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Some of the most striking elevations in triglyceride seen in clinical medicine occur in patients with diabetes mellitus. Mild to moderate elevations in triglycerides are also more frequent in the diabetic population. Most diabetics have plasma lipoprotein concentrations that are well within the normal range. Subtle abnormalities in lipoprotein metabolism and composition, however, have been observed in patients with normal levels of cholesterol and triglyceride, and these abnormalities may contribute to the higher incidence of coronary heart disease, peripheral vascular disease, and cerebrovascular disease seen in diabetes. The frequency and severity of lipoprotein disorders vary with the cause of the diabetes, i.e., IDDM versus NIDDM. In addition, a series of common genetic variations in lipoprotein metabolism are superimposed on the metabolic pertubations of diabetes.
Insulin-Dependent Diabetes Mellitus (IDDM)
A) Triglyceride- Rich Lipoproteins (Chylomicrons and very-low-Density Lipoprotein)
Elevated plasma triglycerides are frequently observed in the newly diagnosed or untreated patient with insulin deficiency, ketosis and hyperglycemia. This may be due to higher rates of production of triglyceride-rich, very-low- density lipoprotein (VLDL) by the liver and to decreased removal of triglycerides by peripheral tissues-primarily adipose tissue and muscle. Maintenance of stored fat in adipose tissue depends on the suppression of the hormone- sensitive lipase by insulin. The high blood glucose and free fatty acid levels that result from insulin deficiency provide a superabundance of substrate for synthesis of triglyceride in the liver with its subsequent packaging into VLDL for secretion into the plasma. The outpouring of hepatic VLDL for plasma may prevent fatty liver, but if plasma levels are to remain within bounds, peripheral tissues must be able to clear the triglycerides.
When insulin is severely deficient, the VLDL production rates decline, but the hypertriglyceridemia may be maintained by the failing clearance mechanisms. Lipoprotein lipase the major enzyme in removing plasma lipoprotein triglyceride, has been found significantly reduced in IDDM before adequate insulin treatment. Furthermore, the structural composition of the VLDL itself may change with increases in protein components such as apolipoprotein CIII, which inhibits the lipase enzymes and the uptake of VLDL remnants by the liver. Triglyceride levels ranging up to 10, 000 mg/dl or even higher may be observed in IDDM patients. Such values fall rapidly after insulin therapy.
B) Cholesterol Rich Lipoproteins (LDL and HDL)
In untreated or poorly controlled IDDM patients, however, the plasma concentrations of LDL may be increased, and HDL may be reduced. The structure and composition of these lipoproteins have also been found to be abnormal when insulin treatment is inadequate. LDL production rates are reported to be elevated in IDDM but return to normal after insulin. This may reflect the increased synthesis to precursor VLDL or the impaired removal of VLDL remnants, which are often measured as a component of LDL. The increased presence of VLDL remnants could also explain the observed increase in the cholesterol- to-apolipoprotein B (apo B) ratio in IDDM. Impaired receptor- mediated clearance of LDL has also been postulated because of glycosylation of the apo B or deficient cell surface binding. HDL cholesterol concentrations have been reported to be low in several groups of insulin-deficient diabetics. The major reduction is found in the larger, less dense HDL2 fraction. The HDL3 concentrations are often no different from normal but may be smaller and enriched in triglyceride.
Lower HDL may be due to reduced lipoprotein lipase activity, which is responsible for the transfer of apolipoprotems and phospholipids to HDL during lipolysis of VLDL and chylomicrons. HDL normally loses cholesterol ester of VLDL and chylomicrons in exchange for triglyceride through the action of the cholesterol ester transfer protein. This process appears to be increased in IDDM, particularly when the triglyceride-rich lipoprotein are increased. Finally, the triglyceride added to HDL can be hydrolyzed by the hepatic triglyceride lipase (HTGL), which lines the sinusoids of the liver and which, similar to lipoprotein lipase, is released by heparin. HTGL is increased in diabetes and is inversely correlated with HDL concentrations. Increased urinary loss of HLD has been demonstrated in patients with IDDM and with albuminuria.
C) Lipoprotein (a)
In IDDM patients with poor metabolic control and particularly in those with proteinuria, higher levels of lipoprotein (a) have been found.
7. Lipid and lipoprotein abnormalities in IDDM
| VLDL(VLDL1, VLDL2 & VLDL3 LDL (including small dense LDL) |
Increased Marginally reaised |
|
HDL
Triglyceride
Cholesterol
|
Low or normal depending on glycemic status and insulin therapy
Increased
Esterified cholesterol is diminished
|
8. Lipid and lipoprotein abnormalities in NIDDM
|
VLDL
IDL and remnant particles
LDL (also small dense LDL)
HDL
Triglycerides
Cholesterol
|
More of larger VLDL consequent to poor clearance-more of circulating ApoB100.
Increased
More of unesterified cholesterol prolonged half-life, higher quantities of circulating small dense LDL
Normal/raised but may be low in obese patients with hypercholesterolemia
Increased
May be increased or normal free cholesterol lecithin ratio increased in Lipoproteins.
|
9. Drugs for lipid and lipoprotein disorders in diabetes
| Chylomicronaemia Syndrome (Chylomicrons VLDL) |
Bezafibrate, Gemfibrozil, Acipimox, Nicotinic acid, Maxepa |
| Endogenous Hypertriglyceridaemia (VLDL) |
Bezafibrate, Gemfibrozil, Acipimox, Nicotinic acid, Maxepa |
| Combined Hyperlipidaemia (VLDL LDL) |
Bezafibrate, Gemfibrozil, Acipimox |
| Dysbetalipoproteinaemia(remnant particles) |
Bezafibrate, Gemfibrozil, Nicotinic acid |
| Hypercholesterolaemia(LDL) |
Exchange resins, Bezafibrate, Gemfibrozil, Acipimox, Nicotinic acid, Probucol, Guar fibre, Lovastatin. |
Treatment of dyslipidemia
Reassess - Satisfactory - Measure fasting chol.
