Milk signalling in the pathogenesis of type 2 diabetes
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
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Present address: Department of Dermatology, Environmental Medicine and Health Theory, University of Osnabrück, Sedanstrasse 115, D-49090 Osnabrück, Germany.