New Concepts in Diabetes and Its Treatment - part 7 pdf

It is suggested that arrhythmias may play a role in the early mortality, especially in type 2 diabetic patients, and the observation that in trials in patients at riskb-blockers are espe

Table 2 How antihypertensive agents may be combined in diabetes

b-Blockers Yes (diuretics

often required)

ACE inhibition Yes (diuretics Yes Yes (theoretically interesting

or angiotensin often required) combination, results promising)

receptor blockers

Ca blockers 1

Yes (diuretics Yes (rarely used) Yes (rarely used) Yes (often used;

Careful clinical metabolic and BP monitoring always required, including control of serum electrolytes and serum creatinine of GFR index (combination therapy used in more than 50% of patients).

Mechanisms of BP Elevation and Choice of Therapy in Nephropathy

Based upon the known mechanisms operating in the genesis of sion, some interesting concepts regarding selection of antihypertensive treat-ment are evolving in diabetes The abnormalities in renal function, wherehyperfusion, hyperfiltration and increased glomerular pressure may be impor-tant mediators, favor the use of ACE inhibitors, since these agents tend to

glomerular pressure, may even to some extent be independent of systemichypertension or systemic BP level The sodium retention evident in both type

2 and type 1 diabetes supports the use of diuretics and sodium restriction inantihypertensive programs in diabetes The early cardiac hyperfunction inmicroalbuminuric patients may suggest the use of cardioselectiveb-blockers

to reduce this hyperfunction Obviously, the generalized BP reduction seenwith all these agents may be of prime importance, but these mechanismscould also favor the use of combined treatment: ACE inhibitors, diuretics andpossibly b1-blockers (or other agents) in diabetic patients (table 2) Calciumblockers reduce BP, and may be important in therapy although some, butdecreasing, controversy exists

Table 3 Diabetes-related side effects and favorable effects related to antihypertensive treatment in diabetics (mainly type 1 diabetes)

Diuretics (thiazide Noncardio- Cardioselective ACE inhibitors Triple treatment: Calcium blockers Angiotensin

or loop) selective b-blockers diuretic b 1 -blockers/ receptor

Glucose intolerance Yes, type 2, but No problem No problem No side effects Limited or no change No No

related strongly Insulin sensitivity (with small dosages)

clinically Hypoglycemic No Yes, mainly A problem, but Not seen Limited or no change No No

diabetes few patients Unfavorable lipid Yes, but not with Likely Limited or No side effects ? No No

Other unfavorable May cause Less physical Less physical Coughing and Limited (with Foot edema seen No effects sodium depletion exercise exercise capacity drug-related side small dosages) in few patients

(uncommon) Favorable effects Elimination of Reduction of Reduction of Elimination Probably also No potentiation Under (apart from BP edema cardiovascular cardiovascular sodium excess combination of of peripheral investigation reduction) morbidity/ morbidity/ and possibly favorable effects ischemia?

mortality mortality restoration of (stable GFR?) Normalization Normalization glomerular

of cardiac of cardiac pressure gradients arrhythmias? arrhythmias?

Effect on Not well Not well Yes, but relatively Very consistent Addition of ACE Related to BP Yes abnormal documented documented few studies exist finding inhibition reduces reduction

Reducing fall rate Not documented Not Yes Yes GFR stable on Not documented Ungoing

Obviously, from a theoretical point of view, potential additional beneficial

suggested specifically reduce the localized increased pressures seen in these

patients, as originally observed in animal studies The presence of edema of

course favors the use of diuretics It is suggested that arrhythmias may play

a role in the early mortality, especially in type 2 diabetic patients, and the

observation that in trials in patients at riskb-blockers are especially effective

in diabetic patients points to additional beneficial effects of b-blockers in the

