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Articles

Diabetes Mellitus and Associated Hypertension, Vascular Disease, andNephropathy

An Update

1. James R. Sowers,2. Murray Epstein

+Author Affiliations

1. From Wayne State University (Detroit, Mich) and Miami (Fla) University Schools of

Medicine and VA Medical Centers.

1. Correspondence to James R. Sowers, MD, Wayne State University School of Medicine, UHC-4H, 4201 St

Antoine, Detroit, MI 48201.

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Abstract

Abstract Because considerable important information has been published since our previous review, this updateconcentrates on new findings with regard to cardiovascular and renal risk factors contributing to the striking

morbidity and mortality of these coexisting diseases. For example, a large body of investigative data has

recently emerged suggesting or delineating a pathogenic role for hyperglycemic-related glycosylation and

oxidation of lipoproteins and vascular and renal tissues. Great strides have recently been made in the

understanding of platelet, coagulation, lipoprotein, and endothelial abnormalities in the pathogenesis of

cardiovascular and renal disease associated with diabetes mellitus and hypertension. Major progress has beenmade in clarifying the pathophysiology of glomerulosclerosis and other processes involved in the progression of

diabetic nephropathy. Furthermore, accumulating data surveyed in this review address new and promising

pharmacological interventions that specifically address these pathophysiological mechanisms.

Key Words:

diabetes mellitus

cardiovascular disease diabetic nephropathy

Diabetes mellitus and hypertension are interrelated diseases that strongly predispose an individual to

atherosclerotic cardiovascular disease.12An estimated 3 million Americans have both diabetes and

hypertension.2Hypertension is about twice as frequent in individuals with diabetes as in those without.2Lifestyle

and genetic factors are important factors contributing to both hypertension and diabetes mellitus. The prevalenceof coexisting hypertension and diabetes appears to be increasing in industrialized nations because populations

are aging and both hypertension and NIDDM incidence increases with age.12Data obtained from death

certificates show that hypertensive disease has been implicated in 4.4% of deaths coded to diabetes, and diabetes

was involved in 10% of deaths coded to hypertensive disease.12Indeed, an estimated 35% to 75% of diabetic

cardiovascular and renal complications can be attributed to hypertension.12Hypertension also contributes to

diabetic retinopathy, which is the leading cause of newly diagnosed blindness in the United States.2For all thesereasons, hypertension and diabetes should be recognized and treated early and aggressively.

Essential hypertension accounts for the majority of hypertension in individuals with diabetes, particularly thosewith NIDDM (type II diabetes), who constitute more than 90% of people with a dual diagnosis of diabetes and

hypertension.12Hypertension often antedates and likely contributes to the development of nephropathy in many

diabetic individuals.34Diabetic nephropathy, which occurs after 15 years of diabetes in one third of people with

IDDM (type I diabetes) and 20% of those with NIDDM, is an important contributing factor to the development

of hypertension in the diabetic individual.12The high BP associated with diabetic nephropathy is usually

characterized by sodium and fluid retention and increased peripheral vascular resistance .12Isolated systolic

hypertension is considerably more common in diabetics, and supine hypertension with orthostatic hypotension is

not uncommon in diabetic individuals with autonomic neuropathy.12

Increasing investigation has delineated an important role for several mechanisms acting together in mediatingthe pathogenesis of vascular disease in the diabetic hypertensive patient. We will review some of the more

important mechanisms of cardiovascular and renal injury associated with diabetes mellitus and hypertension.

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Mechanisms Contributing to Systemic Vascular Disease

Platelet Adhesion and Platelet AggregationPlatelet adhesion and platelet aggregation are often enhanced in both diabetes mellitus and hypertension (Table

1). The precise etiology of enhanced platelet reactivity in both disorders is complex, but it appears that

abnormalities in platelet intracellular divalent cation metabolism may play an integral role. Both platelet

intracellular calcium ([Ca2+

]i) and magnesium ([Mg2+

]i) have seminal roles in plateletactivation.567891011Platelet aggregation is associated with an elevation in [Ca 2+]i, a necessary first event in the

aggregation process. Enhanced platelet [Ca2+]i responses to LDL cholesterol have been observed in NIDDM

patients with and without hypertension.6Similarly, parallel hyperaggregation and platelet release reactions have

been observed in NIDDM patients with and without hypertension.56In vitro, increased [Mg2+]ican exert an

inhibitory effect on platelet aggregation.7There is considerable evidence that many patients with essential

hypertension, as well as those with diabetes mellitus, have elevated platelet [Ca2+]iand decreased

[Mg2+]i.789Consequently, this altered balance between the relative intracellular concentrations of these divalent

cations may contribute to the enhanced platelet aggregation in individuals with diabetes and hypertension.View this table:

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Table 1.

