Advanced

Pathogenesis of type 2 diabetes -role of defects in insulin secretion and insulin sensitivity

Tripathy, Devjit LU (2003)
Abstract (Swedish)
Popular Abstract in Swedish

Bakgrund: Diabetes är en sjukdom som karakteriseras av kroniskt förhöjt blodsocker och som obehandlad kan leda till svåra komplikationer i blodkärl, ögon, njurar, nerver m.m. Sjukdomen beror på kroppens oförmåga att producera (typ 1 diabetes) eller svara på effekt av (typ 2 diabetes) hormonet insulin. Det finns ca 150 miljoner personer med diabetes i världen idag, och siffran förväntas passera 220 miljoner år 2010. Det har uppskattats att ca 4% av den svenska befolkningen har diabetes(360,000), men det finns mycket som tyder på att siffran är högre, 6-7%. Förutom att diabetes förorsakar ett stort personligt lidande kostar sjukdomen samhället ca 25-30,000 kr/år per patient i direkta... (More)
Popular Abstract in Swedish

Bakgrund: Diabetes är en sjukdom som karakteriseras av kroniskt förhöjt blodsocker och som obehandlad kan leda till svåra komplikationer i blodkärl, ögon, njurar, nerver m.m. Sjukdomen beror på kroppens oförmåga att producera (typ 1 diabetes) eller svara på effekt av (typ 2 diabetes) hormonet insulin. Det finns ca 150 miljoner personer med diabetes i världen idag, och siffran förväntas passera 220 miljoner år 2010. Det har uppskattats att ca 4% av den svenska befolkningen har diabetes(360,000), men det finns mycket som tyder på att siffran är högre, 6-7%. Förutom att diabetes förorsakar ett stort personligt lidande kostar sjukdomen samhället ca 25-30,000 kr/år per patient i direkta sjukvårdskostnader.



Den klassiska indelningen av diabetes i typ 1 (15%) och typ 2 diabetes (85%) har visat sig vara en grov förenkling. Sjukdomen har visat sig vara mycket mer heterogen än så. Ca 10% av patienterna har en sent debuterande typ 1 diabetes, sk. LADA. Dessutom finns det en tydlig genetisk interaktion mellan de båda diabetesformerna. Under senare år har man framgångsrikt beskrivit de molekylära störningarna för ett antal monogena diabetesformer, MODY. Tyvärr har det inte varit lika lätt att finna de molekylära störningarna till den vanligaste diabetesformen, typ 2 diabetes förenad med metabolt syndrom. Mycket tyder dock på att sjukdomen som ofta börjar med ansamling av fett kring buken (bukfetma) beror på att fettet dumpas i fel organ, dvs. lever, muskel och pankreas. Vanliga variationer i gener som reglerar nedbrytningen av fett ser ut att öka risken för typ 2 diabetes. Men det krävs i regel att man har flera sådana variationer och att man utsätter dem för den ogynnsamma miljö vår västerländska livsstil med högt kaloriintag och låg energiförbrukning medför.



Målsättning: Avhandlingens mål har varit att beskriva tidiga metabola störningar som leder till typ 2 diabetes, att värdera och utveckla metoder för att mäta insulin sekretion och insulin känslighet, att undersöka dessa störningar vid olika undergrupper av diabetes och hur de påverkas av en stark familjär belastning för diabetes eller avvariationer i gener som ökar risken för att insjukna i diabetes.



