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The Forgotten Role of Glucose Effectiveness in the Regulation of Glucose Tolerance

  • Simmi Dube
  • Isabel Errazuriz-Cruzat
  • Ananda Basu
  • Rita BasuEmail author
Pathogenesis of Type 2 Diabetes and Insulin Resistance (RM Watanabe, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Pathogenesis of Type 2 Diabetes and Insulin Resistance

Abstract

Glucose effectiveness (S G) is the ability of glucose per se to stimulate its own uptake and to suppress its own production under basal/constant insulin concentrations. In an individual, glucose tolerance is a function of insulin secretion, insulin action and S G. Under conditions of declining insulin secretion and action (e.g. type 2 diabetes), the degree of S G assumes increasing significance in determining the level of glucose tolerance both in fasted and postprandial states. Although the importance of S G has been recognized for years, mechanisms that contribute to S G are poorly understood. Research data on modulation of S G and its impact in glucose intolerance is limited. In this review, we will focus on the role of S G in the regulation of glucose tolerance, its evaluation, and potential advantages of therapies that can enhance glucose-induced stimulation of glucose uptake and suppression of its own production in conditions of impaired insulin secretion and action.

Keywords

Glucose effectiveness Glucose tolerance Diabetes 

Notes

Compliance with Ethics Guidelines

Conflict of Interest

Simmi Dube, Isabel Errazuriz-Cruzat, Ananda Basu and Rita Basu declare that they have no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Hoffman RP, Armstrong PT. Glucose effectiveness, peripheral and hepatic insulin sensitivity, in obese and lean prepuberal children. Int J Obes Relat Metab Disord. 1996;20:521–5.PubMedGoogle Scholar
  2. 2.
    Firth RG, Bell PM, Marsh HM, et al. Postprandial hyperglycemia in patients with non-insulin-dependent diabetes mellitus. J Clin Invest. 1986;77:1525–32.CrossRefPubMedCentralPubMedGoogle Scholar
  3. 3.
    Mitrakou A, Kelley D, Veneman T, et al. Contribution of abnormal muscle and liver glucose metabolism to postprandial hyperglycemia in NIDDM. Diabetes. 1990;39:1381–90.CrossRefPubMedGoogle Scholar
  4. 4.
    Ferrannini E, Simonson DC, Katz LD, et al. The disposal of an oral glucose load in patients with non-insulin-dependent diabetes. Metabolism. 1988;37:79–85.CrossRefPubMedGoogle Scholar
  5. 5.
    DeFronzo RA, Ferrannini E, Hendler R, et al. Regulation of splanchnic and peripheral glucose uptake by insulin and hyperglycemia in man. Diabetes. 1983;32:35–45.CrossRefPubMedGoogle Scholar
  6. 6.
    Ader M, Ni T, Bergman RN. Glucose effectiveness assessed under dynamic and steady-state conditions. J Clin Invest. 1997;99:1187–99.CrossRefPubMedCentralPubMedGoogle Scholar
  7. 7.
    Yki-Jarvinen H, Young AA, Lamkin C, et al. Kinetics of glucose disposal in whole body and across the forearm in man. J Clin Invest. 1987;79:1713–9.CrossRefPubMedCentralPubMedGoogle Scholar
  8. 8.
    Rossetti L, Giaccari A, Barzilai N, et al. Mechanism by which hyperglycemia inhibits hepatic glucose production in conscious rats. J Clin Invest. 1993;92:1126–34.CrossRefPubMedCentralPubMedGoogle Scholar
  9. 9.
    Rizza RA, Mandarino LJ, Gerich JE. Dose-response characteristics for effects of insulin on production and utilization of glucose in man. Am J Physiol. 1981;240:E630–9.PubMedGoogle Scholar
  10. 10.
    Kolterman OG, Gray RS, Griffin J, et al. Receptor and postreceptor defects contribute to the insulin resistance in non-insulin-dependent diabetes mellitus. J Clin Invest. 1981;68:957–69.CrossRefPubMedCentralPubMedGoogle Scholar
  11. 11.
    Liljenquist J, Meuller G, Cherrington A, et al. Hyperglycemia per se can inhibit glucose production in man. J Clin Endocrinol Metab. 1979;48:171–5.CrossRefPubMedGoogle Scholar
