Skip to main content

Advertisement

SpringerLink
Log in

Insulin and its role in chronic kidney disease

  • Review
  • Published:
Pediatric Nephrology Aims and scope Submit manuscript

Abstract

The body’s resistance to the actions of insulin (type II diabetes defect) results in compensatory increased production and secretion by the pancreas and leads to hyperinsulinemia in order to maintain euglycemia. When insulin secretion cannot be increased adequately (type I diabetes defect) to overcome insulin resistance in maintaining glucose homeostasis, hyperglycemia and glucose intolerance ensues. Insulin resistance and glucose intolerance has been well recognized in patients with advanced chronic kidney diseases (CKD). The etiology may involve uremic toxins from protein catabolism, vitamin D deficiency, metabolic acidosis, anemia, poor physical fitness, inflammation, and cachexia. Glucose and insulin abnormalities in nondiabetic CKD patients are implicated in the pathogenesis of hyperlipidemia and may represent important risk factors for accelerated atherosclerosis in these patients. Insulin secretion inadequacy has been associated with growth retardation in adolescents with CKD. Normal adolescents demonstrate an increase in insulin secretion as they go into puberty. It seems that the puberty growth spurt in adolescents both with normal health and renal failure may require increased insulin secretion as one of its hormonal requirements. Finally, insulin resistance has been associated with CKD. Whether insulin resistance is an antecedent of CKD or a consequence of impaired kidney function has been a subject of debate. The goal of this review was to provide an update of the literature on insulin pathophysiology in CKD, current understanding of its mechanisms, and epidemiological association of insulin resistance and CKD.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. DeFronzo RA, Alvestrand A, Smith D, Hendler R, Wahren J (1981) Insulin resistance in uremia. J Clin Invest 67:563–568

    PubMed  CAS  Google Scholar 

  2. Mak RH, Haycock GB, Chantler C (1983) Glucose intolerance in children with chronic renal failure. Kidney Int 24(Suppl 15):S22–S26

    Google Scholar 

  3. Mak RH, DeFronzo RA (1992) Glucose and insulin metabolism in uremia. Nephron 61:377–382

    PubMed  CAS  Google Scholar 

  4. Wahba I, Mak RH (2007) Obesity and obesity-initiated metabolic syndrome: mechanistic links to chronic kidney disease. Clin J Am Soc Nephrol 2:550–562

    Article  PubMed  CAS  Google Scholar 

  5. Rabkin R, Simon NM, Steiner S, Colwell JA (1970) Effect of renal disease on renal uptake and excretion of insulin in man. N Engl J Med 282:182–187

    Article  PubMed  CAS  Google Scholar 

  6. Mondon CE, Dolkas CB, Reaven GM (1978) Effect of acute uremia on insulin removal by the isolated perfused rat liver and muscle. Metabolism 27:133–142

    Article  PubMed  CAS  Google Scholar 

  7. Friedman JE, Dohm GL, Elton CW, Rovira A, Chen JJ, Leggett-Frazier N, Atkinson SM, Thomas FT, Long SD, Caro JF (1991) Muscle insulin resistance in uremic humans: glucose transport, glucose transporters and insulin receptors. Am J Physiol 261:E87–E94

    PubMed  CAS  Google Scholar 

  8. Alvestrand A (1997) Carbohydrate and insulin metabolism in renal failure. Kidney Int 52(Suppl 62):S48–S52

    Google Scholar 

  9. Contreras I, Caro JF, Aveledo L, Diaz K, Durrego P, Weisinger JR (1992) In chronic uremia, insulin activates receptor kinase but not pyruvate dehydrogenase. Nephron 61:77–81

    PubMed  CAS  Google Scholar 

  10. Bailey JL, Zheng B, Hu Z, Prive SR, Mitch WE (2006) Chronic kidney disease causes defects in signaling through insulin receptor substrate/phosphoinositol 3-kinase/Akt pathway: Implications for muscle wasting. J Am Soc Nephrol 17:1388–1394

