Beale, Elmus G. PhD
“The most exciting phrase to hear in science, the one that heralds new discoveries, is not ‘Eureka!’ (I found it!) but ’That’s funny ...” Isaac Asimov
The American Federation for Medical Research sponsored a mini-symposium entitled “Angiotensin-Insulin Cross Talk—A True Translational Story from Bedside to Bench” at the 2011 annual meeting of the American Physiological Society. There were 2 “that’s funny” stories that led to the “Bedside to Bench” theme of this symposium. The first was a report that insulin resistance could be the main etiology underlying essential hypertension.1 The second story comes from a collection of observations indicating that interference with angiotensin signaling improves insulin sensitivity. Folli2 and Prabhakar3 discussed these discoveries in more detail. The purpose of this article was to connect these 2 “that’s funny” events by providing an overview of insulin action and insulin resistance. Navar4 provides an overview of rennin/angiotensin signaling in this context.
INSULIN FUNCTION AND PHYSIOLOGY
Cheng et al.5 described the physiology of insulin action by saying: “The insulin signaling system coordinates systemic growth and development with peripheral and central nutrient homeostasis, fertility and lifespan.” This simple statement underscores the importance of insulin action in a powerful way. Indeed, insulin regulates glucose uptake, glycogen synthesis, gluconeogenesis, lipid metabolism, hunger, cell growth and division, gene expression and protein synthesis, and vasodilatation.5–7
Consider for a moment the signaling symphony that occurs constantly within our bodies. Cells, tissues, and organs continually sense and integrate food availability, dietary composition, adiposity, cellular adenosine triphosphate and reduced nicotinamide adenine dinucleotide, inflammation, and many other factors.5,8 At the systemic level, this requires neuroendocrine pathways involving the brain, gut, pancreas, and adipose tissue.9–11 At the target tissue level, insulin signaling provides one of the major inputs responsible for fuel homeostasis, and a major output that integrates many of these input signals is the regulation of insulin sensitivity in target tissues. For example, elevated plasma fatty acids results in a physiological resistance to the action of insulin.12,13
INSULIN SIGNALING PATHWAYS
The reader is referred to reviews and texts for details of insulin action; for example, see Cheng et al.,5 Shepherd,6 and Spiegel et al.7 Figure 1 presents a brief overview of the 2 known insulin-signaling pathways. These pathways are activated when insulin binds to the insulin receptor (IR) at the plasma membrane (note that IR-A and IR-B are splicing variants with slightly different properties and functions). Insulin interaction with its receptor activates an intrinsic tyrosine protein kinase, which autophosphorylates the receptor and downstream substrates. In the dominant pathway, a family of proteins known as IR substrates serves as the immediate downstream substrates, which activate a cascade of serine-protein kinases. Akt (protein kinase B) is a major branch point with numerous downstream substrates leading to a variety of physiological functions including the regulation of fuel homeostasis. The alternate pathway ( “ras/mitogen-activated protein kinase”) is also a serine-protein kinase cascade. However, this pathway regulates transcription, cell growth and differentiation, and protein synthesis.7,17
Cross talk occurs at multiple levels in both of these signaling pathways as a result of signaling from other pathways. The focus of the symposium was cross talk with the angiotensin-signaling pathway. The mechanisms of this cross talk are described by Folli2 and Prabhakar.3
METABOLIC SYNDROME (INSULIN RESISTANCE SYNDROME)
Reaven18 originally described metabolic syndrome. It is clinically defined by having at least 3 of the following conditions: hypertension, elevated fasting blood sugar, obesity, low high-density lipoprotein cholesterol, and elevated triglycerides.19,20 These conditions increase the risk of complications including atherosclerosis, type 2 diabetes, heart attack, kidney disease, fatty liver, vascular disease, stroke, and numerous other diseases.19,20 Whereas the “typical” individual with metabolic syndrome has central obesity, individuals can be obese but metabolically lean, and lean but metabolically obese.20 Another view of the metabolic syndrome is the presence of one or more of these complications in individuals who are insulin resistant. Although somewhat controversial, many have argued that the underlying etiology could be insulin resistance.1,20,21 This is not to imply that insulin resistance is directly responsible. Indeed, the chronic hyperinsulinemia that accompanies insulin resistance (before β-cell insufficiency) could be responsible for much of the pathology of metabolic syndrome through a constant “hyperactivation” of insulin and insulin-like growth factor 1 receptors.
