Mendelian randomization studies do not support a role for raised circulating triglyceride levels influencing type 2 diabetes, glucose levels, or insulin resistance.

N. Maneka G. De Silva, Rachel M. Freathy, Tom M. Palmer, Louise A. Donnelly, Jian'an Luan, Tom Gaunt, Claudia Langenberg, Michael N. Weedon, Beverley Shields, Beatrice A. Knight, Kirsten J. Ward, Manjinder S. Sandhu, Roger M. Harbord, Mark I. McCarthy, George Davey Smith, Shah Ebrahim, Andrew T. Hattersley, Nicholas Wareham, Debbie A. Lawlor, Andrew D. Morris & 2 others Colin N. A. Palmer, Timothy M. Frayling

    Research output: Contribution to journalArticle

    47 Citations (Scopus)

    Abstract

    OBJECTIVE-The causal nature of associations between circulating triglycerides, insulin resistance, and type 2 diabetes is unclear. We aimed to use Mendelian randomization to test the hypothesis that raised circulating triglyceride levels causally influence the risk of type 2 diabetes and raise normal fasting glucose levels and hepatic insulin resistance.

    RESEARCH DESIGN AND METHODS-We tested 10 common genetic variants robustly associated with circulating triglyceride levels against the type 2 diabetes status in 5,637 case and 6,860 control subjects and four continuous outcomes (reflecting glycemia and hepatic insulin resistance) in 8,271 nondiabetic individuals from four studies.

    RESULTS-Individuals carrying greater numbers of triglyceride-raising alleles had increased circulating triglyceride levels (SD 0.59 [95% CI 0.52-0.65] difference between the 20% of individuals with the most alleles and the 20% with the fewest alleles). There was no evidence that the carriers of greater numbers of triglyceride-raising alleles were at increased risk of type 2 diabetes (per weighted allele odds ratio [OR] 0.99 [95% CI 0.97-1.01]; P = 0.26). In nondiabetic individuals, there was no evidence that carriers of greater numbers of triglyceride-raising alleles had increased fasting insulin levels (SD 0.00 per weighted allele [95% CI -0.01 to 0.02]; P = 0.72) or increased fasting glucose levels (0.00 [-0.01 to 0.01]; P = 0.88). Instrumental variable analyses confirmed that genetically raised circulating triglyceride levels were not associated with increased diabetes risk, fasting glucose, or fasting insulin and, for diabetes, showed a trend toward a protective association (OR per 1-SD increase in log(10) triglycerides: 0.61 [95% CI 0.45-0.83]; P = 0.002).

    CONCLUSIONS-Genetically raised circulating triglyceride levels do not increase the risk of type 2 diabetes or raise fasting glucose or fasting insulin levels in nondiabetic individuals. One explanation for our results is that raised circulating triglycerides are predominantly secondary to the diabetes disease process rather than causal. Diabetes 60:1008-1018, 2011

    Original languageEnglish
    Pages (from-to)1008-1018
    Number of pages11
    JournalDiabetes
    Volume60
    Issue number3
    DOIs
    Publication statusPublished - Mar 2011

    Keywords

    • PANCREATIC BETA-CELL
    • CORONARY-ARTERY-DISEASE
    • LIPOPROTEIN-LIPASE
    • FASTING GLUCOSE
    • BLOOD-PRESSURE
    • PLASMA TRIGLYCERIDES
    • RISK-FACTORS
    • FATTY LIVER
    • MELLITUS
    • BEZAFIBRATE