  12. 12.
    Bergman RN, Bucolo RJ. Interaction of insulin and glucose in the control of hepatic glucose balance. Am J Physiol. 1974;227:1314–22.PubMedGoogle Scholar
  13. 13.
    Shulman G, Liljenquist J, Williams P, et al. Glucose disposal during insulinopenia in somatostatin-treated dogs: the roles of glucose and glucagon. J Clin Invest. 1978;62:487–91.CrossRefPubMedCentralPubMedGoogle Scholar
  14. 14.
    Sacca L, Cicala M, Trimarco B, et al. Differential effects of insulin on splanchnic and peripheral glucose disposal after an intravenous glucose load in man. J Clin Invest. 1982;70:117–26.CrossRefPubMedCentralPubMedGoogle Scholar
  15. 15.
    Cherrington A, Williams P, Harris M. Relationship between the plasma glucose level and glucose uptake in the conscious dog. Metabolism. 1978;27:787–91.CrossRefPubMedGoogle Scholar
  16. 16.
    Verdonk C, Rizza R, Gerich J. Effects of plasma glucose concentration on glucose utilization and glucose clearance in normal man. Diabetes. 1981;30:535–7.CrossRefPubMedGoogle Scholar
  17. 17.
    Best J, Taborsky G, Halter J, et al. Glucose disposal is not proportional to plasma glucose level in man. Diabetes. 1981;30:847–50.CrossRefPubMedGoogle Scholar
  18. 18.
    Lewis S, Schultz T, Westbie D, et al. Insulin glucose dynamics during flow through perfusion of the isolated rat hind limb. Horm Metab Res. 1977;9:190–5.CrossRefPubMedGoogle Scholar
  19. 19.
    Bell PM, Firth RG, Rizza RA. Assessment of insulin action in insulin-dependent diabetes mellitus using [61 4C]glucose, [33H]glucose, and [23H]glucose. J Clin Invest. 1986;78:1479–86.CrossRefPubMedCentralPubMedGoogle Scholar
  20. 20.
    Vranic M, Fono P, Kovacevic N, et al. Glucose kinetics and fatty acids in dogs on matched insulin infusion after glucose load. Metabolism. 1971;20:954–67.CrossRefPubMedGoogle Scholar
  21. 21.
    Ishiwata K, Hetenyi Jr G, Vranic M. Effect of D-glucose or D-ribose on the turnover of glucose in pancreatectomized dogs maintained on a matched intraportal infusion of insulin. Diabetes. 1969;18(12):820–7.CrossRefPubMedGoogle Scholar
  22. 22.
    Sacca L, Hendler R, Sherwin RS. Hyperglycemia inhibits glucose production in man independent of changes in glucoregulatory hormones. J Clin Endocrinol Metab. 1978;47:1160–3.CrossRefPubMedGoogle Scholar
  23. 23.
    Del Prato S, Matsuda M, Simonson DC, et al. Studies on the mass action effect of glucose in NIDDM and IDDM: evidence for glucose resistance. Diabetologia. 1997;40:687–97.CrossRefPubMedGoogle Scholar
  24. 24.
    Petersen KF, Laurent D, Rothman DL, et al. Mechanism by which glucose and insulin inhibit net hepatic glycogenolysis in humans. J Clin Invest. 1998;101:1203–9.CrossRefPubMedCentralPubMedGoogle Scholar
  25. 25.
    Bucolo RJ, Bergman RN, Marsh DJ, et al. Dynamics of glucose auto-regulation in the isolated, blood-perfused canine liver. Am J Physiol. 1974;221:209–17.Google Scholar
  26. 26.
    Best J, Kahn SE, Ader M, et al. Role of glucose effectiveness in the determination of glucose tolerance. Diabetes Care. 1996;19:1018–30.CrossRefPubMedGoogle Scholar
  27. 27.
    Galante P, Mosthaf L, Kellerer M, et al. Acute hyperglycemia provides an insulin-independent inducer for GLUT4 translocation in C2C12 myotubes and rat skeletal muscle. Diabetes. 1995;44:646–51.CrossRefPubMedGoogle Scholar
  28. 28.
    Nolte LA, Rincon J, Wahlstrom EO, et al. Hyperglycemia activates glucose transport in rat skeletal muscle via a Ca2+-dependent mechanism. Diabetes. 1995;44:1345–8.CrossRefPubMedGoogle Scholar
  29. 29.•
    Schwartz MW, Seeley RJ, Tschöp MH, et al. Cooperation between brain and islet in glucose homeostasis and diabetes. Nature. 2013;503(7474):59–66. This review article discusses the role of brain-centric glucoregulatory systems in lowering blood glucose levels via insulin-independent and -dependent mechanisms.CrossRefPubMedCentralPubMedGoogle Scholar
