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Understanding the Roles of Organs and Tissues Important in Glucose Homeostasis FACULTY REVIEWER Anne Peters, MD Director, USC Clinical Diabetes Program Professor, Keck School of Medicine of USC Los Angeles, CA Anne Peters, MD, is a paid consultant for Janssen Pharmaceuticals, Inc.

Understanding the Roles of Organs and Tissues Important in Glucose Homeostasis


ore than 25 million adults 20 years of age and older in the United States have diabetes. Based on fasting glucose or hemoglobin A1C levels, an additional 79 million have prediabetes.1 Even with ongoing physician-managed care, only about half of patients with type 2 diabetes mellitus (T2DM) achieve A1C treatment goals, despite the availability of a number of distinct classes of antihyperglycemic agents.2-4 


Glucose Regulation is dysfunctional in patients with diabetes

Director, USC Clinical Diabetes Program Professor, Keck School of Medicine of USC Los Angeles, CA

A number of organs and tissues are involved in dysfunctional glucose homeostasis, the primary metabolic disturbance in patients with T2DM.5 Chronic hyperglycemia, a sustained increase in circulating plasma glucose concentration, leads to peripheral insulin resistance in liver and muscle cells as well as impaired insulin secretion by -cells in the pancreas. These core pathophysiologic defects of T2DM further contribute to the abnormal glucose homeostasis that characterizes T2DM.5-7 In addition, the kidneys, brain, pancreatic -cells, gastrointestinal (GI) tract, and adipocytes also play important roles in the maintenance of glucose homeostasis.5,6,8,9 Collectively, the multiple pathophysi­ologic defects seen in T2DM may require treatment with multiple drugs used in combination.6 Therapy should be based not only on reducing A1C levels and ameliorating comorbidities, such as obesity and hypertension, but also on reversing the pathophys­iologic effects of chronic hyperglycemia.6

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Glucose homeostasis

I. Kidneys

The role of the kidneys in glucose homeostasis is to reabsorb glucose filtered at the glomerulus via sodium-glucose transporters (SGLTs) located in the proximal convoluted tubule. SGLT-2 is a lowaffinity, high-capacity glucose transport protein that reabsorbs 80%-90% of filtered glucose, while the high-affinity, low-capacity SGLT-1 transporter reabsorbs the approximate 10% remaining.7-10 This adaptive mechanism helps ensure that the body’s energy needs are met during fasting periods.7 In healthy adults, nearly all filtered glucose is reabsorbed into the bloodstream, leaving the urine essentially free of glucose.8-10 However, in patients with T2DM, chronic hyperglycemia leads to a marked increase in the filtered glucose load,10 which may exceed the capacity for tubular glucose reabsorption and result in glycosuria.11 In addition, both the expression and the activity of SGLT-2 are increased in patients with poorly controlled T2DM, resulting in up to 20% more glucose being reabsorbed and exacerbating hyperglycemia.7,10 There are no currently approved therapies targeting renal glucose handling. However, blocking renal glucose reabsorption via inhibition of SLGT-2 may lead to increased glucose excretion and thus may help improve plasma glucose levels without the need for modulating insulin secretion or peripheral insulin sensitivity.7,9-11 II. Brain

The brain responds to both hyperglycemia and hypoglycemia.12 There are a number of sites of glucose sensing located January 2013

within the brain, mostly in the hypothalamus and brainstem, regions that are involved in regulation of feeding, energy expenditure, and glucose homeostasis.12 Autonomic neural effectors are controlled by central glucose-sensing cells; the effectors in turn regulate function of peripheral organs and tissues, including liver, adipocytes, muscle, and - and -cells in the pancreas.12 Historically, insulin-independent brain glucose uptake has led to the hypothesis that the brain is insulin-insensitive.13 However, animal studies suggest that insulin acts as a trigger for appetite suppression in the brain.6 In obese individuals, this appetite regulation by insulin may be impaired.6 A dopamine receptor agonist, bromocriptine mesylate, improves glycemic control in adults with T2DM without increasing plasma insulin levels, although the improvement is relatively small.14 III. Pancreatic -cells