management of hypertension in diabetics where cardial disease and silent

b-blockers are increasingly being used according to new trials, e.g the Merit

HF Study

Clearly, side effects are important and these are usually dose related For

example, the well-known diabetogenic effect of diuretics may be dose dependent

with sufficient BP reduction with small doses that are not diabetogenic

Potas-sium loss is important but can readily be restored by potasPotas-sium

supplemen-tation or by the use of ACE inhibition Also small doses of diuretics may

not impair lipid parameters A side effect that has caused some concern is

b-blockers but is only of minor importance with cardioselectiveb-blockers andthe phenomenon is not important in type 2 diabetics that may especially benefit

possess any diabetogenic effects, rather they are neutral Thus there is nonegative effect on glucose metabolism or lipid homeostasis; a positive effecthas in fact been observed in some studies This positive or rather neutralpattern may therefore favor the use of ACE inhibitors in diabetic patients.Importantly, no increased frequency of hypoglycemia is seen in clinical practice.Coughing as a side effect is surprisingly rare in diabetic patients, possibly due

to diabetic neuropathic changes The new angiotensin II receptor antagonistscould be considered in this situation, also with other side effects caused byACE inhibitors

Problems of Optimized Glycemic Control During Antihypertensive Treatment

In recent years it has become increasingly clear that good glycemic control

is of clear importance in the prevention and postponement of diabetic renaldisease As documented in the DCCT, good glycemic control can reduce thenumber of patients that develop advancing renal disease Improved metaboliccontrol seems also to protect against deterioration in renal function in patientswith microalbuminuria However, it is important to stress that it is quite often

difficult to obtain good metabolic control, especially in patients with incipient

or overt renal disease There are no formalized long-term trials with a sufficientnumber of patients on the effect of optimized diabetes care in patients withovert renal disease However, new studies strongly suggest a correlation betweenprogression in renal disease, as measured by fall rate of GFR and level ofHbA1c If HbA1c is satisfactory, with values around 7–8% (reference value5.5%), progression is slow This observation was recently confirmed In patientswith type 2 diabetes, progression can be reduced by early intervention Withovert nephropathy there is no correlation between progression and HbA1c TheUKPDS clearly documented the role of good glycemic control in preventingmicrovascular complications

Intervention Trials in Normoalbuminuria

Even in type 1 diabetic patients with normal BP and normal albuminexcretion, renal hemodynamics may be beneficially influenced by ACE inhibi-tion This study was of experimental nature and treatment of such individualscannot be recommended, although a trial should be conducted in high-risk

(?9–10%)) However, the Euclid Study did not document any clear effect innormoalbuminuria in a 2-year trial, but longer intervention is likely to bepositive, according to unpublished studies from Denmark.

Microalbuminuria and Antihypertensive Treatment

Several intervention studies have been published, some with self-controlled

or crossover design, some double-blinded without being long term and somelong term and randomized without being blinded All these trials generallyshowed a reduction or a stabilization in microalbuminuria In a recent random-ized double-blind large-scale placebo-controlled study, the effect of an ACEinhibitor was investigated with respect to progression to clinical nephropathy

in normotensive type 1 diabetic patients with microalbuminuria The major

In this large study, treatment delayed the progression to overt renal disease

in normotensive, type 1 diabetic patients with microalbuminuria

Interestingly, in all these studies confirmed from 1985 to 1999, patientswere included purely on the basis of microalbuminuria and indeed in moststudies patients should not be hypertensive (often an exclusion criterion forparticipation) Therefore, in most studies BP was close to normal, and in some

of the patients BP was in the middle of the range as seen in healthy youngindividuals (mean arterial pressureB90 mm Hg) There seems to be a tendencytowards a correlation between reduction in BP and reduction in albuminuria.The clinical consequence is that the indication for antihypertensive treat-ment should be microalbuminuria (as in the clinical trials) rather than someelevation of BP (fig 2) Obviously any elevation of BP or any increasing BPwould further strengthen the indication, because there is a correlation betweenrate of progression of microalbuminuria and BP; still the conclusion fromthese studies would mean that antihypertensive treatment should be initiatedwhenever microalbuminuria is consistently found A more cautious view would

