koltowska-Häggström M, Thunander M, Góth M, Verhelst J, et al. Incidence of diabetes mellitus and evolution of glucose parameters in growth hormone-deficient subjects during growth hormone replacement therapy: a long-term observational study. Diabetes Care. 2012;35:57-62.).

Regarding the mechanisms involved in GH-induced SI worsening, a 2 x 2 factorial design study using the EHC method showed that acipimox, a lipolysis-blocking drug, prevents GH-induced IS worsening in patients with GHD (7171. Nielsen S, Møller N, Christiansen JS, Jørgensen JO. Pharmacological antilipolysis restores insulin sensitivity during growth hormone exposure. Diabetes. 2001;50:2301-8.). These results have been confirmed by other authors, suggesting that the decrease in IS caused by GH may be related to its lipolytic effect that increases serum levels of free fatty acid and intramyocellular triglyceride content, worsening IS (7272. Segerlantz M, Bramnert M, Manhem P, Laurila E, Groop LC. Inhibition of lipolysis during acute GH exposure increases insulin sensitivity in previously untreated GH-deficient adults. Eur J Endocrinol. 2003;149:511-9.-7373. Krag MB, Gormsen LC, Guo Z, Christiansen JS, Jensen MD, Nielsen S, et al. Growth hormone-induced insulin resistance is associated with increased intramyocellular triglyceride content but unaltered VLDL-triglyceride kinetics. Am J Physiol Endocrinol Metab. 2007;292:920-7.). In this context it is plausible that obese GHD patients have low FFA turnover as an explanation for normal insulin sensitivity. The mechanisms involved in the relationship between FFA and insulin resistance were initially associated with competition between FFA and pyruvate substrates, inhibiting the glycolytic pathway (7474. Randle PJ, Garland PB, Hales CN, Newsholme EA. The glucose fatty-acid cycle. Its role in insulin sensitivity and the metabolic disturbances of diabetes mellitus. Lancet. 1963;1:785-9.). This evidence was later confirmed in a study that evaluated the effects of GH on IS using the EHC method (7575. Nellemann B, Vendelbo MH, Nielsen TS, Bak AM, Høgild M, Pedersen SB, et al. Growth hormone-induced insulin resistance in human subjects involves reduced pyruvate dehydrogenase activity. Acta Physiol (Oxf). 2014;210:392-402.). In addition, it is believed that FFA levels act on the insulin signaling pathway, inhibiting of insulin receptor substrate (IRS-11. Cuneo RC, Salomon F, McGauley GA, Sonksen PH. The growth hormone deficiency syndrome in adults. Clin Endocrinol. 1992;37:387-97.) and PI3K in the skeletal muscle and liver, which results in reduced GLUT4 translocation, leading to decreased IS (7676. Dresner A, Laurent D, Marcucci M, Griffin ME, Dufour S, Cline GW, et al. Effects of free fatty acids on glucose transport and IRS-1-associated phosphatidylinositol 3-kinase activity. J Clin Invest. 1999;103:253-59.,7777. Aguirre V, Uchida T, Yenush L, Davis R, White MF. The c-Jun NH2-terminal Kinase Promotes Insulin Resistance during Association with Insulin Receptor Substrate-1 and Phosphorylation of Ser307. J Biol Chem. 2000;275:9047–54.).

Specifically in skeletal muscle, GH promotes the uptake of FFA through increased activity of lipoprotein lipase (7878. LeRoith D, Yakar S. Mechanisms of disease: metabolic effects of growth hormone and insulin-like growth factor 1. Nat Clin Pract Endocrinol Metab. 2007;3:302-10.) and accumulate intramyocellular triglyceride content (7373. Krag MB, Gormsen LC, Guo Z, Christiansen JS, Jensen MD, Nielsen S, et al. Growth hormone-induced insulin resistance is associated with increased intramyocellular triglyceride content but unaltered VLDL-triglyceride kinetics. Am J Physiol Endocrinol Metab. 2007;292:920-7.). In this process there is an accumulation of diacylglycerol and ceramides in skeletal muscle. It is known that these lipid intermediates inhibit insulin signaling pathways. In this sense, studies showed that diacylglycerol inhibits IRS-1 through the activation of the protein kinase C theta that induces insulin receptor phosphorylation in serine leading to insulin resistance. Ceramide inhibits an important mediator of insulin signaling pathway such as Akt/protein kinase B, an important mediator of insulin signaling pathway (7979. Coen PM, Goodpaster BH. Role of intramyocelluar lipids in human health. Trends Endocrinol Metab. 2012;23:391-8.).

In adipose tissue, GH suppresses glucose uptake, as it has been shown that expression of the GLUT1 and GLUT4 transporters in the adipocyte cell membrane has been suppressed after GH administration (8080. Kilgour E, Baldwin SA, Flint DJ. Divergent regulation of rat adipocyte GLUT1 and GLUT4 glucose transporters by GH. J Endocrinol. 1995;145:27-33.). This mechanism is regulated by a subunit called p85, which negatively regulates PI3K-dependent insulin signaling, which in turn is important for the transfer and expression of GLUT1 and GLUT4 transporters, inducing insulin resistance (8181. del Rincon JP, Iida K, Gaylinn BD, McCurdy CE, Leitner JW, Barbour LA, et al. Growth hormone regulation of p85alpha expression and phosphoinositide 3-kinase activity in adipose tissue: mechanism for growth hormone-mediated insulin resistance. Diabetes. 2007;56:1638-46.).

