Enzymes Involved In The Lipoprotein Metabolism Biology Essay

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Three apolipoproteins of the C-series also participate in the metabolism of triglyceride-rich lipoproteins. They are present in all the lipoproteins and are synthesized in the liver. The exact function of apoC-I is not known but over expression of apoC-I in transgenic mice inhibits uptake of chylomicrons and VLDL remnants by liver. ApoC-II is an essential activator of enzyme lipoprotein lipase (LPL), which hydrolyses triglycerides in chylomicrons and VLDL. Individuals lacking apoC-II show severe hypertriglyceridemia. ApoC-III inhibits LPL and it's over expression in the transgenic mice causes' severe hypertriglyceridemia.50,56

Apolipoprotein (a), a large glycoprotein that shares high degree of sequence homology with plasma zymogen plasminogen, is made by liver and is secreted into plasma where it forms covalent linkage with apoB-100 of LDL to form lipoprotein (a). The physiological role of lipoprotein (a) is not known but elevated levels are associated with increased risk of atherosclerosis.50


Lipoprotein Lipase (LPL), a glycoprotein is synthesized in fat and muscle cells. It is secreted in the interstitial space and transported across the endothelial cells and bind to their luminal surface in the capillary beds. On the luminal surface, LPL mediates hydrolysis of triglycerides of chylomicrons and VLDL to generate free fatty acids.55

Dietary fat stimulates adipose tissue LPL and inhibits muscle LPL where as fasting seems to do the opposite. Insulin stimulates the synthesis and secretion of LPL. Reduced level or activity of insulin in diabetes mellitus may lead to impaired triglyceride clearance.55

Hepatic triglyceride lipase (HTGL) is synthesized in liver and binds to endothelial cells in hepatic sinusoids. HTGL plays a role in removing triglycerides from partially catabolised VLDL or IDL and therefore plays a role in conversion of VLDL to LDL. It may also play a role in metabolism of chylomicron remnants. It plays a role in HDL metabolism. Genetic deficiency of HTGL produces hypertriglyceridemia with however normal HDL level.52

LCAT, lecithin cholesterol acyl transferase, is synthesized in liver and mediates transfer of linoleate from lecithin to free cholesterol in plasma resulting in formation of cholesteryl ester.51

Cholesteryl ester transfer protein (CEPT) is synthesized in liver and is circulated in plasma with HDL. CEPT mediates exchange of cholesteryl ester from chylomicrons or VLDL, leading to small dense LDL.56



The exogenous pathway of lipoprotein metabolism permits efficient transport of dietary lipids. Dietary triglycerides are hydrolyzed by pancreatic lipases within the intestinal lumen and are emulsified with bile acids to form micelles. Dietary cholesterol and retinol are esterified (by the addition of a fatty acid) in the enterocyte to form cholesteryl esters and retinyl esters, respectively. 47

Longer-chain fatty acids (_12 carbons) are incorporated into triglycerides and packaged with apoB-48, cholesteryl esters, retinyl esters, phospholipids, and cholesterol to form chylomicrons. Nascent chylomicrons are secreted into the intestinal lymph and delivered directly to the systemic circulation, where they are extensively processed by peripheral tissues before reaching the liver.50

The particles encounter lipoprotein lipase (LPL), which is anchored to proteoglycans that decorate the capillary endothelial surfaces of adipose tissue, heart, and skeletal muscle. The triglycerides of chylomicrons are hydrolyzed by LPL, and free fatty acids are released; apoC-II, which is transferred to circulating chylomicrons, acts as a cofactor for LPL in this reaction.55

The released free fatty acids are taken up by adjacent myocytes or adipocytes and either oxidized or reesterified and stored as triglyceride. Some free fatty acids bind albumin and are transported to other tissues, especially the liver.53 The chylomicron particle progressively shrinks in size as the hydrophobic core is hydrolyzed and the hydrophilic lipids (cholesterol and phospholipids) on the particle surface are transferred to HDL. The resultant smaller, more cholesterol ester - rich particles are referred to as chylomicron remnants. The remnant particles are rapidly removed from the circulation by the liver in a process that requires apoE. Consequently, few, if any, chylomicrons are present in the blood after a 12 hour fast, except in individuals with disorders of chylomicron metabolism.54