be to start antihypertensive treatment if microalbuminuria is clearly increasing(5–10% per year), but the variability in UAE makes this approach somewhat

difficult in the practical clinical setting All studies document a reduction orstabilization in microalbuminuria, irrespective of the treatment used; however,most studies were conducted with ACE inhibitors as the principal agent withfew or no side effects Diuretics were systematically added in one importantstudy Thus the scenario for the use of antihypertensive treatment, in particularACE inhibitors, is moving from the indication of elevated BP to the indication

of increased or increasing UAE as proposed in recently published guidelines.Combination therapy is also very useful in such patients

Fig 2 Microalbuminuria (MA) in type 1 diabetic patients below 60 years of age.

New studies suggest similar e ffects in the relative young and lean type 2 diabetic patients A/C >Albumin/creatinine ratio Modified from Mogensen et al.

In type 2 diabetic patients, microalbuminuria can be reduced by ACEinhibition and two long-term studies suggest a beneficial effect on GFR Thefall rate of GFR correlates to BP This important topic has recently beenreviewed by Cooper and McNally, and ACE inhibition as early treatmentseems equally important in type 1 and type 2 diabetes

Table 4 ACE inhibitors in type 1 diabetic patients:

ob-served e ffects in clinical trials (stages as described in table 1)

1 No trials in newly diagnosed patients

2 Normoalbuminuria reduced

BP not significantly changed

Filtration fraction reduced (in normoalbuminuria)

3 Microalbuminuria reduced

BP reduced (diastolic and systolic)

Fall in GFR prevented or postponed

4 Proteinuria reduced

BP reduced (diastolic and systolic)

Fall rate of GFR reduced

5 End-stage renal disease and mortality postponed

Trials in Patients with Proteinuria or Overt Diabetic Nephropathy

In the untreated situation there is a correlation between the fall rate ofGFR and BP, but interestingly the correlation between the fall rate of GFRand albuminuria is equally strong It has been suggested that a pronouncedfall in proteinuria after start of antihypertensive treatment predicts a morebenign course of renal disease in type 1 diabetic patients, compatible with animportant role for the level of albuminuria in the rate of progression in renaldisease Several studies have documented that antihypertensive treatment un-equivocally reduces the fall rate of GFR This is invariably accompanied byreduction of albuminuria Therefore, antihypertensive treatment is the majortherapeutic option for these patients The use of ACE inhibitors often withdiuretics is popular, though antihypertensive programs, e.g with b1-blocker,have been reported equally effective, but possibly with more side effects Therecent important study by Lewis et al showed that the number of patients withdoubling of S-creatinine could be reduced by ACE inhibition, thus confirmingearlier studies However, BP was 3–4 mm Hg lower in the ACE-I group A

noted however Thus, ACE inhibitors work in all stages of diabetic renaldisease (table 4) Pregnant diabetic patients require special attention and ACEinhibitors are contraindicated here

In proteinuric type 2 diabetic patients it has also been shown that duringtreatment there is a correlation between BP elevation and the rate of decline

in GFR, suggesting that elevated BP in type 2 diabetic patients is also importantfor the rate of progression in renal disease When these patients exhibit overt

proteinuria, they generally have a poor prognosis No very long-term tion trials over several years with the fall rate of GFR as endpoint have beenconducted recently in type 2 diabetes Fall rate is generally high, and in some

similar effect on outcome Important large-scale studies are now ongoing usingangiotensin II receptor antagonists and results are keenly awaited in this high-risk population