When blood glucose levels rise, pancreatic  -cells secrete insulin, which facilitates uptake and storage of glucose in tissues such as skeletal muscle and fat.5,6 -cells are particularly susceptible to damage from glucotoxicity and oxidative stress due to fluctuations in blood glucose; persistent hyperglycemic fluctuations may eventually lead to the loss of glucose-stimulated insulin release.15 Genetic factors also play a role in -cell dysfunction.16 In patients with T2DM, the decline in -cell function begins as early as 12 years before diagnosis and continues throughout the disease process.16 Targeted therapy to stimulate insulin secretion directly includes sulfonylureas,

meglitinides, incretin mimetics, and dipeptidyl peptidase 4 (DPP-4) inhibitors.17 Ghrelin (a 28-amino acid peptide hormone predominantly produced by the stomach) and its receptor (GRLN-R), which is present on pancreatic -cells, play a regulatory role in insulin secretion.18 IV. Pancreatic -cells

In the fasting state, low blood glucose/low  insulin levels trigger increased secretion of glucagon by pancreatic -cells.5 Glucagon mobilizes stored glycogen, causing blood glucose levels to rise.5 Postprandially, the glucose load causes insulin to rise and glucagon to fall, leading to a reversal of these processes.5 Increased levels of glucagon in the blood play a pivotal role in the pathogenesis of fasting hyperglycemia in T2DM.6 According to a recent study in mice, uncoupling protein 2 (UCP2) contributes to the production of reactive oxygen species (ROS). ROS signals mediate changes in -cell morphology and glucagon secretion that are associated with dysfunctional glucose homeostasis.19 Currently available therapies that target pancreatic -cells include pramlintide, the incretin mimetics, and DPP-4 inhibitors, which reduce the secretion of glucagon.5,17 V. Liver

The role of the liver in glucose homeostasis lies in its ability to switch between glucose-producing mode and glucose-utilizing mode, depending on the blood glucose concentration and hormonal signals.20 When serum insulin

levels are high, the liver stores glucose as glycogen; when insulin levels are low, the liver produces glucose and breaks down stored glycogen.5 One of the core pathophysiologic defects in T2DM, hepatic insulin resistance, is manifested by overproduction of glucose during the basal state, despite the presence of fasting hyperinsulinemia, and impaired suppression of glucose production in response to insulin, as occurs following a meal.6 A recent study in rats suggests that metabolism of the amino acid leucine in the mediobasal hypothalamus—a key center involved in nutrient-dependent metabolic regulation—may control glucose production in the liver.21 Currently approved therapies that target the liver include biguanides, which decrease hepatic glucose production, and thiazolidinediones, which increase insulin sensitivity.17 VI. Muscle

Skeletal muscle is the major site of insulinstimulated uptake of glucose as well as the major site of insulin resistance, one of the core pathophysiologic defects in T2DM.6,22 Under conditions of normal glucose homeostasis, insulin triggers uptake of glucose by skeletal muscle cells for immediate use and storage.5,6 However, insulin resistance leads to impaired glucose uptake by muscle following ingestion of a carbohydrate meal, resulting in postprandial hyperglycemia.6 The thiazolidinediones increase insulin sensitivity in skeletal muscle.17 The mechanism of the interactions among hyperglycemia, insulin sensitivity, and glycogen kinetics in skeletal muscle is still being elucidated.22 january 2013