In hepatocytes, the increase in GH-induced FFA uptake leads to an increase in lipid oxidation and accumulation of acetyl coenzyme A. This coenzyme induces an increase in blood glucose levels through the stimulation of two enzymes that participate in glyconeogenesis such as pyruvate carboxylase and phosphenolpyruvate carboxykinase and it stimulate the glucose 6 phosphatase, which increases the release of glucose in the liver (8282. Kovacs P, Stumvoll M. Fatty acids and insulin resistance in muscle and liver. Best Pract Res Clin Endocrinol Metab. 2005;19:625-35.).

Regarding the hyperglycemic effect, some studies do not show increased incidence of diabetes in patients using GH, but pharmacoepidemiological studies with a large number of patients showed a small increase in incidence of type 2 diabetes mellitus when compared to the normal population, especially in children with risk factors for diabetes. such as family history, corticoid use and obesity (8383. Blethen SL, Allen DB, Graves D, August G, Moshang T, Rosenfeld R. Safety of recombinant deoxyribonucleic acid-derived growth hormone: The National Cooperative Growth Study experience. J Clin Endocrinol Metab. 1996;81:1704-10.

84. Cutfield WS, Wilton P, Bennmarker H, Albertsson-Wikland K, Chatelain P, Ranke MB, et al. Incidence of diabetes mellitus and impaired glucose tolerance in children and adolescents receiving growth-hormone treatment. Lancet. 2000;355:610-3.
-8585. Child CJ, Zimmermann AG, Scott RS, Cutler GB Jr, Battelino T, Blum WF; GeNeSIS International Advisory Board. Prevalence and incidence of diabetes mellitus in GH-treated children and adolescents: analysis from the GeNeSIS observational research program. J Clin Endocrinol Metab. 2011;96:1025-34.).

INSULIN SENSITIVITY IN GHD

As shown in Table 2, the literature is controversial regarding the results of IS in patients with GHD. Some studies show that these patients have insulin resistance (8686. Johansson JO, Fowelin J, Landin K, Lager I, Bengtsson BA. Growth hormone-deficient adults are insulin resistant. Metabolism. 1995;44:1126-9.

87. Hew FL, Koschmann M, Christopher M, Rantzau C, Vaag A, Ward G, et al. Insulin resistance in growth hormone-deficient adults: defects in glucose utilization and glycogen synthase activity. J Clin Endocrinol Metab. 1996;81:555-64.

88. Ukropec J, Penesová A, Skopková M, Pura M, Vlcek M, Rádiková Z, et al. Adipokine protein expression pattern in growth hormone deficiency predisposes to the increased fat cell size and the whole body metabolic derangements. J Clin Endocrinol Metab. 2008;93:2255-62.

89. Balaž M, Ukropcova B, Kurdiova T, Vlcek M, Surova M, Krumpolec P, et al. Improved adipose tissue metabolism after 5-year growth hormone replacement therapy in growth hormone deficient adults: The role of zinc-α2-glycoprotein. Adipocyte. 2014;4:113-22.
-9090. Pincelli AI, Brunani A, Scacchi M, Dubini A, Borsotti R, Tibaldi A, et al. The serum concentration of tumor necrosis factor alpha is not an index of growth-hormone- or obesity-induced insulin resistance. Horm Res. 2001;55:57-64.) and others show that IS is similar to the gender, age and BMI matched controls (4141. Ciresi A, Guarnotta V, Pizzolanti G, Giordano C. Comparison between euglycemic hyperinsulinemic clamp and surrogate indices of insulin sensitivity in children with growth hormone deficiency. Growth Horm IGF Res. 2018;39:40-4.,4242. Castillo AR, de Souza AL, Alegre SM, Atala YB, Zantut-Wittmann DE, Garmes HM. Insulin Sensitivity Is Not Decreased in Adult Patients With Hypopituitarism Without Growth Hormone Replacement. Front Endocrinol. 2019;10:534.,8888. Ukropec J, Penesová A, Skopková M, Pura M, Vlcek M, Rádiková Z, et al. Adipokine protein expression pattern in growth hormone deficiency predisposes to the increased fat cell size and the whole body metabolic derangements. J Clin Endocrinol Metab. 2008;93:2255-62.,9090. Pincelli AI, Brunani A, Scacchi M, Dubini A, Borsotti R, Tibaldi A, et al. The serum concentration of tumor necrosis factor alpha is not an index of growth-hormone- or obesity-induced insulin resistance. Horm Res. 2001;55:57-64.

91. Bülow B, Link K, Ahrén B, Nilsson AS, Erfurth EM. Survivors of childhood acute lymphoblastic leukaemia, with radiation-induced GH deficiency, exhibit hyperleptinaemia and impaired insulin sensitivity, unaffected by 12 months of GH treatment. Clin Endocrinol (Oxf). 2004;61:683-91.
-9292. Krusenstjerna-Hafstrøm T, Clasen BF, Møller N, Jessen N, Pedersen SB, Christiansen JS, et al. Growth hormone (GH)-induced insulin resistance is rapidly reversible: an experimental study in GH-deficient adults. J Clin Endocrinol Metab. 2011;96:2548-57.).