Resultat: Kvoten av insulin och glukos vid 30 min av en sockerbelastning är ett rätt bra och enkelt mått på insulinsekretionen. Däremot är vi tveksamma till att använda produkten av faste insulin och glukos (det sk. HOMA värdet) som ett surrogastmått på insulinkänslighet. Vi har i stället utvecklat och värderat ett nytt test, den sk. Botnia clampen som under samma test ger tillförlitliga värden på insulinsekretion och insulinkänslighet. Det sker en parallell och gradvis försämring i insulinkänslighet och insulinsekretion när man går från normal till diabetisk glukostolerans och den här försämringen korrelerar med ökningen av bukfett.Denhär försämringen accelereras om man är bärare av risk i gen för typ 2 diabetes, ex. Calpain 10. Fyndet tyder således på att en likartad störning kan ske i tre målorgan för diabetes, dvs. lever, muskel och pankreas. En familjär belastning för typ 2 diabetes påverkar dessa störningar, i synnerhet om föräldrarna har en tidigt debuterande typ 2 diabetes eller tydlig bukfetma. Avhandlingen har således gett instrument för att tidigt påvisa störningar hos personer med ökad risk att utveckla diabetes. Förhoppningsvis kommer denna kunskap i framtiden att göra det möjligt att förhindra uppkomst av sjukdomen. (Less)
Abstract
Type 2 diabetes is characterised by defects in insulin sensitivity, insulin secretion and increased endogenous glucose production. The relative contribution of each of these defects remains controversial. In order to characterise the metabolic defects in various stages of glucose tolerance, the insulin sensitivity and insulin secretion was measured in a large population based study in Finland and Sweden (Btonia study) The first aim was to evaluate surrogate markers of insulin sensitivity and insulin secretion in subjects with varying degree of glucose tolerance. The insulinogenic index provides a good surrogate estimate of the early insulin response to iv glucose. In contrast, the HOMA IR and indices from OGTT do not describe insulin... (More)
Type 2 diabetes is characterised by defects in insulin sensitivity, insulin secretion and increased endogenous glucose production. The relative contribution of each of these defects remains controversial. In order to characterise the metabolic defects in various stages of glucose tolerance, the insulin sensitivity and insulin secretion was measured in a large population based study in Finland and Sweden (Btonia study) The first aim was to evaluate surrogate markers of insulin sensitivity and insulin secretion in subjects with varying degree of glucose tolerance. The insulinogenic index provides a good surrogate estimate of the early insulin response to iv glucose. In contrast, the HOMA IR and indices from OGTT do not describe insulin sensitivity in the same way as glucose uptake measured during a clamp. The latter measures also suffer from the problem that insulin sensitivity is dependent upon the amount of insulin secreted. The second aim was therefore to validate a method for independent estimates of insulin sensitivity and insulin secretion during the same test; the so called Botnia clamp. The test fulfilled the expectations and provides a useful tool for metabolic studies. The results also underscore the importance of adjusting insulin secretion for insulin sensitivity. A third aim was to characterise the metabolic defects leading to type 2 diabetes. Our cross sectional data show that defects in muscle, liver, and islets occur in parallel and correlate with an increase in abdominal obesity and circulating FFA concentrations. They thus support the hypothesis that peripheral and hepatic insulin resistance as well as β-cell dysfunction in type 2 diabetes could be caused by similar defects. They further demonstrate that these defects are influenced by variations in the calpain 10 gene. A fourth aim was to compare insulin secretion and insulin sensitivity in the prediabetic and diabetic state between subtypes of diabetes. We could demonstrate that carriers of MODY mutations are able to maintain normal glucose tolerance by up regulating insulin sensitivity. The last aim was to evaluate the impact of a family history of common type 2 diabetes and the particular phenotype of the proband on anthropometric and metabolic variables in normoglycemic first degree relatives. The data underscore the importance to consider age at onset when selecting patients for genetic studies as the metabolic phenotype of the probands is shared by relatives of probands with early but not of late-onset diabetes. They further emphasize the value of stratifying for a phenotype characterised by abdominal obesity as this also shows a high degree of familiality. Taken together the results demonstrate a linear decrease in peripheral (muscle) glucose uptake, hepatic insulin sensitivity and β cell function which precede onset of type 2 diabetes, and strongly correlate with an increase in abdominal obesity. They though emphasize the importance to consider changes in one variable when describing the change in the other. (Less)