Glucose homeostasis

VII. Gastrointestinal tract

A number of hormones secreted by neuroendocrine cells in the GI tract play a role in glucose homeostasis. The incretins glucagonlike peptide 1 (GLP-1) and glucose-​ dependent insulinotropic polypeptide (GIP) amplify glucose-stimulated insulin secretion and suppress glucagon secretion.5,6 In individuals with T2DM, there is a reduced GLP-1 effect as well as resistance to the action of GIP, resulting in decreased secretion of insulin.6 Ghrelin, produced predominantly by the stomach, plays a regulatory role in insulin secretion and may be diabetogenic.18 The transporter SGLT-1 is responsible for absorption of glucose in the small intestine.9,23 A receptor for sweet-tasting compounds is also expressed in the GI tract, where it is involved in intestinal absorption, metabolic regulation, and glucose homeostasis.24 Changes in gut microbiota may lead to low-grade inflammation, which in turn leads to development of insulin resistance.25 Therapies targeting the GI tract include -glucosidase inhibitors, which slow intestinal carbohydrate digestion and absorption, and biguanides, which reduce glucose absorption.17 VIII. Adipocytes

Adipocytes also play a pivotal role in glucose homeostasis and hyperglycemia. Obesity, particularly in the abdomen, is thought to contribute to the pathogenesis of T2DM.5 Hypertrophied adipocytes become insulin-resistant, and their capacity to store fat is diminished.6,26 January 2013

Moreover, obesity induces a release of proinflammatory cytokines from hypertrophied adipocytes and inflammatory cells, leading to impaired insulin signaling.25 Adipocytes also secrete free fatty acids—which impair glucose utilization in skeletal muscle, promote glucose production by the liver, and impair -cell function—and adipokines—which can cause insulin resistance in skeletal muscle and the liver.5,25 The biguanides and thiazolidinediones increase peripheral insulin sensitivity in patients with T2DM.17 Unmet needs in the management of diabetes

Early therapeutic intervention is important in T2DM to preserve -cell function, increase insulin sensitivity, and prevent micro- and macrovascular complications.7 A number of organs and tissues that play key roles in the regulation of glucose homeostasis in healthy individuals, as well as in the dysfunctional glucose homeostasis exhibited in individuals with T2DM, are targets for current and emerging therapies. Most of the currently available non-insulin pharmacologic interventions—which can be used alone or in combination to target key organs and tissues—generally rely on residual insulin signaling to be effective.27 Multiple agents are currently available to improve glycemic control in patients for whom diet and exercise alone are insufficient; however, many patients with T2DM still do not achieve their treatment goals.2,3 Emerging data regarding novel pathophysiologic mechanisms responsible for glucose homeostasis may point to new treatment options in T2DM. These could potentially include pharmacologic targeting of key organs and tissues with mechanisms dissociated from insulin and pancreatic function. ■

References 1. Centers for Disease Control and Prevention (CDC). National diabetes fact sheet: national estimates and general information on diabetes and prediabetes in the United States, 2011. Atlanta, GA: US Dept of Health and Human Services, Centers for Disease Control and Prevention; 2011. 2. Vouri SM, Shaw RF, Waterbury NV, et al. Prevalence of achievement of A1c, blood pressure, and cholesterol (ABC) goal in veterans with diabetes. J Manag Care Pharm. 2011;17(4):304-312. 3. Braga MF, Casanova A, Teoh H, et al; Diabetes Registry to Improve Vascular Events [DRIVE] Investigators. Poor achievement of guidelines-recommended targets in type 2 diabetes: findings from a contemporary prospective cohort study. Int J Clin Pract. 2012;66(5):457-464. 4. Morrison F, Shubina M, Turchin A. Lifestyle counseling in routine care and long-term glucose, blood pressure, and cholesterol control in patients with diabetes. Diabetes Care. 2012;35(2):334-341. 5. Powers AC. Diabetes mellitus. In: Kasper DL, Braunwald E, Hauser S, Fauci AS, Longo DL, Jameson JL, eds. Harrison’s Principles of Internal Medicine. 16th ed. New York, NY: McGraw Hill; 2005:2152-2180. 6. DeFronzo RA. From the triumvirate to the ominous octet: a new paradigm for the treatment of type 2 diabetes mellitus. Diabetes. 2009;58(4):773-795. 7. DeFronzo RA, Davidson JA, Del Prato S. The role of the kidneys in glucose homeostasis: a new path towards normalizing glycaemia. Diabetes Obes Metab. 2012;14(1):5-14. 8. Gerich JE. Role of the kidney in normal glucose homeostasis and in the hyperglycaemia of diabetes mellitus: therapeutic implications. Diabet Med. 2010;27(2):136-142. 9. Neumiller JJ, White JR Jr, Campbell RK. Sodium-glucose co-transport inhibitors: progress and therapeutic potential in type 2 diabetes mellitus. Drugs. 2010;70(4):377-385. 10. Abdul-Ghani MA, DeFronzo RA. Inhibition of renal glucose reabsorption: a novel strategy for achieving glucose control in type 2 diabetes mellitus. Endocr Pract. 2008;14(6):782-790. 11. Bailey CJ. Renal glucose reabsorption inhibitors to treat diabetes. Trends Pharmacol Sci. 2011;32(2):63-71. 12. Thorens B. Sensing of glucose in the brain. Handb Exp Pharmacol. 2012;209(3):277-294. 13. Ghasemi R, Haeri A, Dargahi L, Mohamed Z, Ahmadiani A. Insulin in the brain: sources, localization and functions. Mol Neurobiol. 2012 Sep 7. [Epub ahead of print]

