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Hypertriglyceridemia in Type I Diabetes Mellitus
A. Deficiency in apoprotein C-II
B. Increased hepatic triglyceride synthesis
C. Decreased lipoprotein lipase activity
D. Deficiency in LDL receptors
E. Absence of hormone-sensitive lipase.
The correct answer is-C- Decreased Lipoprotein lipase activity.
Circulating lipoproteins are just as dependent on insulin as is the plasma glucose, it is because, the lipoprotein lipase that catalyzes the degradation of circulating lipoproteins is activated by insulin.
Lipoprotein lipase is located on the walls of blood capillaries, anchored to the endothelium by negatively charged proteoglycan chains of Heparan sulfate. It has been found in heart, adipose tissue, spleen, lung, renal medulla, aorta, diaphragm, and lactating mammary gland, although it is not active in adult liver.
Figure-1- Action of lipoprotein lipase (LpL).
It is not normally found in blood; however, following injection of heparin, lipoprotein lipase is released from its heparan sulfate binding into the circulation. Due to this reason ‘heparin’ is called a “clearing factor”, as it causes release of lipoprotein lipase that promotes utilization and clearance of lipoproteins from the plasma.
Activators and inhibitors of lipoprotein lipase
Both phospholipids and apo C-II are required as cofactors for lipoprotein lipase activity (figure-1), while apo A-II and apo C-III act as inhibitors. Hydrolysis takes place while the lipoproteins are attached to the enzyme on the endothelium.
Hypertriglyceridemia in Type 1 Diabetes Mellitus
Dyslipidemia is a common metabolic abnormality in uncontrolled diabetes mellitus. Dyslipidemia includes; hypercholesterolemia, hypertriglyceridemia, raised LDLc and LDLc, but low levels of HDLc.
Biochemical basis of dyslipidemia in uncontrolled DM
One major role of insulin is to stimulate the storage of food energy following the consumption of a meal.This energy storage is in the form of glycogen in hepatocytes and skeletal muscle. Additionally, insulin stimulates synthesis of triglycerides in hepatocytes and promotes their storage in adipose tissue. In opposition to increased adipocyte storage of triglycerides is insulin-mediated inhibition of lipolysis (insulin inhibits adipolysis because the enzyme hormone- sensitive lipase, that catalyzes adipolysis is stimulated by Glucagon and inhibited by Insulin).
Lipolysis and its implications in Type 1 DM
In uncontrolled IDDM since the lipolysis is promoted, thus there is a rapid mobilization of triglycerides leading to increased levels of plasma free fatty acids. The free fatty acids are taken up by numerous tissues (however, not the brain) and metabolized to provide energy. Free fatty acids are also taken up by the liver.
Increased fatty acid oxidation
Normally, the levels of malonyl-CoA are high in the presence of insulin. These high levels of malonyl-CoA inhibits carnitine acyl Transferase I, the enzyme required for the transport of fatty acyl-CoA’s into the mitochondria where they are subject to oxidation for energy production. Thus, in the absence of insulin, malonyl-CoA levels fall and transport of fatty acyl-CoA’s into the mitochondria increases. Mitochondrial oxidation of fatty acids generates acetyl-CoA which can be further oxidized in the TCA cycle.
Suppressed TCA cycle and its implications
In hepatocytes the majority of the acetyl-CoA is not oxidized by the TCA cycle but is metabolized into the ketone bodies, Acetoacetate and β-hydroxybutyrate.These ketone bodies leave the liver and are used for energy production by the brain, heart and skeletal muscle. In IDDM, the increased availability of free fatty acids and ketone bodies exacerbates the reduced utilization of glucose furthering the ensuing hyperglycemia. Production of ketone bodies, in excess of the body’s ability to utilize them leads to ketoacidosis. In diabetics, this can be easily diagnosed by smelling the breath. A spontaneous breakdown product of acetoacetate is acetone which is volatilized by the lungs producing a distinctive odor.
The unutilized Acetyl Co A, due to suppressed TCA cycle, is also channeled towards the pathway of cholesterol biosynthesis resulting in hypercholesterolemia.
Basis of hypertriglyceridemia
Normally, plasma triglycerides are acted upon by lipoprotein lipase (LPL). In particular, LPL activity allows released fatty acids to be taken from circulating triglycerides for storage in adipocytes. The activity of LPL requires insulin and in its absence a hypertriglyceridemia results (figure-2).
In type 1 diabetes, moderately deficient control of hyperglycemia is associated with only a slight elevation of LDL cholesterol and serum triglycerides and little if any change in HDL cholesterol. Once the hyperglycemia is corrected, lipoprotein levels are generally normal. However, in obese patients with type 2 diabetes, a distinct “diabetic dyslipidemia” is characteristic of the insulin resistance syndrome. Its features are a high serum triglyceride level (300–400 mg/dL), a low HDL cholesterol (less than 30 mg/dL), and a qualitative change in LDL particles, producing a smaller dense particle whose membrane carries supranormal amounts of free cholesterol. These smaller dense LDL particles are more susceptible to oxidation, which renders them more atherogenic. Since low HDL cholesterol is a major feature predisposing to macro vascular disease, the term “dyslipidemia” has preempted the term “hyperlipidemia,” which mainly denoted the elevated triglycerides. Measures designed to correct the obesity and hyperglycemia, such as exercise, diet, and hypoglycemic therapy, are the treatment of choice for diabetic dyslipidemia, and in occasional patients in whom normal weight was achieved, all features of the lipoprotein abnormalities cleared.
As regards other options
Deficiency in apoprotein C-II
Apo CII is an activator of lipoprotein lipase, but its concentration is not decreased in diabetes mellitus.
Increased hepatic triglyceride synthesis
The Acetyl Co A carboxylase, the key regulatory enzyme of fatty acid biosynthetic pathway, is activated by insulin, thus, de novo fatty acid synthesis is decreased in insulin deficiency. However, the fatty acids mobilized from adipose tissue are used for esterification to form triglycerides which are transported from liver as VLDL. The excess flux of fatty acids that cannot be transported out as VLDL results in fatty liver. The hypertriglyceridemia in uncontrolled DM can be because of excess hepatic triglyceride synthesis, but mainly it is due to non degradation of circulating chylomicrons (carriers of dietary lipids) and VLDL (carriers of endogenous triglycerides) by the inactive lipoprotein lipase (figure-2).
Deficiency in LDL receptors
LDL receptors internalize LDL, their deficiency cannot cause hypertriglyceridemia, and otherwise also, they are not deficient in diabetes mellitus.
Absence of hormone-sensitive lipase
Hormone- sensitive lipase catalyzes the breakdown of triglycerides in adipose cells. It is activated by glucagon and catecholamines; inhibited by insulin. It is not absent; instead it is overactive in uncontrolled type 1 diabetes mellitus.
Figure-2- Diabetic dyslipidemia. In normal health, VLDL released from liver, carrying endogenous triglycerides and Chylomicrons released from intestinal cells carrying dietary lipids, are acted upon by lipoprotein lipase (LPL), and the resultant fatty acids are taken up by peripheral cells, whereas the lipoprotein remnants are taken up by liver. VLDL is converted to LDL, through intermediate formation of IDL (intermediate density lipoprotein). In diabetes mellitus, in the absence of active LPL, the lipoprotein metabolism is disturbed resulting in hypertriglyceridemia, hypercholesterolemia, small dense LDL, low HDL and a fatty liver.
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