Lipoprotein (a) is associated with basal insulin levels in patients with type 2 Diabetes Mellitus

Abstracts

FUNDAMENTO: Ainda não foi claramente estabelecido se a resistência/deficiência insulínica leva diretamente à aterogênese ou através de sua associação com outros fatores de risco como os níveis de lipoproteína (a)[Lp(a)]. OBJETIVO: O objetivo do estudo foi estabelecer a relação entre os níveis basais de insulina, lípides e lipoproteína (a) em pacientes com diabetes mellitus (DM) tipo 2. MÉTODOS: Amostras de sangue foram colhidas em jejum e os níveis de insulina, lipoproteína (a), colesterol total (CT), triglicérides (TG), lipoproteína de baixa densidade (LDL-C), lipoproteína de alta densidade (LDL-C), glicose e hemoglobina glicada (HbA1c) foram medidos em 60 pacientes com DM tipo 2 e 28 indivíduos saudáveis. Nós dividimos os pacientes em dois grupos baseados nos níveis basais de insulina: > 10 µIU/ml e < 10 µIU/ml. RESULTADOS: Os níveis de insulina eram mais altos nos indivíduos diabéticos do que nos controles [p < 0,05]. Os níveis de CT (p< 0,01), LDL-C (p< 0,05), razão CT/HDL (p< 0,01), e TG (p< 0,05) eram mais altos e os níveis de HDL- C eram significantemente mais baixos em ambos os grupos de diabéticos, quando comparados aos controles. Os níveis de Lp(a) eram significantemente mais baixos em diabéticos com insulina basal > 10 µIU/ml comparados com aqueles que apresentavam insulina basal < 10 µIU/ml (p < 0.05). A análise de regressão mostrou uma relação significante da Lp(a) com os níveis de insulina (r = 0,262, p < 0,05) e razão Insulina/Glicose(r = 0,257, p < 0,05). CONCLUSÃO: Os níveis de Lp(a) se correlacionam inversamente com os níveis de insulina em pacientes com DM tipo 2. Os níveis de Lp(a) podem ser um dos fatores de risco cardiovascular em pacientes com DM tipo 2 com maior duração da doença. (Arq Bras Cardiol 2009;93(1):28-33)

Diabetes mellitus; dislipidemias; lipoproteína(a); insulina basal

FUNDAMENTO: Todavía no se aclaró totalmente si la resistencia/deficiencia insulínica lleva directamente a la aterogénesis o a través de su asociación con otros factores de riesgo como los niveles de lipoproteína (a) [Lp(a)]. OBJETIVO: : El objetivo del estudio fue establecer la relación entre los niveles basales de insulina, lípidos y lipoproteína (a) en pacientes con diabetes mellitus (DM) tipo 2. MÉTODOS: Se extrajeron muestras de sangre en ayuno y se determinaron los niveles de insulina, lipoproteína (a), colesterol total (CT), triglicéridos (TG), lipoproteína de baja densidad (LDL-C), lipoproteína de alta densidad (LDL-C), glucosa y hemoglobina glicosilada (HbA1c) en 60 pacientes con DM tipo 2 y 28 individuos sanos. Dividimos a los pacientes en dos grupos basados en los niveles basales de insulina: > 10 µIU/ml y < 10 µIU/ml. RESULTADOS: : Los niveles de insulina eran más altos en los individuos diabéticos que en los controles [p < 0,05]. Los niveles de CT (p< 0,01), LDL-C (p< 0,05), razón CT/HDL (p< 0,01), y TG (p< 0,05) eran más altos y los niveles de HDL- C eran significantemente más bajos en ambos grupos de diabéticos, cuando comparados a los controles. Los niveles de Lp(a) eran significantemente más bajos en diabéticos con insulina basal > 10 µIU/ml comparados con aquellos que presentaban insulina basal < 10 µIU/ml (p < 0.05). El análisis de regresión evidenció una relación significante de la Lp(a) con los niveles de insulina (r = 0,262, p < 0,05) y razón insulina glucosa(r = 0,257, p < 0,05). CONCLUSIÓN: Los niveles de Lp(a) se correlacionan inversamente con los niveles de insulina en pacientes con DM tipo 2. Los niveles de Lp(a) pueden ser uno de los factores de riesgo cardiovascular en pacientes con DM tipo 2 con mayor duración de la enfermedad.

