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Insulinogenic Effects of Milk- and Other Dietary Proteins, Mechanisms and metabolic implications

Nilsson, Mikael LU (2006)
Abstract (Swedish)
Popular Abstract in Swedish

Förekomsten av sjukdomar inom det sk metabola syndromet (typ 2 diabetes, insulinresistans, övervikt, högt blodtryck och hjärt-kärlsjukdomar) ökar kraftigt i västvärlden. En viktig faktor för utvecklandet av detta syndrom är en försämrad insulinkänslighet. När kroppen utsätts för kontinuerligt höga insulinnivåer försämras känsligheten för detta hormon vilket resulterar i svårigheter att reglera blodsockernivån. För att kompensera för det höga blodsockret frisätts ännu mer insulin vilket i sin tur minskar cellernas känslighet för insulin ytterligare och det utvecklas en "ond cirkel" mellan höga insulinnivåer (hyperinsulinemi) och en ökad insulinresistans. Livsmedel som ger låga blodsocker- och... (More)
Popular Abstract in Swedish

Förekomsten av sjukdomar inom det sk metabola syndromet (typ 2 diabetes, insulinresistans, övervikt, högt blodtryck och hjärt-kärlsjukdomar) ökar kraftigt i västvärlden. En viktig faktor för utvecklandet av detta syndrom är en försämrad insulinkänslighet. När kroppen utsätts för kontinuerligt höga insulinnivåer försämras känsligheten för detta hormon vilket resulterar i svårigheter att reglera blodsockernivån. För att kompensera för det höga blodsockret frisätts ännu mer insulin vilket i sin tur minskar cellernas känslighet för insulin ytterligare och det utvecklas en "ond cirkel" mellan höga insulinnivåer (hyperinsulinemi) och en ökad insulinresistans. Livsmedel som ger låga blodsocker- och insulinnivåer och/eller specifikt förbättrar insulinkänsligheten är därför gynnsamma.



För de flesta kolhydratrika livsmedel finns det en positiv korrelation mellan blodsocker- och insulinnivåer, dvs livsmedel som ger ett lågt blodsocker ger även låga insulinnivåer och vice versa. Vissa livsmedel, framförallt mjölkprodukter, avviker dock från detta samband och kännetecknas av höga insulinsvar och låga blodsockersvar. Denna obalans mellan blodsocker och insulin är inte relaterad till kolhydratkomponenten (laktos) i mjölk. En tänkbar mekanism bakom mjölkprodukters insulinstimulerande effekt är via proteinfraktionen och det är känt att vissa livsmedelsproteiner stimulerar insulinfrisättning efter måltid. Det är oklart vilken betydelse protein-stimulerad hyperinsulinemi har på metabola riskfaktorer.



Syftet med den nu aktuella avhandlingen var att identifiera livsmedelskomponenten bakom mjölkprodukters insulinstimulerande effekt. Som jämförelse inkluderades även andra animaliska och vegetabiliska proteiner. Effekten av mjölkproteiners insulinstimulerande effekt studerades på friska och på patienter med typ 2 diabetes genom att följa blodsocker, insulin, aminosyror och inkretina hormoner (GIP och GLP-1).



Vassleproteiner gav upphov till en större obalans mellan blodsocker- och insulinnivåer jämfört med mjölk. Insulinresponsen efter en vasslemåltid var dubbelt så stor som efter vitt bröd, ett livsmedel som normalt anses vara väldigt insulinfrisättande. Andra livsmedelsprotein, torsk och gluten, hade däremot marginell effekt på insulinfrisättningen. En anledning till vasslefraktionens insulinfrisättande egenskaper är sannolikt att proteinkomponenten snabbt spjälkas i mag-tarmkanalen vilket bidrar till höga nivåer av specifika aminosyror i blodet. En positiv korrelation sågs mellan höga insulinnivåer och förekomsten av flera aminosyror i blodet, framförallt leucin, isoleucin, valin, lysin och treonin.



För att utreda sambandet mellan dessa aminosyror och insulinfrisättning serverades drycker innehållande leucin, isoleucin, valin, lysin och treonin i olika kombinationer tillsammans med glukos till friska försökspersoner. Den dryck som innehöll samtliga fem aminosyror och glukos resulterade inte bara i ett högt insulinsvar utan återskapade även obalansen mellan låga blodsocker- och höga insulinnivåer som ses efter vassle. Dessa resultat förstärker ytterligare hypotesen att vassle orsakar höga insulinnivåer genom att ge ett snabbt och högt aminosyrasvar.