Protein-Reduced Diet

In normoalbuminuric type 1 diabetic patients, hyperfiltration can be duced by normalizing dietary protein intake, a potential beneficial effect.Studies suggest that microalbuminuria can be reduced on a 2-year interventionbasis by a low protein diet, but so far, no long-term results are available, andcompliance may pose a problem

re-In diabetic nephropathy, new data have recently been published indicatingthat the rate of decline of GFR can be reduced by a low protein diet Patientswere monitored on their usual dietary intake of proteins and thereafter patientswere put on a low protein diet A remarkable reduction in the fall rate ofGFR was observed, although the response varied considerably Patients served

as their own controls without a parallel nontreated group and it cannot beexcluded that late or long-term action of antihypertensive treatment mayexplain at least part of the observed beneficial effect In a randomized parallelstudy, Zeller et al also documented beneficial effect on the fall rate of GFR

in these patients The MDRD Study was not convincingly positive but thistrial only included few diabetics Nyberg et al did not find correlation betweendietary protein intake and status of renal disease in type 1 diabetic patients

At this point, the general consensus may be to prescribe a protein intake

the patient with overt nephropathy However, it has been suggested that oncethe GFR begins to fall, further restriction to 0.6 g/kg/day may prove useful

in slowing the decline of GFR in selected patients On the other hand, nutritiondeficiency may occur in some individuals and may be associated with muscleweakness Protein-restricted meal plans should be designed by a registereddietitian familiar with all components of the dietary management of diabetes

Cardiovascular and Cerebrovascular Trials Along with Renal Endpoints

Cardio- and also cerebrovascular diseases are important causes of death

in both type 1 and type 2 diabetes, especially when the kidney is affected.Although the concept of controlled clinical or therapeutical trial has evolved

Table 5 Positive effect on cardiovascular endpoints in type 2 diabetes by

antihypertensive treatment

Favors

1 Shep [Curb et al.] Diurectics vs placebo

2 ABCD [Estacio et al.] ACE-I vs CCB

3 Facet [Tatti et al.] ACE-I vs CCB

4 HOT [Hansen et al.] Strict control (CCB-based)

5 UKPDS [Turner et al.] Strict control (ACE-I +b-blocker-based)

7 CAPP [Hansson et al.] ACE-I vs conventional

8 Syst-Eur [Toumilehto et al.] CCB vs placebo

9 Hope-study [Yusef et al.] ACE-I vs placebo

CCB >Calcium channel blockers.

over the past 50 years, only a few large trials have been conducted in diabetes,the first being the UGDP (University Group Diabetes Program) which nowafter the UKPDS, is mainly of historical interest No real large-scale controlledtrials were done when introducing sulfonylureas, biguanides or insulin, butthis has changed now with the UKPDS There has therefore been an increasinginterest in cerebro- and cardiovascular endpoints, especially in type 2 diabeteswith respect to effective modulation, mainly with antihypertensive treatmentstrategies, which show a beneficial effect (table 5) Most studies employ ACEinhibitors but it is noteworthy that any reduction of BP seems to be important.Certain trials show ACE inhibitors to be superior to calcium blockers andalso conventional treatment Importantly, the UKPDS showed a similar out-

the use of ACE inhibitors This study also clearly showed that careful BP

end-points very considerably (around 30%) Therefore, antihypertensive treatmentshould be given a great priority in the management of patients with type 2

due to the nature of the trial this was not so evident However, combined

is around 130–135/80–85 mm Hg

Guidelines with Origin in Pathophysiological and Clinical Trials

The World Health Organization-International Society of Hypertension(WHO-ISH) Liaison Committee on Hypertension was established in the mid-

Table 6 Suggested target BPs during antihypertensive treatment (systolic

and diastolic should be attained, e.g =140/85 mm Hg means =140 systolic

and =85 diastolic)

no diabetes 1 diabetes no diabetes 1 diabetes

In those with high cardiovascular risk and initial BP 140–159/90–99 mm Hg

there could be a case for adopting the targets for diabetic patients (British

Hypertension Society 1999).