Diabetes mellitus; dislipidemias; lipoproteína(a); insulina basal

ORIGINAL ARTICLE

^IKing Khalid University Hospital, King Saud University, Riyadh, Saudi Arabia

^IIArmy Medical College, Rawalpindi, Pakistan

Mailing address

SUMMARY

BACKGROUND: It has not been clearly established whether insulin resistance/deficiency leads directly to atherogenesis or through its association with other risk factors such as Lipoprotein(a) [Lp(a)].

OBJECTIVE: This project aimed at studying the association between basal Insulin, Lipids and Lipoprotein(a) levels in Patients with Type 2 diabetes mellitus.

METHODS: Fasting blood samples were analyzed for Insulin, Lipoprotein(a), total cholesterol (TC), triglycerides (TG), low density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C), glucose and glycosylated hemoglobin (HbA1c) levels in 60 patients with type 2 diabetes mellitus (DM) and 28 healthy subjects. We divided patients into two groups based on basal insulin levels: > 10 µIU/ml and < 10 µIU/ml.

RESULTS: Insulin levels were higher in diabetic versus control individuals [p < 0.05]. TC (p< 0.01), LDL-C (p< 0.05), TC/HDL ratio (p< 0.01) and TG levels (p< 0.05) were higher and HDL- C levels were significantly lower (p < 0.001) in both diabetic groups as compared to control. Lp(a) levels were significantly higher in both diabetic groups, when compared to the control group. Lp(a) levels were significantly lower in diabetics with basal insulin > 10 µIU/ml when compared to those with basal insulin < 10 µIU/ml (p < 0.05). Regression analysis revealed a significant relationship of Lp(a) with insulin levels (r = 0.262, p < 0.05) and Insulin Glucose ratio (r = 0.257, p < 0.05).

CONCLUSION: Lp(a) levels correlate inversely with insulin levels in type 2 diabetic patients. Lp(a) may be one of the cardiovascular risk factor in type 2 diabetic patients with longer duration of dm.

Key words:Diabetes mellitus; dyslipidemias; lipoprotein (a), insulin.

Introduction

Among the most common chronic disorders of modern times, diabetes mellitus (dm) remains unique because of its multisystem ramifications. The combination of hypertension, dyslipidemia, insulin resistance, hyperinsulinemia, glucose intolerance and obesity, particularly central obesity, has been termed "metabolic syndrome"^1,2, which is a powerful determinant of type 2 DM and cardiovascular disease³.

Patients with type 2 DM have defects in insulin secretion in response to a glucose load and resistance to insulin action^4,5. Three phases can be recognized in the pathogenesis of type 2 dm^4,6,7. In the first phase, plasma glucose remains normal despite insulin resistance because insulin levels are elevated. In the second phase, insulin resistance worsens despite elevated insulin concentration and glucose intolerance manifests as postprandial hyperglycemia. In the third phase, insulin secretion decreases, with progressive loss of beta cells⁸. Plasma insulin concentrations are determined by both insulin resistance and insulin secretion.

Insulin resistance best correlates with metabolic abnormalities and is linked to the development of cardiovascular disease in patients with type 2 diabetes⁹.

Hyperinsulinemia and insulin resistance have been associated with coronary artery disease (CAD), type 2 DM, dyslipidemia and hypertension. Insulin resistance has been proposed as an independent risk factor for cad¹⁰.

Lp(a) has been reported to be an independent risk factor for premature CAD and other thromboembolic disorders¹¹. Many studies have reported that Lp(a) is elevated in type 2 DM. Moreover, the frequency of high risk levels has been reported to be much higher in type 2 diabetics^12,13.

The present study aimed at studying the association between basal insulin levels, lipids and lipoprotein(a) concentrations in patients with type 2 diabetes mellitus.

