**Lipid Disorders in Type 1 Diabetes**

Bruno Vergès

*Service Endocrinologie, Diabétologie et Maladies Métaboliques Dijon University Hospital France* 

#### **1. Introduction**

44 Type 1 Diabetes – Complications, Pathogenesis, and Alternative Treatments

World Health Organization (WHO). (2008). "Fact sheet N°310 The top 10 causes of death."

Yusuf, S., S. Hawken, et al. (2004). "Effect of potentially modifiable risk factors associated

Zeller K, Whittaker E, et al. (1991). "Effect of restricting dietary protein on the progression of

with myocardial infarction in 52 countries (the INTERHEART study): case-control

renal failure in patients with insulin-dependent diabetes mellitus." The New

http://www.who.int/mediacentre/factsheets/fs310/en/index.html

Retrieved 21 March, 2011, from

study." Lancet. 364(9438): 937-952.

England Journal of Medicine 324(2): 78-84.

Cardiovascular disease is the major cause of death in persons with type 1 diabetes (Libby et al., 2005). Dyslipidemia has been shown to be a significant coronary heart disease risk factor in type 1 diabetes (Soedamah-Muthu et al., 2004; Grauslund et al., 2010). Thus, it seems important to pay attention to lipid abnormalities, in patients with type 1 diabetes, in order to reduce cardiovascular disease in this population.

Patients with type 1 diabetes show lipid disorders, mostly qualitative abnormalities of lipoproteins, which may promote atherogenesis. The pathophysiology of these lipid abnormalities is not totally explained, but hyperglycemia and peripheral hyperinsulinemia, due to the subcutaneous route of insulin administration, are likely to play a role. After a brief review of lipoprotein metabolism and some information on the role of insulin on lipid metabolism, quantitative abnormalities then qualitative abnormalities of lipoproteins, in type 1 diabetes, will be discussed.

#### **2. Brief review of lipoprotein metabolism**

Lipoproteins, which transport non-water soluble cholesterol and triglycerides in plasma, are spherical particles composed of a central core of non-polar lipids (cholesterol esters, triglycerides) and a surface monolayer of phospholipids, free cholesterol and apolipoproteins. Lipoproteins are generally classified according to their density as chylomicron, Very Low Density Lipoprotein (VLDL), Intermediate Density Lipoprotein (IDL), Low Density Lipoprotein (LDL) and High Density Lipoprotein (HDL). An overview of lipoprotein metabolism is shown in Figure 1.

#### **2.1 Chylomicrons**

Chylomicrons, the largest lipoprotein particles, are responsible for the transport of dietary triglycerides and cholesterol. Chylomicrons are composed of triglycerides (85-90%), cholesterol esters, phospholipids and apolipoproteins (mainly apoB48 but also apoA-I and apoA-IV). The formation of chylomicrons takes place in the enterocytes, and the process associating the lipid components (triglycerides, cholesterol esters, phospholipids) and the apoB48 is performed by the MTP (Microsomal Tranfer Protein). Chylomicrons are secreted into the lymphatic circulation before entering the bloodstream. In plasma, triglycerides of chylomicrons are hydrolyzed by the lipoprotein lipase leading to the formation of smaller, triglyceride-poorer particles known as chylomicron-remnants. Chylomicron-remnants are

Lipid Disorders in Type 1 Diabetes 47

both triglyceride lipase and phospholipase activities, is involved in this metabolic process

LDL is the final product of the VLDL-IDL-LDL cascade. LDL is the main cholesterol-bearing lipoprotein in plasma. Each LDL particle contains one molecule of apoB100, which plays an important role in LDL metabolism, particularly recognition of its dedicated LDL B/E receptor. Clearance of LDL is mediated by the LDL B/E receptor. Seventy percent of LDL

HDL particles are secreted by the hepatocytes as small lipid-poor lipoproteins, containing mostly apoA-I, which receive, in the circulation, phospholipids, apoCs and apoE from chylomicrons and VLDLs. Nascent or lipid-poor HDLs get from peripheral cells free cholesterol and phospholipids through ABCA1 transporter (ATP Binding Cassette A1 transporter), allowing the transport of free cholesterol and phospholipids from the cell cytoplasm into the HDL particles (Oram & Lawn, 2001). Within HDL particles, free cholesterol is esterified by LCAT (Lecithin Cholesterol AcylTransferase) leading to the formation of HDL3 particles. The fusion of 2 HDL3 particles, which is promoted by PLTP (PhosphoLipid Transfer Protein), leads to the formation of one larger size HDL2 particle. HDL2 lipoproteins, rich in cholesterol ester, are degraded by the hepatic lipase and the endothelial lipase, leading to the formation of HDL remnant particles that are cleared by the liver after

B/E receptors are located on hepatic cells and 30% on the other cells of the body.

recognition by SR-B1 receptor (Scavenger Receptor class B type 1) (Jian et al., 1998).