Table 2
Insulin sensitivity (IS) by euglicemic hyperinsulinemic clamp in GHD patients

These discrepancies in study results may be related to several factors, such as the etiologies of hypopituitarism that are related to decreased IS regardless of decreased GH levels, as in patients with craniopharyngioma who have more incidence of metabolic syndrome (9393. Wijnen M, Olsson DS, van den Heuvel-Eibrink MM, Hammarstrand C, Janssen JAMJL, van der Lely AJ, et al. The metabolic syndrome and its components in 178 patients treated for craniopharyngioma after 16 years of follow-up. Eur J Endocrinol. 2018;178:11-22.). Another factor that could influence IS would be hormone replacement therapy, especially corticosteroid replacement, but also thyroid and sexual hormone replacement. It is known that corticosteroid therapy may induce elevations in circulating glucose and insulin levels (9494. Al-Shoumer KAS, Beshyah SA, Niththyananthan R, Johnston DG. Effect of glucocorticoid replacement therapy on glucose tolerance and intermediary metabolites in hypopituitary adults. Clin Endocrinol (Oxf). 1995;42:85-90.) and that the dose of corticosteroids used in these patients has decreased in current guidelines compared to older ones. In this sense, the two studies that used EHC to assess IS, published in the 1990s (8686. Johansson JO, Fowelin J, Landin K, Lager I, Bengtsson BA. Growth hormone-deficient adults are insulin resistant. Metabolism. 1995;44:1126-9.,8787. Hew FL, Koschmann M, Christopher M, Rantzau C, Vaag A, Ward G, et al. Insulin resistance in growth hormone-deficient adults: defects in glucose utilization and glycogen synthase activity. J Clin Endocrinol Metab. 1996;81:555-64.), used an average cortisone dose of 25 mg/day slightly above the recommended dose by current guidelines (9595. Fleseriu M, Hashim IA, Karavitaki N, Melmed S, Murad MH, Salvatori R, et al. Hormonal Replacement in Hypopituitarism in Adults: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2016;101:3888-921.).

Obesity could also influence IS assessments in GHD patients, since the study using EHC has demonstrated that IS is similar to the control group matched for BMI, age and gender when patients are classified as obese and is decreased when the thin patients are compared to their paired controls (8888. Ukropec J, Penesová A, Skopková M, Pura M, Vlcek M, Rádiková Z, et al. Adipokine protein expression pattern in growth hormone deficiency predisposes to the increased fat cell size and the whole body metabolic derangements. J Clin Endocrinol Metab. 2008;93:2255-62.).

Decreased lean mass and physical performance are associated with GHD, however, despite the known beneficial effects of physical activity on insulin sensitivity, there are few studies relating the effects of exercise on IS in GHD patients. In this sense, a study in patients with functional GHD after bariatric surgery showed that a physical activity program prevented deterioration in glucose metabolism after GH use for 6 months (9696. Savastano S, Di Somma C, Angrisani L, Orio F, Longobardi S, Lombardi G, et al. Growth hormone treatment prevents loss of lean mass after bariatric surgery in morbidly obese patients: results of a pilot, open, prospective, randomized, controlled study. J Clin Endocrinol Metab. 2009;94:817-26.).

Another important factor that may lead to controversial results is the method used to assess IS. This review has already discussed the reasons why EHC is the most reliable method for assessing IS in patients with disorders in the production of counterregulatory hormones such as hypopituitarism. As an example we can cite studies from our group, we showed increased insulin sensitivity in patients with GHD compared to control group paired by age, gender and BMI using HOMA-IR (9797. Castillo AR, Zantut-Wittmann DE, Neto AM, Jales RM, Garmes HM. Panhypopituitarism Without GH Replacement: About Insulin Sensitivity, CRP Levels, and Metabolic Syndrome. Horm Metab Res. 2018;50(9):690-5.), but the IS was similar in both groups using EHC (4242. Castillo AR, de Souza AL, Alegre SM, Atala YB, Zantut-Wittmann DE, Garmes HM. Insulin Sensitivity Is Not Decreased in Adult Patients With Hypopituitarism Without Growth Hormone Replacement. Front Endocrinol. 2019;10:534.). However, performing EHC and evaluating its results requires special care, it is noteworthy the importance of similar serum levels of hyperinsulinemia during clamp between the patient group and the control, making the blockade of tissue glucose production similar in both groups avoiding possible interference in the results from the action of counterregulating hormones, which is present only in the control group. Thus the evaluation of insulin sensitivity is performed under equal conditions in both groups.

Another factor, little discussed in the literature, that could influence these discrepancies could be the type of fat tissue present in patients with GHD. The relationship between fat tissue and IS is different between patients with normal GH levels and those with GH deficiency. While obesity is directly related to insulin resistance in healthy humans, this relationship is compromised in patients with GH deficiency. Despite the classic increase in fat mass in patients with GHD, the lack of decreased IS in these patients could be justified by the need for a minimum circulating GH level to act in the fat tissue to promote insulin resistance. In addition, animal studies have shown that the transfer of visceral fat tissue from GH receptor mutated mice to normal mice induces improved insulin sensitivity in these animals (9898. Bennis MT, Schneider A, Victoria B, Do A, Wiesenborn DS, Spinel L, et al. The role of transplanted visceral fat from the long-lived growth hormone receptor knockout mice on insulin signaling. Geroscience. 2017;39:51-9.). Interestingly, evaluation of IS by the EHC method in patients with GHD showed that patients with onset of GHD in early life had better IS when compared with controls paired by sex, age, and BMI, while patients with hypopituitarism who started hormone deficiency later in life have IS similar to the control group, suggesting that adipose tissue that did not undergo the physiological action of GH during early childhood should be different from adipose tissue that experienced this action at this stage of life, since the former is more sensitive to insulin action, results not yet published (9999. Rosell Castillo A. Hypopituitarism without growth hormone replacement in the adult patients: evaluation of insulin sensitivity and body composition. 2019. 1 online resource (117 p.). PhD Thesis – Faculty of Medical Sciences, State University of Campinas, Campinas, SP, Brazil.).