Methods

This study was carried out at the department of physiology, army medical college, rawalpindi. This study was approved by the army medical college ethics review board. Sixty patients with type 2 DM were selected as per selection criteria and 28 non-diabetic, age and sex-matched healthy individuals were selected for the control group.

The patients participating in the study were diagnosed as having type 2 DM; thirty-two patients were males and twenty-eight were females. Their height was measured in centimeters with patients barefoot and weight was measured in kilograms with patients wearing light clothes.

Clinical information, date of the diagnosis and medical history were obtained through the review of medical files and patients' interviews. All patients presented stable metabolic conditions. Patients presenting any disease that could affect their metabolic status and the parameters studied such as nephrotic syndrome, acute or chronic renal failure, thyroid disorders, acute infections, stroke, diabetic ketoacidosis and nonketotic hyperosmolar syndrome were excluded^11,14. The patients with history of familial hypercholesterolemia or acute myocardial infarction were also excluded from the study^15,16. The history of medication was recorded and the patients taking insulin, lipid lowering agents, oral contraceptives and steroids were also excluded^17,18.

We grouped diabetic subjects based on fasting (basal) insulin concentrations in two groups: insulin levels > 10 µiu/ml and insulin levels < 10 µiu/ml groups^7,19,20.

The subjects included in the control group were age and sex matched healthy individuals selected from the staff members of afip (armed forces institute of pathology) and army medical college. They did not present any acute infection or any metabolic or psychological disorder and had no family history of hypercholesterolemia or dm. Their lipid profiles and fasting blood glucose levels were measured, showing they had normal lipid profiles and fasting plasma glucose (fpg) levels < 6.1 Mmol/l (110 mg/dl).

Fasting blood samples were taken from the antecubital vein and the serum was separated, separated in aliquots and then frozen at -70 ºc. Glucose was measured through the GOD-PAP (glucose oxidase phenyl ampyrone) method, an enzymatic colorimetric method with a supplied kit (linear chemicals, barcelona, spain). Total cholesterol was measured by CHOD-PAP (cholesterol oxidase phenol ampyrone), an enzymatic colorimetric kit (linear chemicals). GPO-PAP (glycerol phosphate oxidase), an enzymatic colorimetric kit was used for serum triglycerides measurement (linear chemicals). The CHOD-PAP method was used for HDL-c and LDL-c measurement (merck systems, san antonio, TX, USA). Serum Lp(a) levels were measured immunochemically using a sandwich ELISA method with a mouse monoclonal anti-Apo(a) antibody as the solid phase antibody and a sheep anti-apo B-100 polyclonal antibody (antibody against B-100) as the detection antibody. The antibodies used in this assay identify all known isoforms of Apo(a). There was no cross-reactivity with plasminogen and LDL. The kits used were supplied by innogenetics biotechnology for health care, gent, belgium. Ion exchange resin separation method was used for estimation of glycosylated hemoglobin (stanbio glycohemoglobin, boerne, TX, USA) for which ethylenediaminetetraacetic acid (EDTA)-added whole blood was used. Insulin was measured by a chemiluminescence method, which is a sandwich assay. The kit was supplied by diagnostic products corporation, usa and instrument used was immulite 2000. The immulite system utilizes assay-specific antibody-coated plastic beads as the solid phase, in a specifically designed test unit. The test unit serves as the reaction vessel for the immune reaction, incubation, washing and signal development. Light emission from the chemiluminescent substrate, which reacts with the enzyme conjugate bound to the bead, is proportional to the amount of analyte originally present in the sample. However, c-peptide levels were not measured in this study.

Statistical analysis

The data were analyzed by the computer software program "statistical package for social sciences" (spss version 10). Data were expressed as means and standard error of the mean (sem). The tests applied for statistical analysis were ANOVA and bonferroni (multiple comparisons). A value of p < 0.05 Was considered statistically significant. Spearman's correlation coefficients were also determined between basal insulin levels, insulin glucose ratio and clinical characteristics. Levels of lp(a), insulin and insulin glucose ratio were also analyzed by linear regression analysis with 95% confidence intervals after log transformation of insulin and insulin glucose ratio.

