Volume 65, No. 4
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Pathophysiology of Type 2 Diabetes: The Evolution of Our Understanding

Key Points
  • Diabetes was initially believed to be a disorder of the pancreas that led to insulin deficiency.
  • It is now understood that type 2 diabetes is a multisystem disorder, impacting the pancreas, muscle tissue, liver, fat cells, kidneys, and brain.
  • The multisystem pathophysiology of type 2 diabetes requires a multifaceted approach to treatment that combines therapies with complementary mechanisms of action.


Abstract

Type 2 diabetes (T2D) is now understood to be a complex disorder that involves multiple organ systems. However, in the early 1900s, scientists believed diabetes to be a simple disorder of insulin deficiency, rooted in the pancreas. Since then, several other systems have been recognized for their role in the pathophysiology of T2D. Contributing pathologies include reduced glucose reuptake in skeletal muscle, increased hepatic glucose production in the liver, a reduced incretin effect in the gut, increased glucagon secretion from pancreatic α cells, increased lipolysis in fat cells, increased glucose retention by the kidneys, and even hypothalamic insulin resistance within the brain. More recently, additional work has suggested that catecholamines, vitamin D, the renin–angiotensin system, and testosterone may also impact T2D. Combining therapies with complementary mechanisms of action allows for a multifaceted and individualized approach to treatment. As the scientific understanding of T2D grows, opportunities for improved treatment will continue to develop.


Introduction

Type 2 diabetes (T2D) is a heterogeneous, complex multisystem disorder, with multiple associated comorbidities, requiring a multifaceted and individualized approach to treatment. While the complexity of T2D is now more fully understood, in the 1920s the scientific community believed diabetes to be a simple disorder of the pancreas.1,2 Over the last 30 years, an improved understanding of past findings coupled with new insight have brought to light more and more important contributors, including the liver, muscle, kidney, fat cell, brain, α cell, and gut, as well as various hormones and even factors such as systemic inflammation, genetics, and environment (Figure 1).1,3-11 As the scientific understanding of T2D pathophysiology deepens, new treatment options become possible, expanding the potential for improved control of this complex disorder. This review examines the evolution of our understanding of T2D and how current theories about its underlying pathophysiology guide our approach to treatment.


Figure 1. The evolution of the understanding of diabetes1,3-11




More than the β Cell

In 1936, Himsworth challenged the notion that diabetes was simply a disease of pancreatic insulin deficiency by proposing that it could be differentiated into subtypes based on insulin sensitivity.5 This concept gained support in 1960 when Yalow and Berson demonstrated that patients with adult-onset diabetes had higher than normal levels of circulating insulin.6 From these findings, 2 different diabetic pathologies emerged: insulin-dependent diabetes (now known as type 1 diabetes) and non–insulin-dependent diabetes (now known as T2D).


The Triumvirate

In keeping with this growing complexity, in 1987 DeFronzo presented the idea that T2D resulted from deficits in the pancreatic β cell, muscle, and the liver. DeFronzo noted that, in normal-weight patients with T2D, the relationship between fasting glucose and the insulin response to an oral glucose tolerance test follows an inverted U-shape (Figure 2).7 This pattern recapitulates the natural progression of T2D in an individual: an increase in fasting glucose initially stimulates a compensatory increase in insulin production from the β cells, but as fasting glucose increases further, the β cells cannot maintain this increased output. As a result, insulin output is disproportionately low relative to the patient’s high fasting plasma glucose. Thus, when considering the chronic hyperglycemia characteristic of T2D, seemingly normal levels of insulin secretion are actually a reflection of β cell dysfunction.


Figure 2. Schematic of the relationship between fasting plasma glucose and the mean plasma insulin response during an OGTT (known as Starling’s curve of the pancreas) in normal-weight patients with T2D



In addition to a disproportionate insulin response in patients with T2D, the effects of insulin are blunted throughout the body. In other words, patients with T2D are insulin resistant, which further increases the demands on the β cells. DeFronzo noted the effects of insulin resistance in the peripheral muscle tissue and the liver (which, with the pancreas, he referred to as the "triumvirate"). In contrast to healthy individuals, glucose uptake in response to insulin is markedly reduced in the peripheral muscle tissue of patients with T2D.12 Additionally, hepatic glucose production was found to be elevated despite fasting hyperinsulinemia, demonstrating insulin resistance in the liver.13 Although the mechanism for this insulin resistance was unknown at the time, it was clear that T2D was a multisystem disorder.


