Medical Hypotheses 76 (2011) 553–559

Contents lists available at ScienceDirect

Medical Hypotheses

journal homepage: www.elsevier .com/locate /mehy

Milk signalling in the pathogenesis of type 2 diabetes

Bodo C. Melnik ⇑,1

Department of Dermatology, Environmental Medicine and Health Theory, University of Osnabrück, Germany

a r t i c l e i n f o

Article history:Received 25 July 2010Accepted 23 December 2010

0306-9877/$ - see front matter � 2010 Elsevier Ltd. Adoi:10.1016/j.mehy.2010.12.017

Abbreviations: AA, amino acids; BTC, betacelluliendoplasmic reticulum; GH, growth hormone; GI, gldependent insulinotropic polypeptide; GLP-1, glu5-hydroxytryptamine (serotonin); FoxO1, forkheadIAPP, islet amyloid polypeptide; II, insulinaemic indefactor-1; IPF-1, insulin promoter factor-1; a-LA, a-ltriglycerides; MAPK, mitogen-activated protein kinasehomeobox factor-1; PI3K, phosphoinositol-3 kinase;prolactin; STAT5, signal transducer and activator oftype 2 diabetes mellitus; Trp, tryptophan.⇑ Tel.: +49 5241 988060; fax: +49 5241 25801.

E-mail address: melnik@t-online.de1 Present address: Department of Dermatology, E

Health Theory, University of Osnabrück, SedanstrasGermany.

a b s t r a c t

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

� 2010 Elsevier Ltd. All rights reserved.

Introduction humans with T2D have reinforced early observations concerning

It is generally accepted that environmental and life style factorsplay a predominant role in the epidemic of type 2 diabetes (T2D).Degeneration of pancreatic islet b-cells is increasingly ranked as akey disease mechanism in T2D [1–3] but it is not entirely clearwhat the underlying molecular processes might be and how theyimpair insulin production and ultimately cause b-cell loss [4,5].Quantitative measurements in postmortem pancreatic tissue from

ll rights reserved.

n; CCK, cholecystokinin; ER,ycaemic index; GIP, glucose-cagon-like peptide-1; 5-HT,

box transcription factor-1;x; IGF-1, insulin-like growthactalbumin; LCT, long-chain; Pdx-1, pancreatic duodenalPL, placental lactogen; PRL,transcription factor-5; T2D,

nvironmental Medicine andse 115, D-49090 Osnabrück,

the probable role of lowered b-cell numbers [6,7], and pointed toa linkage between b-cell disappearance and b-cell apoptosis [8,9].Thus, most attention is recently focused on the mechanisms in-volved in b-cell apoptosis. However, pancreatic b-cell mass regula-tion is a matter of proliferation and apoptosis. Over lifetime, in T2Dpatients b-cells exhibit both an increased rate of proliferation andapoptosis when compared with non-diabetic subjects (Fig. 1)[10,11].

A remarkable burst of b-cell proliferation occurs during theearly postnatal period, the time of exclusive milk exposure bybreast feeding. In humans, only very limited information concern-ing the physiological role of milk for adequate postnatal b-cell pro-liferation and mass expansion is available.

For the required metabolic adaptations to pregnancy a signifi-cant rise in b-cell proliferation and mass expansion occurs. Prolac-tin receptor-mediated signalling has been recognised to play animportant role in pregnancy-associated b-cell proliferation inrodents [12]. Several tyrosine kinase- and G-protein-coupled recep-tors expressed on b-cells are implicated in the regulation of b-cellproliferation, 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),

E N ADULT

β-cell proliferation

T2D

Normal

T2D

Normal

β-cell apoptosis

BF Continued milk consumption

Fig. 1. Comparison of b-cell proliferation and apoptosis over lifetime in normalsubjects and patients with type 2 diabetes (T2D) in relation to physiological breastfeeding (BF) and continued milk consumption. E = late embryonic period; N = neo-natal period; figure modified according to Rhodes [10] and Ackermann et al. [11].

554 B.C. Melnik / Medical Hypotheses 76 (2011) 553–559

glucose-dependent insulinotropic polypeptide (GIP), glucagon-likepeptide-1 (GLP-1) and cholecystokinin (CCK) [13].

It is of crucial importance to regard mammalian milk not onlyas a complex nutrient for the newborn but as a most importantendocrine signalling system regulating adequate b-cell proliferationand maturation for growth requirements. There is biochemical evi-dence that milk drives pituitary signalling pathways and involvesthe entero-insular axis by mediating incretin-signalling. To under-stand the development of T2D in industrialised countries, milk’ssophisticated mitogenic signalling cascades have to be dissectedin more detail. Milk’s ‘‘secret’’ of efficient growth factor signallingresides in its excessive insulinotropic activity characterised bymilk’s high insulinaemic index [14–16]. Despite low glycaemicindexes (GI: 15–30) milk and dairy products produce three to six-fold higher insulinaemic indices (II: 90–98). A large and similar dis-sociation 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) [14–16]. In-creased daily intake of milk but not meat significantly raised basalinsulin serum and IGF-1 levels in 8-year old prepubertal Danishboys [17,18]. This is in accordance with the observation that skimmilk is a potent insulin secretagogue in T2D patients [19]. It istherefore a common belief that milk and milk protein consumptionhave beneficial dietary effects in patients with developing or man-ifest T2D. Thus, no one challenges the health value of persistentmilk consumption because milk promotes linear growth and dis-plays most beneficial effects for neonatal growth and survival.However, when milk intake is continued by humans after theweaning period into adulthood, milk-derived signalling may exertlong-term adverse signalling effects as those proposed here affect-ing pancreatic b-cell homeostasis and subsequent development ofT2D.