The endogenous pathway of lipoprotein metabolism refers to the hepatic secretion and metabolism of VLDL to IDL and LDL. VLDL particles resemble chylomicrons in protein composition but contain apoB-100 rather than apoB-48 and have a higher ratio of cholesterol to triglyceride.56

The triglycerides of VLDL are derived predominantly from the esterification of long chain fatty acids. The packaging of hepatic triglycerides with the other major components of the nascent VLDL particle (apoB-100, cholesteryl esters, phospholipids, and vitamin E) requires the action of the enzyme microsomal transfer protein (MTP). After secretion into the plasma, VLDL acquires multiple copies of apoE and apolipoproteins of the C series. The triglycerides of VLDL are hydrolyzed by LPL, especially in muscle and adipose tissue. As VLDL remnants undergo further hydrolysis, they continue to shrink in size and become IDL, which contain similar amounts of cholesterol and triglyceride.48

The liver removes 40 to 60% of VLDL remnants and IDL by LDL receptor-mediated endocytosis via binding to apoE. The remainder of IDL is remodelled by hepatic lipase (HL) to form LDL; during this process, most of the triglyceride in the particle is hydrolyzed and all apolipoproteins except apoB-100 are transferred to other lipoproteins.49

The cholesterol in LDL accounts for 70% of the plasma cholesterol in most individuals. Approximately 70% of circulating LDLs are cleared by LDL receptor-mediated endocytosis in the liver. Lipoprotein (a) [Lp (a)] is a lipoprotein similar to LDL in lipid and protein composition, but it contains an additional protein called apolipoprotein (a) [apo(a)]. Apo(a) is synthesized in the liver and is attached to apoB-100 by a disulfide linkage. The mechanism by which Lp (a) is removed from the circulation is not known.56


All nucleated cells synthesize cholesterol but only hepatocytes can efficiently metabolize and excrete cholesterol from the body. The predominant route of cholesterol elimination is by excretion into the bile, either directly or after conversion to bile acids.56

Cholesterol in peripheral cells is transported from the plasma membranes of peripheral cells to the liver by an HDL-mediated process termed reverse cholesterol transport. Nascent HDL particles are synthesized by the intestine and the liver. The newly formed discoidal HDL particles contain apoA-I and phospholipids (mainly lecithin) but rapidly acquire unesterified cholesterol and additional phospholipids from peripheral tissues via transport by the membrane protein ATP-binding cassette protein A1 (ABCA1).50

Once incorporated in the HDL particle, cholesterol is esterified by lecithin cholesterol acyl transferase (LCAT), a plasma enzyme associated with HDL. As HDL acquires more cholesteryl ester it becomes spherical, and additional apolipoproteins and lipids are transferred to the particles from the surfaces of chylomicrons and VLDL during lipolysis. HDL cholesterol is transported to hepatocytes by both an indirect and a direct pathway. HDL cholesteryl esters are transferred to apoB-containing lipoproteins in exchange for triglyceride by the cholesteryl ester transfer protein (CETP). The cholesteryl esters are then removed from the circulation by LDL receptor-mediated endocytosis. HDL cholesterol can also be taken up directly by hepatocytes via the scavenger receptor class BI (SR-BI), a cell-surface receptor that mediates the selective transfer of lipids to cells.56

HDL particles undergo extensive remodelling within the plasma compartment as they transfer lipids and proteins to lipoproteins and cells. For example, after CETP-mediated lipid exchange, the triglyceride enriched HDL becomes a substrate for HL, which hydrolyzes the triglycerides and phospholipids to generate smaller HDL particles.50