14. Cycloset® (bromocriptine mesylate). Prescribing Information. San Diego, CA: Santarus, Inc.; 2010. 15. Kohnert K-D, Freyse E-J, Salzsieder E. Glycaemic variability and pancreatic -cell dysfunction. Curr Diabetes Rev. 2012;8(5):345-354. 16. Fonseca VA. Defining and characterizing the progression of type 2 diabetes. Diabetes Care. 2009;32(suppl 2):S151-S156. 17. American Diabetes Association. Standards of medical care in diabetes—2012. Diabetes Care. 2012;35(suppl 1):S11-S63. 18. Verhulst P-J, Depoortere I. Ghrelin’s second life: from appetite stimulator to glucose regulator. World J Gastroenterol. 2012;18(25):3183-3195. 19. Robson-Doucette CA, Sultan S, Allister EM, et al. Beta-cell uncoupling protein 2 regulates reactive oxygen species production, which influences both insulin and glucagon secretion. Diabetes. 2011;60(11):2710-2719. 20. König M, Bulik S, Holzhütter H-G. Quantifying the contribution of the liver to glucose homeostasis: a detailed kinetic model of human hepatic glucose metabolism. PLoS Comput Biol. 2012;8(6):e1002577. 21. Su Y, Lam TK, He W, et al. Hypothalamic leucine metabolism regulates liver glucose production. Diabetes. 2012;61(1):85-93. 22. Vind BF, Birk JB, Vienberg SG, et al. Hyperglycaemia normalises insulin action on glucose metabolism but not the impaired activation of AKT and glycogen synthase in the skeletal muscle of patients with type 2 diabetes. Diabetologia. 2012;55(5):1435-1445. 23. Wright EM, Martin MG, Turk E. Intestinal absorption in health and disease—sugars. Best Pract Res Clin Gastroenterol. 2003;17(6):943-956. 24. Sigoillot M, Brockhoff A, Meyerhof W, Briand L. Sweet-taste-suppressing compounds: current knowledge and perspectives of application. Appl Microbiol Biotechnol. 2012;96(3):619-630. 25. Dali-Youcef N, Mecili M, Ricci R, Andrès E. Metabolic inflammation: connecting obesity and insulin resistance. Ann Med. 2012 Jul 26. [Epub ahead of print] 26. DeFronzo RA. Pathogenesis of type 2 diabetes mellitus. Med Clin North Am. 2004;88(4):787-835. 27. Lorenzati B, Zucco C, Miglietta S, Lamberti F, Bruno G. Oral hypoglycemic drugs: pathophysiological basis of their mechanism of action. Pharmaceuticals (Basel). 2010;3(9):3005-3020.

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Glucose Homeostasis and T2DM