The Ominous Octet

By 2009, in light of the growing complexity of the understanding of T2D, DeFronzo expanded his model of T2D from the triumvirate to what he called the “ominous octet.” The “ominous octet” model recognized the role of fat cells, the gastrointestinal tract, pancreatic α cells, kidneys, and brain, together with muscle, liver, and β cells, in the pathogenesis of T2D.9 In fat cells of healthy individuals, insulin inhibits lipolysis, thereby suppressing the release of free fatty acids.14 For patients with T2D, insulin resistance prevents insulin from acting on fat cells, leading to increased lipolysis and elevated free fatty acid concentration. The excess free fatty acids cause lipotoxicity, which further promotes insulin resistance.15 Additionally, in the gut, the incretin hormone glucagon-like peptide-1 (GLP-1; and to a lesser extent, GIP [glucose-dependent insulinotropic peptide]) activates receptors on the β cells of the pancreas. These G protein-coupled receptors stimulate insulin secretion at elevated plasma glucose levels, contributing to the postprandial insulin response.16 GLP-1 also acts on pancreatic α cells to reduce glucagon secretion and delay gastric emptying. In patients with T2D, the incretin effect is reduced, potentially reflecting decreased secretion or efficacy of the incretins.11,17

Consistent with damage to pancreatic α cells, individuals with T2D may also have higher than expected glucagon levels, especially considering that glucagon secretion would normally be suppressed in the presence of hyperglycemia and hyperinsulinemia.18 Glucagon is secreted by α cells and essentially acts to counter the effects of insulin, increasing hepatic glucose production and ensuring the glucose supply to the brain is maintained. In patients with T2D, an infusion of somatostatin (which suppresses both insulin and glucagon) decreases hepatic glucose production.19 A separate infusion of somatostatin with insulin (collectively suppressing the effects of glucagon) further decreases hepatic glucose production.19 This observation links glucagon to a proportionate hepatic glucose output, and subsequently links the elevated hepatic glucose production seen in T2D to elevated glucagon, implicating α cell dysfunction as a key contributor to fasting hyperglycemia. Furthermore, amylin, which is released from the pancreatic β cells with insulin, suppresses glucagon release from the pancreatic α cells, delays gastric emptying, and increases satiety.20 As β cell function and insulin secretion decline, amylin secretion declines as well, further contributing to hyperglycemia.21

Additionally, glucose is filtered by the kidneys and nearly all of it is subsequently reabsorbed, largely via the sodium-glucose cotransporter 2 (SGLT-2).22 In healthy individuals, if blood glucose levels increase above the maximum renal glucose transport capacity of the SGLT-2, excess glucose is excreted in the urine in order to maintain glucose homeostasis. In patients with T2D, evidence suggests that both SGLT-2 expression and the threshold for excretion of excess glucose are increased, leading the kidney to continue to reabsorb glucose, despite elevated plasma glucose, rather than excreting it in the urine.23

Finally, even the brain is affected by insulin resistance, although the mechanism is less clear. A study in rats found that activation of hypothalamic insulin signaling was necessary for insulin to inhibit endogenous glucose production.24 As such, insulin resistance in the hypothalamus may disrupt the maintenance of glucose homeostasis and contribute to the pathogenesis of T2D. In humans, a functional magnetic resonance imaging study examining the hypothalamic regions of the brain associated with appetite regulation found that patients with obesity had a diminished inhibitory response following glucose ingestion compared with lean controls.25 DeFronzo suggested this may be a manifestation of insulin resistance in the brain and proposed a role for this potential insulin resistance in obesity and its potential impact on the development of T2D.9

