Parallel insulin resistance and beta cell decompensation in Type 2 diabetes

Devjit Tripathy, K. F. Eriksson, M. Orho-Melander, J. Fredriksson, G. Ahlqvist, L. Groop

Research output: Contribution to journalArticle

51 Citations (Scopus)

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 [3-3H]-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 prediabetic 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.

Original languageEnglish (US)
Pages (from-to)782-793
Number of pages12
JournalDiabetologia
Volume47
Issue number5
DOIs
StatePublished - May 2004
Externally publishedYes

Fingerprint

Type 2 Diabetes Mellitus
Insulin Resistance
Glucose
Liver
Genotype
Insulin
Nonesterified Fatty Acids
Fasting
Prediabetic State
Indirect Calorimetry
Glucose Clamp Technique
Glucose Tolerance Test
Genes
Arginine
Muscles

Keywords

  • Beta cell function
  • Calpain-10 gene
  • Disposition index
  • Endogenous glucose production
  • Glucose tolerance
  • Hepatic insulin sensitivity
  • Insulin resistance
  • Insulin secretion
  • Type 2 Diabetes

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

Tripathy, D., Eriksson, K. F., Orho-Melander, M., Fredriksson, J., Ahlqvist, G., & Groop, L. (2004). Parallel insulin resistance and beta cell decompensation in Type 2 diabetes. Diabetologia, 47(5), 782-793. https://doi.org/10.1007/s00125-004-1393-8

Parallel insulin resistance and beta cell decompensation in Type 2 diabetes. / Tripathy, Devjit; Eriksson, K. F.; Orho-Melander, M.; Fredriksson, J.; Ahlqvist, G.; Groop, L.

In: Diabetologia, Vol. 47, No. 5, 05.2004, p. 782-793.

Research output: Contribution to journalArticle

Tripathy, D, Eriksson, KF, Orho-Melander, M, Fredriksson, J, Ahlqvist, G & Groop, L 2004, 'Parallel insulin resistance and beta cell decompensation in Type 2 diabetes', Diabetologia, vol. 47, no. 5, pp. 782-793. https://doi.org/10.1007/s00125-004-1393-8
Tripathy D, Eriksson KF, Orho-Melander M, Fredriksson J, Ahlqvist G, Groop L. Parallel insulin resistance and beta cell decompensation in Type 2 diabetes. Diabetologia. 2004 May;47(5):782-793. https://doi.org/10.1007/s00125-004-1393-8
Tripathy, Devjit ; Eriksson, K. F. ; Orho-Melander, M. ; Fredriksson, J. ; Ahlqvist, G. ; Groop, L. / Parallel insulin resistance and beta cell decompensation in Type 2 diabetes. In: Diabetologia. 2004 ; Vol. 47, No. 5. pp. 782-793.
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N2 - 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 [3-3H]-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 prediabetic 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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