Annually TG, HDL, CHOL.
Unsatisfactory
Assess and treat other CHD risk factors
assess and treat other causes of secondary
hypertriglyceridemia
3 months.
Reassess Satisfactory Reassess plasma lipids glucose
annually lipids control dietary compliance.
Unsatisfactory with optimum glucose control
and best dietary compliance.
Screen Family Treat as primary
hyperlipidemia
Lipid lowering diet
3 months poor.
Satisfactory Reassess plasma lipids dietary
Lipids compliance.
Reassess Unsatisfactory on
best dietary compliance
Add lipid lowering agents.
Non-Insulin-Dependent Diabetes MelHtus (NIDDM)
Many patients with NIDDM have excessive plasma insulin levels both in the postprandial and in the fasting state. In others, insulin levels may be near normal or even suppressed. Failure or tissues to respond to insulin leads to increased mobilization of free fatty acids (FFA), and higher glucose itself may potentiate the release to FFA from adipose tissue. Most patients with NIDDM have adequate insulin to maintain basic hepatic functions, such as protein synthesis. In this context, the synthesis of triglycerides and VLDL continues in response to the FFA, glucose, and aminoacid substrates.
A) Hypertriglyceridemia in Non-Insulin-Dependent Diabetes Mellitus
The mean level of triglycerides in NIDDM subjects drawn from large population usually exceeds that found in control populations by 25% to 100% and in most studies, the majority of diabetics have triglycerides below 250 mg/dl, when triglycerides exceed 400 mg/dl, it is highly probable that a genetic disorder of lipoprotein metabolism is contributing to the elevation in plasma triglycerides. When triglycerides are elevated above 200 mg/dl, higher production rates of triglycerides and VLDL particles have been the most commonly identified metabolic abnormalities. Many hypertriglyceridemic NIDDM patients also appear to have a defect in the clearance of triglyceride-rich lipoproteins. VLDL apo B elevations usually accompany hypertriglyceridemia, and decreased removal rates as well as increased synthesis of VLDL apo B have been described in NIDDM patients.
i) Although reduced clearance of VLDL triglycerides has been found frequently in patients with mild to moderate hypertriglyceridemia, the reason for this abnormality is not clear.
ii) In patients with higher triglycerides levels (500mg/dl) defects in clearance appear to
play a large role. Under these conditions, not only are VLDL elevated, but chylomicrons are found in a fasting plasma. Chylomicron remnant clearance has been reported to be defective in diabetics with mild to moderate hypertiglyceridemia, but when the triglycerides exceed lOOOmg/dl significant numbers of large chylomicrons are usually present in plasma. In these severe cases, competition for common clearance pathways by the very large amounts of VLDL as well as reduced capacity of the lipoprotein lipase can be coexistent problems.
B) Non-insulin-Dependent Diabetes Mellitus and Low-Density Lipoproteins
The plasma concentrations of LDL apo B are usually found to be within normal limits in NIDDM patients. In those with moderate to severe hypertriglyceridemia, LDL levels are often in the lower range of normal. This may reflect the balance of two physiologic abnormalities because fewer of the large VLDL are actually converted to LDL, but those LDL that are generated may be cleared more slowly. A variety of abnormalities in LDL composition have been described in diabetics. An increase in the proportion of triglyceride in LDL has been frequently observed. Others have found differing population of LDL within same individual. So LDL vary in size as well as its protein and lipid composition (Polydisperse LDL). When plasma glucose levels are high, aonormal LDL may also be generated by the glycosylation of the lysine residues on apo B in LDL. This chemical addition of glucose to the protein can be sufficient to inhibit the normal metabolism of LDL by the LDL receptor.
C) Non-Insulin-Dependent Diabetes Mellitus and High-Density Lipoproteins (HDL)
HDL cholesterol levels are frequently found to be reduced in patients with NIDDM. When HDL cholesterol is reduced, it usually reflects marked and preferential decrease in HDL2. In contrast to the cholesterol, the triglyceride component of HDL has often been found to be increased. The higher triglyceride levels in plasma often induce exchange of cholesterol ester and HDL for the triglyceride in VLDL through the action of cholesterol ester transfer protein. The addition of triglyceride to HDL provides a substrate, which is removed by HTGL, an enzyme known to be increased in diabetes mellitus. The reduced cholesterol ester in HDL has been found to correlate with the higher triglyceride content in some but nor all patients with NIDDM.
D) Lipoprotein (a) in NIDDM
Lipoprotein (a) concentrations have been elevated in groups of NIDDM patients compared with controls, but in other studies no differences have been found. In contrast with IDDM, there appears to be no association between lipoprotein (a) levels and glycemic control in NIDDM.
REFERENCES
1. D.J.Better!dge, Diabetes, Lipoprotein metabolism and Atherosclerosis: British Medical
Bulletin (1989) Vol.45, No.l Page 283-31.
2. W. Virgil Brown, M.D. Lipoprotein disorder in Diabetes Mellitus, Medical clinics of
North America Vol.78, No.l page 143, Jan 1994
3. John A, Farmer, Antonio M. Gotto. Jr. Dyshpidemia and other risk factors for coronary
artery disease heart disease. Braunwald Vol.2 Chapter 35, 5th edition.
4. EN- Durrington, Lipids and Lipoprotein Disorders, OTM Vol. 2 Edition Illrd Page 349.
5. Sidhartha, Das. Lipid Profiles - Standards and Interpretations. Novo Nordisk Diabetes
update 1995 Proceedings Feb 17-19,1995.
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