    Article  PubMed  CAS  Google Scholar 

  11. McCaleb ML, Izzo MS, Lockwood DH (1985) Characterization and partial purification of a factor from uremic serum that induces insulin resistance. J Clin Invest 75:391–396

    PubMed  CAS  Google Scholar 

  12. Dzuric R, Spustova V, Lajdova I (1993) Inhibition of glucose utilization in isolated rat soleus muscle by pseudouridine: Implications for renal failure. Nephron 65:108–110

    Google Scholar 

  13. Mak RH (1996) Insulin resistance in uremia: Effect of dialysis modality. Pediatr Res 40:304–308

    Article  PubMed  CAS  Google Scholar 

  14. Mak RH, Turner C, Thompson T, Haycock GB, Chantler C (1986) The effect of dietary protein restriction and amino acid/keto acid supplements on glucose metabolism in uremic children. J Clin Endocrinol Metabol 63:985–989

    CAS  Google Scholar 

  15. Rigalleau V, Combe C, Blanche V, Aubertin J, Apacicio M, Gin H (1997) Low protein diet in uremia. Effect of glucose metabolism and energy production rate. Kidney Int 51:1222–1227

    Article  PubMed  CAS  Google Scholar 

  16. Mak RH (1998) 1,25 vitamin D3 corrects insulin and lipid abnormalities in uremia. Kidney Int 53:1353–1357

    Article  PubMed  CAS  Google Scholar 

  17. Mak RH (1998) Effect of metabolic acidosis on insulin action and secretion in uremia. Kidney Int 54:603–607

    Article  PubMed  CAS  Google Scholar 

  18. Ford ES, Ajani UA, McGuire LC, Liu S (2005) Concentrations of serum vitamin D and the metabolic syndrome among U.S. adults. Diabetes Care 28:1228–1230

    Article  PubMed  CAS  Google Scholar 

  19. Chonchol M, Scragg R (2007) 25-Hydroxyvitamin D, insulin resistance, and kidney function in the Third National Health and Nutrition Examination Survey. Kidney Int 71:134–139

    Article  PubMed  CAS  Google Scholar 

  20. Eidmak I, Feldt-Rasmussen B, Kanstrup IL, Nielsen SL, Schmitz O, Strangaard S (1995) Insulin resistance and hyperinsulinemia in mild to moderate progressive chronic renal failure and its association with aerobic work capacity. Diabetologia 38:565–572

    Article  Google Scholar 

  21. Goldberg A, Hagberg J, Delmez J, Haynes ME, Harter HR (1989) The metabolic effects of exercise training in hemodialysis patients. Kidney Int 18:754–761

    Article  Google Scholar 

  22. Mak RH (1996) Correction of anemia by erythropoietin reverses insulin resistance and hyperinsulinemia in uremia. Am J Physiol 270:F839–F894

    PubMed  CAS  Google Scholar 

  23. Mak RH (1996) The effect of erythropoietin on insulin, amino acid and lipid metabolism in uremia. J Pediatr 129:97–104

    Article  PubMed  CAS  Google Scholar 

  24. Mak RH (1998) Metabolic effects of erythropoietin in uremic patients on peritoneal dialysis. Pediatr Nephrol 12:660–665

    Article  PubMed  CAS  Google Scholar 

  25. Siew ED, Pupim LB, Majchrzak KM, Shintani A, Flakoll PJ, Ikizler TA (2007) Insulin resistance is associated with skeletal muscle breakdown in non-diabetic chronic hemodialysis patients. Kidney Int 71:146–152

    Article  PubMed  CAS  Google Scholar 

  26. Church JM, Hill GL (1988) Impaired glucose metabolism in surgical patients improved by intravenous nutrition: assessment by euglycemic-hyperinsulinemic clamp. Metabolism 37:505–509