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

From studies of maternal b-cell adaptation in pregnancy wehave learnt that PRL-signalling plays an important role in b-cellproliferation [12]. However, the strongest increase in b-cell prolif-eration, the postnatal b-cell burst, is observed during the breastfeeding period (Fig. 1) [10,11]. In analogy with PRL-mediated b-cellproliferation of pregnancy, the neonatal b-cell burst appears to

require PRL-signalling. In late gestation, fetal PRL plasma levels riseexponentially. After birth, colostrum, first milk and neonatal plas-ma contain exceptionally high concentrations of PRL [20–22]. Dur-ing the first weeks of postnatal life when the intestinal barrier isstill highly permeable, PRL appears to be absorbed in the intestinefrom mammalian milk [23,24]. After maturation of the intestinalpermeability barrier, however, milk provides a second indirectmechanism to maintain PRL-signalling for continued b-cell prolif-eration and islet adaption to meet increasing insulin requirementsof the growing neonate.

Milk: a neurotransmitter precursor for pituitary hormonesignalling

The protein fraction of milk is composed of the casein proteinsand the easily hydrolysed and fast absorbed whey proteins whichcontain the bulk of milk’s growth factors like IGF-1, BTC, PRL, PLand others [25]. A most important multifunctional whey proteinis a-lactalbumin (a-LA) which is involved in lactose synthesisand osmotic regulation of milk flow [26]. a-LA is unique amongother proteins with regard to its four- to fivefold increased concen-tration of the essential amino acid tryptophan (Trp) [26]. Thus,milk is a transport system to provide sufficient amounts of Trp tothe newborn. There is a straight relationship between the dietarysupply of Trp and the brain’s ability to synthesise the neurotrans-mitter serotonin (5-hydroxytryptamin) [27]. a-LA increases theplasma ratio of Trp to other large neutral amino acids which isimportant for the preferred Trp-uptake by the blood–brain barrier,the rate-limiting step for serotonin synthesis [27,28]. Pituitary syn-thesis and secretion of PRL and GH are stimulated by serotonergicsignals [28–30]. In fact, milk and especially whey protein (a-LA)consumption increase plasma levels of PRL and GH [29–31]. Inges-tion of hyperglycaemic carbohydrates further increases Trp-uptakeby the brain because the other large neutral amino acids are pref-erentially taken up by peripheral tissues due to carbohydrate-med-iated insulin signalling [28]. GH is a potent inducer of hepatic IGF-1secretion and epidemiological studies confirmed that milk anddairy protein consumption significantly raise plasma IGF-1 levels[32–34]. Thus, mammalian milk has to be regarded as a neuro-transmitter precursor for maintaining PRL- and GH/IGF-1-signal-ling which all stimulate b-cell proliferation [13] (Fig. 2).

Milk: an entero-insular incretin signalling system

Whey proteins, especially hydrolysed whey proteins, hydrolyseda-LA and their released amino acids evoke the synthesis and releaseof GIP by enteroendocrine K-cells, GLP-1 by L-cells and CCK by I-cells(Fig. 2) [35–39]. CCK secretion is also mediated by long-chain fattyacids of triglycerides, the predominant fatty acids of bovine milk.Whey protein/a-LA-mediated incretin-signalling thus appears tobe the third most important signalling mechanism of milk toensure adequate b-cell proliferation and maturation. Milk-signalling interacts with multiple tyrosine kinase receptors andG-protein-coupled receptors expressed on b-cells which finally acti-vate signal transducer and activator of transcription-5 (STAT5),phosphoinositol-3-kinase (PI3K)/Akt and MAPK pathways, allknown to activate b-cell proliferation [13]. A common target of allthese pathways is the metabolic sensor and transcription factorFoxO1 which is either down-regulated at the promoter level bySTAT5 or inactivated by posttranslational modification due toPI3K/Akt-mediated phosphorylation and subsequent nuclear extru-sion (Fig. 2) [40]. FoxO1 is an inhibitor of b-cell’s master transcrip-tion factor Pdx-1 in rodents (IPF-1 = insulin promoter factor 1 inhumans) [41]. Inhibition of FoxO1 by milk-derived growth factor-and incretin-signalling thus activates Pdx-1/IPF-1. The later controls

Fig. 2. Proposed mechanism of milk signalling on pancreatic b-cell homeostasis. Whey proteins and a-lactalbumin stimulate pituitary- and incretin-signalling and down-regulate the master transcription factor FoxO1. Decreased nuclear levels of FoxO1 promote b-cell proliferation and increase formation of islet amyloid polypeptide (IAPP),endoplasmic reticulum stress (ER) and toxic IAPP oligomer formation with early replicative b-cell senescence and b-cell apoptosis. L = enteroendocrine L-cell, K = K-cell,I = I-cell.

B.C. Melnik / Medical Hypotheses 76 (2011) 553–559 555

several checkpoints of cell cycle progression. Furthermore, IPF-1activates the promoter of islet amyloid polypeptide (IAPP) [42], aprotein implicated in intracellular toxic oligomer formation withresultant b-cell apoptosis. Islet amyloid deposits are found in T2Dpatients and are implicated to play a major role for accelerated b-cellapoptosis and b-cell loss [3,43].

Milk: an accelerator of early b-cell senescence and b-cellapoptosis

Recent studies in rodents confirmed that adult b-cells are notreplaced by stem cell-driven neogenesis but by self-duplication ofdifferentiated b-cells [44,45]. This finding is of fundamental biolog-ical importance because the rate of cell divisions limits the life andfunction of a somatic cell by induction of replicative cell senescence.Increased mitogenic milk signalling via incretins (GIP, GLP-1), lact-ogens (PRL, PL), mediators of the somatotropic axis (GH, IGF-1) andinsulin itself may all trigger the early onset of b-cell senescence andb-cell apoptosis when these mitogenic signals are active in in-creased extent and frequency and over prolonged periods of time,a constellation not intended by the evolutionary mammalian pro-gram of milk signalling physiologically restricted to the neonatalperiod.