1970s and has subsequently produced several guidelines, the first in 1975 Newguidelines have recently appeared also related to hypertension in diabetes.Several of these new guidelines have a similar approach There is a clearemphasis on early and effective antihypertensive treatment in patients withdiabetes suggesting a lower threshold for the start of the treatment and also

a lower goal during treatment ACE inhibitors are often preferred as initialagents but combination therapy is often warranted In view of the recentobservation that different types of drugs (ACE-I, b-blockers, calcium channelblockers and diuretics) reduce cardiovascular risks in type 2 diabetes, thereare different treatment options In diabetic renal disease, ACE-I is howeverpreferred We should aim to achieve a BP around 135/85 mm Hg duringtreatment, or lower

The British Hypertension Society proposes: (1) ‘ The threshold for

=130/80 mm Hg, or lower (=125/75 mm Hg) when there is proteinuriaq1 g/24 h’ And (2): ‘Trials support treatment of all patients with type 2

(3) ‘ Thus there is evidence from outcome trials in hypertensive patients withdiabetes for the efficacy and safety of ACE inhibitors, b-blockers, dihydropyrid-ines, and low-dose thiazides The choice among these drug classes should bemade using the criteria set out for nondiabetic patients BP control will usuallyrequire more than one antihypertensive drug, and about 30% of hypertensivepatients with diabetes need three or more agents in combination.’ A similarapproach is seen in table 6

The problem is that it may be difficult to achieve such BP with patientswith proteinuria and overt renal disease and also in others with cardiovascularproblems Therefore, it is strongly advocated to start treatment early, e.g withdevelopment of microalbuminuria, even in patients with normal BP It hasalso been proposed to start treatment even before microalbuminuria Sincecomplications are so closely associated with BP increase (also in the normalrange) this could easily be recommended in future guidelines as we now have

effective treatment modalites with rather limited side effects

Summary Notes

This chapter clearly documents that excess albuminuria, often nied by increased BP, is associated with actual or subsequent organ damage,not only in the kidney but also in other organs, especially in the eyes and inthe heart In the kidney, abnormal albuminuria starting in the microalbumi-nuric range reflects more advanced glomerular structural lesions, although theexact location of the permeability defect has not been defined at an ultrastruc-tural level BP elevation may not initiate the glomerular permeability defectbut high systemic BP aggravates the course of established lesions and clinicaldisease Transition from micro- to macroalbuminuria is associated with areduction in GFR, the key parameter in evaluation of renal function.Biochemical and hemodynamic hypotheses have been put forward sup-ported by animal models, but these notions are difficult to substantiate inhumans, where isolated phenomena cannot be studied, and direct measurement

accompa-of e.g glomerular wall charge and intraglomerular pressure is not feasible Aunifying concept would be attractive, comprising biochemical aberrations, such

as charge defects, changes in enzymatic activities and glycation phenomena aswell as hemodynamic changes such as hyperfiltration with elevated glomerularpressure, aggravated by early systemic BP rise This may be seen along withvascular and endothelial changes, reflected by increases in von Willebrandfactor, circulating prorenin as well as increased transcapillary escape rate ofalbumin and dyslipidemia Antioxidant status may also play a role A commonpathway explaining all or most of these abnormalities should be pursued,with the basis in prolonged hyperglycemia and related biochemical changes,characteristic for the diabetic state

However, when diabetic complications are evolving as a consequence ofhyperglycemia, increasing BP remains a decisive factor in promoting organdamage in the kidney, and antihypertensive treatment seems to be the thera-peutic cornerstone in ameliorating deterioration in organ function A lowprotein diet may also reduce albuminuria and the fall rate in GFR However,

strict antihypertensive therapy may limit the need for any dramatic reduction

of the protein content of the diet

Suggested Reading

American Diabetes Association: Diabetic nephropathy Diabetes Care 2000;23(suppl 1): 69–72 Charurvedi N: HOPE and extension of the indications for ACE-inhibitors? Lancet 2000;355, in press Curb JD, Pressel SL, Cutler JA, Savage PJ, Applegate WB, Black H, et al: E ffect of diuretic-based antihypertensive treatment on cardiovascular disease risk in older diabetic patients with isolated systolic hypertension Systolic Hypertension in the Elderly Program Cooperative Research Group JAMA 1996;276:1886–1892.

