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Published in: Diabetologia 8/2007

01-08-2007 | Article

Proinsulin:insulin and insulin:glucose ratios as predictors of carotid plaque growth: a population-based 7 year follow-up of the Tromsø Study

Authors: J. Kronborg, S. H. Johnsen, I. Njølstad, I. Toft, B. O. Eriksen, T. Jenssen

Published in: Diabetologia | Issue 8/2007

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Abstract

Aims/hypothesis

Proinsulin is increased in persons at cardiovascular risk. Increased secretion of proinsulin relative to insulin has been suggested as a sign of defective conversion of proinsulin to insulin and C-peptide and is associated with beta cell dysfunction. It has also been suggested that proinsulin has more of a pro-atherogenic effect than insulin, the levels of which are also increased in the insulin resistance state. In this prospective population-based study, we examined whether the proinsulin:insulin ratio (PIR) or insulin:glucose ratio (IGR, an insulin resistance surrogate) predicted carotid plaque size in nondiabetic participants.

Materials and methods

The study included 1,859 men and 1,998 women aged 25–82 years from the Tromsø Study, who were examined with B-mode high resolution ultrasound at baseline in 1994–1995 and at follow-up in 2001–2002. All images were computer processed to yield mm2 measures of plaque. Proinsulin and insulin were measured at baseline. All analyses were stratified for sex.

Results

After adjusting for age, baseline plaque area, BMI, cholesterol, HDL-cholesterol, HbA1c, IGR, albumin:creatinine ratio, fibrinogen, BP and lifestyle factors (tobacco smoking, alcohol consumption, physical activity), PIR was significantly associated with plaque size at follow-up in women but not men. For each SD in the PIR in women, the mean plaque area increased by 0.97 mm2 (95% CI 0.44–1.50). IGR was not associated with carotid plaque size.