    Cite this

    De Silva, N. Maneka G. ; Freathy, Rachel M. ; Palmer, Tom M. ; Donnelly, Louise A. ; Luan, Jian'an ; Gaunt, Tom ; Langenberg, Claudia ; Weedon, Michael N. ; Shields, Beverley ; Knight, Beatrice A. ; Ward, Kirsten J. ; Sandhu, Manjinder S. ; Harbord, Roger M. ; McCarthy, Mark I. ; Smith, George Davey ; Ebrahim, Shah ; Hattersley, Andrew T. ; Wareham, Nicholas ; Lawlor, Debbie A. ; Morris, Andrew D. ; Palmer, Colin N. A. ; Frayling, Timothy M. / Mendelian randomization studies do not support a role for raised circulating triglyceride levels influencing type 2 diabetes, glucose levels, or insulin resistance. In: Diabetes. 2011 ; Vol. 60, No. 3. pp. 1008-1018.
    @article{407d22097c9f4814a0c738ef57cb61e3,
    title = "Mendelian randomization studies do not support a role for raised circulating triglyceride levels influencing type 2 diabetes, glucose levels, or insulin resistance.",
    abstract = "OBJECTIVE-The causal nature of associations between circulating triglycerides, insulin resistance, and type 2 diabetes is unclear. We aimed to use Mendelian randomization to test the hypothesis that raised circulating triglyceride levels causally influence the risk of type 2 diabetes and raise normal fasting glucose levels and hepatic insulin resistance.RESEARCH DESIGN AND METHODS-We tested 10 common genetic variants robustly associated with circulating triglyceride levels against the type 2 diabetes status in 5,637 case and 6,860 control subjects and four continuous outcomes (reflecting glycemia and hepatic insulin resistance) in 8,271 nondiabetic individuals from four studies.RESULTS-Individuals carrying greater numbers of triglyceride-raising alleles had increased circulating triglyceride levels (SD 0.59 [95{\%} CI 0.52-0.65] difference between the 20{\%} of individuals with the most alleles and the 20{\%} with the fewest alleles). There was no evidence that the carriers of greater numbers of triglyceride-raising alleles were at increased risk of type 2 diabetes (per weighted allele odds ratio [OR] 0.99 [95{\%} CI 0.97-1.01]; P = 0.26). In nondiabetic individuals, there was no evidence that carriers of greater numbers of triglyceride-raising alleles had increased fasting insulin levels (SD 0.00 per weighted allele [95{\%} CI -0.01 to 0.02]; P = 0.72) or increased fasting glucose levels (0.00 [-0.01 to 0.01]; P = 0.88). Instrumental variable analyses confirmed that genetically raised circulating triglyceride levels were not associated with increased diabetes risk, fasting glucose, or fasting insulin and, for diabetes, showed a trend toward a protective association (OR per 1-SD increase in log(10) triglycerides: 0.61 [95{\%} CI 0.45-0.83]; P = 0.002).CONCLUSIONS-Genetically raised circulating triglyceride levels do not increase the risk of type 2 diabetes or raise fasting glucose or fasting insulin levels in nondiabetic individuals. One explanation for our results is that raised circulating triglycerides are predominantly secondary to the diabetes disease process rather than causal. Diabetes 60:1008-1018, 2011",
    keywords = "PANCREATIC BETA-CELL, CORONARY-ARTERY-DISEASE, LIPOPROTEIN-LIPASE, FASTING GLUCOSE, BLOOD-PRESSURE, PLASMA TRIGLYCERIDES, RISK-FACTORS, FATTY LIVER, MELLITUS, BEZAFIBRATE",
    author = "{De Silva}, {N. Maneka G.} and Freathy, {Rachel M.} and Palmer, {Tom M.} and Donnelly, {Louise A.} and Jian'an Luan and Tom Gaunt and Claudia Langenberg and Weedon, {Michael N.} and Beverley Shields and Knight, {Beatrice A.} and Ward, {Kirsten J.} and Sandhu, {Manjinder S.} and Harbord, {Roger M.} and McCarthy, {Mark I.} and Smith, {George Davey} and Shah Ebrahim and Hattersley, {Andrew T.} and Nicholas Wareham and Lawlor, {Debbie A.} and Morris, {Andrew D.} and Palmer, {Colin N. A.} and Frayling, {Timothy M.}",
    year = "2011",
    month = "3",
    doi = "10.2337/db10-1317",
    language = "English",
    volume = "60",
    pages = "1008--1018",
    journal = "Diabetes",
    issn = "0012-1797",
    publisher = "American Diabetes Association",
    number = "3",