  30. 30.
    Vicini P, Caumo A, Cobelli C. Glucose effectiveness and insulin sensitivity from the minimal models: consequences of undermodeling assessed by Monte Carlo simulation. IEEE Trans Biomed Eng. 1999;46(2):130–7.CrossRefPubMedGoogle Scholar
  31. 31.
    Pacini G, Tonolo G, Sambataro M, et al. Insulin sensitivity and glucose effectiveness: minimal model analysis of regular and insulin-modified FSIGT. Am J Physiol. 1998;274(4 Pt 1):E592–9.PubMedGoogle Scholar
  32. 32.
    Bordenave S, Brandou F, Manetta J, et al. Effects of acute exercise on insulin sensitivity, glucose effectiveness and disposition index in type 2 diabetic patients. Diabetes Metab. 2008;34(3):250–7.CrossRefPubMedGoogle Scholar
  33. 33.
    Ni TC, Ader M, Bergman RN. Reassessment of glucose effectiveness and insulin sensitivity from minimal model analysis: a theoretical evaluation of the single-compartment glucose distribution assumption. Diabetes. 1997;46(11):1813–21.CrossRefPubMedGoogle Scholar
  34. 34.
    Caumo A, Vicini P, Zachwieja JJ, et al. Undermodeling affects minimal model indexes: insights from a two-compartment model. Am J Physiol. 1999;276(6 Pt 1):E1171–93.PubMedGoogle Scholar
  35. 35.
    Martin BC, Warram JH, Krolewski AS, et al. Role of glucose and insulin resistance in development of type 2 diabetes mellitus: results of a 25-year follow-up study. Lancet. 1992;340:925–9.CrossRefPubMedGoogle Scholar
  36. 36.
    Lorenzo C, Wagenknecht LE, Rewers MJ, et al. Disposition index, glucose effectiveness, and conversion to type 2 diabetes: the Insulin Resistance Atherosclerosis Study (IRAS). Diabetes Care. 2010;33(9):2098–103.CrossRefPubMedCentralPubMedGoogle Scholar
  37. 37.
    Henriksen JE, Alford F, Handberg A, et al. Increased glucose effectiveness in normoglycemic but insulin-resistant relatives of patients with non-insulin-dependent diabetes mellitus. J Clin Invest. 1994;94:1196–204.CrossRefPubMedCentralPubMedGoogle Scholar
  38. 38.
    Bergman RN. Lilly lecture 1989. Toward physiological understanding of glucose tolerance. Minimal-model approach. Diabetes. 1989;38:1512–27.CrossRefPubMedGoogle Scholar
  39. 39.
    Doi K, Taniguchi A, Nakai Y, et al. Decreased glucose effectiveness but not insulin resistance in glucose-tolerant offspring of Japanese non-insulin-dependent diabetic patients: a minimal-model analysis. Metabolism. 1997;46(8):880–3.CrossRefPubMedGoogle Scholar
  40. 40.
    Osei K, Cottrell DA, Orabella MM. Insulin sensitivity, glucose effectiveness, and body fat distribution pattern in nondiabetic offspring of patients with NIDDM. Diabetes Care. 1991;14:890–6.CrossRefPubMedGoogle Scholar
  41. 41.
    Nielsen MF, Nyholm B, Caumo A, et al. Prandial glucose effectiveness and fasting gluconeogenesis in insulin-resistant first-degree relatives of patients with type 2 diabetes. Diabetes. 2000;49(12):2135–41.CrossRefPubMedGoogle Scholar
  42. 42.
    Alzaid AA, Dinneen SF, Turk DJ, et al. Assessment of insulin action and glucose effectiveness in diabetic and nondiabetic humans. J Clin Invest. 1994;94:2341–8.CrossRefPubMedCentralPubMedGoogle Scholar
  43. 43.
    Basu A, Caumo A, Bettini F, et al. Impaired basal glucose effectiveness in NIDDM: contribution of defects in glucose disappearance and production, measured using an optimized minimal model independent protocol. Diabetes. 1997;46:421–32.CrossRefPubMedGoogle Scholar
  44. 44.
    Nielsen MF, Basu R, Wise S, et al. Normal glucose induced suppression of glucose production but impaired stimulation of glucose disposal in type 2 diabetes: evidence for a concentration-dependent defect in uptake. Diabetes. 1998;47:1735–47.CrossRefPubMedGoogle Scholar
  45. 45.
    Basu A, Dalla Man C, Basu R, et al. Effects of type 2 diabetes on insulin secretion, insulin action, glucose effectiveness, and postprandial glucose metabolism. Diabetes Care. 2009;32(5):866–72.CrossRefPubMedCentralPubMedGoogle Scholar