In this regard, animal studies showed that the secretion of adipokines from fat tissue is different between GH receptor mutated rats and normal rats (100100. Masternak MM, Bartke A, Wang F, Spong A, Gesing A, Fang Y, et al. Metabolic effects of intra-abdominal fat in GHRKO mice. Aging Cell. 2012;11:73-81.). The removal of visceral fat in these mutated rats induces worsening IS, whereas in normal rats it induces improvement, showing opposite differences in the characteristics of these fatty tissues in modulating IS (100100. Masternak MM, Bartke A, Wang F, Spong A, Gesing A, Fang Y, et al. Metabolic effects of intra-abdominal fat in GHRKO mice. Aging Cell. 2012;11:73-81.).

It is noteworthy that EHC is a complex and expensive method, so in most studies the number of patients is small and because of this, minor variations in the population studied could influence the evaluation of IS, changing the results and favoring conflicting conclusions.

CONCLUSION

In this review, we describe the physiological basis for understanding insulin signaling in the whole spectrum of GH deficiency, showing the conflicting results of scientific studies in this regard, and discuss factors that could influence these results. Finally, we point out that there is no evidence in the literature to classify GHD patients in general as having insulin resistance, despite the well-established increase in fat mass present in these patients. Further studies are needed for a better understanding of IS in patients with GHD and the factors that may influence the results of this evaluation, such as those related to the characteristics of patients with GHD and to the methodology for IS evaluation.