Conclusions/interpretation

The PIR is associated with progressive carotid artery plaque size in women.
Literature
1.
go back to reference Yudkin JS, May M, Elwood P, Yarnell JW, Greenwood R, Davey Smith G (2002) Concentrations of proinsulin like molecules predict coronary heart disease risk independently of insulin: prospective data from the Caerphilly Study. Diabetologia 45:327–336PubMedCrossRef Yudkin JS, May M, Elwood P, Yarnell JW, Greenwood R, Davey Smith G (2002) Concentrations of proinsulin like molecules predict coronary heart disease risk independently of insulin: prospective data from the Caerphilly Study. Diabetologia 45:327–336PubMedCrossRef
2.
go back to reference Haffner SM, D’Agostino R, Mykkänen L et al (1998) Proinsulin and insulin concentrations in relation to carotid wall thickness: Insulin Resistance Atherosclerosis Study. Stroke 29:1498–1503PubMed Haffner SM, D’Agostino R, Mykkänen L et al (1998) Proinsulin and insulin concentrations in relation to carotid wall thickness: Insulin Resistance Atherosclerosis Study. Stroke 29:1498–1503PubMed
3.
go back to reference Haffner SM, Mykkänen L, Valdez RA et al (1994) Disproportionately increased proinsulin levels are associated with the insulin resistance syndrome. J Clin Endocrinol Metab 79:1806–1810PubMedCrossRef Haffner SM, Mykkänen L, Valdez RA et al (1994) Disproportionately increased proinsulin levels are associated with the insulin resistance syndrome. J Clin Endocrinol Metab 79:1806–1810PubMedCrossRef
4.
go back to reference Perry IJ, Wannamethee SG, Whincup PH, Shaper AG, Walker MK, Alberti KG (1996) Serum insulin and incident coronary heart disease in middle-aged British men. Am J Epidemiol 144:224–234PubMed Perry IJ, Wannamethee SG, Whincup PH, Shaper AG, Walker MK, Alberti KG (1996) Serum insulin and incident coronary heart disease in middle-aged British men. Am J Epidemiol 144:224–234PubMed
5.
go back to reference Båvenholm P, Proudler A, Tornvall P et al (1995) Insulin, intact and split proinsulin, and coronary artery disease in young men. Circulation 92:1422–1429PubMed Båvenholm P, Proudler A, Tornvall P et al (1995) Insulin, intact and split proinsulin, and coronary artery disease in young men. Circulation 92:1422–1429PubMed
6.
go back to reference Kahn SE, Leonetti DL, Prigeon RL, Boyko EJ, Bergstrom RW, Fujimoto WY (1995) Relationship of proinsulin and insulin with noninsulin-dependent diabetes mellitus and coronary heart disease in Japanese-American men: impact of obesity clinical research center study. J Clin Endocrinol Metab 80:1399–1406PubMedCrossRef Kahn SE, Leonetti DL, Prigeon RL, Boyko EJ, Bergstrom RW, Fujimoto WY (1995) Relationship of proinsulin and insulin with noninsulin-dependent diabetes mellitus and coronary heart disease in Japanese-American men: impact of obesity clinical research center study. J Clin Endocrinol Metab 80:1399–1406PubMedCrossRef
7.
go back to reference Zethelius B, Lithell H, Hales CN, Berne C (2005) Insulin sensitivity, proinsulin and insulin as predictors of coronary heart disease. A population-based 10-year, follow-up study in 70-year old men using the euglycaemic insulin clamp. Diabetologia 48:862–867PubMedCrossRef Zethelius B, Lithell H, Hales CN, Berne C (2005) Insulin sensitivity, proinsulin and insulin as predictors of coronary heart disease. A population-based 10-year, follow-up study in 70-year old men using the euglycaemic insulin clamp. Diabetologia 48:862–867PubMedCrossRef
8.
go back to reference Lindahl B, Dinesen B, Eliasson M, Røder M, Hallmans G, Stegmayr B (2000) High proinsulin levels precede first-ever stroke in a nondiabetic population. Stroke 31:2936–2941PubMed Lindahl B, Dinesen B, Eliasson M, Røder M, Hallmans G, Stegmayr B (2000) High proinsulin levels precede first-ever stroke in a nondiabetic population. Stroke 31:2936–2941PubMed
9.