Please use this url to cite or link to this publication:
author
opponent
  • Prof Alberti, Sir George
organization
publishing date
type
Thesis
publication status
published
subject
keywords
diabetology, Endokrinologi, sekretion, diabetologi, Endocrinology, secreting systems, Calpain 10 gene, genetics of type 2 diabetes, MODY, Endogenous glucose production, Disposition index, Botnia clamp, IGT, IFG, HOMA, insulin sensitivity, insulin secretion
pages
192 pages
publisher
Devjit Tripathy,
defense location
Aula, Entrance 35, MAS, Malmö
defense date
2003-05-09 10:15
ISBN
91-628-5583-2
language
English
LU publication?
yes
id
9091b21d-1c1a-440d-a398-e7646d90c3f9 (old id 465656)
date added to LUP
2007-10-01 14:23:20
date last changed
2016-09-19 08:45:11
@phdthesis{9091b21d-1c1a-440d-a398-e7646d90c3f9,
  abstract     = {Type 2 diabetes is characterised by defects in insulin sensitivity, insulin secretion and increased endogenous glucose production. The relative contribution of each of these defects remains controversial. In order to characterise the metabolic defects in various stages of glucose tolerance, the insulin sensitivity and insulin secretion was measured in a large population based study in Finland and Sweden (Btonia study) The first aim was to evaluate surrogate markers of insulin sensitivity and insulin secretion in subjects with varying degree of glucose tolerance. The insulinogenic index provides a good surrogate estimate of the early insulin response to iv glucose. In contrast, the HOMA IR and indices from OGTT do not describe insulin sensitivity in the same way as glucose uptake measured during a clamp. The latter measures also suffer from the problem that insulin sensitivity is dependent upon the amount of insulin secreted. The second aim was therefore to validate a method for independent estimates of insulin sensitivity and insulin secretion during the same test; the so called Botnia clamp. The test fulfilled the expectations and provides a useful tool for metabolic studies. The results also underscore the importance of adjusting insulin secretion for insulin sensitivity. A third aim was to characterise the metabolic defects leading to type 2 diabetes. Our cross sectional data show that defects in muscle, liver, and islets occur in parallel and correlate with an increase in abdominal obesity and circulating FFA concentrations. They thus support the hypothesis that peripheral and hepatic insulin resistance as well as β-cell dysfunction in type 2 diabetes could be caused by similar defects. They further demonstrate that these defects are influenced by variations in the calpain 10 gene. A fourth aim was to compare insulin secretion and insulin sensitivity in the prediabetic and diabetic state between subtypes of diabetes. We could demonstrate that carriers of MODY mutations are able to maintain normal glucose tolerance by up regulating insulin sensitivity. The last aim was to evaluate the impact of a family history of common type 2 diabetes and the particular phenotype of the proband on anthropometric and metabolic variables in normoglycemic first degree relatives. The data underscore the importance to consider age at onset when selecting patients for genetic studies as the metabolic phenotype of the probands is shared by relatives of probands with early but not of late-onset diabetes. They further emphasize the value of stratifying for a phenotype characterised by abdominal obesity as this also shows a high degree of familiality. Taken together the results demonstrate a linear decrease in peripheral (muscle) glucose uptake, hepatic insulin sensitivity and β cell function which precede onset of type 2 diabetes, and strongly correlate with an increase in abdominal obesity. They though emphasize the importance to consider changes in one variable when describing the change in the other.},
  author       = {Tripathy, Devjit},
  isbn         = {91-628-5583-2},
  keyword      = {diabetology,Endokrinologi,sekretion,diabetologi,Endocrinology,secreting systems,Calpain 10 gene,genetics of type 2 diabetes,MODY,Endogenous glucose production,Disposition index,Botnia clamp,IGT,IFG,HOMA,insulin sensitivity,insulin secretion},
  language     = {eng},
  pages        = {192},
  publisher    = {Devjit Tripathy,},
  school       = {Lund University},
  title        = {Pathogenesis of type 2 diabetes -role of defects in insulin secretion and insulin sensitivity},
  year         = {2003},
}