REFERENCES

  • 1
    Cuneo RC, Salomon F, McGauley GA, Sonksen PH. The growth hormone deficiency syndrome in adults. Clin Endocrinol. 1992;37:387-97.
  • 2
    Molitch ME, Clemmons DR, Malozowski S, Merriam GR, Vance ML; Endocrine Society. Evaluation and Treatment of Adult Growth Hormone Deficiency: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2011;96:1587-609.
  • 3
    Toogood AA, Stewart PM. Hypopituitarism: Clinical features, diagnosis, and management. Endocrinol Metab Clin North Am. 2008;37:235-61.
  • 4
    Rosen T, Wiren L, Wilhelmsen L, Wiklund I, Bengtsson BA. Decreased psychological well-being in adult patients with growth hormone deficiency. Clin Endocrinol (Oxf). 1994;40:111-6.
  • 5
    De Boer H, Blok GJ, Voerman HJ, De Vries PM, van der Veen EA. Body composition in adult growth hormone-deficient men, assessed by anthropometry and bioimpedance analysis. J Clin Endocrinol Metab. 1992;75:833-7.
  • 6
    Rosen T, Wilhelmsen L, Landin-Wilhelmsen K, Lappas G, Bengtsson BA. Increased fracture frequency in adult patients with hypopituitarism and GH deficiency. Eur J Endocrinol. 1997;137:240-5.
  • 7
    Patti M-E, Kahn CR. The Insulin Receptor – A Critical Link in Glucose Homeostasis and Insulin Action. J Basic Clin Physiol Pharmacol. 1998;9:2-4.
  • 8
    Saad MJ, Araki E, Miralpeix M, Rothenberg PL, White MF, Kahn CR. Regulation of insulin receptor substrate-1 in liver and muscle of animal models of insulin resistance. J Clin Invest. 1992;90: 1839-49.
  • 9
    Huang PL. A comprehensive definition for metabolic syndrome. Dis Model Mech. 2009;2:231-7.
  • 10
    Himsworth HP. RBK. Insulin-sensitive and insulin-insensitive types of diabetes mellitus. Clin Sci. 1939;4:119-52.
  • 11
    Taylor SI, Accili D, Imai Y. Insulin resistance or insulin deficiency. Which is the primary cause of NIDDM?. Diabetes. 1994;43:735-40.
  • 12
    Tsai YC, Cooke NE, Liebhaber SA. Long-range looping of a locus control region drives tissue-specific chromatin packing within a multigene cluster. Nucleic Acids Res. 2016;44:4651-64.
  • 13
    Melmed S. Acromegaly pathogenesis and treatment. J Clin Invest. 2009;119:3189-202.
  • 14
    Casanueva FF, Camiña JP, Carreira MC, Pazos Y, Varga JL, Schally AV. Growth hormone-releasing hormone as an agonist of the ghrelin receptor GHS-R1a. Proc Natl Acad Sci U S A. 2008;105:20452-7.
  • 15
    Yamashita S, Melmed S. Insulin-like growth factor I action on rat anterior pituitary cells: suppression of growth hormone secretion and messenger ribonucleic acid levels. Endocrinology. 1986;118:176-82.
  • 16
    Roth J, Glick SM, Yalow RS, Berson SA. Hypoglycemia: a potent stimulus to secretion of growth hormone. Science. 1963;140:987-8.
  • 17
    Luger A, Watschinger B, Deuster P, Svoboda T, Clodi M, Chrousos GP. Plasma growth hormone and prolactin responses to graded levels of acute exercise and to a lactate infusion. Neuroendocrinology. 1992;56:112-17.
  • 18
    Vila G, Maier C, Riedl M, Noworny P, Ludvik B, Luger A, et al. Bacterial endotoxin induces biphasic changes in plasma ghrelin in healthy humans. J Clin Endocrinol Metab. 2007;92:3930-4.
  • 19
    Hartman ML, Clayton PE, Johnson ML, Celniker A, Perlman AJ, Alberti KG, et al. A low dose euglycemic infusion of recombinant human insulin-like growth factor I rapidly suppresses fasting-enhanced pulsatile growth hormone secretion in humans. J Clin Invest. 1993;91:2453-62.
  • 20
    Casanueva F, Villanueva L, Penalva A, Vila T, Cabezas-Cerrato J. Free fatty acid inhibition of exercise-induced growth hormone secretion. Horm Metab Res. 1981;13:348-50.
  • 21
    Brooks AJ, Dai W, O’Mara ML, Abankwa D, Chhabra Y, Pelekanos RA, et al. Mechanism of activation of protein kinase JAK2 by the growth hormone receptor. Science. 2014;344:1249783.
  • 22
    Carter-Su C, Schwartz J, Argetsinger LS. Growth hormone signaling pathways. Growth Horm IGF Res. 2016;28:11-5.
  • 23
    Rotwein P. Mapping the growth hormone–Stat5b–IGF-I transcriptional circuit. Trends Endocrinol Metab. 2012;23:186-93.
  • 24
    Kofoed EM, Hwa V, Little B, Woods KA, Buckway CK, Tsubaki J, et al. Growth hormone insensitivity associated with a STAT5b mutation. N Engl J Med. 2003; 349: 1139-1147.
  • 25
    Yakar S, Liu JL, Stannard B, Butler A, Accili D, Sauer B, et al. Normal growth and development in the absence of hepatic insulin-like growth factor I. Proc Natl Acad Sci U S A. 1999;96:7324-9.
  • 26
    Kupfer SR, Underwood LE, Baxter RC, Clemmons DR. Enhancement of the anabolic effects of growth hormone and insulin-like growth factor I by use of both agents simultaneously. J Clin Invest. 1993;91:391-6.
  • 27
    Chikani V, Ho KK. Action of GH on skeletal muscle function: molecular and metabolic mechanisms. J Mol Endocrinol. 2013;52:R107-23.
  • 28
    Vijayakumar A, Yakar S, Leroith D. The intricate role of growth hormone in metabolism. Front Endocrinol (Lausanne). 2011;2:32.
  • 29
    Zhao JT, Cowley MJ, Lee P, Birzniece V, Kaplan W, Ho KK. Identification of novel GH-regulated pathway of lipid metabolism in adipose tissue: a gene expression study in hypopituitary men. J Clin Endocrinol Metab. 2011;96:E1188-96.
  • 30
    Mazziotti G, Frara S, Giustina A. Pituitary diseases and bone. Endocr Rev. 2018;39:440-88.
  • 31