Estacio RO, Je ffers BW, Hiatt WR, Biggerstaff SL, Gifford N, Schrier RW: The effect of nisoldipine as compared with enalapril on cardiovascular outcomes in patients with non-insulin-dependent diabetes and hypertension N Engl J Med 1998;338:645–652.

Feldt-Rasmussen B, Mathiesen ER, Jensen T, Lauritzen T, Deckert T: E ffect of improved metabolic control on loss of kidney function in type 1 (insulin-dependent) diabetic patients: An update of the Steno studies Diabetologia 1991;34:164–170.

Forsblom C, Trenkwalder P, Dahl K, Mulder H, on behalf of the Multicenter Study Group: Angiotensin

II receptor blockers in type 2 diabetic patients with microalbuminuria Nephrol Dial Transplant 1998;13:1069.

Gæde P, Vedel P, Parving HH, Pedersen O: Intensified multifactorial intervention in patients with type

2 diabetes mellitus and microalbuminuria: The Steno type 2 randomised study Lancet 1999;353: 617–622.

Guidelines (1999) for the management of hypertension: Memorandum from a World Health Organization/ International Society of Hypertension Meeting J Hypertens 1999;17:151–183.

Hansson L , Lindholm LH, Niskanen L, et al: E ffect of angiotensin-converting enzyme inhibition compared with conventional therapy on cardiovascular morbidity and mortality in hypertension: The Captopril Prevention Project (CAPPP) Randomised Trial Lancet 1999;353:611–616.

Hansson L, Zanchetti A, Carruthers SG, et al, for the HOT Study Group: E ffects of intensive BP lowering and low-dose aspirin in patients with hypertension: Principal results of the Hypertension Optimal Treatmen (HOT) randomised trial Lancet 1998;351:1755–1762.

Jacobsen P, Rossing K, Rossing P, Tartow L, Mallet C, Poirier O, Cambien F, Parving HH: Angiotensin converting enzyme gene polymorphism and ACE inhibition in diabetic nephropathy Kidney Int 1998;53:1002–1006.

Lewis EJ, Hunsicker LG, Bain RP, Rhode RD: The e ffect of angiotensin-converting-enzyme inhibition

on nephropathy N Engl J Med 1993;329:1456–1462.

Mathiesen ER, Hommel E, Hansen HP, Parving HH: Preservation of normal GFR in type 1 diabetic patients with microalbuminuria under long-term (8 years) ACE inhibition Nephrol Dial Transplant 1998;13:1062.

Microalbuminuria Collaborative Study Group, UK: Intensive therapy and progression to clinical nuria in patients with insulin-dependent diabetes mellitus and microalbuminuria BMJ 1995;311: 973–977.

albumi-Mogensen CE: Combined high BP and glucose in type 2 diabetes: Double jeopardy (editorial) BMJ 1998;317:693–694.

Mogensen CE (ed): The Kidney and Hypertension in Diabetes mellitus Boston, Kluwer Academic, 2000.

Mogensen CE: Microalbuminuria, blood pressure and diabetic renal disease: Origin and development of ideas Diabetologia 1999;42:263–285.

Mogensen CE, Keane WF, Bennett PH, Jerums G, Parving HH, Passa P, Ste ffes MW, Striker GE, Viberti GC: Prevention of diabetic renal disease with special reference to microalbuminuria Lancet 1995; 346:1080–1084.

sion-associated diabetic renal disease Int J Clin Pract 1997;90(suppl):52–58.

Nørgaard K, Rasmussen E, Jensen T, Giese J, Feldt-Rasmussen B: Essential hypertension and type 1 diabetes Am J Hypertens 1993;6:830–836.