    }

    De Silva, NMG, Freathy, RM, Palmer, TM, Donnelly, LA, Luan, J, Gaunt, T, Langenberg, C, Weedon, MN, Shields, B, Knight, BA, Ward, KJ, Sandhu, MS, Harbord, RM, McCarthy, MI, Smith, GD, Ebrahim, S, Hattersley, AT, Wareham, N, Lawlor, DA, Morris, AD, Palmer, CNA & Frayling, TM 2011, 'Mendelian randomization studies do not support a role for raised circulating triglyceride levels influencing type 2 diabetes, glucose levels, or insulin resistance.', Diabetes, vol. 60, no. 3, pp. 1008-1018. https://doi.org/10.2337/db10-1317

    Mendelian randomization studies do not support a role for raised circulating triglyceride levels influencing type 2 diabetes, glucose levels, or insulin resistance. / De Silva, N. Maneka G.; Freathy, Rachel M.; Palmer, Tom M.; Donnelly, Louise A.; Luan, Jian'an; Gaunt, Tom; Langenberg, Claudia; Weedon, Michael N.; Shields, Beverley; Knight, Beatrice A.; Ward, Kirsten J.; Sandhu, Manjinder S.; Harbord, Roger M.; McCarthy, Mark I.; Smith, George Davey; Ebrahim, Shah; Hattersley, Andrew T.; Wareham, Nicholas; Lawlor, Debbie A.; Morris, Andrew D.; Palmer, Colin N. A.; Frayling, Timothy M.

    In: Diabetes, Vol. 60, No. 3, 03.2011, p. 1008-1018.

    Research output: Contribution to journalArticle

    TY - JOUR

    T1 - Mendelian randomization studies do not support a role for raised circulating triglyceride levels influencing type 2 diabetes, glucose levels, or insulin resistance.

    AU - De Silva, N. Maneka G.

    AU - Freathy, Rachel M.

    AU - Palmer, Tom M.

    AU - Donnelly, Louise A.

    AU - Luan, Jian'an

    AU - Gaunt, Tom

    AU - Langenberg, Claudia

    AU - Weedon, Michael N.

    AU - Shields, Beverley

    AU - Knight, Beatrice A.

    AU - Ward, Kirsten J.

    AU - Sandhu, Manjinder S.

    AU - Harbord, Roger M.

    AU - McCarthy, Mark I.

    AU - Smith, George Davey

    AU - Ebrahim, Shah

    AU - Hattersley, Andrew T.

    AU - Wareham, Nicholas

    AU - Lawlor, Debbie A.

    AU - Morris, Andrew D.

    AU - Palmer, Colin N. A.

    AU - Frayling, Timothy M.