    Leung K, Rajkovic IA, Peters E, Markus I, Van Wyk JJ, Ho KK. Insulin-like growth factor I and insulin down-regulate growth hormone (GH) receptors in rat osteoblasts: evidence for a peripheral feedback loop regulating GH action. Endocrinology. 1996;137:2694-702.
  • 32
    Jones JI, Clemmons DR. Insulin-like growth factors and their binding proteins: biological actions. Endocr Rev. 1995;16:3-34.
  • 33
    Frara S, Maffezzoni F, Mazziotti G, Giustina A. Current and emerging aspects of diabetes mellitus in acromegaly. Trends Endocrinol Metab. 2016;27:470-83.
  • 34
    Di Cola G, Cool MH, Accili D. Hypoglycemic effect of insulin-like growth factor-1 in mice lacking insulin receptors. J Clin Invest. 1997;99:2538-544.
  • 35
    Froesch ER, Schmid C, Schwander J, Zapf J. Actions of insulin like growth factors. Annu Rev Physiol. 1985;47:443-67.
  • 36
    Bergman RN, Phillips LS, Cobelli C. Physiologic evaluation of factors controlling glucose tolerance in man: measurement of insulin sensitivity and beta-cell glucose sensitivity from the response to intravenous glucose. J Clin Invest. 1981;68:1456-67.
  • 37
    Andres R, Swerdloff R, Pozefsky T, Coleman D. Manual feedback technique for the control of blood glucose concentration. In: Skeggs LT Jr (ed.): Automation in analytical chemistry. New York: Mediad. 1966;486-91.
  • 38
    Ferrannini E, Mari A. How to measure insulin sensitivity. J Hypertens. 1998;16:895-906.
  • 39
    Bonadonna RC, Groop L, Kraemer N, Ferrannini E, Del Prato S, DeFronzo RA. Obesity and insulin resistance in humans: a dose-response study. Metabolism. 1990;39:452-9.
  • 40
    Liu JL, Coschigano KT, Robertson K, Lipsett M, Guo Y, Kopchick JJ, et al. Disruption of growth hormone receptor gene causes diminished pancreatic islet size and increased insulin sensitivity in mice. Am J Physiol Endocrinol Metab. 2004;287:405-13.
  • 41
    Ciresi A, Guarnotta V, Pizzolanti G, Giordano C. Comparison between euglycemic hyperinsulinemic clamp and surrogate indices of insulin sensitivity in children with growth hormone deficiency. Growth Horm IGF Res. 2018;39:40-4.
  • 42
    Castillo AR, de Souza AL, Alegre SM, Atala YB, Zantut-Wittmann DE, Garmes HM. Insulin Sensitivity Is Not Decreased in Adult Patients With Hypopituitarism Without Growth Hormone Replacement. Front Endocrinol. 2019;10:534.
  • 43
    Coschigano KT, Holland AN, Riders ME, List EO, Flyvbjerg A, Kopchick JJ. Deletion, but not antagonism, of the mouse growth hormone receptor results in severely decreased body weights, insulin, and insulin-like growth factor I levels and increased life span. Endocrinology. 2003;144:3799-810.
  • 44
    Lubbers ER, List EO, Jara A, Sackman-Sala L, Cordoba-Chacon J, Gahete MD, et al. Adiponectin in mice with altered GH action: links to insulin sensitivity and longevity? J Endocrinol. 2013;216:363-74.
  • 45
    Junnila RK, Duran-Ortiz S, Suer O, Sustarsic EG, Berryman DE, List EO, et al. Disruption of the GH Receptor Gene in Adult Mice Increases Maximal Lifespan in Females. Endocrinology. 2016;157:4502-13.
  • 46
    Luque RM, Lin Q, Córdoba-Chacón J, Subbaiah PV, Buch T, Waisman A, et al. Metabolic impact of adult-onset, isolated, growth hormone deficiency (AOiGHD) due to destruction of pituitary somatotropes. PLoS One. 2011;19:15767.
  • 47
    List EO, Berryman DE, Buchman M, Jensen EA, Funk K, Duran-Ortiz S. GH “knockout” mice have increased subcutaneous adipose tissue with decreased fibrosis and enhanced insulin sensitivity. Endocrinology. 2019;160:1743-56.
  • 48
    Haluzik M, Yakar S, Gavrilova O, Setser J, Boisclair Y, LeRoith D. Insulin resistance in the liver-specific IGF-1 gene-deleted mouse is abrogated by deletion of the acid-labile subunit of the IGF-binding protein-3 complex: relative roles of growth hormone and IGF-1 in insulin resistance. Diabetes. 2003;52:2483-9.
  • 49
    Yakar S, Setser J, Zhao H, Stannard B, Haluzik M, Glatt V, et al. Inhibition of growth hormone action improves insulin sensitivity in liver IGF-1-deficient mice. J Clin Invest. 2004;113:96-105.
  • 50
    Cordoba-Chacon J, Gahete MD, McGuinness OP, Kineman RD. Differential impact of selective GH deficiency and endogenous GH excess on insulin-mediated actions in muscle and liver of male mice. Am J Physiol Endocrinol Metab. 2014;307:928-34.
  • 51
    Duran-Ortiz S, Noboa V, Kopchick JJ. Disruption of the GH receptor gene in adult mice and in insulin sensitive tissues. Growth Horm IGF Res. 2018;38:3-7.
  • 52
    Gomes-Santos E, Salvatori R, Ferrão TO, Oliveira CRP, Diniz RDCA, Santana JAM, et al. Increased Visceral Adiposity and Cortisol to Cortisone Ratio in Adults With Congenital Lifetime Isolated GH Deficiency. J Clin Endocrinol Metab. 2014;99:3285-9.
  • 53
    Oliveira CR, Salvatori R, Barreto-Filho JA, Rocha IE, Mari A, Pereira RM, et al. Insulin Sensitivity and β-Cell Function in Adults with Lifetime, Untreated Isolated Growth Hormone Deficiency. J Clin Endocrinol Metab. 2012;97:1013-9.
  • 54
    Laron Z, Ginsberg S, Lilos P, Arbiv M, Vaisman N. Body composition in untreated adult patients with Laron syndrome (primary GH insensitivity). Clin Endocrinol (Oxf). 2006;65:114-7.
  • 55
    Laron Z, Avitzur Y, Klinger B. Carbohydrate metabolism in primary growth hormone resistance (Laron syndrome) before and during insulin-like growth factor-I treatment. Metabolism [Internet]. 1995;44:113-8.
  • 56