Lipoprotein metabolism is largely influenced by lipid transfer proteins. Among these, two play an important role: CETP (Cholesteryl Ester Transfer Protein) and PLTP (PhosphoLipid Transfer Protein). CETP facilitates the transfer of triglycerides from triglyceride-rich lipoproteins (mainly VLDLs) toward HDLs and LDLs and the reciprocal transfer of cholesteryl esters from HDLs and LDLs toward VLDLs (Lagrost, 1994). PLTP facilitates the transfer of phospholipids and -tocopherol between lipoproteins. PLTP is also involved in the formation of HDL2 lipoproteins from HDL3 particles (Lagrost et al., 1998). Any modification of CETP or PLTP activities is likely to promote significant qualitative

Insulin plays a central role in the regulation of lipid metabolism (Vergès, 2001). The main

In adipose tissue, insulin inhibits the hormone-sensitive lipase. Thus, insulin has an antilipolytic action, promoting storage of triglycerides in the adipocytes and reducing release of

Insulin inhibits VLDL production from the liver. In normal subjects, it has been shown that insulin induces a 67% decrease of VLDL-triglyceride production and a 52% decrease of VLDL-apoB production (Lewis et al., 1993; Malmström et al., 1998). Insulin reduces VLDL production by diminishing circulating free fatty acids (due to its antilipolytic effect), which

sites of action of insulin on lipoprotein metabolism are shown in Figure 2.

generating LDL particles from IDLs.

**2.3 LDLs** 

**2.4 HDLs** 

**2.5 Lipid transfer proteins** 

abnormalities of lipoproteins.

**3. Insulin and lipoprotein metabolism** 

free fatty acids from adipose tissue in the circulation.

cleared by the liver through LDL B/E receptor or LRP receptor (LDL-receptor related protein).

*VLDL*: Very Low Density Lipoprotein; *IDL*: Intermediate Density Lipoprotein, *LDL*: Low Density Lipoprotein; *HDL*: High Density Lipoprotein; *LPL*: LipoProtein Lipase; *HL*: Hepatic Lipase; *CETP*: Cholesteryl Ester Transfer Protein; *LCAT*: Lecithin-Cholesterol Acyl Transferase; *FFA*: Free Fatty Acids ; *B/E rec*.: B/E receptor (LDL receptor); *TG*: Triglycerides; *CE*: Cholesterol Esters; *ABCA1*: ATP Binding Cassette A1 transporter.

Fig. 1. Human lipoprotein metabolism.

#### **2.2 VLDLs and IDLs**

VLDL particles, which are secreted by the liver, consist of endogenous triglycerides (55% to 65%), cholesterol, phospholipids and apolipoproteins (apoB100 as well as apoCs and apoE). In the hepatocyte, the formation of VLDL occurs in two major steps. In the first step, which takes place in the rough endoplasmic reticulum, apoB is co-translationally and posttranslationally lipidated by the MTP (Microsomal Tranfer Protein). MTP transfers lipids (mainly triglycerides but also cholesterol esters and phospholipids) to apoB. This first step leads to the formation of pre-VLDL (Olofsson et al., 2000). In the second step, pre-VLDL is converted to VLDL in the smooth membrane compartment. This step is driven by ADP ribosylation factor-1 (ARF-1) and its activation of phospholipase D, needed for the formation of VLDL from pre-VLDL (Olofsson , 2000).

In plasma, triglycerides of VLDLs are hydrolyzed by the lipoprotein lipase. As VLDLs become progressively depleted in triglycerides, a portion of the surface including phospholipids and apolipoproteins C and E is transferred to HDLs. This metabolic cascade leads to the formation of IDL particles, which are either cleared by the liver through LDL B/E receptor or further metabolized to form LDLs. The enzyme, hepatic lipase, which has both triglyceride lipase and phospholipase activities, is involved in this metabolic process generating LDL particles from IDLs.

### **2.3 LDLs**

46 Type 1 Diabetes – Complications, Pathogenesis, and Alternative Treatments

cleared by the liver through LDL B/E receptor or LRP receptor (LDL-receptor related

**VLDL LDL**

**IDL**

**CE TG**

**LPL**

**HDL HDL3 <sup>2</sup>**

**CETP**

**CHU**

**Dijon**

**liver**

*B/E rec.*

**Cell Periph.**

*B/E rec.*

protein).