Results

Clinical characteristics

Clinical characteristics of the control group and diabetic patients are shown in table 1. SBP (systolic blood pressure), DBP (diastolic blood pressure) fasting plasma glucose and hba1c were significantly higher in both groups of diabetic patients (p < 0.0001), When compared to the nondiabetic, healthy subjects. There was a non-significant difference regarding age and BMI between the diabetic patients and the control group (p > 0.05). Diabetics with insulin < 10 µiu/ml were significantly older and had longer duration of DM when compared to the patients with insulin levels > 10 µiu/ml (p < 0.05).

Insulin levels

Serum insulin levels were significantly higher in diabetic patients (16.94 ± 3.21), When compared with the nondiabetic, control subjects (7.88 ±1.01) [P < 0.05].

The serum insulin/glucose ratio, which is a marker of insulin resistance, was significantly higher in diabetic patients with insulin levels > 10 µiu/ml (p < 0.0001) When compared to the group with insulin levels < 10 µiu/ml. Moreover, HOMA-ir values were significantly higher in the group with higher insulin levels, when compared to the control group (p < 0.0001) And the diabetic patients with lower insulin levels (p < 0.01).

Lipid profile and Lp(a) profile

Total cholesterol (p< 0.01), LDL-c (p< 0.05), Total cholesterol /HDL ratio (p< 0.01) And TG (p< 0.05) Were significantly higher and HDL- c was significantly lower (p < 0.001) In both groups of diabetic patients when compared to the control group.

Lp(a) was significantly higher in patients with basal insulin < 10 µiu/ml (p < 0.01) And in those with insulin levels > 10 µiu/ml (p < 0.05 ) When compared with the control group [table 2]. Lp(a) levels were significantly lower in DM patients with basal insulin > 10 µiu/ml, when compared to the ones with insulin levels < 10 µiu/ml ( p < 0.05).

Insulin glucose ratio was negatively correlated with fpg (r = - 0.49, P < 0.001 And HBA1c levels (r = - 0.343, P < 0.01). Serum insulin levels were negatively correlated with age (r = - 0.300, P < 0.05) And positively correlated with HDL (r = 0.306, P < 0.05). The logistic regression analysis revealed a significant association between Lp(a) as a dependent variable and the insulin levels as an independent variable (r = 0.262, P < 0.05) (Figure 1). The association with insulin/glucose ratio was also significant (r = 0.257, P < 0.05) (Figure 2).

Discussion

It has been observed that patients with type 2 DM have increased morbidity and mortality due to coronary risk events. This increased risk has been shown to be independent from conventional risk factors²¹.

Different factors have been found to be responsible for an increased prevalence of CAD in DM. One of these are the elevated levels of serum lp(a)¹¹. Our study has revealed that Lp(a) levels were significantly elevated in dm patients. Type 2 diabetic patients with hypoinsulinemia had longer duration of diabetes and higher concentrations of Lp(a), when compared to those with hyperinsulinemia. The present study also showed a significant inverse relationship between serum insulin, insulin glucose ratio and Lp(a) levels. A study carried out with elderly individuals also showed that fasting insulin was inversely correlated with Lp(a) levels. Lp(a) was significantly associated with tc and LDL-c, tg and Apo B. These results suggest that fasting insulin levels significantly influence LDL-c metabolism in the elderly. Although Lp(a) levels seem to be mostly genetically inherited, an indirect relation with insulin through adiposity and/or other associated lipid abnormalities cannot be ruled out²². Fasting insulin was has also been shown to be inversely correlated with Lp(a) in both sexes. However, the reported coefficients were weak²³.

In the later stages of type 2 DM, insulin secretion declines, with progressive loss of beta cells as well as worsening of the glycemic control¹². The risk of cardiovascular mortality and morbidity also increases with longer duration of DM²⁴.

In united kingdom prospective diabetes study (UKPDS) 9 years of follow up showed that regardless of the assigned therapy, fasting plasma glucose and HBA1c levels increased, with the increased duration of DM, and maintaining near-normal glycemia was difficult. Not even with insulin therapy the therapeutic goal of near-normal glycemia was achieved due to the difficulty in treating marked hyperglycemia and the risk of hypoglycemic episodes²⁵.