  46. 46.
    Taniguchi A, Nakai Y, Fukushima M, et al. Pathogenic factors responsible for glucose intolerance in patients with NIDDM. Diabetes. 1992;41:1540–6.CrossRefPubMedGoogle Scholar
  47. 47.
    Wajchenberg BL, Santomauro ATMG, Porrelli RN. Effect of a sulfonylurea (gliclazide) treatment on insulin sensitivity and glucose-mediated glucose disposal in patients with non-insulin-dependent diabetes mellitus (NIDDM). Diabetes Res Clin Pract. 1993;20:147–54.CrossRefPubMedGoogle Scholar
  48. 48.
    Welch S, Gebhart SSP, Bergman RN, et al. Minimal model analysis of intravenous glucose tolerance test-derived insulin sensitivity in diabetic subjects. J Clin Endocrinol Metab. 1990;71:1508–18.CrossRefPubMedGoogle Scholar
  49. 49.
    Avogaro A, Vicini P, Valerio A, et al. The hot but not the cold minimal model allows precise assessment of insulin sensitivity in NIDDM subjects. Am J Physiol. 1996;270:E532–40.PubMedGoogle Scholar
  50. 50.
    Quon MJ, Cochran C, Taylor SI, et al. Non-insulin-mediated glucose disappearance in subjects with IDDM. Diabetes. 1994;43:890–6.CrossRefPubMedGoogle Scholar
  51. 51.
    Finegood DT, Tzur D. Reduced glucose effectiveness associated with reduced insulin release: an artifact of the minimal-model method. Am J Physiol. 1996;271(3 Pt 1):E485–95.PubMedGoogle Scholar
  52. 52.
    Cobelli C, Vicini P, Caumo A. If the minimal model is too minimal, who suffers more: SG or SI ? Diabetologia. 1997;40:362–3.PubMedGoogle Scholar
  53. 53.
    Schwartz MW, Porte Jr D. Diabetes, obesity, and the brain. Science. 2005;307:375–9.CrossRefPubMedGoogle Scholar
  54. 54.
    Sandoval D, Cota D, Seeley RJ. The integrative role of CNS fuel-sensing mechanisms in energy balance and glucose regulation. Annu Rev Physiol. 2008;70:513–35.CrossRefPubMedGoogle Scholar
  55. 55.
    Elmquist JK, Coppari R, Balthasar N, et al. Identifying hypothalamic pathways controlling food intake, body weight, and glucose homeostasis. J Comp Neurol. 2005;493:63–71.CrossRefPubMedGoogle Scholar
  56. 56.
    Obici S, Zhang BB, Karkanias G, et al. Hypothalamic insulin signaling is required for inhibition of glucose production. Nat Med. 2008;8:1376–82.CrossRefGoogle Scholar
  57. 57.
    Lam TK, Gutierrez-Juarez R, Pocai A, et al. Regulation of blood glucose by hypothalamic pyruvate metabolism. Science. 2005;309:943–7.CrossRefPubMedGoogle Scholar
  58. 58.
    Coppari R, Ichinose M, Lee CE, et al. The hypothalamic arcuate nucleus: a key site for mediating leptin’s effects on glucose homeostasis and locomotor activity. Cell Metab. 2005;1:63–72.CrossRefPubMedGoogle Scholar
  59. 59.
    Morton GJ, Gelling RW, Niswender KD, et al. Leptin regulates insulin sensitivity via phosphatidylinositol-3-OH kinase signaling in mediobasal hypothalamic neurons. Cell Metab. 2005;2:411–20.CrossRefPubMedGoogle Scholar
  60. 60.
    D’Alessio DA, Kahn SE, Leusner CR, et al. Glucagon-like peptide 1 enhances glucose tolerance both by stimulation of insulin release and by increasing insulin-independent glucose disposal. J Clin Invest. 1994;93:2263–6.CrossRefPubMedCentralPubMedGoogle Scholar
  61. 61.
    Sandoval DA, Bagnol D, Woods SC, et al. Arcuate glucagon-like peptide 1 receptors regulate glucose homeostasis but not food intake. Diabetes. 2008;57:2046–54.CrossRefPubMedCentralPubMedGoogle Scholar
  62. 62.
    Hardie DG, Carling D, Carlson M. The AMP-activated/SNF1 protein kinase subfamily: metabolic sensors of the eukaryotic cell? Annu Rev Biochem. 1998;67:821–55.CrossRefPubMedGoogle Scholar
  63. 63.
    Musi N, Hirshman MF, Nygren J, et al. Metformin increases AMPactivated protein kinase activity in skeletal muscle of subjects with type 2 diabetes. Diabetes. 2002;51:2074–81.CrossRefPubMedGoogle Scholar
  64. 64.
