Elsevier

Medical Hypotheses

Volume 76, Issue 4, April 2011, Pages 553-559
Medical Hypotheses

Milk signalling in the pathogenesis of type 2 diabetes

https://doi.org/10.1016/j.mehy.2010.12.017Get rights and content

Abstract

The presented hypothesis identifies milk consumption as an environmental risk factor of Western diet promoting type 2 diabetes (T2D). Milk, commonly regarded as a valuable nutrient, exerts important endocrine functions as an insulinotropic, anabolic and mitogenic signalling system supporting neonatal growth and development. The presented hypothesis substantiates milk’s physiological role as a signalling system for pancreatic β-cell proliferation by milk’s ability to increase prolactin-, growth hormone and incretin-signalling. The proposed mechanism of milk-induced postnatal β-cell mass expansion mimics the adaptive prolactin-dependent proliferative changes observed in pregnancy. Milk signalling down-regulates the key transcription factor FoxO1 leading to up-regulation of insulin promoter factor-1 which stimulates β-cell proliferation, insulin secretion as well as coexpression of islet amyloid polypeptide (IAPP). The recent finding that adult rodent β-cells only proliferate by self-duplication is of crucial importance, because permanent milk consumption beyond the weaning period may continuously over-stimulate β-cell replication thereby accelerating the onset of replicative β-cell senescence. The long-term use of milk may thus increase endoplasmic reticulum (ER) stress and toxic IAPP oligomer formation by overloading the ER with cytotoxic IAPPs thereby promoting β-cell apoptosis. Both increased β-cell proliferation and β-cell apoptosis are hallmarks of T2D. This hypothesis gets support from clinical states of hyperprolactinaemia and progeria syndromes with early onset of cell senescence which are both associated with an increased incidence of T2D and share common features of milk signalling. Furthermore, the presented milk hypothesis of T2D is compatible with the concept of high ER stress in T2D and the toxic oligomer hypothesis of T2D and may explain the high association of T2D and Alzheimer disease.

Introduction

It is generally accepted that environmental and life style factors play a predominant role in the epidemic of type 2 diabetes (T2D). Degeneration of pancreatic islet β-cells is increasingly ranked as a key disease mechanism in T2D [1], [2], [3] but it is not entirely clear what the underlying molecular processes might be and how they impair insulin production and ultimately cause β-cell loss [4], [5]. Quantitative measurements in postmortem pancreatic tissue from humans with T2D have reinforced early observations concerning the probable role of lowered β-cell numbers [6], [7], and pointed to a linkage between β-cell disappearance and β-cell apoptosis [8], [9]. Thus, most attention is recently focused on the mechanisms involved in β-cell apoptosis. However, pancreatic β-cell mass regulation is a matter of proliferation and apoptosis. Over lifetime, in T2D patients β-cells exhibit both an increased rate of proliferation and apoptosis when compared with non-diabetic subjects (Fig. 1) [10], [11].

A remarkable burst of β-cell proliferation occurs during the early postnatal period, the time of exclusive milk exposure by breast feeding. In humans, only very limited information concerning the physiological role of milk for adequate postnatal β-cell proliferation and mass expansion is available.

For the required metabolic adaptations to pregnancy a significant rise in β-cell proliferation and mass expansion occurs. Prolactin receptor-mediated signalling has been recognised to play an important role in pregnancy-associated β-cell proliferation in rodents [12]. Several tyrosine kinase- and G-protein-coupled receptors expressed on β-cells are implicated in the regulation of β-cell proliferation, i.e., receptors for insulin, insulin-like growth factor-1 (IGF-1), epidermal growth factor (EGF) and betacellulin (BTC), prolactin (PRL), placental lactogen (PL), growth hormone (GH), glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-1 (GLP-1) and cholecystokinin (CCK) [13].