The concentration of glycosylated Lp(a) is increased in the circulation of diabetic subjects. It is evident that glycosylation prolongs the half-life of lipoproteins and likewise for Lp(a). This can lead to elevated levels of Lp(a) in diabetic individuals²⁶.

In a study by alagozlu et al²⁷, non-obese type 2 DM patients were studied. They were divided into 3 groups according to the type of treatment administered: i.E. Insulin, sulphonylureas and an untreated group. There was no significant difference in Apo A I, Apo B and triglyceride levels in the different groups of diabetic individuals. Hdl levels were significantly lower and Lp(a) levels were significantly higher in the untreated group. It was concluded that gaining metabolic control may also have favorable effects on lp(a) levels²⁷.

Plasma Lp(a) concentrations are primarily controlled at the level of the gene that encodes Apo(a), and an inverse correlation has been shown between plasma Lp(a) concentration and Apo(a) size that may arise, at least in part, from the relatively inefficient secretion of the larger Apo(a) isoforms from the hepatocytes. Additionally, the level of Lp(a) in human plasma is largely unaffected by diet, physical activity, and conventional hypolipidemic therapy²⁸.

In a study by haffner and colleagues, no association was found between lp(a) concentrations and insulin levels²⁹. In most cases, diabetic dyslipidemia is preceded by hyperinsulinemia, resulting from insulin resistance. Because patients with type 2 diabetes and insulin resistance are at a markedly increased risk of atherosclerosis, and because strict control of glycemia has proved beneficial in reducing microangiopathy but not macroangiopathy, the treatment of diabetic dyslipidemia should be aggressive³⁰.

The insulin resistance syndrome (IRS), which is very common in subjects with type 2 diabetes, has been suggested to be one of the factors increasing the cardiovascular risk in type 2 diabetic men and predicted CHD events in elderly diabetic men³¹. The mechanisms by which irs enhances atherothrombosis are largely unknown, but adverse changes, indirectly through cardiovascular risk or directly through hyperinsulinemia, may accelerate atherothrombosis³².

Lp(a) has been found to be metabolized differently from triglyceride-rich lipoproteins. Acute hyperglycemia-induced hyperinsulinemia has a different effect on plasma Apo B and Lp(a) levels in healthy subjects³³. In a study by Klaus G. Parhofer et al³⁴, it was observed that unlike Ldl, Lp(a) production, and not catabolism, determined plasma concentrations and the inverse association of Lp(a) concentrations with Apo(a) isoforms was due to differences in production and not catabolism.

One of the risk factors in long standing dm may be increasing Lp(a) levels. The association of Lp(a) levels in DM has been a matter of some controversies. The major reasons for the discrepant results of the prospective studies have been attributed to the variation in study design, collection and storage of samples, methods used for statistical analysis and population differences that reflect the known ethnic variability in the distribution of Lp(a) levels and Apo(a) size isoforms³⁵.

Conclusions

Type 2 DM is associated with atherogenic lipid disorder and high fasting insulin/glucose ratio. Lp(a) levels inversely correlate with insulin levels in type 2 diabetic patients. Lp(a) may be one of the cardiovascular risk factors in type 2 diabetic patients with longer duration of DM. This study may partially explain the higher incidence of cardiovascular problems with the increasing duration of DM. However, long-term prospective studies are needed in diabetic patients to disclose the true mechanistic links to cardiovascular problems.

Acknowledgements

The authors wish to thank Mr. Tahseen for technical assistance.

Potential conflict of interest

No potential conflict of interest relevant to this article was reported.

Sources of funding

There were no external funding sources for this study.

Study association

This study is not associated with any post-graduation program.

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Lipoprotein (a) is associated with basal insulin levels in patients with type 2 diabetes mellitus

Syed Shahid Habib; Muhammad Aslam; Syed Fayaz Ahmad Shah; Abdul Khaliq Naveed

Publication Dates

• Publication in this collection
  13 Oct 2009
• Date of issue
  July 2009

History

• Accepted
  03 Mar 2008
• Received
  08 Dec 2007
• Reviewed
  08 Feb 2008