Since eukaryotic cells have linear chromosomes, each chromo-some shortens from the ends, or telomeres, during every round ofcell division due to the biochemistry of DNA replication. Human cellsundergo intrinsic senescence in response to repeated cell divisions[46]. Adult somatic cells display low or absent telomerase activityfor telomere extension. This absence or reduced activity of telome-rase activity is correlated with telomeric shortening with age [47].Hayflick first defined the finite proliferative capacity or replicativesenescence, called the Hayflick limit, as the cell’s inability to divide[48]. The Hayflick limit is defined as the point when normal cells stopproliferating. Besides various biochemical abnormalities, senescent

cells display telomere shortening. Normal human adult somatic cellshave strict restriction of telomerase expression. As a consequence,the telomeres shorten with each cell division because of incompleteDNA replication. Telomere shortening to a critical length triggers theDNA damage response machinery [49,50]. Telomere dysfunctioninduces two types of cellular responses: cellular senescence andapoptosis [51]. The induction of senescence or apoptosis in vivodepends on the cellular level of telomere dysfunction and differen-tially on p53 gene function. Senescent cells are cleared by compo-nents of the innate immune system, particularly natural killer(NK) cells [52].

Milk and whey protein consumption as major staples ofWestern diet have to be regarded as chronic stimuli for increasedb-cell replication. Permanent overstimulation of pancreatic b-cellreplication by milk may explain the secretory defects of senescentb-cells and increased b-cell apoptosis observed in diabetic patientscompared to normal subjects [10,11] (Fig. 1).

At least three milk-mediated mechanisms for increased b-cellapoptosis in T2D patients should be considered. b-Cell senescenceper se is associated with an elevated rate of apoptosis. Secondly,milk’s mitogenic effects may chronically up-regulate IPF-1-stimu-lated formation of IAPPs [42]. Abundant formation of intracellulartoxic IAPP oligomers (toxic oligomer hypothesis of T2D) may accel-erate b-cell apoptosis [43]. Thirdly, milk-derived GIP-signallingwith accumulation of intracellular lipids may increase b-cell lipo-toxicity further increasing apoptosis in T2D [53].

Milk signalling mimics clinical states of increased growthhormone and prolactin

It is known that GH induces insulin resistance and administra-tion of GH to dogs induces diabetes [54]. Acromegaly is oftenassociated with T2D and the administration of human GH resultsin glucose intolerance and hyperinsulinaemia [55]. T2D is also a

556 B.C. Melnik / Medical Hypotheses 76 (2011) 553–559

frequent adverse effect of antipsychotic drugs which inhibit thedopaminergic system resulting in increased pituitary PRL secretionand hyperprolactinaemia [56]. Hyperprolactinaemia in patientswith prolactinoma has been associated with impaired oral glucosetolerance and increased prevalence of T2D [57]. A group of diabeticmale patients exhibited significantly higher serum PRL levels thancontrols [58]. Both PRL and GH are regarded as diabetogenic hor-mones [54,55,57]. Chronic and exaggerated milk consumptionmay over-stimulate pancreatic b-cells proliferation by increasedGH- and PRL-signal transduction accelerating replicative b-cellsenescence.

Increased incidence of T2D in genetic disorders associated withearly cell senescence

Rare genetic diseases with early onset of cell senescence due toinherited defects of telomerase function, especially Werner’ssyndrome and Bloom’s syndrome, are associated with early onsetof T2D. Progressive pancreatic b-cell senescence and failure arekey features of T2D [59]. Up-regulation of DNA-repair mechanismsand oxidative damage has been shown to be a feature of b-cells inpatients with T2D [60]. In cultures of human adult pancreatic isletcells, accelerated telomere shortening has been reported to predictthe risk of b-cell growth arrest and senescence [61]. In diversemodels of islet hyperplasia the level of telomerase expression aswell as telomere length correlated with the replicative capabilityof b-cells [62]. At present, most data on telomere length in patientswith T2D are obtained from studies of peripheral blood cells. InT2D patients the mean telomere length of monocytes and leuko-cytes was significantly lower as compared to controls withoutT2D [63,64].

Werner’s syndrome and the related Bloom’s syndrome are bothassociated with early onset of T2D [65–68]. They are caused byloss-of-function mutations in WRN and BLM, respectively, whichencode 30–50 DNA helicases of the RecQ family [69,70]. There is evi-dence that WRN and BLM protein play important roles in telomeremaintenance [71]. It has been observed that serially passaged Wer-ner’s syndrome fibroblasts shorten telomeres more rapidly thancontrols and senesce prematurely [72].

It is conceivable that milk-mediated overstimulation of b-cellproliferation induces early onset of b-cell senescence, a mechanismwhich appears to be reminiscent of the development of early T2Din patients with genetic defects leading to early cell senescence.Werner’s and Bloom’s syndrome are thus experiments of naturewhich underline to the association between early cell senescenceand T2D and most likely between early b-cell senescence and T2D.

Milk combined with hyperglycaemic carbohydrates potentiatesb-cell proliferation

Besides the high amount of milk and dairy consumption,Western diet provides high loads of sugar and carbohydrates witha high GI [73]. Intriguingly, milk consumption in combination withhigh GI carbohydrates potentiates the insulinaemic response incomparison to either single component [74]. The common combi-nations of milk and hyperglycaemic carbohydrates observed inWestern diet may thus augment the adverse effect of milk on b-cellproliferation. Glucose, the most important stimulus for insulinsecretion, is known to down-regulate the nuclear level of FoxO1in b-cells through insulin receptor signalling and thus augmentsinsulin-induced b-cell proliferation [75]. Intriguingly, mitogenicsignalling of milk and glucose via insulin may both aggravate theeffect of Western diet on b-cell proliferation, subsequent inductionof early b-cell senescence, up-regulation of IAPP synthesis associ-ated with increased b-cell endoplasmic reticulum (ER) stress and

toxic IAPP oligmer formation. All these events affect b-cell homeo-stasis and promote early b-cell senescence, b-cell apoptosis and fi-nally impair insulin secretion (Fig. 2).