Collectively, this expansive model of the pathophysiology of T2D provides a direction for therapeutic intervention to address long-term glucose control and reduce the risk of diabetic complications. DeFronzo used this model to suggest that the multisystem dysfunction of T2D requires combinations of treatments targeting the multiple pathophysiological defects, rather than using monotherapy to target only one defect, such as high blood glucose.9


Future Contenders

As research in this therapeutic area continues, additional potential contributors to T2D pathophysiology are emerging. Kalra and colleagues have proposed 4 additions to the ominous octet, expanding the list to the “dirty dozen.”10 First are catecholamines, including dopamine, which were identified in the 1970s for their role in regulating cardiovascular and metabolic homeostasis and are targeted by bromocriptine, a dopamine modulator approved for the treatment of T2D since 2009.10,26 Next are vitamin D, low levels of which have been associated with increased risk for diabetes and insulin resistance, and the renin–angiotensin system, which is known to impact insulin resistance and be involved in many of the comorbidities associated with T2D (hypertension, retinopathy, nephropathy, and cardiovascular disease).27,28 Finally, Kalra and and colleagues10 implicate testosterone, which, in men, correlates positively with insulin sensitivity.29 Additionally, men with low testosterone have a higher prevalence of the metabolic syndrome.29 While the impact of these hormones is not as well characterized as some of the initial suspects in T2D pathogenesis, their emerging relationship to T2D indicates that our understanding of the complexity of T2D is still growing.


A Therapeutic Roadmap

The 2015 update to the position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes echoed previous versions of these organizations’ recommended guidelines and continued to stress the individual needs of each patient, which must be considered when developing a treatment plan.30,31 The ADA recommends that therapies with complementary actions be added sequentially as a patient’s A1C exceeds an individualized goal—typically 7.0%—and the American Association of Clinical Endocrinologists and the American College of Endocrinology recommend initiating dual therapy for patients with an A1C of >7.5%.32,33 With multiple drug classes available, physicians can help their patients improve or maintain glycemic control by targeting specific elements of diabetic pathology.

DeFronzo’s portrayal of the pathogenesis of T2D offers 8 key targets for therapeutic intervention.34 Figure 3 shows the pathophysiological defects targeted by different classes of currently available antihyperglycemic medications, including metformin, GLP-1 receptor agonists (GLP-1RAs), dipeptidyl peptidase-4 (DPP-4) inhibitors, thiazolidinediones (TZDs), and SGLT-2 inhibitors. Metformin, the most commonly prescribed oral antihyperglycemic agent, acts on the liver to reduce hepatic glucose production.31 GLP-1RAs echo the effects of GLP-1 and affect multiple aspects of diabetic pathology.35 In the α and β cells of the pancreas, GLP-1RAs increase insulin and amylin secretion and inhibit glucagon secretion, while in the gut gastric emptying is delayed, and in the brain satiety is increased. GLP-1RAs also increase insulin sensitivity in the muscle and decrease glucose production in the liver. Inhibitors of the enzyme DPP-4, which degrade GLP-1, increase the effects of GLP-1, particularly with respect to stimulation of insulin release (the β cell) and suppression of glucagon release (the α cell).36 DPP-4 inhibitors also degrade GIP. TZDs have pleiotropic effects, acting on the defects in the fat cell, inhibiting lipolysis, and reducing the concentration of free fatty acids.14 TZDs also increase insulin sensitivity in muscle and the liver. Finally, SGLT-2 inhibitors work in the kidneys to decrease glucose reabsorption and increase the amount of glucose excreted.22

In addition to the drug classes shown in Figure 3, insulin is an important therapeutic option for many patients, while sulfonylureas have a long history as oral antihyperglycemic agents.11 Amylinomimetics increase amylin levels and are taken with insulin to target postprandial glucagon secretion.21 Use of these different medications in various combinations allows for the development of individualized treatment goals and targeted outcomes for each patient. A future review will expand on this multifaceted approach to treatment.