Lipid abnormalities in type 2 diabetes are characterised by high triglyceride concentrations, low high density lipoprotein-cholesterol concentrations, normal total and low density lipoprotein-cholesterol (LDL-c) concentrations.23, 1, 33 LDL particles, however, are small and dense. The lipid changes associated with diabetes mellitus are attributed to increased free fatty acid flux secondary to insulin resistance.23


In both the fasting and post-prandial states, reduced action of insulin on adipocytes causes reduced suppression of lipolysis, that is, reduced suppression of hydrolysis of stored triglyceride, and so greater release of non-esterified fatty acids (NEFA).34 The resulting increased NEFA delivery to the liver increases hepatic triglyceride production which in turn serves to drive hepatic VLDL production. Reduced action of insulin on abdominal visceral adipocytes may be particularly relevant, since NEFA from abdominal visceral adipocytes are released into the portal circulation and so pass directly to the liver.1

In both the fasting and post-prandial states, reduced action of insulin on hepatocytes results in reduced suppression of VLDL production. VLDL is the major triglyceride-carrying lipoprotein particle in the fasting state, and the production of VLDL, particularly the largest, most triglyceride-rich VLDL particle (termed VLDL1), is suppressed by insulin.35 In the post-prandial state, VLDL production is normally suppressed by high circulating insulin concentrations. However, reduced action of insulin at the hepatocyte level results in failure to suppress VLDL production and therefore increases post-prandial lipidaemia, reduced action of insulin on the lipolytic enzyme lipoprotein lipase results in reduced clearance of the triglyceride-rich lipoproteins, VLDL and chylomicron.24


Apolipoprotein A1 and phospholipid shed from the surface of VLDL as lipoprotein lipase hydrolyses VLDL core triglyceride can associate to form nascent HDL particles. This pathway of HDL production is therefore decreased in the insulin resistant state due to decreased lipoprotein lipase activity. In insulin resistance, the esterification of cholesterol (mediated by lecithin-cholesterol acyl transferase) is either modestly increased or unaltered, whereas CETP activity is increased. CETP depletes HDL of its cholesteryl ester and its increased activity contributes to the lowering of HDL cholesterol levels.35

Cholesterol ester transfer protein (CETP) redistributes triglyceride and esterified cholesterol between different lipoprotein species, and between different particles within individual lipoprotein species, by exchanging triglyceride for esterified cholesterol.36 Triglyceride levels (substrate) are a major determinant of CETP activity. Therefore, in the presence of increased triglyceride-rich lipoproteins, CETP activity is increased so that all circulating lipoproteins become enriched in triglyceride, in particular HDL and LDL particles. VLDL and chylomicron remnant particles, although still triglyceride rich, become relatively enriched in esterified cholesterol, and possibly more atherogenic.25


LDL particles that are triglyceride enriched due to the hypertriglyceridemia and increased CETP activity; they are converted by the triglyceride lipase activity of hepatic lipase into smaller and denser particles. Whereas large buoyant LDL is cleared rapidly by the LDL receptor pathway, small dense LDL is removed more slowly. Small dense LDL particles are more easily modified by oxidation and, particularly in type 2 diabetes, by glycation, and are more atherogenic.36

Postprandial lipemia- patients with type 2 diabetes have a slower clearance of chylomicrons from the blood after dietary intake. This increased postprandial lipemia is especially marked in women. The failure to suppress FFA in the postprandial period, due to the decreased activity of lipoprotein lipase (LPL), the rise in plasma FFA due to increased adipocyte lipolysis and decreased LDL receptors in the liver are the key mechanisms behind the increased hepatic very low density lipoproteins (VLDL)-TG secretion.25,26