It is of crucial importance to regard mammalian milk not only as a complex nutrient for the newborn but as a most important endocrine signalling system regulating adequate β-cell proliferation and maturation for growth requirements. There is biochemical evidence that milk drives pituitary signalling pathways and involves the entero-insular axis by mediating incretin-signalling. To understand the development of T2D in industrialised countries, milk’s sophisticated mitogenic signalling cascades have to be dissected in more detail. Milk’s “secret” of efficient growth factor signalling resides in its excessive insulinotropic activity characterised by milk’s high insulinaemic index [14], [15], [16]. Despite low glycaemic indexes (GI: 15–30) milk and dairy products produce three to sixfold higher insulinaemic indices (II: 90–98). A large and similar dissociation of the GI and II exists for both whole milk (GI: 42 ± 5; II: 148 ± 14) and skim milk (GI: 37 ± 9; II: 140 ± 13) [14], [15], [16]. Increased daily intake of milk but not meat significantly raised basal insulin serum and IGF-1 levels in 8-year old prepubertal Danish boys [17], [18]. This is in accordance with the observation that skim milk is a potent insulin secretagogue in T2D patients [19]. It is therefore a common belief that milk and milk protein consumption have beneficial dietary effects in patients with developing or manifest T2D. Thus, no one challenges the health value of persistent milk consumption because milk promotes linear growth and displays most beneficial effects for neonatal growth and survival. However, when milk intake is continued by humans after the weaning period into adulthood, milk-derived signalling may exert long-term adverse signalling effects as those proposed here affecting pancreatic β-cell homeostasis and subsequent development of T2D.

Section snippets

Milk: a rich postnatal source of prolactin for β-cell proliferation

From studies of maternal β-cell adaptation in pregnancy we have learnt that PRL-signalling plays an important role in β-cell proliferation [12]. However, the strongest increase in β-cell proliferation, the postnatal β-cell burst, is observed during the breast feeding period (Fig. 1) [10], [11]. In analogy with PRL-mediated β-cell proliferation of pregnancy, the neonatal β-cell burst appears to require PRL-signalling. In late gestation, fetal PRL plasma levels rise exponentially. After birth,

Milk: a neurotransmitter precursor for pituitary hormone signalling

The protein fraction of milk is composed of the casein proteins and the easily hydrolysed and fast absorbed whey proteins which contain the bulk of milk’s growth factors like IGF-1, BTC, PRL, PL and others [25]. A most important multifunctional whey protein is α-lactalbumin (α-LA) which is involved in lactose synthesis and osmotic regulation of milk flow [26]. α-LA is unique among other proteins with regard to its four- to fivefold increased concentration of the essential amino acid tryptophan

Milk: an entero-insular incretin signalling system

Whey proteins, especially hydrolysed whey proteins, hydrolysed α-LA and their released amino acids evoke the synthesis and release of GIP by enteroendocrine K-cells, GLP-1 by L-cells and CCK by I-cells (Fig. 2) [35], [36], [37], [38], [39]. CCK secretion is also mediated by long-chain fatty acids of triglycerides, the predominant fatty acids of bovine milk. Whey protein/α-LA-mediated incretin-signalling thus appears to be the third most important signalling mechanism of milk to ensure adequate

Milk: an accelerator of early β-cell senescence and β-cell apoptosis

Recent studies in rodents confirmed that adult β-cells are not replaced by stem cell-driven neogenesis but by self-duplication of differentiated β-cells [44], [45]. This finding is of fundamental biological importance because the rate of cell divisions limits the life and function of a somatic cell by induction of replicative cell senescence. Increased mitogenic milk signalling via incretins (GIP, GLP-1), lactogens (PRL, PL), mediators of the somatotropic axis (GH, IGF-1) and insulin itself may

Milk signalling mimics clinical states of increased growth hormone and prolactin

It is known that GH induces insulin resistance and administration of GH to dogs induces diabetes [54]. Acromegaly is often associated with T2D and the administration of human GH results in glucose intolerance and hyperinsulinaemia [55]. T2D is also a frequent adverse effect of antipsychotic drugs which inhibit the dopaminergic system resulting in increased pituitary PRL secretion and hyperprolactinaemia [56]. Hyperprolactinaemia in patients with prolactinoma has been associated with impaired

Increased incidence of T2D in genetic disorders associated with early cell senescence

Rare genetic diseases with early onset of cell senescence due to inherited defects of telomerase function, especially Werner’s syndrome and Bloom’s syndrome, are associated with early onset of T2D. Progressive pancreatic β-cell senescence and failure are key features of T2D [59]. Up-regulation of DNA-repair mechanisms and oxidative damage has been shown to be a feature of β-cells in patients with T2D [60]. In cultures of human adult pancreatic islet cells, accelerated telomere shortening has

Milk combined with hyperglycaemic carbohydrates potentiates β-cell proliferation

Besides the high amount of milk and dairy consumption, Western diet provides high loads of sugar and carbohydrates with a high GI [73]. Intriguingly, milk consumption in combination with high GI carbohydrates potentiates the insulinaemic response in comparison to either single component [74]. The common combinations of milk and hyperglycaemic carbohydrates observed in Western diet may thus augment the adverse effect of milk on β-cell proliferation. Glucose, the most important stimulus for

The milk hypothesis of T2D is compatible with the toxic oligomer hypothesis of T2D

The proposed milk hypothesis is in excellent agreement with the toxic oligomer hypothesis of T2D [43] and with the recently proposed concept of β-cell rest as a treatment goal in T2D [76]. The major goal of T2D prevention at the nutrigenomic level is the maintenance of adequate nuclear concentrations of FoxO1 in pancreatic β-cells.