The milk hypothesis of T2D is compatible with the toxicoligomer hypothesis of T2D

The proposed milk hypothesis is in excellent agreement withthe toxic oligomer hypothesis of T2D [43] and with the recently pro-posed concept of b-cell rest as a treatment goal in T2D [76]. The ma-jor goal of T2D prevention at the nutrigenomic level is themaintenance of adequate nuclear concentrations of FoxO1 in pan-creatic b-cells.

Furthermore, the proposed milk hypothesis is in accordancewith the concept of increased ER stress in the pathogenesis of T2D[77]. The accumulation of unfolded and misfolded proteins in theER is directly related to b-cell dysfunction and death during theprogression of T2D [77]. In most cases the basis for protein mis-folding is a consequence of an imbalance between the delivery ofnascent protein to the ER and the capacity of the ER to fold, traffic,and process the protein [78]. Support for the concept of a thresholdexpression rate above ER fails to adequately process IAPP isprovided by human IAPP transgenic rodent models [43,79]. It hasrecently been shown in rats that IAPP-induced ER stress distin-guishes the successful versus unsuccessful islet adaptation to ahigh-fat diet [80]. Permanent growth factor signalling of milkmay chronically down-regulate nuclear levels of FoxO1. NuclearFoxO1 reduction would result in an imbalance and activation ofthe b-cell master transcription factor IPF-1, the most importantactivator of the IAPP promoter stimulating IAPP synthesis [42](Fig. 2). Over-stimulated IAPP-synthesis may overload the ER thusexerting ER stress with the subsequent formation of IAPP toxicoligomers inducing b-cell apoptosis.

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

Alzheimer disease (AD), also characterised as ‘‘brain-type diabe-tes’’, and T2D are both degenerative diseases with cell loss (eitherb-cell loss or loss of neurocortical neurons) and cytotoxic amyloidformation (either IAPP or b-amyloid protein, Ab). One major hall-mark of AD is accumulation of toxic b-amyloid peptides (Ab1–40

and Ab1–42). It is well known that patients with AD are more vul-nerable to T2D. According to recent data of the Mayo Clinic, 81%of patients with AD had either T2D or impaired fasting glucose[81]. Thus, a common pathogenetic mechanism responsible forthe loss of brain cells and b-cells has been proposed for both dis-eases. It has been demonstrated that IGF-1 is increased in serumand cerebrospinal fluid of AD patients in comparison to normalcontrols [82]. Several short-term as well as large epidemiologicalstudies confirmed that milk consumption significantly increasesserum IGF-1 levels [17,18,32–34]. In the worm Caenorhabditis ele-gans, the DAF-2 pathway is ortholog to mammalian insulin recep-tor/IGF-1 receptor signalling which modifies the transcriptionfactor FoxO1 that controls longevity. Decreased DAF-2 signallingcauses up to a threefold lifespan extension. Intriguingly, knockingdown DAF-2 in C. elegans reduces the formation of Ab1–42 [83]. Thisobservation points to a role of increased insulin/IGF-1 signalling, amajor mechanism of milk signalling, in the regulation of neuronalAb homeostasis. Intriguingly, recent evidence in a mouse model ofAD demonstrated that impaired IGF-1/IRS-2 signalling preventspremature death and delays amyloid accumulation [84]. Theseobservations support the unfavourable effect of increased insulin/IGF-1 signalling in amyloid homeostasis of b-cells and neuronalcells. It is conceivable that increased milk-mediated insulin/IGF-1

B.C. Melnik / Medical Hypotheses 76 (2011) 553–559 557

signalling may contribute to both disease pathologies. A recentprospective cohort study investigated the dietary pattern associ-ated with a lower risk of AD. A lower risk of AD was characterizedby higher intakes of salad dressing, nuts, fish, tomatoes, poultry,cruciferous vegetables, fruits, and dark and green leafy vegetablesand a lower intake of high-fat dairy products, red meat, organmeat, and butter [85].

Beneficial short-term and adverse long-term effects of milksignalling?

Two large prospective studies in middle-aged men and womenusing a semiquantitative food frequency questionnaire demon-strated a modestly lower risk of T2D in association with dairy intake[86,87]. The observed inverse association between dairy intake andT2D has been explained by the insulinotropic and incretin (GIP,GLP-1)-stimulating effects of milk proteins [87]. Skim milk has beenshown to act as a potent insulin secretagogue [19]. There is nodoubt that milk protein exerts glucose-lowering effects mimickingthe beneficial effects of incretin-based therapies of T2D [88]. How-ever, the short-term effects of milk signalling on the capacity ofinsulin secretion and insulin release have to be strictly differenti-ated from the long-term adverse effects of persistent milk signal-ling on b-cell homeostasis, i.e., increased b-cell proliferation withaccelerated b-cell senescence and apoptosis. At present, no studiesare available which followed the association between persistentmilk consumption from early childhood to adulthood in dairy-con-suming and non dairy consuming subpopulations. Intriguingly, T2Dand other chronic Western diseases are rare in non-Westernizedpopulations which do not consume dairy products and exhibitlow basal serum insulin levels like Kitavan islanders [89,90]. In con-trast, acculturated hunter-gatherer populations who have adoptedWestern diets frequently are hyperinsulinaemic and insulin resis-tant and have high rates of T2D [91,92]. These epidemiologicalobservations imply that chronic consumption of insulinotropic foodlike hyperglycaemic carbohydrates and insulinotropic dairy prod-ucts may play an important role in the pathogenesis of T2D, a pro-cess which develops slowly and unnoticed over decades.

