Skip to main content Accessibility help

The impact of dietary protein restriction on insulin secretion and action

  • Mark J. Holness (a1)


The goal of this review is to develop the hypothesis, and review the evidence, that protein restriction, through synergistic effects on multiple organ systems predisposes to loss of normal regulation of fuel homeostasis that plays the central role in the development of type 2 (non-insulin-dependent) diabetes mellitus. The ability of insulin to regulate glucose production and disposal varies between individuals. These differences, together with the various compensatory mechanisms that are invoked to attempt to normalize fuel homeostasis, are of fundamental importance in the development and clinical course of type 2 diabetes mellitus. Protein deprivation impacts on both insulin secretion and insulin action. These effects may persist even when a diet containing adequate protein is presented subsequently. Data are presented that suggest that protein restriction results in an impaired ability of pancreatic β-cells to compensate adequately for the defect in insulin action in insulin-resistant individuals. This persistent impairment of insulin secretion resulting from protein restriction predisposes to loss of glucoregulatory control and impaired insulin action after the subsequent imposition of a diabetogenic challenge. This inability to maintain the degree of compensatory hyperinsulinaemia necessary to prevent loss of glucose tolerance may have relevance to the increased incidence of diabetes on changing from a nutritionally-poor diet to a Western diet, and to the hypothesis that some cases of type 2 diabetes in adulthood may be related to poor early nutrition.

    • Send article to Kindle

      To send this article to your Kindle, first ensure is added to your Approved Personal Document E-mail List under your Personal Document Settings on the Manage Your Content and Devices page of your Amazon account. Then enter the ‘name’ part of your Kindle email address below. Find out more about sending to your Kindle. Find out more about sending to your Kindle.

      Note you can select to send to either the or variations. ‘’ emails are free but can only be sent to your device when it is connected to wi-fi. ‘’ emails can be delivered even when you are not connected to wi-fi, but note that service fees apply.

      Find out more about the Kindle Personal Document Service.

      The impact of dietary protein restriction on insulin secretion and action
      Available formats

      Send article to Dropbox

      To send this article to your Dropbox account, please select one or more formats and confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your <service> account. Find out more about sending content to Dropbox.

      The impact of dietary protein restriction on insulin secretion and action
      Available formats

      Send article to Google Drive

      To send this article to your Google Drive account, please select one or more formats and confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your <service> account. Find out more about sending content to Google Drive.

      The impact of dietary protein restriction on insulin secretion and action
      Available formats