Effect of Ethnicity and Gender on Dyslipidemia in type 2 DM

Men and women with diabetes were found to have significantly lower concentrations of HDL-c than non-diabetic; the abnormalities in serum lipids were greater in diabetic women than men. These findings were confirmed in the much larger baseline studies from UKPDS in which the elevation of serum triglyceride and reduction in HDL-c were greater in female than male type 2 diabetic subjects compared with controls. This may in part explain why the relative risk of developing CHD is greater in women than in men. In the Rancho Bernado Study, the relative risk of fatal ischemic heart disease was 1.9 in diabetic men compared with

non-diabetic men and 3.3 in diabetic women compared with non-diabetic women. Males with macrovascular disease had higher total and LDL-c concentrations than those without, while in females those with macrovascular disease had higher triglyceride, total cholesterol and LDL-c concentrations, and lower HDL2-c, HDL3-c and apolipoprotein A1 concentrations than those without. On multivariate analysis, LDL-c was the most important association with prevalent macrovascular disease in males and low apolipoprotein A1 in females.

Afro-Caribbean subjects have a higher prevalence of type 2 diabetes and are more insulin resistant for glucose metabolism. However, they are relatively protected from the dyslipidaemia of insulin resistance with lower triglyceride concentrations and higher HDL-c concentrations compared to European type 2 diabetic subjects. This paradox is unexplained. Afro-Caribbean subjects in the UK have lower rates of CHD. Much of the difference in CHD incidence may be explained by the absence of the typical diabetic dyslipidaemia and ethnicity.24

ATP III Classification of Total Cholesterol and

LDL Cholesterol

Total Cholesterol (mg/dL)

LDL Cholesterol (mg/dL)

<200 Desirable

200-239 Borderline High

≥240 High

≥190 Very High

<100 Optimal

100-129 Near optimal

130-159 Borderline High

160-189 High

ATP III Classification of HDL

Serum HDL Cholesterol (mg/dL)

<40 mg/dL Low HDL cholesterol

≥60 mg/dL High HDL cholesterol

Classification of Serum Triglycerides


Category ATP II Levels



Normal triglycerides




High triglycerides


Very high triglycerides





>1000 mg/dL ≥




€¾500 mg/dL

Diabetic Dyslipidemia and Cardio Vascular Disease

Patients with type 2 diabetes mellitus without a history of myocardial infarction have the same risk of a coronary event as patients without diabetes who do have a history of myocardial infarction. This observation was part of the basis for the recommendation by the Adult Treatment

Panel III (ATP III) of the National Cholesterol Education Program that diabetes should be considered "coronary heart disease risk equivalent".28

Two important long-term prospective studies described the importance of lipid abnormalities as predictors of CHD in type 2 diabetes. From the population in the Kuopio University Hospital district in East Finland, 313 type 2 diabetic subjects had detailed lipoprotein analyses and were followed prospectively for seven years for CHD events. High total cholesterol and LDL-c did not predict CHD events. The most important predictor was low HDL-c (< 0.9 mmol/L) followed by high serum triglyceride (> 2.3 mmol/L). The simultaneous presence of low HDL-c and high triglyceride was associated with a four-fold risk of CHD and a two-fold risk of all CHD events. If these two parameters were combined with high total cholesterol, there was a four-fold risk of CHD death and three-fold risk of all CHD events. In another prospective study from the same area, total serum triglyceride, LDL triglyceride and HDL triglyceride were all predictive of CHD mortality in type 2 diabetic subjects, the strongest of these being LDL triglyceride.27 30

The UKPDS study has again provided valuable information. In this study, total and LDL cholesterol were major risk factors for CHD. A 1.57-fold increase in risk was associated with a 1 mmol/L increase in LDL-c. Decreased HDL-c was also significantly and independently associated with increased risk. For a 0.1 mmol/L increment in HDL-c concentration there was a 15% decrease in risk of CHD. Serum triglyceride was a risk factor for CHD after adjustment for age and sex, but was not independent when other variables were included in the multivariate model.29,27

Further important information on the role of HDL and triglycerides have emerged analysis of two secondary CHD prevention studies, CARE and LIPID. Among the 13,173 participants with CHD, 2,607 had baseline LDL-c < 3.2 mmol/L. They were more likely to have diabetes, had higher triglyceride and lower HDL-c than those with LDL-c > 3.2 mmol/L. During the 5.8-year follow-up, HDL-c and triglyceride were both significantly stronger predictors of recurrent CHD events in these subjects than in those with LDL-c of > 3.2 mmol/L.