Abnormalities of Platelet Function in Diabetes Mellitus and Hypertension

In diabetes mellitus the balance between coagulative and fibrinolytic activities in the circulation is affected in a

number of ways1011121314(Table 2). A procoagulant state in diabetes appears to be mediated in part by higher-

than-normal levels of a number of coagulation factors. For example, an increase in the endothelium-derived vonWillebrand factor occurs in diabetes mellitus, particularly in association with endothelial cell

injury,1011121314microvascular and macrovascular damage,10and poor diabetic control.121314High

concentrations of factor VIII are related to hyperglycemia, accelerate the rate of thrombin formation, and

contribute to occlusive vascular disease in diabetic patients. Levels of fibrinogen, factor VII, and thrombin-

antithrombin complexes have also been reported to be elevated in diabetic patients.11Elevated coagulation levels

of these factors, particularly fibrinogen, are important for increasing the survival of the provisional clot matrix

on transformation of fibrinogen to fibrin at the site of injured endothelium.11Indeed, increased levels ofthrombin-antithrombin complexes have been observed in diabetic patients in association with enhanced

thrombin generation.11High PAI-1 levels have been observed in patients with diabetes

mellitus.10111213Furthermore, elevated PAI-1 levels have been reported in untreated hypertensive

individuals13and in men with myocardial infarction at risk for reinfarction. Elevated levels of PAI-1 also appear

to be associated with elevated serum levels of insulin and triglycerides.101113Indeed, insulin has been shown to

stimulate PAI-1 synthesis in hepatocytes.13Thus, it appears that hyperinsulinemia and associated insulin

resistance, in addition to being integral to syndrome X, are independent risk factors, along with diabetes and

hypertension, for an abnormal balance between coagulation and fibrinolysis.14View this table:

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Table 2.

Coagulation and Lipoprotein Abnormalities Seen in Patients With Hypertension and Diabetes Mellitus

Lipoprotein AbnormalitiesAlthough hypertension and diabetes mellitus are both independent risk factors for ischemic heart disease, insulinresistance and hyperinsulinemia associated with hypertension and NIDDM also likely contribute to accelerated

atherogenesis15161718(Table 2). A number of metabolic abnormalities are often present in patients with diabetes

and hypertension (Table 2). Plasma levels of lipoprotein(a) have been noted to be elevated in diabetic

individuals, particularly those with poor glycemic control.16By inhibiting fibrinolysis, possibly via fibrinbinding attributable to structural homology with apolipoprotein(a), lipoprotein(a) may delay thrombolysis and

thus contribute to plaque progression. Augmented lipoprotein oxidation has also been observed in diabetic

states.1718Ox-LDL is not recognized by the classic LDL receptor but by the macrophage scavenger

receptors.1718Foam cell uptake of LDL via the scavenger pathway is enhanced by oxidative modification of

LDL. Once taken up by the foam cell, however, Ox-LDL degradation is impaired, which leads to further
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accumulation in the cell. Ox-LDL is toxic to endothelial cells, altering both structure and function.18Ox-LDL

increases adhesion of circulating monocytes to damaged endothelium, increasing their migration into the

vascular intima.18

Glycosylation, the nonenzymatic linkage of glucose to proteins, has also been found to alter LDL particles in

vivo.18Importantly, apolipoprotein B, which regulates receptor-mediated uptake of LDL, can undergo

glycosylation, thereby facilitating its atherogenicity in diabetic individuals. Similar to Ox-LDL, glycated LDL

can enhance foam cell formation and is less well recognized by the native LDL receptor.18

Glycated LDL is alsoimmunogenic, forming antibody-lipoprotein complexes that stimulate foam cell formation and enhance platelet

aggregation.18Compared with normal LDL, glycated LDL sequestered in the arterial intima has a greaterpropensity to become bound by glucose-mediated cross-links to local matrix proteins. Once this occurs, the LDL

particles may undergo even more extensive glycative and oxidative modification.18Finally, evidence is

accumulating that glycation in itself may render the particle more susceptible than normal to further oxidative

damage.18

Endothelial Dysfunction in Diabetes and HypertensionA number of anatomic and functional abnormalities of the vascular endothelium are associated with both

diabetes mellitus and hypertension19(Table 3). In insulin-resistant states, endothelial cell lipoprotein lipase

activity is decreased, as is the conversion of cholesterol esterenriched very-low-density lipoprotein to LDL.