Corresponding author

Corresponding Author: Dr Mark J. Holness, fax +44 (0)181 981 8836, email


Hide All
Barker, DJP, Hales, CN, Fall, CH, Osmond, C, Phipps, K & Clark, PM (1993) Type 2 (non-insulin-dependent) diabetes mellitus, hypertension and hyperlipidaemia (syndrome X): relation to reduced fetal growth. Diabetologia 36, 6267.
Becker, DJ (1983) The endocrine responses to protein calorie malnutrition. Annual Review of Nutrition 3, 187212.
Becker, DJ, Pimstone, BL, Hansen, JD & Hendricks, S (1971) Insulin secretion in protein-calorie malnutrition. I. Quantitative abnormalities and response to treatment. Diabetes 20, 542551.
Bowie, MD (1964) Intravenous glucose tolerance in kwashiorkor and marasmus. South African Medical Journal 38, 328329.
Cherif, H, Reusens, B, Ahn, MT, Hoet, JJ & Remacle, C (1998) Effects of taurine on the insulin secretion of rat fetal islets from dams fed a low-protein diet. Journal of Endocrinology 159, 341348.
Cohen, MP, Stern, E, Rusecki, Y & Zeidler, A (1988) High prevalence of diabetes in young adult Ethiopian immigrants to Israel. Diabetes 37, 824828.
Collins, VR, Dowse, GK, Toelupe, PM, Imo, TT, Aloaina, FL, Spark, RA & Zimmet, PZ (1994) Increasing prevalence of NIDDM in the Pacific island population of Western Samoa over a 13-year period. Diabetes Care 17, 288296.
Dahri, S, Snoeck, A, Reusens-Billen, B, Remacle, C & Hoet, JJ (1991) Islet function in offspring of mothers on low-protein diet during gestation. Diabetes 40, Suppl. 2, 115120.
Desai, M, Crowther, NJ, Ozanne, SE, Lucas, A & Hales, CN (1995) Adult glucose and lipid metabolism may be programmed during fetal life. Biochemical Society Transactions 23, 331335.
Dollet, JM, Beck, B, Villaume, C, Max, JP & Debry, G (1985) Progressive adaptation of the endocrine pancreas during long-term protein deficiency in rats: effects on blood glucose homeostasis and on pancreatic insulin, glucagon and somatostatin concentrations. Journal of Nutrition 115, 15811588.
Dowse, GK, Zimmet, PZ, Finch, CF & Collins, VR (1991) Decline in incidence of epidemic glucose intolerance in Nauruans: implications for the ‘thrifty genotype’. American Journal of Epidemiology 133, 10931104.
Escriva, F, Kergoat, M, Bailbe, D, Pascual-Leone, AM & Portha, B (1991) Increased insulin action in the rat after protein malnutrition early in life. Diabetologia 34, 559564.
Habicht, JP, Lechtig, A, Yarbrough, C & Klein, RE (1974) Maternal nutrition, birth weight and infant mortality. In Size at Birth. Ciba Foundation Symposium no. 27, pp. 353377. Amsterdam: Excerpta Medica.
Hales, CN (1997) Fetal and infant growth and impaired glucose tolerance in adulthood: the ‘thrifty phenotype’ hypothesis revisited. Acta Paediatrica 422, Suppl., 7377.
Hales, CN & Barker, DJP (1992) Type 2 (non-insulin-dependent) diabetes mellitus: the thrifty phenotype hypothesis. Diabetologia 35, 595601.
Hales, CN, Barker, DJP, Clark, PM, Cox, LJ, Fall, C, Osmond, C & Winter, PD (1991) Fetal and infant growth and impaired glucose tolerance at age 64. British Medical Journal 303, 10191022.
Hales, CN, Desai, M, Ozanne, S & Crowther, NJ (1996) Fishing in the stream of diabetes: from measuring insulin to the control of fetal organogenesis. Biochemical Society Transactions 24, 341350.
Holness, MJ (1996 a) The influence of sub-optimal protein nutrition on insulin hypersecretion evoked by high-energy/high-fat feeding in rats. FEBS Letters 396, 5356.
Holness, MJ (1996 b) Impact of early growth retardation on glucoregulatory control and insulin action in mature rats. American Journal of Physiology 270, E946E954.
Holness, MJ, Fryer, LGD, Priestman, DA & Sugden, MC (1998) Moderate protein restriction during pregnancy modifies the regulation of triacylglycerol turnover by insulin and leads to dysregulation of insulin’s anti-lipolytic action. Molecular and Cellular Endocrinology 142, 2533.
Holness, MJ & Sugden, MC (1990) Glucose utilization in heart, diaphragm and skeletal muscle during the fed-to-starved transition. Biochemical Journal 270, 245249.
Holness, MJ & Sugden, MC (1996) Suboptimal protein nutrition in early life later influences insulin action in pregnant rats. Diabetologia 39, 1221.
Holness, MJ & Sugden, MC (1999) Antecedent protein restriction exacerbates the development of impaired insulin action after high-fat feeding. American Journal of Physiology 276, E85E93.
Levine, LS, Wright, PG & Marcus, F (1983) Failure to secrete immunoreactive insulin by rats fed a low protein diet. Acta Endocrinologica 102, 240245.
Lumey, LH (1992) Decreased birthweights in infants after maternal in utero exposure to the Dutch famine of 1944–1945. Paediatric and Perinatal Epidemiology 6, 240253.
