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Cited by 74Pancreatic function and diabetesDiabetes, Cardiovascular Risks, and LipoproteinsCalpain Protease Function and Regulation

Parallel manifestation of insulin resistance and beta cell decompensation is compatible with a common defect in type 2 diabetes

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Tripathy, D., Eriksson, K. F., Orho-Melander, M., Fredriksson, J., Ahlqvist, G., Groop, L.·2004·Diabetologia
DOI 10.1007/s00125-004-1393-8
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Abstract

Aims/hypothesis The aim of the study was to evaluate the relationship between insulin sensitivity, beta cell function and glucose tolerance, and its dependence on variants in the newly identified Type 2 diabetes susceptibility gene, calpain-10 ( CAPN10).Methods We studied 203 men of the same age but with varying degrees of glucose tolerance. These men participated in (i) an oral glucose tolerance test, (ii) a euglycaemic clamp combined with indirect calorimetry and infusion of [3-(3)H]-glucose and (iii) a stepwise assessment of acute insulin response to arginine (AIR) at three different glucose concentrations (fasting, 14 and 28 mmol/l).Results There was a linear increase in NEFA levels ( p<0.0005) and WHR ( p<0.0005) and decrease in glucose uptake due to a reduction in glucose storage over the entire range of glucose tolerance ( r=-0.404; p<0.005). No increase in endogenous glucose production (EGP) was seen until patients had manifest diabetes. However, when EGP was expressed relative to fasting insulin concentrations, there was a linear deterioration of basal hepatic insulin sensitivity ( r=-0.514; p<0.005). The AIR followed a bell-shaped curve with an initial rise and subsequent decrease. However, AIR adjusted for insulin sensitivity (disposition index) showed a linear decrease with increasing glucose concentrations ( r=-0.563; p<0.001) starting already in subjects with normal glucose tolerance. There was an inverse correlation between increase in WHR and NEFA and peripheral as well as hepatic insulin sensitivity. Subjects with the genotype combination of CAPN10 consisting of SNP44 TT and SNP43 GG genotypes had significantly lower insulin-stimulated glucose uptake than carriers of the other genotype combinations (5.3+/-0.4 vs 7.2+/-0.4 mg.ffm kg(-1).min(-1).mU.l(-1); p<0.005).Conclusions/interpretation We conclude that the pre-diabetic state is characterised by a similar linear deterioration of peripheral and hepatic insulin sensitivity as beta cell function and that variants in the CAPN10 gene modify this relationship. These findings are compatible with a common defect in muscle, liver and beta cells in the pathogenesis of Type 2 diabetes.

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  • Insulin resistance in muscle is the earliest demonstrable defect in the natural history of type 2 diabetes, but overt type 2 diabetes occurs only in individuals whose β-cells cannot compensate.

    “Because the great majority of glucose disposal after intravenous glucose administration occurs in muscle, these results provide strong evidence that insulin resistance in muscle is the earliest demonstrable defect in the natural history of type 2 diabetes, but that the development of overt type 2 diabetes occurs only in those individuals whose β-cells are unable to compensate for the defect in”

    From Skeletal Muscle Insulin Resistance Is the Primary Defect in Type 2 Diabetes (2009) · cites this paper as [49]

    The Introduction reports an earlier prospective study in which insulin sensitivity declined early and β-cell compensation failed later, before diabetes appeared. It does not establish muscle insulin resistance as the earliest defect; the Discussion instead describes parallel declines in insulin sensitivity and adjusted insulin secretion, and the paper notes that its cross-sectional design cannot establish their sequence. (LLM, conf=0.85)

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Authors
Tripathy, D., Eriksson, K. F., Orho-Melander, M., Fredriksson, J., Ahlqvist, G., & Groop, L.
Affiliations
Lund University (SE)
Corresponding author
Groop, L.
ORCID
Venue
Diabetologia
Publisher
Springer Science and Business Media LLC
Published
2004-05-01
Volume
47
Issue
5
Pages
782-793
ISSN
  • 0012-186X (ISSN-L)
  • 1432-0428
DOI
10.1007/s00125-004-1393-8
OpenAlex
W2104640556
Cited by
74
References
54
Citations by year
2024: 1 · 2023: 2 · 2022: 2 · 2021: 3 · 2020: 3 · 2019: 3 · 2018: 5 · 2017: 3 · 2016: 1 · 2014: 5 · 2013: 3 · 2012: 3
FWCI
6.63
Type
journal article
Language
en
Open access
Licence
www.springer.com/tdm (tdm)
Locations
  • Diabetologia (publishedVersion)
  • PubMed (publishedVersion)
  • Lund University Publications (Lund University) (submittedVersion)
Funders
  • Novo Nordisk
  • Medical Research Council
Topics
  • Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Calpain Protease Function and Regulation
Keywords
type 2 diabetes, insulin resistance, beta-cell dysfunction, CAPN10, genetic susceptibility, glucose tolerance, hepatic insulin sensitivity, peripheral insulin sensitivity, endogenous glucose production, disposition index, waist-to-hip ratio, free fatty acids, prediabetes, glucose uptake, euglycaemic clamp
MeSH terms
Adult, Aged, Blood Glucose, Calpain, Diabetes Mellitus, Exercise Test, Fatty Acids, Nonesterified, Genotype, Glucose, Glucose Tolerance Test, Humans, Insulin Resistance, Islets of Langerhans, Oxygen Consumption, Glucose Clamp Technique, Glucose Intolerance, Genetic Predisposition to Disease, Body Size

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