Currently Viewing:
Supplements Understanding the Mechanisms to Maintain Glucose Homeostasis: A Review for Managed Care [CPE]

Examining the Mechanisms of Glucose Regulation

Curtis L. Triplitt, PharmD, CDE
DM is a group of metabolic diseases characterized by hyperglycemia. The hallmark state of chronic hyperglycemia is associated with long-term damage, dysfunction, and potential failure of different organs, especially the eyes, kidneys, nerves, heart, and blood vessels.14 Numerous factors contribute to the development of T2DM, with the central defects being inadequate insulin secretion (insulin deficiency) and/ or diminished tissue responses to insulin (insulin resistance) at 1 or more points in the complex pathways of hormone action.14 Insulin deficiency and insulin resistance frequently coexist, though the contribution to hyperglycemia can vary widely along the spectrum of T2DM.

The pancreas has a remarkable capacity to adapt to conditions of increased insulin demand (eg, in obesity, pregnancy, cortisol excess) to maintain normoglycemia. Compensatory hyperinsulinemia maintains glucose homeostasis. However, when β-cell secretion of insulin becomes inadequate for the glucose load, hyperglycemia occurs. Progressive deterioration in β-cell function and mass is well known to occur over time in T2DM and the resultant state of impaired insulin secretion is found uniformly in T2DM patients of all ethnic backgrounds.4,15 Research has shown that at time of diagnosis, islet cell function/responsiveness to glucose is approximately 30% to 50% of normal, and β-cell mass is reduced by about 60%; both of these are important determinants of the amount of insulin that is secreted.4 Based on analyses from the United Kingdom Prospective Diabetes Study, a direct correlation exists between progressive loss in β-cell function and poor glycemic control (as measured by A1C levels).16 The major factors implicated in progressive loss of β-cell function and mass include glucotoxicity, lipotoxicity, proinflammatory cytokines, leptin, and islet cell amyloid. Research indicates that progressive impaired β-cell function and possibly β-cell mass may be arrested, though clinical evidence in humans remains scarce.15

Impaired insulin secretion is often exacerbated by insulin resistance, which is characterized by the inability of insulin to decrease plasma glucose levels through suppression of hepatic glucose production and stimulation of glucose utilization in skeletal muscle and adipose tissue.10 In the presence of physiologically possible levels of insulin in humans, there is decreased glucose uptake in subjects with T2DM versus normal subjects, confirming that glucose uptake is severely impaired due to insulin resistance (Figure 3).4,17 As a consequence of insulin resistance, inefficient glucose utilization is eventually replaced by cellular utilization of fats and proteins for energy. Insulin resistance is contributed to by genetic and environmental factors. Family history can contribute directly to insulin resistance, but multiple environmental factors such as obesity, comorbidities, and central adiposity (visceral) can all contribute. The exact cause of insulin resistance in any given patient is complex, but may include defects in insulinmediated cell signaling pathways, reduced insulin-stimulated muscle glycogen synthesis,18 or even potentially fewer insulin receptors (particularly in skeletal muscle, liver, and adipose tissue in obese subjects).6

The relative contribution of insulin secretion and insulin resistance to the development of hyperglycemia may differ due to the heterogeneity of T2DM. Under most circumstances, insulin resistance is the earliest detectable defect in individuals with prediabetes.19 Initially, enhanced insulin secretion may compensate for the insulin resistance; however, early phase insulin secretion is impaired. In the transition from normal glucose tolerance to impaired glucose tolerance and DM, insulin sensitivity deteriorates about 40%, whereas insulin secretion deteriorates 3- to 5-fold.19 In DM, chronic hyperglycemia may result in further deterioration of insulin sensitivity and secretion (glucotoxicity), which is aggravated by elevated free fatty acids (lipotoxicity).19

Other increasingly more well-understood mechanisms contributing to the pathophysiology of T2DM include increased hepatic glucose output and adipocyte dysfunction. Following glucose ingestion, insulin is normally secreted into the portal vein, where it is taken up by the liver and suppresses hepatic glucose output. However, if the liver does not perceive this insulin signal and continues to produce glucose, the 2 sources of glucose input (from the liver and the gastrointestinal tract) will result in marked hyperglycemia.4 The increased hepatic glucose output seen in T2DM is thought to be related partly to insulin resistance and is closely correlated with the severity of fasting hyperglycemia. To the latter point, it has been shown that while the postabsorptive level of chronic hyperinsulinemia seen in mild hyperglycemia (<140 mg/dL) is enough to offset hepatic insulin resistance and maintain a normal basal rate of hepatic glucose output, moderate fasting hyperglycemia is associated with significant increases in hepatic glucose output.4 In individuals with T2DM with overt fasting hyperglycemia (>140 mg/dL), an excessive rate of hepatic glucose output is considered the major abnormality responsible for the elevated fasting plasma glucose.4 Although hyperinsulinemia and hyperglycemia (both certainly present in T2DM) are potent inhibitors of hepatic glucose output, they do not appear to fully correct excessive glucose output by the liver, which is suggestive of existing hepatic resistance to insulin and potential hyperglucagonemia contributing to an elevated plasma glucose.4