Pathological insulin resistance develops through complex interactions of genotype and lifestyle (lack of exercise and overnutrition).22–25 It is important to recognize that insulin sensitivity in target tissues is regulated physiologically by circulating factors. These factors include plasma lipids, circulating hormones and adipokines, and their respective signaling pathways.11,26,27 Cross talk among these various signaling pathways with the insulin signaling pathways constantly tunes insulin sensitivity. Adipose tissue, along with the brain and the gut, constitute a neuroendocrine axis that regulates metabolism in large measure by regulating insulin sensitivity in target tissues.26,27
For example, the central role of adipose tissue is illustrated in Figure 2. Adipocytes serve a double duty of: (1) storing fat as triglyceride and releasing it as fatty acids and glycerol as needed; and (2) releasing a variety of hormones collectively known as adipokines. Target tissues such as skeletal muscle can oxidize the fatty acids for fuel. In addition, elevated levels of circulating fatty acids can desensitize target tissues to the actions of insulin as, for example, after a fatty meal.
Adipokine functions can be broken into 2 general categories: those that stimulate and those that inhibit insulin sensitivity. Leptin and adiponectin stimulate insulin action in peripheral tissues.26,27 Leptin is released from adipocytes in proportion to adiposity. In addition to its peripheral actions, it acts on the hypothalamus to suppress appetite. In contrast, adiponectin is released from adipocytes in inverse proportion to adiposity.
The adipokines that inhibit insulin sensitivity include tumor necrosis factor α, resistin, IL-6, and retinol binding protein 4, to name a few.26 These inhibitory factors are released by adipocytes in proportion to adiposity. Collectively, these adipocyte-derived factors regulate metabolism and feeding. However, lifestyle, obesity, and genetics can collaborate to perturb this delicate balance.25
The perturbations caused by obesity are simplistically summarized as follows. Critical changes occur with 2 insulin-sensitizing factors: leptin levels rise and adiponectin levels fall in obese individuals. Hyperleptinemia leads to a paradoxical decrease in insulin sensitivity because it results in insensitivity to the action of leptin in its target tissues.26 Simultaneously, there are changes in insulin-desensitizing factors: the levels of circulating fatty acids and inhibitory adipokines increase during obesity.11,26 Moreover, adipocytes secrete chemoattractant molecules that recruit macrophages such that the number of macrophages present in adipose tissue is increased in obesity.28 These macrophages also contribute to the concentration of circulating tumor necrosis factor α. The collective effect of all of these changes is increased appetite along with a pathological decrease in sensitivity to insulin in target tissues.
The central role of adipose tissue in the regulation of whole body insulin sensitivity is further illustrated by the following: (1) In most individuals, obesity results in insulin resistance and can lead to insulin resistance syndrome. (2) In contrast, lipodystrophy also results in profound insulin resistance and metabolic syndrome.29 Superficially, this is an apparent paradox in that too little body fat also leads to insulin resistance. The underlying reasons can be understood by referring to Figure 2. Briefly, the lack of adipose tissue results in leptin and adiponectin deficiencies along with inadequate stores for lipids. Circulating fatty acids and other lipids are increased for lack of adequate storage depots. These conditions collectively lead to insulin resistance. (3) The central role of leptin is dramatically underscored in the phenotype of individuals who lack either leptin or a normal leptin receptor owing to mutations in the genes that encode these proteins. These individuals become profoundly obese and insulin resistant.30 (4) Finally, drugs of the thiazolidinedione class target peroxisome proliferator-activated receptor γ (PPARγ) in adipose tissue to improve insulin sensitivity in other tissues, an effect that has recently been shown to center on PPARγ phosphorylation by cdk5 and normalization of adipocyte-derived factors (Fig. 2).31
Despite this mass of information, much remains to be learned about the mechanisms that cause insulin resistance and the mechanisms by which insulin resistance causes disease. During the past few years, numerous genomewide association studies have been directed at identifying the genes that cause type 2 diabetes mellitus.32 Because type 2 diabetes is caused by a combination of insulin resistance along with insulin insufficiency, it was expected that “diabetes genes” would map to β-cell function and insulin resistance. As of 2011, approximately 38 diabetes genes had been reported.32 Surprisingly, most of these diabetes genes affect β cells or are of unknown function. Only a few map to insulin resistance. Known genes that map to insulin resistance include the insulin receptor, IR substrate 1, glucokinase regulator, IGF-I, and PPARγ.32 It is expected that numerous additional “insulin resistance genes” are yet to be discovered and that they will map to various components of the insulin signaling pathway.