Figure 3. Pathophysiological defects contributing to glucose intolerance in type 2 diabetes (the “ominous octet”, as described by DeFronzo) targeted by currently available antihyperglycemic medications

Conclusions

The scientific understanding of diabetes has advanced far beyond its original classification as an insulin- and pancreas-centered disorder, resulting in the development of a wider selection of medications affecting multiple disease mechanisms. However, despite the depth of the current model of T2D, research will continue to further our understanding of this multisystem disorder. With each step forward and every advance, there is the potential for new treatments and enhanced management of the growing population of patients with T2D.


References
  1. Polonsky KS. The past 200 years in diabetes. N Engl J Med. 2012;367(14):1332-1340.
  2. Banting FG, Best CH, Collip JB, Campbell WR, Fletcher AA. Pancreatic extracts in the treatment of diabetes mellitus. Can Med Assoc J. 1922;12(3):141-146.
  3. von Mering JV, Minkowski O. Diabetes mellitus nach Pankrcasexstirpation. Zbl Kiln Med. 1889;10:393.
  4. Banting FG, Best CH. Pancreatic extracts. 1922. J Lab Clin Med. 1990;115(2):254-272.
  5. Himsworth HP. Diabetes mellitus: its differentiation into insulin-sensitive and insulin-insensitive types. Lancet. 1936;227(5864):127-130.
  6. Yalow RS, Berson SA. Plasma insulin concentrations in nondiabetic and early diabetic subjects. Determinations by a new sensitive immuno-assay technic. Diabetes. 1960;9:254-260.
  7. DeFronzo RA. Lilly lecture 1987. The triumvirate: beta-cell, muscle, liver. A collusion responsible for NIDDM. Diabetes. 1988;37(6):667-687.
  8. James DE, Brown R, Navarro J, Pilch PF. Insulin-regulatable tissues express a unique insulin-sensitive glucose transport protein. Nature. 1988;333(6169):183-185.
  9. DeFronzo RA. Banting Lecture. From the triumvirate to the ominous octet: a new paradigm for the treatment of type 2 diabetes mellitus. Diabetes. 2009;58(4):773-795.
  10. Kalra S, Chawla R, Madhu SV. The dirty dozen of diabetes. Indian J Endocrinol Metab. 2013;17(3):367-369.
  11. Kahn SE, Cooper ME, Del Prato S. Pathophysiology and treatment of type 2 diabetes: perspectives on the past, present, and future. Lancet. 2014;383(9922):1068-1083.
  12. DeFronzo RA, Gunnarsson R, Björkman O, Olsson M, Wahren J. Effects of insulin on peripheral and splanchnic glucose metabolism in noninsulin-dependent (type II) diabetes mellitus. J Clin Invest. 1985;76(1):149-155.
  13. DeFronzo RA, Simonson D, Ferrannini E. Hepatic and peripheral insulin resistance: a common feature of type 2 (non-insulin-dependent) and type 1 (insulin-dependent) diabetes mellitus. Diabetologia. 1982;23(4):313-319.
  14. Bays H, Mandarino L, DeFronzo RA. Role of the adipocyte, free fatty acids, and ectopic fat in pathogenesis of type 2 diabetes mellitus: peroxisomal proliferator-activated receptor agonists provide a rational therapeutic approach. J Clin Endocrinol Metab. 2004;89(2):463-478.
  15. Kashyap S, Belfort R, Gastaldelli A, et al. A sustained increase in plasma free fatty acids impairs insulin secretion in nondiabetic subjects genetically predisposed to develop type 2 diabetes. Diabetes. 2003;52(10):2461-2474.
  16. Drucker DJ. The biology of incretin hormones. Cell Metab. 2006;3(3):153-165.
  17. Nauck MA, Vardarli I, Deacon CF, Holst JJ, Meier JJ. Secretion of glucagon-like peptide-1 (GLP-1) in type 2 diabetes: what is up, what is down? Diabetologia. 2011;54(1):10-18.
  18. Dunning BE, Gerich JE. The role of alpha-cell dysregulation in fasting and postprandial hyperglycemia in type 2 diabetes and therapeutic implications. Endocr Rev. 2007;28(3):253-283.