In conclusion, persistent milk and dairy consumption in coun-tries of Western life style and nutrition has been hypothesised tobe an overlooked environmental dietary factor accelerating thedevelopment of T2D. The life-long persistence of mitogenic milksignalling beyond the physiological postnatal milk feeding periodmay exert long-term adverse effects on b-cell homeostasis withover-stimulated b-cell proliferation and early onset of replicativeb-cell senescence. The mitogenic and insulinotropic effect of milkmay not only appear to be the driving force for early b-cell senes-cence but also for accelerated islet cell amyloidosis acceleratingb-cell apoptosis and neuronal cell loss (Fig. 2). Thus, the presentedhypothesis is in accordance with recent concepts of increasedIAPP-induced b-cell ER stress and the related toxic oligomerhypothesis of T2D [79].

A reduction of hyperglycaemic food as well as insulinotropicdairy products will increase nuclear levels of FoxO1 in pancreaticb-cells, resulting in a state of metabolic diapause [76]. In the longperspective, down-regulation of the mitotic and secretory activityof b-cells by restriction of milk signalling may have a protectivelong-term effect on b-cell homeostasis and function by up-regula-tion of nuclear levels of FoxO1 (Fig. 2). Thus, the proposed hypoth-esis of the role of milk signalling in the pathogenesis of T2D mayoffer a new strategy for diabetes prevention by controlling theamount of insulinotropic dairy intake. Morevover, the hypothesisoffers a chance for the prevention of T2D by reducing the insulinae-mic index of milk (II: 89–115) to levels reported for cheese (II: 45)or beef (II: 51) [16].

There is urgent need for prospective studies comparing the inci-dence of T2D diabetes in individuals consuming increased amountsof insulinotropic dairy products versus individuals not consuminginsulinotropic dairy products from early childhood to adulthood.These studies and more data on studies between dairy-consumingand dairy-free subpopulations of the same genetic backgroundmay substantiate the proposed role of milk consumption as a pro-moter of T2D, Alzheimer disease and other chronic diseases ofWestern civilization [93].

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 pancre-atic b-cells which depends on the branched-chain amino acid leu-cine [94]. High amounts of leucine are provided by human (11.3%)and bovine a-lactalbumin (10.4%) [26]. Leucine stimulates genetranscription and protein synthesis in pancreatic b-cells via bothmTOR-dependent and -independent pathways and increases cellproliferation [94]. Thus, permanent uptake of increased amountsof leucine with whey proteins may overstimulate b-cell proteinsynthesis and b-cell proliferation promoting early b-cell senes-cence and apoptosis, the hallmarks of T2D.

References

[1] Hamming KS, Soliman D, Matemisz LC, Niazi O, Lang Y, Gloyn AL, et al.Coexpression of the type 2 diabetes susceptibility gene variants KCNJ11 E23Kand ABCC8 S1369A alter the ATP and sulfonyl-urea sensitivities of the ATP-sensitive K+ channel. Diabetes 2009;58:2419–24.

[2] Jonsson A, Isomaa B, Tuomi T, Taneera J, Salehi A, Nilsson P, et al. A variant inthe KCNQ1 gene predicts future type 2 diabetes and mediates impaired insulinsecretion. Diabetes 2009;58:2409–13.

[3] Cooper GJS, Aitken JF, Zhang S. Is type 2 diabetes an amyloidosis and does itreally matter (to patients)? Diabetologia 2010;53:1011–6.

[4] Leahy JL. Natural history of b-cell dysfunction in NIDDM. Diabetes Care1990;13:992–1010.

[5] Leahy JL. b-cell dysfunction in type 2 diabetes. In: Kahn CR, Weir GC,King GL, Jacobson AM, Moses AC, Smith RJ, editors. Joslin’s diabetesmellitus. Philadelphia: Lippincott, Williams and Wilkins; 2005. p. 449–61.

[6] Gepts W. Islet changes in human diabetes. In: Cooperstein GJ, Watkins D,editors. The islets of Langerhans. New York: Academic; 1981. p. 321–56.

[7] Clark A, Wells CA, Buley ID, Cruickshank JK, Vanhegan RI, Matthews DR, et al.Islet amyloid, increased A-cells, reduced B-cells and exocrine fibrosis:quantitative changes in the pancreas of type 2 diabetic patients. DiabetesRes 1988;9:151–9.

[8] Butler AE, Janson J, Bonner-Weir S, Ritzel R, Rizza RA, Butler PC. D-cell deficitand increased b-cell apoptosis in humans with type 2 diabetes. Diabetes2003;52:102–10.

[9] Deng S, Vatamaniuk M, Huang X, Doliba N, Lian MM, Frank A, et al. Structuraland functional abnormalities in the islets isolated from type 2 diabeticsubjects. Diabetes 2004;53:624–32.

[10] Rhodes CJ. Type 2 diabetes – a matter of b-cell life and death? Science2005;307:380–4.

[11] Ackermann AM, Gannon M. Molecular regulation of pancreatic b-cell massdevelopment, maintenance, and expansion. J Mol Endocrinol 2007;38:193–206.

[12] Sorenson RL, Brelje TC. Prolactin receptors are critical to the adaptation ofislets to pregnancy. Endocrinology 2009;150:1566–9.

[13] Vasavada RC, Gonzalez-Pertusa JA, Fujinaka Y, Fiaschi-Taesch N, Cozar-Castellano I, Garcia-Ocaña A. Growth factors and b-cell replication. Int JBiochem Cell Biol 2006;38:931–50.