With regard to adipocyte dysfunction, considerable evidence implicates deranged metabolism and altered disposition of fat in the pathogenesis of glucose intolerance in T2DM.20 Because fat cells are resistant to insulin’s antilipolytic effect, the resultant chronically elevated plasma free fatty acid levels stimulate gluconeogenesis, induce hepatic/ muscle insulin resistance, and impair insulin secretion in predisposed individuals.20 These free fatty acid–induced disturbances are referred to as lipotoxicity. Beyond this phenomenon, dysfunctional fat cells also produce excessive amounts of insulin resistance–inducing, inflammatory, and atherosclerotic-provoking cytokines and fail to secrete normal amounts of insulin-sensitizing adipocytokines (adiponectin).20 Also, the pattern of fat disposition in T2DM is abnormal, essentially because enlarged adipocytes (in visceral fat) are insulin-resistant and have diminished capacity to store fat, which leads to lipid overflow into muscle, liver, and potentially β-cells, further exacerbating muscle/hepatic insulin resistance and impaired insulin secretion. They are also major sources of proinflammatory adipocytokines. Within liver cells, the elevated free fatty acids are converted to triglycerides, which accumulate and cause steatosis (or fatty liver) and consequently may increase the chances of nonalcoholic steatohepatitis (NASH) and even cirrhosis.10 These disturbances in adipocyte function are particularly relevant in light of the fact that many individuals with T2DM are obese.

The development of glucose intolerance in T2DM involves multiple systems including the muscle, liver, β-cell, fat cell (accelerated lipolysis), gastrointestinal tract (incretin deficiency/resistance), α-cell (hyperglucagonemia), kidney (increased glucose reabsorption), and brain (insulin resistance).21 Collectively, these 8 players comprise the ominous octet and dictate the need for combination therapy. Treatment should be based upon reversal of known pathogenic abnormalities and should not be directed simply at the reduction of A1C. Early initiation of therapy may help to prevent or slow progressive β-cell failure.21

Clinical Manifestations of T2DM

The majority of patients with T2DM are either obese (with obesity itself contributing to insulin resistance) or have an increased proportion of body fat in the abdominal region. Many factors increase the risk of developing T2DM, including family history, age, obesity, and lack of physical activity. Also, DM occurs more frequently in women with prior gestational DM and in individuals with hypertension or dyslipidemia.14 T2DM is frequently undiagnosed for many years, since the hyperglycemia develops gradually and, at least in the early stages, is not severe enough to cause clinical symptoms. Symptoms of marked hyperglycemia include polyuria, polydypsia, weight loss, polyphagia, and blurred vision.14

Although the degree of hyperglycemia seen with T2DM may not cause symptoms initially, it is sufficient to cause pathologic and functional changes in target tissues, and as such, will increase the risk of microvascular and macrovascular complications.14 Hyperglycemia, or long-term glycemic burden, appears to be cumulative, increasing the chances of complications with longer exposure. These long-term complications include retinopathy with potential loss of vision; nephropathy leading to renal failure; peripheral neuropathy with risk of foot ulcers, amputations, and Charcot joints; and autonomic neuropathy causing gastrointestinal, genitourinary, and cardiovascular symptoms and sexual dysfunction. Diabetic patients also have an increased incidence of atherosclerotic cardiovascular, peripheral arterial, and cerebrovascular disease.14


Glucose, a vital energy source for many cells and tissues, is tightly regulated via a complex interaction between pancreatic β-cells and α-cells, associated organs (eg, intestines, liver, skeletal muscle, adipose tissue), and respective hormones (ie, insulin, glucagon, GLP-1, GIP, amylin, and others). A summary of the major factors responsible for maintenance of normal glucose tolerance in healthy subjects is provided in the Table.4 Beyond these primary controllers of glucose regulation, incretin hormones (GIP and GLP-1) further assist in maintenance of normal plasma glucose and a host of transport proteins (GLUT molecules) facilitate movement of glucose through otherwise impermeable cellular membranes. The primary tissues involved in glucose utilization include the brain, muscle, fat, and the splanchnic area, with muscle tissue comprising the most important site of peripheral glucose uptake.