Effekten av fria aminosyror studerades även in vitro, i försök med insulinproducerande cellaggregat från mus (Langerhanska öar). Leucin, treonin och isoleucin visade sig i dessa försök stimulera frisättningen av insulin, medan lysin och valin inte hade någon effekt. Störst insulinfrisättning in vitro sågs dock när en blandning av alla fem aminosyror testades.



När vassle ingick i måltiden hos typ 2 diabetiker ökade insulinfrisättningen med 31 % efter frukost och 57 % efter lunch. Efter lunchen med vassle minskade dessutom blodsockerresponsen med 21 % till följd av de högre insulinnivåerna. Totalt över dagen ledde vassle supplementering till en minskad svängning i blodsocker. Effekten vid lunch var lika effektiv som vid behandling med vissa läkemedel.



Trots att vassle orsakar ett högt insulinpåslag direkt efter måltid, erhölls inga negativa effekter på glukostolerans vid en efterföljande standardiserad måltid hos friska försökspersoner.



Sammanfattningsvis kan det konstateras att det höga insulinsvar som ses efter mjölkprodukter främst är relaterat till vasslefraktionen. En trolig mekanism är att vassleproteinet snabbt spjälkas och orsakar höga nivåer av specifika aminosyror i blodet. Det höga insulinsvar och låga blodsockersvar som ses efter en vasslemåltid erhölls även med en dryck innehållande leucin, isoleucin, valin, treonin, lysin och glukos. Trots att vassle orsakar ett högt insulinsvar sågs ingen negativ påverkan på glukostoleransen vid en efterföljande lunch, när vassle intogs som frukost av friska försökspersoner. Genom att inkludera vassle i frukost- och lunchmåltiderna hos typ 2 diabetiker underlättades deras blodsockerkontroll vilket indikerar att vassle och andra livsmedelsproteinfraktioner kan ha en terapeutisk potential hos dessa individer. (Less)
Abstract
The metabolic syndrome (type 2 diabetes, obesity, hypertension, atherosclerotic cardiovascular disease, dyslipidaemia, and hyperinsulinaemia), is increasing in prevalence world-wide. The progression of this syndrome proceeds through a step-wise deterioration of metabolic events where deterioration of insulin sensitivity appears to have a key role in a ?vicious circle? of hyperinsulinaemia/hyperglycaemia and insulin resistance. Food factors inducing low postprandial glycaemic and insulin responses, and improving insulin sensitivity might thus be advantageous. Recent data suggest that certain proteins and protein-containing foods e.g. milk, may exert insulinotrophic effects in healthy subjects, without a concomitant postprandial... (More)
The metabolic syndrome (type 2 diabetes, obesity, hypertension, atherosclerotic cardiovascular disease, dyslipidaemia, and hyperinsulinaemia), is increasing in prevalence world-wide. The progression of this syndrome proceeds through a step-wise deterioration of metabolic events where deterioration of insulin sensitivity appears to have a key role in a ?vicious circle? of hyperinsulinaemia/hyperglycaemia and insulin resistance. Food factors inducing low postprandial glycaemic and insulin responses, and improving insulin sensitivity might thus be advantageous. Recent data suggest that certain proteins and protein-containing foods e.g. milk, may exert insulinotrophic effects in healthy subjects, without a concomitant postprandial hyperglycaemia. The longer?term metabolic effects of non-glucose mediated insulin secretion remain to be elucidated, and reports concerning the impact of milk proteins, or type and/or amount of other dietary protein sources on metabolic risk factors are, however, contradictory.



The present thesis investigates the role of certain food proteins on insulin secretion and blood glucose regulation, focusing on milk proteins. In particular, the key determinants at food- and physiological level, respectively, have been examined. Dairy proteins, in particular the whey protein fraction, were found to be potent insulin secretagogues in healthy subjects, whereas cod and gluten did not stimulate postprandial insulin release. A positive correlation was seen between postprandial insulinaemia and responses of leucine, isoleucine, valine, threonine and lysine. Whey also induced a high GIP response compared with milk, cheese, cod and, gluten meals.



Breakfast and lunch meals supplemented with whey, as opposed to a protein equivalent amount of ham, increased insulin response by 31 % and 57 % following breakfast and lunch, respectively, in subjects with diabetes type 2. The whey supplementation reduced glycaemia at lunch by 21 % (P<0.05), and reduced glycaemic excursions from fasting value over the course of the day (0-7 h) by 12 % (P<0.05).



Insulinogenic properties of different amino acids, or of postprandial serum obtained following ingestion of whey or white wheat bread (WWB), were investigated in vitro using isolated Langerhans islets. Serum, withdrawn at 15 and 30 min, respectively, after a whey meal, increased insulin release in vitro (+87 % at 15 min, +139 % at 30 min) compared with corresponding serum after WWB. Further, leucine (+105 %), threonine (+97 %) and to a lesser extent isoleucine (+45 %) potentiated insulin secretion in the presence of glucose (8.3 mM), compared with glucose alone, whereas lysine and valine did not. Exposing Langerhans islets to a combination of the above amino acids increased insulin secretion further (+270 %), particularly when also including GIP (+558 %).