**adipose tissue**

Cassette A1 transporter.

**2.2 VLDLs and IDLs** 

**Lipase**

Fig. 1. Human lipoprotein metabolism.

formation of VLDL from pre-VLDL (Olofsson , 2000).

**Remnants Chylomicron-**

**LIVER**

*LRP*

**Chylomicrons**

**LPL**

**HL**

**LCAT FFA**

**HDLn**

*VLDL*: Very Low Density Lipoprotein; *IDL*: Intermediate Density Lipoprotein, *LDL*: Low Density Lipoprotein; *HDL*: High Density Lipoprotein; *LPL*: LipoProtein Lipase; *HL*: Hepatic Lipase; *CETP*: Cholesteryl Ester Transfer Protein; *LCAT*: Lecithin-Cholesterol Acyl Transferase; *FFA*: Free Fatty Acids ; *B/E rec*.: B/E receptor (LDL receptor); *TG*: Triglycerides; *CE*: Cholesterol Esters; *ABCA1*: ATP Binding

VLDL particles, which are secreted by the liver, consist of endogenous triglycerides (55% to 65%), cholesterol, phospholipids and apolipoproteins (apoB100 as well as apoCs and apoE). In the hepatocyte, the formation of VLDL occurs in two major steps. In the first step, which takes place in the rough endoplasmic reticulum, apoB is co-translationally and posttranslationally lipidated by the MTP (Microsomal Tranfer Protein). MTP transfers lipids (mainly triglycerides but also cholesterol esters and phospholipids) to apoB. This first step leads to the formation of pre-VLDL (Olofsson et al., 2000). In the second step, pre-VLDL is converted to VLDL in the smooth membrane compartment. This step is driven by ADP ribosylation factor-1 (ARF-1) and its activation of phospholipase D, needed for the

In plasma, triglycerides of VLDLs are hydrolyzed by the lipoprotein lipase. As VLDLs become progressively depleted in triglycerides, a portion of the surface including phospholipids and apolipoproteins C and E is transferred to HDLs. This metabolic cascade leads to the formation of IDL particles, which are either cleared by the liver through LDL B/E receptor or further metabolized to form LDLs. The enzyme, hepatic lipase, which has LDL is the final product of the VLDL-IDL-LDL cascade. LDL is the main cholesterol-bearing lipoprotein in plasma. Each LDL particle contains one molecule of apoB100, which plays an important role in LDL metabolism, particularly recognition of its dedicated LDL B/E receptor. Clearance of LDL is mediated by the LDL B/E receptor. Seventy percent of LDL B/E receptors are located on hepatic cells and 30% on the other cells of the body.

#### **2.4 HDLs**

HDL particles are secreted by the hepatocytes as small lipid-poor lipoproteins, containing mostly apoA-I, which receive, in the circulation, phospholipids, apoCs and apoE from chylomicrons and VLDLs. Nascent or lipid-poor HDLs get from peripheral cells free cholesterol and phospholipids through ABCA1 transporter (ATP Binding Cassette A1 transporter), allowing the transport of free cholesterol and phospholipids from the cell cytoplasm into the HDL particles (Oram & Lawn, 2001). Within HDL particles, free cholesterol is esterified by LCAT (Lecithin Cholesterol AcylTransferase) leading to the formation of HDL3 particles. The fusion of 2 HDL3 particles, which is promoted by PLTP (PhosphoLipid Transfer Protein), leads to the formation of one larger size HDL2 particle. HDL2 lipoproteins, rich in cholesterol ester, are degraded by the hepatic lipase and the endothelial lipase, leading to the formation of HDL remnant particles that are cleared by the liver after recognition by SR-B1 receptor (Scavenger Receptor class B type 1) (Jian et al., 1998).

#### **2.5 Lipid transfer proteins**

Lipoprotein metabolism is largely influenced by lipid transfer proteins. Among these, two play an important role: CETP (Cholesteryl Ester Transfer Protein) and PLTP (PhosphoLipid Transfer Protein). CETP facilitates the transfer of triglycerides from triglyceride-rich lipoproteins (mainly VLDLs) toward HDLs and LDLs and the reciprocal transfer of cholesteryl esters from HDLs and LDLs toward VLDLs (Lagrost, 1994). PLTP facilitates the transfer of phospholipids and -tocopherol between lipoproteins. PLTP is also involved in the formation of HDL2 lipoproteins from HDL3 particles (Lagrost et al., 1998). Any modification of CETP or PLTP activities is likely to promote significant qualitative abnormalities of lipoproteins.