The extent and severity of coronary artery disease, as determined by coronary angiography, were studied in relation to risk factors in 57 men and seven women with type 2 diabetes and compared with a similar number of non-diabetic subjects. In the diabetic subjects the extent of coronary atheroma related inversely to concentration of HDL particles, whereas in the non-diabetic subjects it related to LDL-c and inversely to HDL. These recent data highlight the importance of low HDL concentration as a risk factor for CHD in type 2 diabetes.30

A useful marker for all apolipoprotein B containing atherogenic lipoproteins is non-HDL-c. This is a simple measurement calculated as the difference between total and HDL-c concentrations. In the Strong Heart Study, a prospective study of CVD in several American-Indian populations, non-HDL-c was a better predictor of CVD in men and women with type 2 diabetes than either LDL-c or triglyceride. In women, it was also a better predictor than total to HDL-c ratio.

A high concentration of small dense LDL particles (pattern B) is associated with a three- to seven-fold increased risk of CHD irrespective of total circulating LDL concentration. Thus although LDL concentration may be normal in type 2 diabetes, its abnormal composition may render it more atherogenic.27

There is some evidence that some cardiovascular risk factors precede the onset of type 2 diabetes. Cardiovascular risk factor status was determined in initially non-diabetic Mexican-Americans. After an eight-year follow-up those who subsequently developed diabetes had higher baseline levels of total and LDL-c, triglyceride, fasting glucose, insulin, BMI, and blood pressure, and lower HDL-c. Haffner introduced the concept of the 'Ticking Clock.' He suggested that in the many years which may precede overt type 2 diabetes, there is insulin resistance and hyperinsulinemia in association with other cardiovascular risk factors, so that in contrast to microvascular complications, macrovascular disease may precede the onset of hyperglycaemia.24

The primary-prevention trial Helsinki Heart Study (HHS) showed that treatment with gemfibrozil led to a significant reduction in major cardiovascular events .Regarding secondary prevention, in the VA-HIT study (Veterans Affairs High-density lipoprotein cholesterol Intervention Trial) - which included 30% of diabetic patients - gemfibrozil reduced the occurrence of major cardiovascular events by 22 % . Similarly, reduction

of cardiovascular disease with gemfibrozil was more pronounced in patients displaying above three of the features of metabolic syndrome .

The 18-year results from the Helsinki Heart Study shows that patients in the original gemfibrozil group had a 23% lower risk of CAD mortality compared with the original placebo group. But those in the highest tertile of both body-mass index and triglyceride level at baseline had the most dramatic risk reductions with gemfibrozil - 71% for CAD mortality.32

Dyslipidemia and Diabetic Retinopathy

Diabetic retinopathy begin with micro aneurysms and progress into exudative changes -leakage of lipoproteins termed as hard exudates and blood as blot haemorrhages that lead to macular ischemic changes -infarcts of the nerve-fibre layer, cotton-wool spots, collateralization (intraretinal microvascular abnormalities) and dilatation of venules (venous beading), and proliferative changes (abnormal vessels on the optic disk and retina, proliferation of fibroblasts, and vitreous haemorrhage).

Persons with mild-to-moderate non proliferative retinopathy have impaired contrast sensitivity and visual fields that cause difficulty with driving, reading, and managing diabetes and other activities of daily living. Visual acuity, as determined with the use of Snellen charts, declines when the central macula is affected by oedema, ischemia, epiretinal membranes, or retinal detachment. The association of dyslipidemia and retinopathy is mainly with the hard exudates comprising of lipoprotein. 71

Dyslipidemia and neuropathy

Pathogenesis of diabetic neuropathy is multi factorial. Microvascular insufficiency has been shown to produce ischemia due to altered function of endoneural and epineural vessels leading to neuropathy.