    Guevara-Aguirre J, Procel P, Guevara C, Guevara-Aguirre M, Rosado V, Teran E. Despite higher body fat content, Ecuadorian subjects with Laron syndrome have less insulin resistance and lower incidence of diabetes than their relatives. Growth Horm IGF Res. 2016;28:76-8.
  • 57
    Guevara-Aguirre J, Guevara A, Bahamonde M. Insulin resistance depends on GH counter-regulation in two syndromes of short stature. Growth Horm IGF Res. 2018;38:44-8.
  • 58
    Hansen I, Tsalikian E, Beaufrere B, Gerich J, Haymond M, Rizza R. Insulin resistance in acromegaly: defects in both hepatic and extrahepatic insulin action. Am J Physiol. 1986;250:269-73.
  • 59
    Karlander S, Vranić M, Efendić S. Increased glucose turnover and glucose cycling in acromegalic patients with normal glucose tolerance. Diabetologia. 1986;29:778-83.
  • 60
    Møller N, Schmitz O, Jøorgensen JO, Astrup J, Bak JF, Christensen SE, et al. Basal- and insulin-stimulated substrate metabolism in patients with active acromegaly before and after adenomectomy. J Clin Endocrinol Metab. 1992;74:1012-19.
  • 61
    Møller N, Jørgensen JOL. Effects of Growth Hormone on Glucose, Lipid, and Protein Metabolism in Human Subjects. Endocr Rev [Internet]. 2009;30:152-77.
  • 62
    Alexopoulou O, Bex M, Kamenicky P, Mvoula AB, Chanson P, Maiter D. Prevalence and risk factors of impaired glucose tolerance and diabetes mellitus at diagnosis of acromegaly: a study in 148 patients. Pituitary. 2014;17:81-9.
  • 63
    Roemmler J, Kuenkler M, Schneider HJ, Dieterle C, Schopohl J. Comparison of glucose and lipid metabolism and bone mineralization in patients with growth hormone deficiency with and without long-term growth hormone replacement. Metabolism. 2010;59:350-8.
  • 64
    Fowelin J, Attvall S, Lager I, Bengtsson BA. Effects of treatment with recombinant human growth hormone on insulin sensitivity and glucose metabolism in adults with growth hormone deficiency. Metabolism 1993;42:1443-7.
  • 65
    Christopher M, Hew FL, Oakley M, Rantzau C, Alford F. Defects of Insulin Action and Skeletal Muscle Glucose Metabolism in Growth Hormone-Deficient Adults Persist after 24 Months of Recombinant Human Growth Hormone Therapy. J Clin Endocrinol Metab. 1998;83:1668-81.
  • 66
    Bramnert M, Segerlantz M, Laurila E, Daugaard JR, Manhem P, Groop L. Growth Hormone Replacement Therapy Induces Insulin Resistance by Activating the Glucose-Fatty Acid Cycle. J Clin Endocrinol Metab. 2003;88:1455-63.
  • 67
    Heptulla RA, Boulware SD, Caprio S, Silver D, Sherwin RS, Tamborlane WV. Decreased Insulin Sensitivity and Compensatory Hyperinsulinemia after Hormone Treatment in Children with Short Stature. J Clin Endocrinol Metab. 1997;82:3234-8.
  • 68
    Ciresi A, Amato MC, Giordano C. Reduction in insulin sensitivity and inadequate β-cell capacity to counteract the increase in insulin resistance in children with idiopathic growth hormone deficiency during 12 months of growth hormone treatment. J Endocrinol Invest. 2015;38:351-9.
  • 69
    Yuen KC, Frystyk J, White DK, Twickler TB, Koppeschaar HP, Harris PE, et al. Improvement in insulin sensitivity without concomitant changes in body composition and cardiovascular risk markers following fixed administration of a very low growth hormone (GH) dose in adults with severe GH deficiency. Clin Endocrinol (Oxf). 2005;63:428-36.
  • 70
    Luger A, Mattsson AF, Koltowska-Häggström M, Thunander M, Góth M, Verhelst J, et al. Incidence of diabetes mellitus and evolution of glucose parameters in growth hormone-deficient subjects during growth hormone replacement therapy: a long-term observational study. Diabetes Care. 2012;35:57-62.
  • 71
    Nielsen S, Møller N, Christiansen JS, Jørgensen JO. Pharmacological antilipolysis restores insulin sensitivity during growth hormone exposure. Diabetes. 2001;50:2301-8.
  • 72
    Segerlantz M, Bramnert M, Manhem P, Laurila E, Groop LC. Inhibition of lipolysis during acute GH exposure increases insulin sensitivity in previously untreated GH-deficient adults. Eur J Endocrinol. 2003;149:511-9.
  • 73
    Krag MB, Gormsen LC, Guo Z, Christiansen JS, Jensen MD, Nielsen S, et al. Growth hormone-induced insulin resistance is associated with increased intramyocellular triglyceride content but unaltered VLDL-triglyceride kinetics. Am J Physiol Endocrinol Metab. 2007;292:920-7.
  • 74
    Randle PJ, Garland PB, Hales CN, Newsholme EA. The glucose fatty-acid cycle. Its role in insulin sensitivity and the metabolic disturbances of diabetes mellitus. Lancet. 1963;1:785-9.
  • 75
    Nellemann B, Vendelbo MH, Nielsen TS, Bak AM, Høgild M, Pedersen SB, et al. Growth hormone-induced insulin resistance in human subjects involves reduced pyruvate dehydrogenase activity. Acta Physiol (Oxf). 2014;210:392-402.
  • 76
    Dresner A, Laurent D, Marcucci M, Griffin ME, Dufour S, Cline GW, et al. Effects of free fatty acids on glucose transport and IRS-1-associated phosphatidylinositol 3-kinase activity. J Clin Invest. 1999;103:253-59.
  • 77
    Aguirre V, Uchida T, Yenush L, Davis R, White MF. The c-Jun NH2-terminal Kinase Promotes Insulin Resistance during Association with Insulin Receptor Substrate-1 and Phosphorylation of Ser307. J Biol Chem. 2000;275:9047–54.
  • 78
    LeRoith D, Yakar S. Mechanisms of disease: metabolic effects of growth hormone and insulin-like growth factor 1. Nat Clin Pract Endocrinol Metab. 2007;3:302-10.