    Article  PubMed  CAS  Google Scholar 

  27. Mak RH Cheung W, Cone R, Marks DL (2005) Orexigenic and anorexigenic mechanisms in the control of nutrition in chronic kidney disease. Pediatr Nephrol 20:427–431

    Article  PubMed  Google Scholar 

  28. Mak RH, Cheung W, Cone R, Marks DL (2006) Energy homeostasis and cachexia in chronic kidney disease. Pediatr Nephrol 21:1807–1814

    Article  PubMed  Google Scholar 

  29. Lai HL, Kartal J, Mitsnefes M (2007) Hyperinsulinemia in pediatric patients with chronic kidney disease: the role of tumor necrosis factor-alpha. Pediatr Nephrol DOI 10.1007/s00467-007-0533-z

  30. Mak RH, Bettinelli A, Turner C, Haycock GB, Chantler C (1985) The influence of hyperparathyroidism on glucose metabolism in uremia. J Clin Endocrinol Metab 60:229–233

    PubMed  CAS  Google Scholar 

  31. Mak RH, Turner C, Haycock GB, Chantler C (1983) Secondary hyperparathyroidism and glucose intolerance in children with uremia. Kidney Int 24(Suppl 16):S128–S133

    Google Scholar 

  32. Akmal M, Massry SG, Goldstein D, DeFronzo RA (1985) The role of parathyroid hormone in the glucose intolerance in uremia. J Clin Invest 75:1037–1044

    PubMed  CAS  Google Scholar 

  33. Mak RH (1992) 1,25 dihydroxycholecalciferol corrects glucose intolerance in hemodialysis patients. Kidney Int 41:1049–1054

    Article  PubMed  CAS  Google Scholar 

  34. DeFronzo RA, Tobin JD, Andres R (1979) Glucose clamp technique: a method for quantifying insulin secretion and resistance. Am J Physiol 237:E214–E223

    PubMed  CAS  Google Scholar 

  35. Horgaard A, Thayssen TH (1929) Clinical investigation into the effect of the intravenous injection of insulin. Acta Med Scand 72:92–95

    Google Scholar 

  36. Bergman RN, Finegood DT, Ader M (1985) Assessment of insulin sensitivity in vivo. Endocr Rev 6:45–48

    PubMed  CAS  Google Scholar 

  37. Bergman RN, Prager R, Volund A, Olefsky JM (1987) Equivalence of the insulin sensitivity index in man derived by the minimal model method and the euglycemic glucose clamp. J Clin Invest 79:790–800

    Article  PubMed  CAS  Google Scholar 

  38. Hosker JP, Matthews DR, Rudenski AS, Naylor BA, Treacher DF, Turner RC (1985) Homeostasis model assessment: insulin resistance and β-cell function from fasting plasma glucose and insulin concentration in man. Diabetologia 28:401–411

    Article  PubMed  CAS  Google Scholar 

  39. Katz A, Nambi SS, Mather K, Baron AD, Follmann DA, Sullivan G, Quon MJ (2000) Quantitative insulin sensitivity check index: a simple, accurate method for assessing insulin sensitivity in humans. J Clin Endocrinol Metab 85:2402–2410

    Article  PubMed  CAS  Google Scholar 

  40. Maddux BA, Chan A, Mandarino LJ, Goldfine ID (2006) IGF-binding protein-1 levels are related to insulin-mediated glucose disposal and are a potential serum marker of insulin resistance. Diabetes Care 29:1535–1537

    Article  PubMed  CAS  Google Scholar 

  41. Reaven G (1997) The kidney: an unwilling accomplice in syndrome X. Am J Kidney Dis 30:928–931

    PubMed  CAS  Google Scholar 

  42. Liu Z (2007) The renin-angiotensin system and insulin resistance. Curr Diab Rep 7:34–42

    Article  PubMed  Google Scholar 

  43. Jandeleit-Dahm KA, Tikellis C, Reid CM, Johnston CI, Cooper ME (2005) Why blockade of the rennin-angiotensin system reduces the incidence of new-onset diabetes. J Hypertens 23:463–473