Various type of nueropathies encountered in diabetes are small fibre neuropathy, large fibre neuropathy, proximal neuropathy, mononueropathies and autonomic neuropathy.72

Dyslipidemia and PVD

Peripheral Vascular disease is a macrovascular complication of diabetes mellitus. Several studies have pointed out that hypertriglyceridemia, hyper cholesterolemia and triglyceride rich lipoprotein contribute to the development of peripheral vascular disease. Duration, degree of hyperglycemia along with hypertension, smoking, cholesterol are risk factors. Risk of peripheral vascular disease (PVD) is increased in diabetic patients, occurs earlier and is often more severe and diffuse. Endothelial dysfunction, vascular smooth muscle cell dysfunction, inflammation and hypercoagulability are the key factors in diabetic arteriopathy. The presence of PVD, apart from its increased risk of claudication, ischemic ulcers, gangrene and possible amputation, is also a marker for generalized atherosclerosis and a strong predictor for cardiovascular ischemic events82

Diabetic Dyslipidemia and Cerebrovascular Disease

Like other macrovascular complication CVA is also commonly associated with type 2 diabetes mellitus. Dyslipidemia, obesity and hypertension associated with type 2 diabetes mellitus leading to accelerated atherosclerosis is the common denominator.83

Dyslipidemia and Obesity

Obesity and type 2 diabetes mellitus often coexist. There is a central pattern of fat distribution as characterised by increased ratio of waist to hip circumference. Increased waist to hip ratio is an independent risk factor for developing type 2 diabetes mellitus. Obesity in type 2 diabetes mellitus is associated with insulin resistance and hyperinsulinemia. Metabolic derangements like hyperinsulinemia, obesity, hypertriglyceridemia, type 2 diabetes mellitus, insulin resistance and hypertension result in development of premature coronary disease in Indians.61

Dyslipidemia and Diabetic Nephropathy

Various stages of diabetic nephropathy are

Stage 1 : Glomerular hyper filtration

Stage 2 : Early Glomerular Lesion

Stage 3 : Incipient diabetic nephropathy - stage of microalbuminuria

Stage 4 : Clinical Nephropathy - microalbuminuria and fall in GFR

Stage 5 : End - Stage renal disease71

Triglyceride levels are found to be elevated in patients with micro -albuminuria and overt proteinuria, glycemic level or insulin resistance are not associated with raised TG level. Intermediate density and remnant cholesterol particles are also elevated. Hepatic lipases along with lipoprotein lipase levels were diminished along with increased levels of von Willebrand factor. Risk of CAD is elevated with diabetic nephropathy.81

Dyslipidemia and Glycemic control

Hyperglycemia, a cardinal manifestation of diabetes, adversely affects vascular function, lipids and coagulation. Results from randomized controlled trials have demonstrated conclusively that the risk of microvascular complications can be reduced by intensive glycemic control in patients with type 2 diabetes.74

Glycated haemoglobin (HbA1c) is a routinely used marker for long-term glycemic control. The amount of glycated haemoglobin (HbA1c) reflects the glycemic control of a patient during the 6 - 8 week period before the blood sample was obtained. The amount of HbA1c correlates well with fasting and postprandial blood glucose levels. At present HbA1c is the best surrogate marker we have for setting goals of treatment.67

The Diabetes complications and control trial (DCCT) established HbA1c as the gold standard of glycemic control. The level of HbA1c value 7.0% was said to be appropriate for reducing the risk of cardiovascular complications.74 In the Diabetes Control and Complications Trial (DCCT), there was a _60% reduction in the development or progression of diabetic retinopathy, nephropathy, and neuropathy between the intensively treated group (goal A1c, _6.05%; mean achieved A1c, _7%) and the standard group (A1c, _9%) over an average of 6.5 years.75 The relationship between glucose control (as reflected by the mean on-study A1c value) and risk of complications was log-linear and extended down to the normal A1c range (_6%) with no threshold noted.75