  • 79
    Coen PM, Goodpaster BH. Role of intramyocelluar lipids in human health. Trends Endocrinol Metab. 2012;23:391-8.
  • 80
    Kilgour E, Baldwin SA, Flint DJ. Divergent regulation of rat adipocyte GLUT1 and GLUT4 glucose transporters by GH. J Endocrinol. 1995;145:27-33.
  • 81
    del Rincon JP, Iida K, Gaylinn BD, McCurdy CE, Leitner JW, Barbour LA, et al. Growth hormone regulation of p85alpha expression and phosphoinositide 3-kinase activity in adipose tissue: mechanism for growth hormone-mediated insulin resistance. Diabetes. 2007;56:1638-46.
  • 82
    Kovacs P, Stumvoll M. Fatty acids and insulin resistance in muscle and liver. Best Pract Res Clin Endocrinol Metab. 2005;19:625-35.
  • 83
    Blethen SL, Allen DB, Graves D, August G, Moshang T, Rosenfeld R. Safety of recombinant deoxyribonucleic acid-derived growth hormone: The National Cooperative Growth Study experience. J Clin Endocrinol Metab. 1996;81:1704-10.
  • 84
    Cutfield WS, Wilton P, Bennmarker H, Albertsson-Wikland K, Chatelain P, Ranke MB, et al. Incidence of diabetes mellitus and impaired glucose tolerance in children and adolescents receiving growth-hormone treatment. Lancet. 2000;355:610-3.
  • 85
    Child CJ, Zimmermann AG, Scott RS, Cutler GB Jr, Battelino T, Blum WF; GeNeSIS International Advisory Board. Prevalence and incidence of diabetes mellitus in GH-treated children and adolescents: analysis from the GeNeSIS observational research program. J Clin Endocrinol Metab. 2011;96:1025-34.
  • 86
    Johansson JO, Fowelin J, Landin K, Lager I, Bengtsson BA. Growth hormone-deficient adults are insulin resistant. Metabolism. 1995;44:1126-9.
  • 87
    Hew FL, Koschmann M, Christopher M, Rantzau C, Vaag A, Ward G, et al. Insulin resistance in growth hormone-deficient adults: defects in glucose utilization and glycogen synthase activity. J Clin Endocrinol Metab. 1996;81:555-64.
  • 88
    Ukropec J, Penesová A, Skopková M, Pura M, Vlcek M, Rádiková Z, et al. Adipokine protein expression pattern in growth hormone deficiency predisposes to the increased fat cell size and the whole body metabolic derangements. J Clin Endocrinol Metab. 2008;93:2255-62.
  • 89
    Balaž M, Ukropcova B, Kurdiova T, Vlcek M, Surova M, Krumpolec P, et al. Improved adipose tissue metabolism after 5-year growth hormone replacement therapy in growth hormone deficient adults: The role of zinc-α2-glycoprotein. Adipocyte. 2014;4:113-22.
  • 90
    Pincelli AI, Brunani A, Scacchi M, Dubini A, Borsotti R, Tibaldi A, et al. The serum concentration of tumor necrosis factor alpha is not an index of growth-hormone- or obesity-induced insulin resistance. Horm Res. 2001;55:57-64.
  • 91
    Bülow B, Link K, Ahrén B, Nilsson AS, Erfurth EM. Survivors of childhood acute lymphoblastic leukaemia, with radiation-induced GH deficiency, exhibit hyperleptinaemia and impaired insulin sensitivity, unaffected by 12 months of GH treatment. Clin Endocrinol (Oxf). 2004;61:683-91.
  • 92
    Krusenstjerna-Hafstrøm T, Clasen BF, Møller N, Jessen N, Pedersen SB, Christiansen JS, et al. Growth hormone (GH)-induced insulin resistance is rapidly reversible: an experimental study in GH-deficient adults. J Clin Endocrinol Metab. 2011;96:2548-57.
  • 93
    Wijnen M, Olsson DS, van den Heuvel-Eibrink MM, Hammarstrand C, Janssen JAMJL, van der Lely AJ, et al. The metabolic syndrome and its components in 178 patients treated for craniopharyngioma after 16 years of follow-up. Eur J Endocrinol. 2018;178:11-22.
  • 94
    Al-Shoumer KAS, Beshyah SA, Niththyananthan R, Johnston DG. Effect of glucocorticoid replacement therapy on glucose tolerance and intermediary metabolites in hypopituitary adults. Clin Endocrinol (Oxf). 1995;42:85-90.
  • 95
    Fleseriu M, Hashim IA, Karavitaki N, Melmed S, Murad MH, Salvatori R, et al. Hormonal Replacement in Hypopituitarism in Adults: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2016;101:3888-921.
  • 96
    Savastano S, Di Somma C, Angrisani L, Orio F, Longobardi S, Lombardi G, et al. Growth hormone treatment prevents loss of lean mass after bariatric surgery in morbidly obese patients: results of a pilot, open, prospective, randomized, controlled study. J Clin Endocrinol Metab. 2009;94:817-26.
  • 97
    Castillo AR, Zantut-Wittmann DE, Neto AM, Jales RM, Garmes HM. Panhypopituitarism Without GH Replacement: About Insulin Sensitivity, CRP Levels, and Metabolic Syndrome. Horm Metab Res. 2018;50(9):690-5.
  • 98
    Bennis MT, Schneider A, Victoria B, Do A, Wiesenborn DS, Spinel L, et al. The role of transplanted visceral fat from the long-lived growth hormone receptor knockout mice on insulin signaling. Geroscience. 2017;39:51-9.
  • 99
    Rosell Castillo A. Hypopituitarism without growth hormone replacement in the adult patients: evaluation of insulin sensitivity and body composition. 2019. 1 online resource (117 p.). PhD Thesis – Faculty of Medical Sciences, State University of Campinas, Campinas, SP, Brazil.
  • 100
    Masternak MM, Bartke A, Wang F, Spong A, Gesing A, Fang Y, et al. Metabolic effects of intra-abdominal fat in GHRKO mice. Aging Cell. 2012;11:73-81.

Publication Dates

  • Publication in this collection
    10 Jan 2020
  • Date of issue
    Nov-Dec 2019

History

  • Received
    28 Aug 2019
  • Accepted
    12 Oct 2019
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