Furthermore, the proposed milk hypothesis is in accordance with the concept of increased ER stress in the pathogenesis of T2D [77]. The accumulation of unfolded and

T2D and Alzheimer pathology may share a common IGF-1 signalling pathway

Alzheimer disease (AD), also characterised as “brain-type diabetes”, and T2D are both degenerative diseases with cell loss (either β-cell loss or loss of neurocortical neurons) and cytotoxic amyloid formation (either IAPP or β-amyloid protein, Aβ). One major hallmark of AD is accumulation of toxic β-amyloid peptides (Aβ1–40 and Aβ1–42). It is well known that patients with AD are more vulnerable to T2D. According to recent data of the Mayo Clinic, 81% of patients with AD had either T2D or

Beneficial short-term and adverse long-term effects of milk signalling?

Two large prospective studies in middle-aged men and women using a semiquantitative food frequency questionnaire demonstrated a modestly lower risk of T2D in association with dairy intake [86], [87]. The observed inverse association between dairy intake and T2D has been explained by the insulinotropic and incretin (GIP, GLP-1)-stimulating effects of milk proteins [87]. Skim milk has been shown to act as a potent insulin secretagogue [19]. There is no doubt that milk protein exerts

Conflict of interest statement

I declare that I have no conflicts of interest.

Note added in proof

There appears to be a fourth milk signalling pathway to pancreatic β-cells which depends on the branched-chain amino acid leucine [94]. High amounts of leucine are provided by human (11.3%) and bovine α-lactalbumin (10.4%) [26]. Leucine stimulates gene transcription and protein synthesis in pancreatic β-cells via both mTOR-dependent and -independent pathways and increases cell proliferation [94]. Thus, permanent uptake of increased amounts of leucine with whey proteins may overstimulate β-cell

References (94)

  • L. Cordain et al.

    Hyperinsulinemic diseases of civilization: more than just Syndrome X

    Comp Biochem Physiol Part A

    (2003)
  • J. Buteau et al.

    Metabolic diapause in pancreatic β-cells expressing a gain-of-function mutant of the forkhead protein Foxo1

    J Biol Chem

    (2007)
  • S. Lindeberg et al.

    Low serum insulin in traditional Pacific Islanders: the Kitava Study

    Metabolism

    (1999)
  • B.C. Melnik

    Milk – the promoter of chronic Western diseases

    Med Hypotheses

    (2009)
  • K.S. Hamming et al.

    Coexpression of the type 2 diabetes susceptibility gene variants KCNJ11 E23K and ABCC8 S1369A alter the ATP and sulfonyl-urea sensitivities of the ATP-sensitive K+ channel

    Diabetes

    (2009)
  • A. Jonsson et al.

    A variant in the KCNQ1 gene predicts future type 2 diabetes and mediates impaired insulin secretion

    Diabetes

    (2009)
  • G.J.S. Cooper et al.

    Is type 2 diabetes an amyloidosis and does it really matter (to patients)?

    Diabetologia

    (2010)
  • J.L. Leahy

    Natural history of β-cell dysfunction in NIDDM

    Diabetes Care

    (1990)
  • J.L. Leahy

    β-cell dysfunction in type 2 diabetes

  • A. Clark et al.

    Islet amyloid, increased A-cells, reduced B-cells and exocrine fibrosis: quantitative changes in the pancreas of type 2 diabetic patients

    Diabetes Res

    (1988)
  • A.E. Butler et al.

    Β-cell deficit and increased β-cell apoptosis in humans with type 2 diabetes

    Diabetes

    (2003)
  • S. Deng et al.

    Structural and functional abnormalities in the islets isolated from type 2 diabetic subjects

    Diabetes

    (2004)
  • C.J. Rhodes

    Type 2 diabetes – a matter of β-cell life and death?