    PY - 2011/3

    Y1 - 2011/3

    N2 - OBJECTIVE-The causal nature of associations between circulating triglycerides, insulin resistance, and type 2 diabetes is unclear. We aimed to use Mendelian randomization to test the hypothesis that raised circulating triglyceride levels causally influence the risk of type 2 diabetes and raise normal fasting glucose levels and hepatic insulin resistance.RESEARCH DESIGN AND METHODS-We tested 10 common genetic variants robustly associated with circulating triglyceride levels against the type 2 diabetes status in 5,637 case and 6,860 control subjects and four continuous outcomes (reflecting glycemia and hepatic insulin resistance) in 8,271 nondiabetic individuals from four studies.RESULTS-Individuals carrying greater numbers of triglyceride-raising alleles had increased circulating triglyceride levels (SD 0.59 [95% CI 0.52-0.65] difference between the 20% of individuals with the most alleles and the 20% with the fewest alleles). There was no evidence that the carriers of greater numbers of triglyceride-raising alleles were at increased risk of type 2 diabetes (per weighted allele odds ratio [OR] 0.99 [95% CI 0.97-1.01]; P = 0.26). In nondiabetic individuals, there was no evidence that carriers of greater numbers of triglyceride-raising alleles had increased fasting insulin levels (SD 0.00 per weighted allele [95% CI -0.01 to 0.02]; P = 0.72) or increased fasting glucose levels (0.00 [-0.01 to 0.01]; P = 0.88). Instrumental variable analyses confirmed that genetically raised circulating triglyceride levels were not associated with increased diabetes risk, fasting glucose, or fasting insulin and, for diabetes, showed a trend toward a protective association (OR per 1-SD increase in log(10) triglycerides: 0.61 [95% CI 0.45-0.83]; P = 0.002).CONCLUSIONS-Genetically raised circulating triglyceride levels do not increase the risk of type 2 diabetes or raise fasting glucose or fasting insulin levels in nondiabetic individuals. One explanation for our results is that raised circulating triglycerides are predominantly secondary to the diabetes disease process rather than causal. Diabetes 60:1008-1018, 2011

    AB - OBJECTIVE-The causal nature of associations between circulating triglycerides, insulin resistance, and type 2 diabetes is unclear. We aimed to use Mendelian randomization to test the hypothesis that raised circulating triglyceride levels causally influence the risk of type 2 diabetes and raise normal fasting glucose levels and hepatic insulin resistance.RESEARCH DESIGN AND METHODS-We tested 10 common genetic variants robustly associated with circulating triglyceride levels against the type 2 diabetes status in 5,637 case and 6,860 control subjects and four continuous outcomes (reflecting glycemia and hepatic insulin resistance) in 8,271 nondiabetic individuals from four studies.RESULTS-Individuals carrying greater numbers of triglyceride-raising alleles had increased circulating triglyceride levels (SD 0.59 [95% CI 0.52-0.65] difference between the 20% of individuals with the most alleles and the 20% with the fewest alleles). There was no evidence that the carriers of greater numbers of triglyceride-raising alleles were at increased risk of type 2 diabetes (per weighted allele odds ratio [OR] 0.99 [95% CI 0.97-1.01]; P = 0.26). In nondiabetic individuals, there was no evidence that carriers of greater numbers of triglyceride-raising alleles had increased fasting insulin levels (SD 0.00 per weighted allele [95% CI -0.01 to 0.02]; P = 0.72) or increased fasting glucose levels (0.00 [-0.01 to 0.01]; P = 0.88). Instrumental variable analyses confirmed that genetically raised circulating triglyceride levels were not associated with increased diabetes risk, fasting glucose, or fasting insulin and, for diabetes, showed a trend toward a protective association (OR per 1-SD increase in log(10) triglycerides: 0.61 [95% CI 0.45-0.83]; P = 0.002).CONCLUSIONS-Genetically raised circulating triglyceride levels do not increase the risk of type 2 diabetes or raise fasting glucose or fasting insulin levels in nondiabetic individuals. One explanation for our results is that raised circulating triglycerides are predominantly secondary to the diabetes disease process rather than causal. Diabetes 60:1008-1018, 2011

    KW - PANCREATIC BETA-CELL

    KW - CORONARY-ARTERY-DISEASE

    KW - LIPOPROTEIN-LIPASE

    KW - FASTING GLUCOSE

    KW - BLOOD-PRESSURE

    KW - PLASMA TRIGLYCERIDES

    KW - RISK-FACTORS

    KW - FATTY LIVER

    KW - MELLITUS

    KW - BEZAFIBRATE

    U2 - 10.2337/db10-1317

    DO - 10.2337/db10-1317

    M3 - Article

    VL - 60

    SP - 1008

    EP - 1018

    JO - Diabetes

    JF - Diabetes

    SN - 0012-1797

    IS - 3

    ER -