[14] Östman EM, Liljeberg Elmstahl HG, Björck IM. Inconsistency between glycemicand insulinemic responses to regular and fermented milk products. Am J ClinNutr 2001;74:96–100.

[15] Hoyt G, Hickey MS, Cordain L. Dissociation of the glycaemic and insulinaemicresponses to whole and skimmed milk. Br J Nutr 2005;93:175–7.

[16] Holt S, Brand Miller J, Petocz P. An insulin index of foods: the insulin demandgenerated by 1000-kJ portions of common foods. Am J Clin Nutr 1997;66:1264–76.

[17] Hoppe C, Mølgaard C, Vaag A, Barkholt V, Michaelsen KF. High intakes of milk,but not meat, increase s-insulin and insulin resistance in 8-year-old boys. Eur JClin Nutr 2005;59:393–8.

558 B.C. Melnik / Medical Hypotheses 76 (2011) 553–559

[18] Hoppe C, Mølgaard C, Dalum C, Vaag A, Michaelsen KF. Differential effects ofcasein versus whey on fasting plasma levels of insulin, IGF-1 and IGF-1/IGFBP-3: results from a randomized 7-day supplementation study in prepubertalboys. Eur J Clin Nutr 2009;63:1076–83.

[19] Gannon MC, Nuttal FQ, Krezowski PA, Billington CJ, Parker S. The serum insulinand plasma glucose responses to milk and fruit in type 2 (non insulindependent) diabetic patients. Diabetologia 1986;29:784–91.

[20] Lucas A, Baker BA, Cole TJ. Plasma prolactin and clinical outcome in preterminfants. Arch Dis Child 1990;65:977–83.

[21] Elmlinger MW, Kühnel W, Ranke MB. Reference ranges for serumconcentrations of lutropin (LH), follitropin (FSH), estradiol (E2), prolactin,progesterone, sex hormone-binding globulin (SHBG), dehydroepiandrosteronesulfate (DHEAS), cortisol and ferritin in neonates, children and young adults.Clin Chem Lab Med 2002;40:1151–60.

[22] Kacsóh B, Toth BE, Avery LM, Deaver DR, Baumrucker CR, Grosvenor CE.Biological and immunological activities of glycosylated and molecular weightvariants of bovine prolactin in colostrums and milk. J Animal Sci1991;69(Suppl. 1):456.

[23] Whitworth NS, Grosvenor CE. Transfer of milk prolactin to the plasma ofneonatal rats by intestinal absorption. J Endocr 1978;79:191–9.

[24] Mulloy AL, Keen SL, Malven PV. Absorption of orally administered bovineprolactin by neonatal rats. Biol Neonate 1979;36:148–53.

[25] Blum JW, Baumrucker CR. Insulin-like growth factors (IGFs), IGF bindingproteins, and other endocrine factors in milk: role in the newborn. In: Bösze Z,editor. Bioactive components of milk. Advances in experimental medicine andbiology, vol. 606. New York: Springer; 2008. p. 397–422.

[26] Lönnerdal B, Lien EL. Nutritional and physiologic significance of alpha-lactalbumin in infants. Nutr Rev 2003;61:295–305.

[27] Wurtman RJ, Hefti F, Melamed E. Precursor control of neurotransmittersynthesis. Pharmacol Rev 1981;32:315–35.

[28] Markus CR. Dietary amino acids and brain serotonin function; implications forstress-related affective changes. Neuromol Med 2008;10:247–58.

[29] Lancranjan I, Wirz-Justice A, Pühringer W, del Pozo E. Effect of 1–5 hydroxy-tryptophan infusion on growth hormone and prolactin secretion in man. J ClinEndocrinol Metab 1977;45:588–93.

[30] Krulich L. Central neurotransmitters and the secretion of prolactin, GH, LH andTSH. Ann Rev Physiol 1979;41:603–15.

[31] Rich-Edwards JW, Ganmaa D, Pollak MN, Nakamoto EK, Kleinman K,Tserendolgor U, et al. Milk consumption and the prepubertal somatotropicaxis. Nutr J 2007;6:28. doi:10.1186/1475-2891-6-2.

[32] Norat T, Dossus L, Rinaldi S, Overvad K, Grønbaek H, Tjønneland A, et al. Diet,serum insulin-like growth factor-I and IGF-binding protein-3 in Europeanwomen. Eur J Clin Nutr 2007;6:91–8.

[33] Qin LQ, Ka HE, Xu JY. Milk consumption and circulating insulin-like growthfactor-I level: a systematic literature review. Int J Food Sci Nutr 2009.doi:10.1080/0963748090315011.

[34] Crowe FL, Key TJ, Allen NE, Appleby PN, Roddam A, Overvad K, et al. IGFBP-1,IGFBP-2, and IGFBP-3 in the European prospective investigation into cancerand nutrition. Cancer Epidemiol Biomarkers Prev 2009;18:1333–40.

[35] Gunnarsson PT, Winzell MS, Deacon CF, Larsen MO, Jelic K, Carr RD, et al.Glucose-induced incretin hormone release and inactivation are differentlymodulated by oral fat and protein in mice. Endocrinology 2006;147:3173–80.

[36] Calbet JAL, Holst JJ. Gastric emptying, gastric secretion and enterogastroneresponse after administration of milk proteins or their peptide hydrolysates inhumans. Eur J Nutr 2004;43:127–39.

[37] Carr RD, Larsen MO, Winzell MS, Jelic K, Lindgren O, Deacon CF, et al. Incretinand islet hormonal responses to fat and protein ingestion in healthy men. Am JPhysiol Endocrinol Metab 2008;295:E779–84.

[38] Nilsson M, Holst JJ. Björck IME (2007) Metabolic effects of amino acid mixturesand whey protein in healthy subjects: studies using glucose-equivalent drinks.Am J Clin Nutr 2007;85:996–1004.