    Science

    (2005)
  • A.M. Ackermann et al.

    Molecular regulation of pancreatic β-cell mass development, maintenance, and expansion

    J Mol Endocrinol

    (2007)
  • R.L. Sorenson et al.

    Prolactin receptors are critical to the adaptation of islets to pregnancy

    Endocrinology

    (2009)
  • G. Hoyt et al.

    Dissociation of the glycaemic and insulinaemic responses to whole and skimmed milk

    Br J Nutr

    (2005)
  • C. Hoppe et al.

    High intakes of milk, but not meat, increase s-insulin and insulin resistance in 8-year-old boys

    Eur J Clin Nutr

    (2005)
  • C. Hoppe et al.

    Differential effects of casein versus whey on fasting plasma levels of insulin, IGF-1 and IGF-1/IGFBP-3: results from a randomized 7-day supplementation study in prepubertal boys

    Eur J Clin Nutr

    (2009)
  • M.C. Gannon et al.

    The serum insulin and plasma glucose responses to milk and fruit in type 2 (non insulin dependent) diabetic patients

    Diabetologia

    (1986)
  • A. Lucas et al.

    Plasma prolactin and clinical outcome in preterm infants

    Arch Dis Child

    (1990)
  • M.W. Elmlinger et al.

    Reference ranges for serum concentrations of lutropin (LH), follitropin (FSH), estradiol (E2), prolactin, progesterone, sex hormone-binding globulin (SHBG), dehydroepiandrosterone sulfate (DHEAS), cortisol and ferritin in neonates, children and young adults

    Clin Chem Lab Med

    (2002)
  • B. Kacsóh et al.

    Biological and immunological activities of glycosylated and molecular weight variants of bovine prolactin in colostrums and milk

    J Animal Sci

    (1991)
  • N.S. Whitworth et al.

    Transfer of milk prolactin to the plasma of neonatal rats by intestinal absorption

    J Endocr

    (1978)
  • A.L. Mulloy et al.

    Absorption of orally administered bovine prolactin by neonatal rats

    Biol Neonate

    (1979)
  • J.W. Blum et al.

    Insulin-like growth factors (IGFs), IGF binding proteins, and other endocrine factors in milk: role in the newborn

  • B. Lönnerdal et al.

    Nutritional and physiologic significance of alpha-lactalbumin in infants

    Nutr Rev

    (2003)
  • R.J. Wurtman et al.

    Precursor control of neurotransmitter synthesis

    Pharmacol Rev

    (1981)
  • C.R. Markus

    Dietary amino acids and brain serotonin function; implications for stress-related affective changes

    Neuromol Med

    (2008)
  • I. Lancranjan et al.

    Effect of 1–5 hydroxy-tryptophan infusion on growth hormone and prolactin secretion in man

    J Clin Endocrinol Metab

    (1977)
  • L. Krulich

    Central neurotransmitters and the secretion of prolactin, GH, LH and TSH

    Ann Rev Physiol

    (1979)
  • J.W. Rich-Edwards et al.

    Milk consumption and the prepubertal somatotropic axis

    Nutr J

    (2007)
  • T. Norat et al.

    Diet, serum insulin-like growth factor-I and IGF-binding protein-3 in European women

    Eur J Clin Nutr

    (2007)
  • L.Q. Qin et al.

    Milk consumption and circulating insulin-like growth factor-I level: a systematic literature review

    Int J Food Sci Nutr

    (2009)
  • F.L. Crowe et al.

    IGFBP-1, IGFBP-2, and IGFBP-3 in the European prospective investigation into cancer and nutrition

    Cancer Epidemiol Biomarkers Prev

    (2009)
  • P.T. Gunnarsson et al.

    Glucose-induced incretin hormone release and inactivation are differently modulated by oral fat and protein in mice

    Endocrinology

    (2006)
  • J.A.L. Calbet et al.

    Gastric emptying, gastric secretion and enterogastrone response after administration of milk proteins or their peptide hydrolysates in humans

    Eur J Nutr

    (2004)
  • R.D. Carr et al.

    Incretin and islet hormonal responses to fat and protein ingestion in healthy men

    Am J Physiol Endocrinol Metab

    (2008)
  • Cited by (16)

    View all citing articles on Scopus
    1

    Present address: Department of Dermatology, Environmental Medicine and Health Theory, University of Osnabrück, Sedanstrasse 115, D-49090 Osnabrück, Germany.

    View full text