go back to reference Galloway JA, Hooper SA, Spradlin CT et al (1992) Biosynthetic human proinsulin. Review of chemistry, in vitro and in vivo receptor binding, animal and human pharmacology studies, and clinical trial experience. Diabetes Care 15:666–692PubMedCrossRef Galloway JA, Hooper SA, Spradlin CT et al (1992) Biosynthetic human proinsulin. Review of chemistry, in vitro and in vivo receptor binding, animal and human pharmacology studies, and clinical trial experience. Diabetes Care 15:666–692PubMedCrossRef
10.
go back to reference Johnsen SH, Mathiesen EB, Fosse E et al (2005) Elevated high-density lipoprotein cholesterol levels are protective against plaque progression: a follow-up study of 1952 persons with carotid atherosclerosis. The Tromsø study. Circulation 112:498–504PubMedCrossRef Johnsen SH, Mathiesen EB, Fosse E et al (2005) Elevated high-density lipoprotein cholesterol levels are protective against plaque progression: a follow-up study of 1952 persons with carotid atherosclerosis. The Tromsø study. Circulation 112:498–504PubMedCrossRef
11.
go back to reference Spence JD (2002) Ultrasound measurement of carotid plaque as a surrogate outcome for coronary artery disease. Am J Cardiol 89:10B–15B, discussion 1PubMedCrossRef Spence JD (2002) Ultrasound measurement of carotid plaque as a surrogate outcome for coronary artery disease. Am J Cardiol 89:10B–15B, discussion 1PubMedCrossRef
12.
go back to reference Mykkänen L, Haffner SM, Hales CN, Rönnemaa T, Laakso M (1997) The relation of proinsulin, insulin, and proinsulin-to-insulin ratio to insulin sensitivity and acute insulin response in normoglycemic subjects. Diabetes 46:1990–1995PubMedCrossRef Mykkänen L, Haffner SM, Hales CN, Rönnemaa T, Laakso M (1997) The relation of proinsulin, insulin, and proinsulin-to-insulin ratio to insulin sensitivity and acute insulin response in normoglycemic subjects. Diabetes 46:1990–1995PubMedCrossRef
13.
go back to reference Jørgensen L, Jenssen T, Johnsen SH et al (2007) Albuminuria as risk factor for initiation and progression of carotid atherosclerosis in non-diabetic persons: the Tromso Study. Eur Heart J 28:363–369PubMedCrossRef Jørgensen L, Jenssen T, Johnsen SH et al (2007) Albuminuria as risk factor for initiation and progression of carotid atherosclerosis in non-diabetic persons: the Tromso Study. Eur Heart J 28:363–369PubMedCrossRef
14.
go back to reference Jorde R, Burhol PG, Schulz TB et al (1981) The effect of a 34-h fast on the meal-induced rises in plasma GIP, serum insulin, and blood glucose in man. Scand J Gastroenterol 16:109–112PubMed Jorde R, Burhol PG, Schulz TB et al (1981) The effect of a 34-h fast on the meal-induced rises in plasma GIP, serum insulin, and blood glucose in man. Scand J Gastroenterol 16:109–112PubMed
15.
go back to reference Fosse E, Johnsen SH, Stensland-Bugge E et al (2006) Repeated visual and computer-assisted carotid plaque characterization in a longitudinal population-based ultrasound study: the Tromsø study. Ultrasound Med Biol 32:3–11PubMedCrossRef Fosse E, Johnsen SH, Stensland-Bugge E et al (2006) Repeated visual and computer-assisted carotid plaque characterization in a longitudinal population-based ultrasound study: the Tromsø study. Ultrasound Med Biol 32:3–11PubMedCrossRef
16.
go back to reference Joakimsen O, Bønaa KH, Stensland-Bugge E (1997) Reproducibility of ultrasound assessment of carotid plaque occurrence, thickness, and morphology. The Tromsø Study. Stroke 28:2201–2207PubMed Joakimsen O, Bønaa KH, Stensland-Bugge E (1997) Reproducibility of ultrasound assessment of carotid plaque occurrence, thickness, and morphology. The Tromsø Study. Stroke 28:2201–2207PubMed
17.
go back to reference Sayer JW, Marchant B, Gelding SV, Cooper JA, Timmis AD (2000) Autonomic dysfunction is related to impaired pancreatic beta cell function in patients with coronary artery disease. Heart 83:210–216PubMedCrossRef Sayer JW, Marchant B, Gelding SV, Cooper JA, Timmis AD (2000) Autonomic dysfunction is related to impaired pancreatic beta cell function in patients with coronary artery disease. Heart 83:210–216PubMedCrossRef
18.