[39] Hall WL, Millward DJ, Long SJ, Morgan LM. Casein and whey exert differenteffects on plasma amino acid profiles, gastrointestinal hormone secretion andappetite. Br J Nutr 2003;89:239–48.

[40] Glauser DA, Schlegel W. The emerging role of FOXO transcription factors inpancreatic b-cells. J Endocrinol 2007;193:195–207.

[41] Kitamura T, Nakae J, Kitamura Y, Kido Y, Biggs 3rd WH, Wright CV, et al. Theforkhead transcription factor FoxO1 links insulin signaling to Pdx1 regulationof pancreatic beta cell growth. J Clin Invest 2002;110:1839–47.

[42] Serup P, Jensen J, Andersen FG, Jørgensen MC, Blume N, Holst JJ, et al. Inductionof insulin and islet amyloid polypeptide production in pancreatic isletglucagonoma cells by insulin promoter factor 1. Proc Natl Acad Sci USA1996;93:9015–20.

[43] Gurlo T, Ryazantsev S, Yeh Huang CJ, MW Reber HA, Hines OJ, O’Brien TD, et al.Evidence for proteotoxicity in beta cells in the type 2 diabetes: toxic islet andamyloid polypeptide oligomers form intracellularly in the secretory pathway.Am J Pathol 2010;176:861–9.

[44] Dor Y, Brown J, Martinez OI, Melton DA. Adult pancreatic beta-cells are formedby self duplication rather than stem-cell differentiation. Nature 2004;429:41–6.

[45] Teta M, Rankin MM, Long SY, Stein GM, Kushner JA. Growth and regenerationof adult b-cells does not involve specialized progenitors. Develop Cell2007;12:817–26.

[46] Itahana K, Campisi J, Dimri GP. Mechanisms of cellular senescence in humanand mouse cells. Biogerontology 2004;5:1–10.

[47] Harley CB, Futcher AB, Greider CW. Telomeres shorten during aging of humanfibroblasts. Nature 1990;345:458–60.

[48] Hayflick L. The limited in vitro lifetime of human diploid cell strains. Exp CellRes 1965;37:614–36.

[49] Shawi M, Autexier C. Telomerase, senescence and ageing. Mech Ageing Dev2008;129:3–10.

[50] Harrington L, Robinson MO. Telomere dysfunction: multiple paths to the sameend. Oncogene 2002;21:592–7.

[51] Lechel A, Satyanarayana A, Ju Z, Plentz RR, Schaetzlein S, Rudolph C, et al. Thecellular level of telomere dysfunction determines induction of senescence orapoptosis in vivo. EMBO Rep 2005;6:275–81.

[52] Hornsby PJ. Senescence and life span. Pflugers Arch Eur J Physiol2010;459:291–9.

[53] Irwin N, Flatt PR. Evidence for beneficial effects of compromised gastricinhibitory polypeptide action in obesity-related diabetes and possibletherapeutic implications. Diabetologia 2009;52:1724–31.

[54] Nielsen JH. Effects of growth hormone, prolactin, and placental lactogen oninsulin content and release, and deoxyribonucleic acid synthesis in culturedpancreatic islets. Endocrinology 1982;110:600–6.

[55] Luft R, Cerasi E, Hamberger CA. Studies on the pathogenesis of diabetes inacromegaly. Acta Endocrinol (Copenh) 1967;45:593–607.

[56] Hammer M. The effects of atypical antipsychotics on serum prolactin levels.Ann Clin Psychiatry 2002;14:163–73.

[57] Landgraf R, Landgraf-Leurs MM, WeismannHörl A, Hörl R, von Werder K,Scriba PC. Prolactin: a diabetogenic hormone. Diabetologia 1977;13:99–104.

[58] Mooradian AD, Morley JE, Billington CJ, Slag MF, Elson MK, Shafer RB.Hyperprolactinaemia in male diabetics. Postrad Med J 1985;61:11–4.

[59] Porte D, Kahn SE. Beta-cell dysfunction and failure in type 2 diabetes: potentialmechanisms. Diabetes 2001;50(Suppl. 1):S160–3.

[60] Sakuraba H, Mizukami H, Yagihashi N, Wada R, Hanyu C, Yagihashi S. Reducedb-cell mass and expression of oxidative stress-related DNA damage in theislets of Japanese type II diabetic patients. Diabetologia 2002;45:85–96.

[61] Halvorsen TL, Beattie GM, Lopez AD, Hayek A, Levine F. Accelerated telomereshortening and senescence in human pancreatic islet cells stimulated to dividein vitro. J Endocrinol 2000;166:103–9.

[62] Liew CW, Holman A, Kulkarni RN. The roles of telomeres and telomerase in b-cell regeneration. Diabetes Obesity Metabolism 2009;11:21–9.

[63] Sampson MJ, Winterbone MS, Hughes JC, Dozio N, Hughes DA. Monocytetelomere shortening and oxidative DNA damage in type 2 diabetes. DiabetesCare 2006;29:283–9.

[64] Adaikalakoteswari A, Balasubramanyam M, Mohan V. Telomere shorteningoccurs in Asian Indian type 2 diabetic patients. Diabet Med 2005;22:1151–6.

[65] Field JB, Loube SD. Observations concerning the diabetes mellitus associatedwith Werner’s syndrome. Metabolism 1960;9:118–24.

[66] Yamada K, Ikegami H, Yoneda H, Miki T, Ogihara T. All patients with Werner’ssyndrome are insulin resistant, but only those who also have impaired insulinsecretion develop overt diabetes. Diabetes Care 1999;22:2094–5.

[67] Davis T, Wyllie FS, Rokicki MJ, Bagley MC, Kipling D. The role of cellularsenescence in Werner syndrome: toward therapeutic intervention in humanpremature aging. Ann NY Acad Sci USA 2007;1100:455–69.