    Article  PubMed  CAS  Google Scholar 

  44. Klahr S, Morrissey JJ (2000) The role of vasoactive compounds, growth factor and cytokines in the progression of renal disease. Kidney Int 75(Suppl):S7–S14

    Article  PubMed  CAS  Google Scholar 

  45. Chan MK, Varghese Z, Moorhead JF (1981) Lipid abnormalities in uremia, dialysis and transplantation. Kidney Int 19:625–637

    Article  PubMed  CAS  Google Scholar 

  46. Saland JM, Ginsberg HN (2007) Lipoprotein metabolism in chronic renal insufficiency. Pediatr Nephrol 22:1095–1112

    Article  PubMed  Google Scholar 

  47. Kaysen GA (2006) Metabolic syndrome and renal failure. Panminerva Med 48:151–164

    PubMed  CAS  Google Scholar 

  48. Fadini GP, Pauletto P, Avogaro A, Rattazzi M (2007) The good and the bad in the link between insulin resistance and vascular calcification. Atherosclerosis 193:241–244

    Article  PubMed  CAS  Google Scholar 

  49. Chen NX, Duan D, O’Neill KD, Moe SM (2006) High glucose increases the expression of Cbfa1 and BMP-2 and enhances the calcification of vascular smooth muscle cells. Nephrol Dial Transplant 21:3435–3442.

    Article  PubMed  CAS  Google Scholar 

  50. Olesen P, Nguyen K, Wogensen L, Ledet T, Rasmussen LM (2007) Calcification of human vascular smooth muscle cells: associations with osteoprotegerin expression and acceleration by high-dose insulin. Am J Physiol Heart Circ Physiol 292:H1058–H1064

    Article  PubMed  CAS  Google Scholar 

  51. Baxter RC, Turtle JR (1978) Regulation of growth hormone receptors by insulin. Biochem Biophy Res Com 84:350–357

    Article  CAS  Google Scholar 

  52. Daughaday WH, Philips LS, Mueller MC (1976) The effects of insulin and growth hormone on the release of somatomedin by the isolated rat liver. Endocrinol 98:1214–1219

    Article  CAS  Google Scholar 

  53. Maes M, Underwood LE, Ketelslegers JM (1986) Low serum somatomedin-C in insulin-dependent diabetes: evidence for a postreceptor mechanism. Endocrinol 118:377–382

    CAS  Google Scholar 

  54. Cotterill AM, Cowell CT, Silink M (1989) Insulin and variation in glucose levels modify the secretion rates of the growth hormone-dependent insulin-like growth factor binding protein-1 in the human hepatoblastoma cell-line Hep G2. J Endocrinol 12:R17–R20

    Article  Google Scholar 

  55. Dunger DB, Cheetham TD (1996) Growth hormone-insulin-like growth factor-I axis in insulin-dependent diabetes mellitus. Horm Res 46:2–6

    PubMed  CAS  Google Scholar 

  56. Mak RH (1995) Insulin secretion and growth in uremia. Pediatr Res 38:379–383

    PubMed  CAS  Google Scholar 

  57. Mak RH (1998) Insulin, branched-chain amino acids and growth failure in uremia. Pediatr Nephrol 12:637–642

    Article  PubMed  CAS  Google Scholar 

  58. Chen J, Muntner P, Hamm LL, Jones DW, Batuman V, Fonseca V, Whelton PK, He J (2004) The metabolic syndrome and chronic kidney disease in US adults. Ann Intern Med 140:167–174

    PubMed  Google Scholar 

  59. Peralta CA, Kurella M, Lo JC, Chertow GM (2006) The metabolic syndrome and chronic kidney disease. Curr Opin Nephrol Hypertens 15:361–365

    PubMed  CAS  Google Scholar 

  60. Kurella M, Lo JC, Chertow GM (2005) Metabolic syndrome and the risk for chronic kidney disease among nondiabetic adults. Am Soc Nephrol 16:2134–2140