It is also expected that pharmacogenomic investigations will also reveal insulin resistance pathways. One exciting development in this regard is the recent genomewide association study searching for genes required for metformin action.33,34 Metformin has been used for many decades to treat type 2 diabetes because it sensitizes insulin target tissues. The study reported that the ataxia telangiectasia mutated (ATM) gene is required for the action of metformin.33,34 The ATM gene encodes a serine protein kinase that phosphorylates LKB1, an adenosine monophosphate (AMP)-activated protein kinase (AMPK-kinase).34 This is important because AMPK is involved in the action of metformin and interfaces with the insulin signaling pathway.34
Insulin has many physiological functions and its signaling pathways are tightly controlled through cross talk. The interplay of genes and lifestyle has led to the obesity epidemic, which underlies the epidemic of metabolic syndrome/insulin resistance syndrome. A large body of evidence indicates that the underlying etiology of the components of insulin resistance syndrome is in fact insulin resistance itself. The etiologies of insulin resistance are numerous and complex. They include hyperinsulinemia, hyperlipidemia leading to lipotoxicity, adipokines from adipose tissue, incretins from the gut, and cytokines from macrophages, all of which cross talk with insulin signaling pathways.
The “bedside to bench” theme of the symposium in 2011 stemmed from the recognition that interference with angiotensin signaling improves insulin sensitivity as discussed by Prabhakar.3 This overview of insulin action and insulin resistance, along with an overview of angiotensin signaling by Navar,4 provides the background for the subsequent descriptions of angiotensin-insulin cross talk by Folli2 and Prabhakar.3
1. Ferrannini E, Buzzigoli G, Bonadonna R, et al.. Insulin resistance in essential hypertension. N Engl J Med
. 1987; 317: 350–357.
2. Folli F. Molecular basis of angiotensin-insulin cross-talk. Clues to the understanding of insulin resistance in arterial hypertension. J Investig Med
. 2012; In press.
3. Prabhakar S. Inhibition of renin-angiotensin system-implications for diabetes control and prevention. J Investig Med
. 2012; In press.
4. Navar LG. Renin and angiotensin system: signaling in health and diabetes. J Investig Med
. 2012; In press.
5. Cheng Z, Tseng Y, White MF. Insulin signaling meets mitochondria in metabolism. Trends Endocrinol Metab
. 2010; 21: 589–598.
6. Shepherd PR. Mechanisms regulating phosphoinositide 3-kinase signalling in insulin-sensitive tissues. Acta Physiol Scand
. 2005; 183: 3–12.
7. Spiegel A, Carter-Su C, Taylor SI, et al.. Mechanism of action of hormones that act at the cell surface. In: Melmed S, Polonsky KS, Larsen PR, et al., eds. Williams Textbook of Endocrinology
. 12th ed. Philadelphia, PA: Saunders Elsevier; 2011: 62–83.
8. Ruderman NB, Xu XJ, Nelson L, et al.. AMPK and SIRT1: a long-standing partnership? Am J Physiol Endocrinol Metab
. 2010; 298: E751–E760.
9. Thaler JP, Schwartz MW. Minireview: inflammation and obesity pathogenesis: the hypothalamus heats up. Endocrinology
. 2010; 151: 4109–4115.
10. Badman MK, Flier JS. The gut and energy balance: visceral allies in the obesity wars. Science
. 2005; 307: 1909–1914.
11. Beale E, Hammer R, Antoine B, et al.. Disregulated glyceroneogenesis: PCK1 as a candidate diabetes and obesity gene. Trends Endocrinol Metab
. 2004; 15: 129–135.
12. Randle PJ. Regulatory interactions between lipids and carbohydrates: the glucose fatty acid cycle after 35 years. Diabetes Metab Rev
. 1998; 14: 263–283.
13. Samuel VT, Petersen KF, Shulman GI. Lipid-induced insulin resistance: unravelling the mechanism. Lancet
. 2010; 375: 2267–2277.