[68] Diaz A, Vogiatzi MG, Sanz MM, German J. Evaluation of short stature,carbohydrate metabolism and other endocrinopathies in Bloom’s syndrome.Horm Res 2006;66:111–7.

[69] Yu CE, Oshima J, Fu YH, Wijsman EM, Hisama F, Alisch R, et al. Positionalcloning of the Werner’s syndrome gene. Science 1996;272:258–62.

[70] Ellis NA, Groden J, Ye TZ, Straughen J, Lennon DJ, Ciocci S, et al. The Bloom’ssyndrome gene product is homologous to RecQ helicases. Cell1995;83:655–66.

[71] Opresko PL, Cheng WH, Von Kobbe C, Harrigan JA, Bohr VA. Werner syndromeand the function of the Werner protein; what they can teach us about themolecular aging process. Carcinogenesis 2003;24:791–802.

[72] Schulz VP, Zakian VA, Ogburn CE, McKay J, Jarzebowicz AA, Edland SD, et al.Accelerated loss of telomeric repeats may not explain accelerated replicativedecline of Werner syndrome cells. Hum Genet 1996;97:750–4.

[73] Cordain L, Eades MR, Eades MD. Hyperinsulinemic diseases of civilization:more than just Syndrome X. Comp Biochem Physiol Part A 2003;136:95–112.

[74] Liljeberg EH, Bjorck I. Milk as a supplement to mixed meals may elevatepostprandial insulinaemia. Eur J Clin Nutr 2001;55:994–9.

[75] Martinez SC, Cras-Méneur C, Bernal-Mizrachi E, Permutt MA. Glucoseregulates FoxO1 through insulin receptor signaling in the pancreatic islet b-cell. Diabetes 2006;55:1581–91.

[76] Buteau J, Shlien A, Foisy S, Accili D. Metabolic diapause in pancreatic b-cellsexpressing a gain-of-function mutant of the forkhead protein Foxo1. J BiolChem 2007;282:287–93.

[77] Oslowski CM, Urano F. The binary switch between life and death ofendoplasmic reticulum-stressed b-cells. Curr Opin Endocrinol Diatestes Obes2010;17:107–12.

[78] Lindholm D, Wootz H, Korhonen L. ER stress and neurodegenerative diseases.Cell Death Differ 2006;13:385–92.

[79] Haataja L, Gurlo T, Huang CJ, Butler PC. Islet amyloid in type 2 diabetes, and thetoxic oligomer hypothesis. Endocr Rev 2008;29:303–16.

[80] Matveyenko AV, Gurlo T, Daval M, Butler AE, Butler PC. Successful versus failedadaptation to high-fat diet-induced insulin resistance. The role of IAPP-induced b-cell endoplasmic reticulum stress. Diabetes 2009;58:906–16.

[81] Janson J, Laedtke T, Parisi JE, O’Brien P, Petersen RC, Butler PC. Increased risk oftype 2 diabetes in Alzheimer disease. Diabetes 2004;53:474–81.

B.C. Melnik / Medical Hypotheses 76 (2011) 553–559 559

[82] Salehi Z, Mashayekhi F, Naji M. Insulin like growth factor-1 and insulin likegrowth factor binding proteins in the cerebrospinal fluid and serum frompatients with Alzheimer’s disease. Biofactors 2008;33:99–106.

[83] Cohen E, Bieschke J, Perciavalle RM, Kelly JW, Dillin A. Opposing activitiesprotect against age-onset proteotoxicity. Science 2006;313:1604–10.

[84] Freude S, Hettich MM, Schumann C, Stöhr O, Koch L, Köhler C, et al. NeuronalIGF-1 resistance reduces Abeta accumulation and protects against prematuredeath in a model of Alzheimer’s disease. FASEB J 2009;23:3315–24.

[85] Gu Y, Nieves JW, Stern Y, Luchsinger JA, Scarmeas N. Food combination andAlzheimer disease risk: a protective diet. Arch Neurol 2010;67:699–706.

[86] Choi HK, Willett WC, Stampfer MJ, Rimm E, Hu FB. Dairy consumption and riskof type 2 diabetes mellitus in men: a prospective study. Arch Intern Med2005;165:997–1003.

[87] Liu S, Choi HK, Ford E, Song Y, Klevak A, Buring JE, et al. A prospective study ofdairy intake and the risk of type 2 diabetes in women. Diabetes Care2006;29:1579–84.

[88] Chia CW, Egan JM. Incretin-based therapies in type 2 diabetes mellitus. J ClinEndocrinol Metab 2008;93:3703–16.

[89] Cordain L, Lindeberg S, Hurtado M, Hill K, Eaton SB, Brand-Miller J. Acnevulgaris: a disease of Western civilization. Arch Dermatol 2002;138:1584–90.

[90] Lindeberg S, Eliasson M, Lindahl B, Ahrén B. Low serum insulin in traditionalPacific Islanders: the Kitava Study. Metabolism 1999;48:1216–9.

[91] Daniel M, Rowley KG, McDermott R, Mylvaganam A, O’Dea K. Diabetesincidence in an Australian aboriginal population: an 8-year follow-up study.Diabetes Care 1999;22:1993-8.

[92] Ebbesson SO, Schraer CD, Risica PM, Adler AI, Ebbesson L, Mayer AM, et al.Diabetes and impaired glucose tolerance in three Alaskan Eskimo populations:the Alaska-Siberia Project. Diabetes Care 1998;21:563–9.

[93] Melnik BC. Milk – the promoter of chronic Western diseases. Med Hypotheses2009;72:631–9.

[94] Yang J, Chi Y, Burkhardt BR, Guan Y, Wolf BA. Leucine metabolism in regulationof insulin secretion from pancreatic beta cells. Nutr Rev 2010;68:270–9.