    Kahn BB, Alquier T, Carling D, et al. AMP-activated protein kinase: ancient energy gauge provides clues to modern understanding of metabolism. Cell Metab. 2005;1:15–25.CrossRefPubMedGoogle Scholar
  65. 65.••
    Pau CT, Keefe C, Duran J, et al. Metformin improves glucose effectiveness, not insulin sensitivity: predicting treatment response in women with polycystic ovary syndrome in an open-label, interventional study. J Clin Endocrinol Metab. 2014;99(5):1870–8. This study provides evidence that a possible mechanism of action of metformin is via improvement of glucose effectiveness.CrossRefPubMedCentralPubMedGoogle Scholar
  66. 66.
    Brun JF, Guintrand-Hugret R, Boegner C, et al. Influence of short-term submaximal exercise on parameters of glucose assimilation analyzed with the minimal model. Metabolism. 1995;44:833–40.CrossRefPubMedGoogle Scholar
  67. 67.
    Hayashi Y, Nagasaka S, Takahashi N, et al. A single bout of exercise at higher intensity enhances glucose effectiveness in sedentary men. J Clin Endocrinol Metab. 2005;90:4035–40.CrossRefPubMedGoogle Scholar
  68. 68.
    Knowler WC, Barrett-Connor E, Fowler SE, et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med. 2002;346:393–403.CrossRefPubMedGoogle Scholar
  69. 69.
    Tuomilehto J, Lindstrom J, Eriksson JG, et al. Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. N Engl J Med. 2001;344:1343–50.CrossRefPubMedGoogle Scholar
  70. 70.
    Zierath JR. Invited review: exercise training-induced changes in insulin signaling in skeletal muscle. J Appl Physiol. 2002;93:773–81.CrossRefPubMedGoogle Scholar
  71. 71.
    Manetta J, Brun JF, Mercier J, et al. The effects of exercise training intensification on glucose disposal in elite cyclists. Int J Sports Med. 2000;21:338–43.CrossRefPubMedGoogle Scholar
  72. 72.
    Manetta J, Brun JF, Callis A, et al. Insulin and non-insulin-dependent glucose disposal in middle-aged and young athletes versus sedentary men. Metabolism. 2001;50:349–54.CrossRefPubMedGoogle Scholar
  73. 73.
    Higaki Y, Kagawa T, Fujitani Y, et al. Effects of a single bout of exercise on glucose effectiveness. J Appl Physiol. 1996;80:754–9.PubMedGoogle Scholar
  74. 74.
    Araujo-Vilar D, Osifo E, Kirk M, et al. Influence of moderate physical exercise on insulin-mediated and non-insulin-mediated glucose uptake in healthy subjects. Metabolism. 1997;46:203–9.CrossRefPubMedGoogle Scholar
  75. 75.
    Boule NG, Weisnagel SJ, Lakka TA, et al. Effects of exercise training on glucose homeostasis: the HERITAGE Family Study. Diabetes Care. 2005;28:108–14.CrossRefPubMedGoogle Scholar
  76. 76.
    Fujitani J, Higaki Y, Kagawa T, et al. Intravenous glucose tolerance test-derived glucose effectiveness in strength-trained humans. Metabolism. 1998;47:874–7.CrossRefPubMedGoogle Scholar
  77. 77.
    Nishida Y, Higaki Y, Tokuyama K, et al. Effect of mild exercise training on glucose effectiveness in healthy men. Diabetes Care. 2001;24:1008–13.CrossRefPubMedGoogle Scholar
  78. 78.
    Kennedy JW, Hirshman MF, Gervino EV, et al. Acute exercise induces GLUT4 translocation in skeletal muscle of normal human subjects and subjects with type 2 diabetes. Diabetes. 1999;48:1192–7.CrossRefPubMedGoogle Scholar
  79. 79.
    Hayashi T, Hirshman MF, Kuth EJ, et al. Evidence for 5′-AMP-activated protein kinase mediation of the effect of muscle contraction on glucose transport. Diabetes. 1998;47:1369–73.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Simmi Dube
    • 2
  • Isabel Errazuriz-Cruzat
    • 3
  • Ananda Basu
    • 1
  • Rita Basu
    • 1
    Email author
  1. 1.Endocrine Research Unit, Division of Endocrinology, Diabetes, Metabolism, and NutritionMayo College of MedicineRochesterUSA
  2. 2.Gandhi Medical CollegeBhopalIndia
  3. 3.Clinica Alemana de Santiago, Facultad de Medicina Clinica AlemanaUniversidad del DesarrolloSantiagoChile

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