Milner, RDG (1971) Metabolic and hormonal responses to glucose and glucagon in patients with infantile malnutrition. Pediatric Research 5, 3339.
Nolan, CJ & Proietto, J (1994) The feto-placental glucose steal phenomenon is a major cause of maternal metabolic adaptation during late pregnancy in the rat. Diabetologia 37, 976984.
Nolan, CJ & Proietto, J (1996) The set point for maternal glucose homeostasis is lowered during late pregnancy in the rat: the role of the islet beta-cell and liver. Diabetologia 39, 785792.
Okitolonda, W, Brichard, SM & Henquin, JC (1987) Repercussions of chronic protein-calorie malnutrition on glucose homeostasis in the rat. Diabetologia 30, 946951.
Ozanne, SE, Nave, BT, Wang, CL, Shepherd, PR, Prins, J & Smith, GD (1997) Poor fetal nutrition causes long-term changes in expression of insulin signaling components in adipocytes. American Journal of Physiology 273, E46E51.
Ozanne, SE, Wang, CL, Coleman, N & Smith, GD (1996) Altered muscle insulin sensitivity in the male offspring of protein-malnourished rats. American Journal of Physiology 271, E1128E1134.
Petry, CJ, Desai, M, Ozanne, SE & Hales, CN (1997) Early and late nutritional windows for diabetes susceptibility. Proceedings of the Nutrition Society 56, 233242.
Phillips, DIW (1996) Insulin resistance as a programmed response to fetal undernutrition. Diabetologia 39, 11191122.
Picarel-Blanchot, F, Alvarez, C, Bailbe, D, Pascual-Leone, AM & Portha, B (1995) Changes in insulin action and insulin secretion in the rat after dietary restriction early in life: influence of food restriction versus low-protein food restriction. Metabolism 44, 15191526.
Rao, RH (1988) Diabetes in the undernourished: coincidence or consequence? Endocrine Reviews 9, 6787.
Rasschaert, J, Reusens, B, Dahri, S, Sener, A, Remacle, C, Hoet, JJ & Malaisse, WJ (1995) Impaired activity of rat pancreatic islet mitochondrial glycerophosphate dehydrogenase in protein malnutrition. Endocrinology 136, 26312634.
Reaven, GM (1995 a) The fourth musketeer - from Alexandre Dumas to Claude Bernard. Diabetologia 38, 313.
Reaven, GM (1995 b) Pathophysiology of insulin resistance in human disease. Physiological Reviews 75, 473486.
Sener, A, Reusens, B, Remacle, C, Hoet, JJ & Malaisse, WJ (1996) Nutrient metabolism in pancreatic islets from protein malnourished rats. Biochemical and Molecular Medicine 59, 6267.
Shepherd, PR, Crowther, NJ, Desai, M, Hales, CN & Ozanne, SE (1997) Altered adipocyte properties in the offspring of protein malnourished rats. British Journal of Nutrition 78, 121129.
Snoeck, A, Remacle, C, Reusens, B & Hoet, JJ (1990) Effect of a low protein diet during pregnancy on the fetal rat endocrine pancreas. Biology of the Neonate 57, 107118.
Sorenson, RL & Brelje, TC (1997) Adaptation of islets of Langerhans to pregnancy: beta-cell growth, enhanced insulin secretion and the role of lactogenic hormones. Hormone and Metabolic Research 29, 301307.
Sugden, MC, Fryer, LG & Holness, MJ (1996) Regulation of hepatic pyruvate dehydrogenase kinase by insulin and dietary manipulation in vivo. Studies with the euglycaemic-hyperinsulinaemic clamp. Biochimica et Biophysica Acta 1316, 114120.
Sugden, MC & Holness, MJ (1995) Modulation of in vivo insulin action by dietary protein during pregnancy. American Journal of Physiology 268, E722E729.
Swenne, I, Borg, LA, Crace, CJ & Schnell, Landstrom A (1992) Persistent reduction of pancreatic beta-cell mass after a limited period of protein-energy malnutrition in the young rat. Diabetologia 35, 939945.
Swenne, I, Crace, CJ & Milner, RD (1987) Persistent impairment of insulin secretory response to glucose in adult rats after limited period of protein-calorie malnutrition early in life. Diabetes 36, 454458.
Van Assche, FA (1975) Foetal endocrine pancreas. In Carbohydrate Metabolism in Pregnancy and the Newborn, pp. 6882 [Sutherland, HW and Stowers, JM, editors]. Edinburgh: Churchill Livingstone.
World Health Organization (1985) Diabetes Mellitus. Technical Report Series no. 727, pp. 2025. Geneva: WHO.
Wilson, MR & Hughes, SJ (1997) The effect of maternal protein deficiency during pregnancy and lactation on glucose tolerance and pancreatic islet function in adult rat offspring. Journal of Endocrinology 154, 177185.



Full text views

Total number of HTML views: 0
Total number of PDF views: 0 *
Loading metrics...

Abstract views

Total abstract views: 0 *
Loading metrics...

* Views captured on Cambridge Core between <date>. This data will be updated every 24 hours.

Usage data cannot currently be displayed