    Article  Google Scholar 

  61. Palaniappan L, Carnethon M, Fortmann SP (2003) Association between microalbuminuria and the metabolic syndrome: NHANES III. Am J Hypertens 16:952–958

    Article  PubMed  CAS  Google Scholar 

  62. Cuspidi C, Meani S, Fusi V, Severgnini B, Valerio C, Catini E, Leonetti G, Magrini F, Zanchetti A (2004) Metabolic syndrome and target organ damage in untreated essential hypertensives. J Hypertens 22:1991–1998

    Article  PubMed  CAS  Google Scholar 

  63. Mule G, Nardi E, Cottone S, Cusimano P, Volpe V, Piazza G, Mongiovì R, Mezzatesta G, Andronico G, Cerasola G (2005) Influence of metabolic syndrome on hypertension-related target organ damage. J Intern Med 257:503–513

    Article  PubMed  CAS  Google Scholar 

  64. Godfrey KM, Barker DJ (2000) Fetal nutrition and adult disease. Am J Clin Nutr 71:1344S–1352S

    PubMed  CAS  Google Scholar 

  65. Hinchliffe SA, Lynch MR, Sergent PH, Howard CV, Van Velzen D (1992) The effect of intrauterine growth retardation on the development of renal nephrons. Br J Obstet Gynaecol 99:296–301

    PubMed  CAS  Google Scholar 

  66. MacDonald MD, Emery JL (1959) The late intrauterine and postnatal development of human renal glomeruli. J Anat 93:331–340

    PubMed  CAS  Google Scholar 

  67. Manalich R, Reyes L, Herrera M, Melendi C, Fundora I (2000) Relationship between weight at birth and the number and size of glomeruli in humans: A histomorphometric study. Kidney Int 58:770–773

    Article  PubMed  CAS  Google Scholar 

  68. Brenner BM, Lawler EV, Mackenzie HS (1996) The hyperfiltration theory: A paradigm shift in nephrology. Kidney Int 49:1774–1777

    Article  PubMed  CAS  Google Scholar 

  69. Brenner BM, Chertow GM (1993) Congenital oligonephropathy: An inborn cause of adult hypertension and progressive renal injury? Curr Opin Nephrol Hypertens 2:691–895

    PubMed  CAS  Google Scholar 

  70. Keller G, Zimmer G, Mall, Ritz E, Amann K (2003) Nephron number in patients with primary hypertension. N Engl J Med 348:101–108

    Article  PubMed  Google Scholar 

  71. Wellen KE, Hotamisligil GS (2003) Obesity-induced inflammatory changes in adipose tisuue. J Clin Invest 112:1785–1788

    Article  PubMed  CAS  Google Scholar 

  72. Engeli S, Sharma AM (2000) Role of adipose tissue for cardiovascular-renal regulation in health and disease. Horm Metab Res 32:485–499

    PubMed  CAS  Google Scholar 

  73. Knight SF, Imig JD (2007) Obesity, insulin resistance and renal function. Microcirculation 14:349–362

    Article  PubMed  CAS  Google Scholar 

  74. Sarafidis PA, Ruilope LM (2006) Insulin resistance, hyperinsulinemia and renal injury: mechanism and implications. Am J Nephrol 26:232–244

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pediatrics, University of California at San Diego, 9500 Gilman Drive, MC0634, La Jolla, CA, 92093-0634, USA

    Robert H Mak

Authors
  1. Robert H Mak
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Robert H Mak.

Additional information

Supported by a Mid-Career Research Development Award K24 DK59574 and U01 DK-03–012 from the National Institute of Health to RHM.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Mak, R.H. Insulin and its role in chronic kidney disease. Pediatr Nephrol 23, 355–362 (2008). https://doi.org/10.1007/s00467-007-0611-2

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00467-007-0611-2

Keywords

Search

Navigation