go back to reference Mohamed-Ali V, Gould MM, Gillies S, Goubet S, Yudkin JS, Haines AP (1995) Association of proinsulin-like molecules with lipids and fibrinogen in non-diabetic subjects—evidence against a modulating role for insulin. Diabetologia 38:1110–1116PubMedCrossRef Mohamed-Ali V, Gould MM, Gillies S, Goubet S, Yudkin JS, Haines AP (1995) Association of proinsulin-like molecules with lipids and fibrinogen in non-diabetic subjects—evidence against a modulating role for insulin. Diabetologia 38:1110–1116PubMedCrossRef
19.
go back to reference Gray RP, Mohamed-Ali V, Patterson DL, Yudkin JS (1995) Determinants of plasminogen activator inhibitor-1 activity in survivors of myocardial infarction. Thromb Haemost 73:261–267PubMed Gray RP, Mohamed-Ali V, Patterson DL, Yudkin JS (1995) Determinants of plasminogen activator inhibitor-1 activity in survivors of myocardial infarction. Thromb Haemost 73:261–267PubMed
20.
go back to reference Haffner SM, Mykkänen L, Stern MP, Valdez RA, Heisserman JA, Bowsher RR (1993) Relationship of proinsulin and insulin to cardiovascular risk factors in nondiabetic subjects. Diabetes 42:1297–1302PubMedCrossRef Haffner SM, Mykkänen L, Stern MP, Valdez RA, Heisserman JA, Bowsher RR (1993) Relationship of proinsulin and insulin to cardiovascular risk factors in nondiabetic subjects. Diabetes 42:1297–1302PubMedCrossRef
21.
go back to reference Festa A, D’Agostino R, Mykkänen L et al (1999) Relative contribution of insulin and its precursors to fibrinogen and PAI-1 in a large population with different states of glucose tolerance. The Insulin Resistance Atherosclerosis Study (IRAS). Arterioscler Thromb Vasc Biol 19:562–568PubMed Festa A, D’Agostino R, Mykkänen L et al (1999) Relative contribution of insulin and its precursors to fibrinogen and PAI-1 in a large population with different states of glucose tolerance. The Insulin Resistance Atherosclerosis Study (IRAS). Arterioscler Thromb Vasc Biol 19:562–568PubMed
22.
go back to reference Bokemark L, Wikstrand J, Wedel H, Fagerberg B (2002) Insulin, insulin propeptides and intima–media thickness in the carotid artery in 58-year-old clinically healthy men. The Atherosclerosis and Insulin Resistance study (AIR). Diabet Med 19:144–151PubMedCrossRef Bokemark L, Wikstrand J, Wedel H, Fagerberg B (2002) Insulin, insulin propeptides and intima–media thickness in the carotid artery in 58-year-old clinically healthy men. The Atherosclerosis and Insulin Resistance study (AIR). Diabet Med 19:144–151PubMedCrossRef
23.
go back to reference Oh JY, Barrett-Connor E, Wedick NM (2002) Sex differences in the association between proinsulin and intact insulin with coronary heart disease in nondiabetic older adults: the Rancho Bernardo Study. Circulation 105:1311–1316PubMedCrossRef Oh JY, Barrett-Connor E, Wedick NM (2002) Sex differences in the association between proinsulin and intact insulin with coronary heart disease in nondiabetic older adults: the Rancho Bernardo Study. Circulation 105:1311–1316PubMedCrossRef
24.
go back to reference Linhart A, Gariepy J, Giral P, Levenson J, Simon A (1996) Carotid artery and left ventricular structural relationship in asymptomatic men at risk for cardiovascular disease. Atherosclerosis 127:103–112PubMedCrossRef Linhart A, Gariepy J, Giral P, Levenson J, Simon A (1996) Carotid artery and left ventricular structural relationship in asymptomatic men at risk for cardiovascular disease. Atherosclerosis 127:103–112PubMedCrossRef
25.
go back to reference Cuspidi C, Lonati L, Macca G et al (2001) Prevalence of left ventricular hypertrophy and carotid thickening in a large selected hypertensive population: impact of different echocardiographic and ultrasonographic diagnostic criteria. Blood Pressure 10:142–149PubMedCrossRef Cuspidi C, Lonati L, Macca G et al (2001) Prevalence of left ventricular hypertrophy and carotid thickening in a large selected hypertensive population: impact of different echocardiographic and ultrasonographic diagnostic criteria. Blood Pressure 10:142–149PubMedCrossRef
26.