In the UK Prospective Diabetes Study (UKPDS), participants newly diagnosed with type 2 diabetes were followed up for 10 years, and intensive control (median A1c, 7.0%) was found to reduce the overall microvascular complication rate by 25% compared with conventional treatment (median A1c, 7.9%).76 In the UKPDS, treatment with either oral hypoglycaemic agents or insulin did not significantly reduce macrovascular end points.78

Epidemiological studies support the concept that increasing levels of glycaemia commensurately increase cardiovascular events.77 In a meta-analysis of more than 95,000 diabetic patients, increases in cardiovascular risk depended directly on plasma glucose concentrations and began with concentrations below the diabetic threshold.78

In the DCCT, there was a trend toward lower risk of CVD events with intensive control (risk reduction, 41%; 95% CI, 10 to 68), but the number of events was small. However, 9-year post-DCCT follow-up of the cohort has shown that participants previously randomized to the intensive arm had a 42% reduction (P_0.02) in CVD outcomes and a 57% reduction (P_0.02) in the risk of nonfatal myocardial infarction (MI), stroke, or CVD death compared with those previously in the standard arm.78

The primary outcome of ACCORD study (MI, stroke, or cardiovascular death) was reduced in the intensive glycemic control group because of a reduction in nonfatal MI, although this finding was not statistically significant when the study was terminated. Other pre specified subset analyses showed that participants with no previous CVD event and those who had a baseline A1c _8% had a statistically significant reduction in the primary CVD outcome.79

In accordance with its function as an indicator for the mean blood glucose level, HbA1c predicts the risk for the development of diabetic complications in diabetes patients. Apart from classical risk factors like dyslipidemia, elevated HbA1c has now been regarded as an independent risk factor for CVD in subjects with or without diabetes.80

Estimated risk of CVD has shown to be increased by 18% for each 1% increase in absolute HbA1c value in diabetic population. Positive relationship between HbA1c and CVD has been demonstrated in non-diabetic cases even within normal range of HbA1c.70


Insulin Therapy in Type 2 DM

It is ideal to offer insulin therapy to every diabetic at diagnosis though it is offered last. Most guidelines indicate insulin initiation in type 2 diabetes mellitus with fasting hyperglycemia above 250 mg%, the cut off of ketogenesis. In India, fasting blood glucose more than 190 mg%-250 mg%; post prandial blood glucose more than 250-300 mg% or glycosylated haemoglobin more than 10-12% must be offered insulin therapy. Insulin therapy is indicated in diabetic ketoacidosis, hyperosmolar non ketotic states, myocardial infarction, vascular events, angioplasty, cardiac bypass surgery, renal failure, liver cell failure and OHA failure.84

Oral Hypoglycaemic Therapy in Type2 DM

Initially the patient is advised diet with exercise followed by biguanide therapy, failure to control the sugar levels warrants the introduction of sulphonylurea group. Each drug should be initiated at lower doses and gradually increased. Postprandial glucose levels can be controlled using alpha glucosidase inhibitor. Thiazolidinediones can be used to decrease the insulin resistance. Newer Incretin based therapy with DPP4 inhibitors along with GLP1 receptor agonists inhibits the secretion of glucagon and potentiates glucose mediated secretion of insulin.85,86

Management of Dyslipidemia

The general scheme for initiation and progression of LDL-lowering drug therapy is to achieve the goal for LDL cholesterol. For this reason an LDL-lowering drug should be started. The usual drug will be a statin, but alternatives are bile acid sequestrant or nicotinic acid. The starting dose of statin will depend on the baseline LDL-cholesterol level.

In persons with only moderate elevations of LDL cholesterol, the LDL-cholesterol goal will be achieved with low or standard doses, and higher doses will not be necessary. The response to drug therapy should be checked in about 6 weeks. If the treatment goal has been achieved, the current dose can be maintained; if not, LDL- lowering therapy can be intensified, either by increasing the statin dose or by combining a statin with a bile acid sequestrant.28