14. Leibiger B, Leibiger IB, Moede T, et al.. Selective insulin signaling through A and B insulin receptors regulates transcription of insulin and glucokinase genes in pancreatic beta cells. Mol Cell
. 2001; 7: 559–570.
15. Vigneri R, Squatrito S, Sciacca L. Insulin and its analogs: actions via insulin and IGF receptors. Acta Diabetol
. 2010; 47: 271–278.
16. Sesti G, Federici M, Lauro D, et al.. Molecular mechanism of insulin resistance in type 2 diabetes mellitus: role of the insulin receptor variant forms. Diabetes Metab Res Rev
. 2001; 17: 363–373.
17. DeFronzo RA. Insulin resistance, lipotoxicity, type 2 diabetes and atherosclerosis: the missing links. The Claude Bernard Lecture 2009. Diabetologia
. 2010; 53: 1270–1287.
18. Reaven GM. Role of insulin resistance in human-disease (Syndrome-X)—an expanded definition. Annu Rev Med
. 1993; 44: 121–131.
19. Grundy SM, Cleeman JI, Daniels SR, et al.. Diagnosis and management of the metabolic syndrome: an American Heart Association/National Heart, Lung, and Blood Institute Scientific Statement. Circulation
. 2005; 112: 2735–2752.
20. Reaven G. The metabolic syndrome or the insulin resistance syndrome? Different names, different concepts, and different goals. Endocrinol Metab Clin North Am
. 2004; 33: 283–303.
21. Steinberger J, Daniels SR, Eckel RH, et al.. Progress and challenges in metabolic syndrome in children and adolescents: a scientific statement from the American Heart Association Atherosclerosis, Hypertension, and Obesity in the Young Committee of the Council on Cardiovascular Disease in the Young; Council on Cardiovascular Nursing; and Council on Nutrition, Physical Activity, and Metabolism. Circulation
. 2009; 119: 628–647.
22. Pratley RE. Gene-environment interactions in the pathogenesis of type 2 diabetes mellitus: lessons learned from the Pima Indians. Proc Nutr Soc
. 1998; 57: 175–181.
23. Stolerman ES, Florez JC. Genomics of type 2 diabetes mellitus: implications for the clinician. Nat Rev Endocrinol
. 2009; 5: 429–436.
24. Muniyappa R, Montagnani M, Koh KK, et al.. Cardiovascular actions of insulin. Endocrine Reviews
. 2007; 28: 463–491.
25. Romao I, Roth J. Genetic and environmental interactions in obesity and type 2 diabetes. J Am Diet Assoc
. 2008; 108: S24–S28.
26. Ahima RS, Lazar MA. Adipokines and the peripheral and neural control of energy balance. Mol Endocrinol
. 2008; 22: 1023–1031.
27. Zac-Varghese S, Tan T, Bloom SR. Hormonal interactions between gut and brain. Discov Med
. 2010; 10: 543–552.
28. Olefsky JM, Glass CK. Macrophages, inflammation, and insulin resistance. Annu Rev Physiol
. 2010; 72: 219–246.
29. Huang-Doran I, Sleigh A, Rochford JJ, et al.. Lipodystrophy: metabolic insights from a rare disorder. J Endocrinol
. 2010; 207: 245–255.
30. Farooqi IS, O’Rahilly S. Mutations in ligands and receptors of the leptin-melanocortin pathway that lead to obesity. Nat Clin Pract Endocrinol Metab
. 2008; 4: 569–577.
31. Choi JH, Banks AS, Estall JL, et al.. Anti-diabetic drugs inhibit obesity-linked phosphorylation of PPARgamma by Cdk5. Nature
. 2010; 466: 451–456.
32. Petrie JR, Pearson ER, Sutherland C. Implications of genome wide association studies for the understanding of type 2 diabetes pathophysiology. Biochem Pharmacol
. 2011; 81: 471–477.
33. Zhou K, Bellenguez C, Spencer CC, et al.. Common variants near ATM are associated with glycemic response to metformin in type 2 diabetes. Nat Genet
. 2011; 43: 117–120.
34. Birnbaum MJ, Shaw RJ. Genomics: drugs, diabetes and cancer. Nature
. 2011; 470: 338–339.
Copyright © 2013 by the American Federation for Medical Research.