go back to reference Adams MR, Nakagomi A, Keech A et al (1995) Carotid intima–media thickness is only weakly correlated with the extent and severity of coronary artery disease. Circulation 92:2127–2134PubMed Adams MR, Nakagomi A, Keech A et al (1995) Carotid intima–media thickness is only weakly correlated with the extent and severity of coronary artery disease. Circulation 92:2127–2134PubMed
27.
go back to reference Hallerstam S, Larsson PT, Zuber E, Rosfors S (2004) Carotid atherosclerosis is correlated with extent and severity of coronary artery disease evaluated by myocardial perfusion scintigraphy. Angiology 55:281–288PubMedCrossRef Hallerstam S, Larsson PT, Zuber E, Rosfors S (2004) Carotid atherosclerosis is correlated with extent and severity of coronary artery disease evaluated by myocardial perfusion scintigraphy. Angiology 55:281–288PubMedCrossRef
28.
go back to reference Brook RD, Bard RL, Patel S et al (2006) A negative carotid plaque area test is superior to other noninvasive atherosclerosis studies for reducing the likelihood of having underlying significant coronary artery disease. Arterioscler Thromb Vasc Biol 26:656–662PubMedCrossRef Brook RD, Bard RL, Patel S et al (2006) A negative carotid plaque area test is superior to other noninvasive atherosclerosis studies for reducing the likelihood of having underlying significant coronary artery disease. Arterioscler Thromb Vasc Biol 26:656–662PubMedCrossRef
29.
go back to reference Aminbakhsh A, Frohlich J, Mancini GB (1999) Detection of early atherosclerosis with B mode carotid ultrasonography: assessment of a new quantitative approach. Clin Invest Med 22:265–274PubMed Aminbakhsh A, Frohlich J, Mancini GB (1999) Detection of early atherosclerosis with B mode carotid ultrasonography: assessment of a new quantitative approach. Clin Invest Med 22:265–274PubMed
30.
go back to reference Huxley R, Barzi F, Woodward M (2006) Excess risk of fatal coronary heart disease associated with diabetes in men and women: meta-analysis of 37 prospective cohort studies. BMJ 332:73–78PubMedCrossRef Huxley R, Barzi F, Woodward M (2006) Excess risk of fatal coronary heart disease associated with diabetes in men and women: meta-analysis of 37 prospective cohort studies. BMJ 332:73–78PubMedCrossRef
31.
go back to reference Levantesi G, Macchia A, Marfisi R et al (2005) Metabolic syndrome and risk of cardiovascular events after myocardial infarction. J Am Coll Cardiol 46:277–283PubMedCrossRef Levantesi G, Macchia A, Marfisi R et al (2005) Metabolic syndrome and risk of cardiovascular events after myocardial infarction. J Am Coll Cardiol 46:277–283PubMedCrossRef
32.
go back to reference Iglseder B, Cip P, Malaimare L, Ladurner G, Paulweber B (2005) The metabolic syndrome is a stronger risk factor for early carotid atherosclerosis in women than in men. Stroke 36:1212–1217PubMedCrossRef Iglseder B, Cip P, Malaimare L, Ladurner G, Paulweber B (2005) The metabolic syndrome is a stronger risk factor for early carotid atherosclerosis in women than in men. Stroke 36:1212–1217PubMedCrossRef
33.
go back to reference Rajala U, Laakso M, Päivänsalo M, Pelkonen O, Suramo I, Keinänen-Kiukaanniemi S (2002) Low insulin sensitivity measured by both quantitative insulin sensitivity check index and homeostasis model assessment method as a risk factor of increased intima–media thickness of the carotid artery. J Clin Endocrinol Metab 87:5092–5097PubMedCrossRef Rajala U, Laakso M, Päivänsalo M, Pelkonen O, Suramo I, Keinänen-Kiukaanniemi S (2002) Low insulin sensitivity measured by both quantitative insulin sensitivity check index and homeostasis model assessment method as a risk factor of increased intima–media thickness of the carotid artery. J Clin Endocrinol Metab 87:5092–5097PubMedCrossRef
Metadata
Title
Proinsulin:insulin and insulin:glucose ratios as predictors of carotid plaque growth: a population-based 7 year follow-up of the Tromsø Study
Authors
J. Kronborg
S. H. Johnsen
I. Njølstad
I. Toft
B. O. Eriksen
T. Jenssen
Publication date
01-08-2007
Publisher
Springer-Verlag
Published in
Diabetologia / Issue 8/2007
Print ISSN: 0012-186X
Electronic ISSN: 1432-0428
DOI
https://doi.org/10.1007/s00125-007-0715-z

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