In healthy subjects, a test drink with leucine, isoleucine, valine, and glucose resulted in higher insulin responses than pure glucose (+40 %), whereas the combination of lysine, threonine, and glucose had no effect. A drink with all five amino acids and glucose mimicked the glycaemic and insulinaemic responses seen after whey ingestion. The drink with the five amino acids also induced similar postprandial plasma amino acid responses, except for leucine which caused a higher increment (P<0.05). The whey meal was accompanied by a higher GIP response (+80 %, P<0.05), whereas the drinks containing free amino acids did not affect GIP.



The effect of milk induced hyperinsulinaemia on semi-acute metabolic responses at a second standardised meal was studied in healthy subjects. Breakfast meals differing in GI/II characteristics were included to study the impact of non-glucose mediated hyperinsulinaemia (whey GI=53/II=140) versus the impact of differences in insulinaemia caused by differences in the rate of glucose delivery to the blood (pasta GI=56/II=32 vs white bread GI=100/GI=100). In addition, a rye bread product with a high GI (81), and a low II (56), mediated by unidentified food factors, was included. The postprandial glycaemia after the standardised lunch post pasta breakfast was lower (-48 %, P<0.05) compared with the WWB breakfast. Although the whey breakfast had low GI properties similar to the pasta, no effect on postprandial glycaemia was seen after the standardised lunch. Nor did whey-induced hyperinsulinaemia (II=140) at breakfast deteriorate glucose tolerance at the proceeding standardised lunch compared with a WWB breakfast (II=100).