Knowledge of the fundamentals of normal glucose homeostasis is essential to understanding the pathophysiologic derangements that may result from glucose imbalance disorders. Conditions such as T2DM are characterized by an imbalance in glucose regulation, causing chronic hyperglycemia and ultimately leading to multiorgan damage. Several factors are implicated in the development of T2DM, including insulin resistance, insulin deficiency, increased hepatic glucose production, and adipocyte dysfunction. An increasingly clear understanding of these derangements has helped both researchers and clinicians to better manage T2DM and improve clinical outcomes.

Author affiliations: Department of Medicine, Division of Diabetes, University of Texas Health Science Center at San Antonio; and Texas Diabetes Institute, San Antonio, TX.
Funding source: This activity is supported by an educational grant from Bristol-Myers Squibb and AstraZeneca LP.
Author disclosure: Dr Triplitt reports being a consultant or a member of the advisory board for Roche and Takeda Pharmaceuticals. He also reports being a member of the speakers’ bureau for Amylin, Eli Lilly, and Pfizer.
Authorship information: Concept and design; drafting of the manuscript; and critical revision of the manuscript for important intellectual content. Address correspondence to: E-mail:
  1. National Diabetes Fact Sheet, 2011. Center for Disease Control and Prevention. Accessed August 21, 2011.
  2. American Diabetes Association. Economic costs of diabetes in the U.S. in 2007. Diab Care. 2008;31(3):596-615.
  3. Bryant NJ, Govers R, James DE. Regulated transport of the glucose transporter GLUT4. Nat Rev Mol Cell Biol. 2002;3(4): 267-277.
  4. DeFronzo RA. Diabetes: pathogenesis of type 2 diabetes mellitus. Med Clin N Am. 2004;88:787-835.
  5. Wardlaw GM, Hampl JS. Perspectives in Nutrition. 7th ed. New York, NY: McGraw-Hill; 2007.
  6. Guyton AC, Hall JE. Textbook of Medical Physiology. 11th ed. Philadelphia, PA: Elsevier Inc; 2006.
  7. Tortora GJ, Grabowski SR. Principles of Anatomy and Physiology. 10th ed. New York, NY: Wiley; 2003.
  8. Gerich JE. Physiology of glucose homeostasis. Diabetes Obes Metab. 2000;2:345-350.
  9. Drucker DJ, Nauck M. The incretin system: glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes. Lancet. 2006;368:1696-1705.
  10. Porte D, Sherwin RS, Baron A. Ellenberg & Rifkin’s Diabetes Mellitus. 6th ed. New York, NY: McGraw-Hill; 2003.
  11. Drucker DJ. The biology of incretin hormones. Cell Metab. 2006;3:153-165.
  12. Wright EM, Hirayama BA, Loo DF. Active sugar transport in health and disease. J Int Med. 2007;261:31-43.
  13. Uldry M, Thorens B. The SLC2 family of facilitated hexose and polyol transporters. Eur J Physiol. 2004;447:480-489.
  14. American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes Care. 2010;33(suppl 1):S62-S69.
  15. Wajchenberg BL. β-cell failure in diabetes and preservation by clinical treatment. Endocr Rev. 2007;28:187-218.
  16. Holman RR. Long-term efficacy of sulfonylureas: a United Kingdom Prospective Diabetes Study perspective. Metabolism. 2006;55(suppl 1):S2-S5.
  17. Groop LC, Bonadonna RC, DelPrato S, et al. Glucose and free fatty acid metabolism in non-insulin-dependent diabetes mellitus. J Clin Invest. 1989;84:205-213.
  18. Petersen KF, Shulman GI. Etiology of insulin resistance. Am J Med. 2006;119(5A):10S-16S.
  19. Groop L. Pathogenesis of type 2 diabetes: the relative contribution of insulin resistance and impaired insulin secretion. Int J Clin Pract Suppl. 2000;(113):3-13.
  20. 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.
  21. 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.
Copyright AJMC 2006-2020 Clinical Care Targeted Communications Group, LLC. All Rights Reserved.
Welcome the the new and improved, the premier managed market network. Tell us about yourself so that we can serve you better.
Sign Up