  19. Baron AD, Schaeffer L, Shragg P, Kolterman OG. Role of hyperglucagonemia in maintenance of increased rates of hepatic glucose output in type II diabetics. Diabetes. 1987;36(3):274-283.
  20. Pillay K, Govender P. Amylin uncovered: a review on the polypeptide responsible for type II diabetes. Biomed Res Int. 2013;2013:826706.
  21. Martin C. The physiology of amylin and insulin: maintaining the balance between glucose secretion and glucose uptake. Diabetes Educ. 2006;32(suppl 3):101S-104S.
  22. DeFronzo RA, Hompesch M, Kasichayanula S, et al. Characterization of renal glucose reabsorption in response to dapagliflozin in healthy subjects and subjects with type 2 diabetes. Diabetes Care. 2013;36(10):3169-3176.
  23. Wilding JP. The role of the kidneys in glucose homeostasis in type 2 diabetes: clinical implications and therapeutic significance through sodium glucose co-transporter 2 inhibitors. Metabolism. 2014;63(10):1228-1237.
  24. Obici S, Zhang BB, Karkanias G, Rossetti L. Hypothalamic insulin signaling is required for inhibition of glucose production. Nat Med.2002;8(12):1376-1382.
  25. Matsuda M, Liu Y, Mahankali S, et al. Altered hypothalamic function in response to glucose ingestion in obese humans. Diabetes. 1999;48(9):1801-1806.
  26. Christensen NJ. Catecholamines and diabetes mellitus. Diabetologia. 1979;16(4):211-224.
  27. Scragg R, Sowers M, Bell C, Third National Health and Nutrition Examination Survey. Serum 25-hydroxyvitamin D, diabetes, and ethnicity in the Third National Health and Nutrition Examination Survey. Diabetes Care. 2004;27(12):2813-2818.
  28. Ribeiro-Oliveira A Jr, Nogueira AI, Pereira RM, Boas WW, Dos Santos RA, Simões e Silva AC. The renin-angiotensin system and diabetes: an update. Vasc Health Risk Manag. 2008;4(4):787-803.
  29. Pitteloud N, Mootha VK, Dwyer AA, et al. Relationship between testosterone levels, insulin sensitivity, and mitochondrial function in men. Diabetes Care. 2005;28(7):1636-1642.
  30. Inzucchi SE, Bergenstal RM, Buse JB, et al. Management of hyperglycemia in type 2 diabetes, 2015: a patient-centered approach: update to a position statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care. 2015;38(1):140-149.
  31. Inzucchi SE, Bergenstal RM, Buse JB, et al; American Diabetes Association; European Association for the Study of Diabetes. Management of hyperglycemia in type 2 diabetes: a patient-centered approach: position statement of the American Diabetes Association and the European Association for the Study of Diabetes [published correction appears in Diabetes Care. 2013;36(2);490]. Diabetes Care. 2012;35(6):1364-1379.
  32. American Diabetes Association. 7. Approaches to glycemic treatment. Diabetes Care. 2016;39(suppl 1):S52-S59.
  33. Handelsman Y, Bloomgarden ZT, Grunberger G, et al. American Association of Clinical Endocrinologists and American College of Endocrinology - clinical practice guidelines for developing a diabetes mellitus comprehensive care plan - 2015. Endocr Pract. 2015;21(suppl 1):1-87.
  34. DeFronzo RA, Triplitt CL, Abdul-Ghani M, Cersosimo E. Novel agents for the treatment of type 2 diabetes. Diabetes Spectr. 2014;27(2):100-112.
  35. Abu-Hamdah R, Rabiee A, Meneilly GS, Shannon RP, Andersen DK, Elahi D. Clinical review: the extrapancreatic effects of glucagon-like peptide-1 and related peptides. J Clin Endocrinol Metab. 2009;94(6):1843-1852.
  36. Campbell RK. Rationale for dipeptidyl peptidase 4 inhibitors: a new class of oral agents for the treatment of type 2 diabetes mellitus. Ann Pharmacother. 2007;41(1):51-60.