It is concluded that milk induced hyperinsulinaemia primarily relates to the whey fraction. The insulinotrophic features of whey could be simulated in healthy subjects with a drink containing a mixture of leucine, isoleucine, valine, threonine and lysine. In accordance with whey, these amino acids increased in postprandial plasma, but with no concomitant increase in GIP, indicating that the insulinotrophic effect of whey is mediated by a rapid postprandial response of these amino acids, rather than by stimulation of the incretin hormones. No detrimental effects of whey-induced hyperinsulinaemia were seen on glucose tolerance in healthy subjects in the perspective from a test breakfast to a standardised lunch. Enclosure of whey at breakfast and lunch facilitated blood glucose regulation in type 2 diabetics, indicating a therapeutic role of certain proteins in individuals with diminished insulin secretory capacity. (Less)
Please use this url to cite or link to this publication:
author
supervisor
opponent
  • Professor Jenkins, David, Department of Nutritional Sciences, University of Toronto, Canada
organization
publishing date
type
Thesis
publication status
published
subject
keywords
Näringslära, Nutrition, Type 2 diabetes, Isolated islets, Incretin hormones, Food proteins, Amino acids, Insulin index, Glycaemic index, Hyperinsulinaemia, Insulin, Blood glucose, Milk, Whey
pages
163 pages
publisher
Division of Applied Nutrition and Food Chemistry, Lund University
defense location
Room K:B, Center for Chemistry and Chemical Engineering, Getingevägen 60, Lund Institute of Technology
defense date
2006-02-16 10:15
ISBN
91-628-6737-7
language
English
LU publication?
yes
id
95047abe-7876-440e-ab9b-00e7e0340fcc (old id 546181)
date added to LUP
2007-10-13 11:24:06
date last changed
2016-09-19 08:45:02
@phdthesis{95047abe-7876-440e-ab9b-00e7e0340fcc,
  abstract     = {The metabolic syndrome (type 2 diabetes, obesity, hypertension, atherosclerotic cardiovascular disease, dyslipidaemia, and hyperinsulinaemia), is increasing in prevalence world-wide. The progression of this syndrome proceeds through a step-wise deterioration of metabolic events where deterioration of insulin sensitivity appears to have a key role in a ?vicious circle? of hyperinsulinaemia/hyperglycaemia and insulin resistance. Food factors inducing low postprandial glycaemic and insulin responses, and improving insulin sensitivity might thus be advantageous. Recent data suggest that certain proteins and protein-containing foods e.g. milk, may exert insulinotrophic effects in healthy subjects, without a concomitant postprandial hyperglycaemia. The longer?term metabolic effects of non-glucose mediated insulin secretion remain to be elucidated, and reports concerning the impact of milk proteins, or type and/or amount of other dietary protein sources on metabolic risk factors are, however, contradictory.<br/><br>
<br/><br>
The present thesis investigates the role of certain food proteins on insulin secretion and blood glucose regulation, focusing on milk proteins. In particular, the key determinants at food- and physiological level, respectively, have been examined. Dairy proteins, in particular the whey protein fraction, were found to be potent insulin secretagogues in healthy subjects, whereas cod and gluten did not stimulate postprandial insulin release. A positive correlation was seen between postprandial insulinaemia and responses of leucine, isoleucine, valine, threonine and lysine. Whey also induced a high GIP response compared with milk, cheese, cod and, gluten meals.<br/><br>
<br/><br>
Breakfast and lunch meals supplemented with whey, as opposed to a protein equivalent amount of ham, increased insulin response by 31 % and 57 % following breakfast and lunch, respectively, in subjects with diabetes type 2. The whey supplementation reduced glycaemia at lunch by 21 % (P&lt;0.05), and reduced glycaemic excursions from fasting value over the course of the day (0-7 h) by 12 % (P&lt;0.05).<br/><br>
<br/><br>
Insulinogenic properties of different amino acids, or of postprandial serum obtained following ingestion of whey or white wheat bread (WWB), were investigated in vitro using isolated Langerhans islets. Serum, withdrawn at 15 and 30 min, respectively, after a whey meal, increased insulin release in vitro (+87 % at 15 min, +139 % at 30 min) compared with corresponding serum after WWB. Further, leucine (+105 %), threonine (+97 %) and to a lesser extent isoleucine (+45 %) potentiated insulin secretion in the presence of glucose (8.3 mM), compared with glucose alone, whereas lysine and valine did not. Exposing Langerhans islets to a combination of the above amino acids increased insulin secretion further (+270 %), particularly when also including GIP (+558 %).<br/><br>
<br/><br>
In healthy subjects, a test drink with leucine, isoleucine, valine, and glucose resulted in higher insulin responses than pure glucose (+40 %), whereas the combination of lysine, threonine, and glucose had no effect. A drink with all five amino acids and glucose mimicked the glycaemic and insulinaemic responses seen after whey ingestion. The drink with the five amino acids also induced similar postprandial plasma amino acid responses, except for leucine which caused a higher increment (P&lt;0.05). The whey meal was accompanied by a higher GIP response (+80 %, P&lt;0.05), whereas the drinks containing free amino acids did not affect GIP.<br/><br>
<br/><br>
The effect of milk induced hyperinsulinaemia on semi-acute metabolic responses at a second standardised meal was studied in healthy subjects. Breakfast meals differing in GI/II characteristics were included to study the impact of non-glucose mediated hyperinsulinaemia (whey GI=53/II=140) versus the impact of differences in insulinaemia caused by differences in the rate of glucose delivery to the blood (pasta GI=56/II=32 vs white bread GI=100/GI=100). In addition, a rye bread product with a high GI (81), and a low II (56), mediated by unidentified food factors, was included. The postprandial glycaemia after the standardised lunch post pasta breakfast was lower (-48 %, P&lt;0.05) compared with the WWB breakfast. Although the whey breakfast had low GI properties similar to the pasta, no effect on postprandial glycaemia was seen after the standardised lunch. Nor did whey-induced hyperinsulinaemia (II=140) at breakfast deteriorate glucose tolerance at the proceeding standardised lunch compared with a WWB breakfast (II=100).<br/><br>
<br/><br>
It is concluded that milk induced hyperinsulinaemia primarily relates to the whey fraction. The insulinotrophic features of whey could be simulated in healthy subjects with a drink containing a mixture of leucine, isoleucine, valine, threonine and lysine. In accordance with whey, these amino acids increased in postprandial plasma, but with no concomitant increase in GIP, indicating that the insulinotrophic effect of whey is mediated by a rapid postprandial response of these amino acids, rather than by stimulation of the incretin hormones. No detrimental effects of whey-induced hyperinsulinaemia were seen on glucose tolerance in healthy subjects in the perspective from a test breakfast to a standardised lunch. Enclosure of whey at breakfast and lunch facilitated blood glucose regulation in type 2 diabetics, indicating a therapeutic role of certain proteins in individuals with diminished insulin secretory capacity.},
  author       = {Nilsson, Mikael},
  isbn         = {91-628-6737-7},
  keyword      = {Näringslära,Nutrition,Type 2 diabetes,Isolated islets,Incretin hormones,Food proteins,Amino acids,Insulin index,Glycaemic index,Hyperinsulinaemia,Insulin,Blood glucose,Milk,Whey},
  language     = {eng},
  pages        = {163},
  publisher    = {Division of Applied Nutrition and Food Chemistry, Lund University},
  school       = {Lund University},
  title        = {Insulinogenic Effects of Milk- and Other Dietary Proteins, Mechanisms and metabolic implications},
  year         = {2006},
}