Nyberg G, Norde´n G, Attman PO, Aurell M, Uddebom G, Lenner RA, Isaksson B: Diabetic nephropathy:

Is dietary protein harmful? J Diabetes Complications 1987;1:37–40.

Østerby R, Schmitz A, Nyberg G, Asplund J: Renal structural changes in insulin-dependent diabetic patients with albuminuria Comparison of cases with onset of albuminuria after short or long duration APMIS 1998;106:361–370.

Parving HH: Renoprotection in diabetes: Genetic and non-genetic risk factors and treatment Diabetologia 1998;41:745–759.

Ravid M, Brosh D, Levi Z, Bar-Dayan Y, Ravid D, Rachmani R: Use of enalapril to attenuate decline

in renal function in normotensive patients with type 2 diabetes mellitus A randomized controlled trial Ann Intern Med 1998;128:982–988.

Tarnow L, Gluud C, Parving HH: Diabetic nephropathy and the insertion/deletion polymorphism of the angiotensin-converting enzyme gene Nephrol Dial Transplant 1998;13:1125–1130.

Tatti P, Pahor M, Byington RP, Di Mauro P, Guarisco RG, Strollo G, Strollo F: Outcome results of the fosinopril versus amlodipine cardiovascular events randomized trials (FACET) in patients with hypertension and NIDDM Diabetes Care 1998;21:597–603.

Turner R, Holman R, Stratton I, Cull C, Frighi V, Manley S, et al, for United Kingdom Prospective Diabetes Study Group: Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: United Kingdom Prospective Diabetes Study 38 BMJ 1998;317: 703–713.

UKPDS 34: E ffect of an intensive blood glucose control policy with metformin on complications in type

2 diabetic patients Lancet 1998;352:854–865.

Zeller K, Whittakerm E, Sullivan L, Raskin P, Jacobson HR: E ffect of restricting dietary protein on the progression of renal failure in patients with insulin-dependent diabetes mellitus N Engl J Med 1991;324:78–84.

Carl Erik Mogensen, Medical Department M (Diabetes and Endocrinology),

Kommunehospitalet, A ˚ rhus University Hospital, DK–8000 A˚rhus C (Denmark)

Tel +45 89492011, Fax +45 86137852, E-Mail cem@afdm.au.dk

Chapter XII

Basel, Karger, 2000, pp 174–185

Lipid Abnormalities and

Lipid Lowering in Diabetes

Metabolism of Lipoproteins in the Normal State

VLDL are produced by the liver and secreted into circulation (step 1 infigure 1) In the liver they are formed by assembling TG, formed through theesterification of FFA (coming from adipose tissue, where they are releasedthrough lipolysis effected by the hormone-sensitive lipase), C, and the apopro-tein B-100 (ApoB-100), besides other components such as phospholipids TheVLDL particles can be distinguished into two subclasses, VLDL1and VLDL2,with Svedberg flotation (Sf) rates of 60–400 and 20–60, respectively Aftersecretion, VLDL reach ‘peripheral tissues’, i.e adipose tissue and muscle (step

Abbreviations

Apo ters; CETP >cholesteryl ester transfer protein; CHD>coronary heart disease; CVD>cardio- vascular disease; FFA >free fatty acids, HDL-R>high-density lipoprotein receptor; HDL >high-density lipoproteins; HL>hepatic lipase; HMG-CoA>hydroxy-methyl-gluta- ryl-CoA; IDL >intermediate density lipoproteins; LCAT>lecithin:cholesterol acyltransfer- ase; LDL-R >LDL receptor (ApoB/ApoE receptor); LDL>low-density lipoproteins; Lp(a) >lipoprotein(a); LPL>lipoprotein lipase; LRP> LDL receptor-related protein;

>Apoproteins;C>cholesterol;CAD>coronaryarterydisease;CE>cholesteryles-TG >triglycerides; UC>unesterified cholesterol; VLDL>very low-density lipoproteins.