The resulting large and abnormal cholesterol esterenriched very-low-density lipoprotein is injurious to

endothelial cells after receptor-mediated uptake.19Hyperglycemia appears to contribute to endothelial

dysfunction as well.19

20

21

Hyperglycemia activates protein kinase C in endothelial cells,20

which in turn mayaccount for increased production of vasoconstrictor prostaglandins, endothelia and ACE, and platelet and

vascular growth factors, which directly and indirectly enhance vasomotor reactivity and vascular remodeling

and growth.17181920Furthermore, hyperglycemia alters endothelial cell matrix production, which may contribute

to basement membrane thickening. Hyperglycemia increases endothelial cell collagen IV and fibronectin

synthesis and increases the activity of enzymes involved in collagen synthesis.21Hyperglycemia also delays cellreplication and increases endothelial cell death in part by enhancing oxidation and glycation.18

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Table 3.

Alterations in Vascular Endothelium Associated With Diabetes Mellitus and Hypertension

Additional metabolic and hemodynamic factors may contribute to endothelial dysfunction in diabetes and

hypertension. Hypercholesterolemia and perhaps hypertriglyceridemia impair endothelium-dependent

relaxation.22Both insulin and IGF have potentially important effects on endothelial cells. Insulin appears to have

a modulating influence on glucose stimulation of protein kinase C and diacylglycerol in endothelial cells.23One

hypothesis for endothelial dysfunction in diabetes relates to elevated protein kinase C activity in diabeticvascular endothelium, which may enhance vascular tone, permeability, and atherosclerosis.23Elevated

diacylglycerol and protein kinase C levels are induced by hyperglycemia; insulin treatment that achieves

euglycemia can prevent the increase in diacylglycerol levels and protein kinase C activity .2324These results

suggest that impaired insulin action, as exists in NIDDM and hypertension, may contribute to the endothelial

dysfunction seen in these disorders. However, a recent report suggests that hypertension is not associated withimpaired carbohydrate metabolism or dyslipidemia, but endothelium-dependent vasodilation is preserved.25This

report provides additional credence to the concept that the metabolic abnormalities that often accompanyhypertension and diabetes mellitus play a pivotal role in the development of endothelial dysfunction.

VSMC Abnormalities: Role of Insulin and IGF-1The concept that decreased insulin action on VSMCs may explain the exaggerated vascular resistance associatedwith both NIDDM and IDDM was carefully reviewed in our previous updates on diabetes mellitus and

hypertension.1214Accordingly, the current material represents an update of the understanding of this important

topic. Research conducted over the past several years has shown that VSMC tissue, like skeletal muscle and

adipocytes, is sensitive to the metabolic effects of both insulin and IGF-1.142627282930In this regard, these

studies have confirmed that insulin and IGF-1 regulate VSMC cation metabolism (Fig 1) and that bothhormones stimulate VSMC glucose uptake and metabolism.142830Insulin and IGF-1 are structurally related,

share receptors, and have similar postreceptor actions. Unlike insulin, which must traverse the endothelium

before acting on VSMCs in vivo, IGF-1 is synthesized by VSMCs and is more likely to act in an autocrine and

paracrine fashion. Importantly, recent investigations indicate that IGF-1, like insulin, attenuates vasoconstrictive

responses and increases blood flow in regional vascular beds and lowers BP in healthy individuals.2627IGF-1 is

expressed, synthesized, and secreted by VSMCs and appears to exert its actions on VSMCs in an autocrine
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fashion.14IGF-1, like insulin,29increases VSMC Na+,K+-ATPase activity, suggesting one mechanism by which

IGF-1 modulates VSMC [Ca2+]i(Fig 1)and attenuates vascular contractility.1430

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Figure 1.Diagram shows mechanisms regulating divalent cation metabolism and contraction in VSMCs and proposed

targets of insulin and IGF-1 action. Pivotal steps in regulation of divalent cation metabolism are indicated by

circled numbers. DAG indicates diacylglycerol; IP3, inositol 1,4,5-trisphosphate.

Roles of Insulin and IGF-1 in AtherosclerosisInsulin and IGF-1 may exert their atherogenic effects through influences on both vascular endothelial cells and

VSMCs.1430Both insulin and IGF-1 increase mitogenic signaling pathways and thymidine incorporation into

DNA in vascular endothelial cells and VSMCs.142430Insulin likely mediates most of its VSMC proliferative

effects through IGF-1 rather than insulin receptors.31Both IGF-1 and IGF-2 enhance proteoglycan synthesis by

microvascular and large-vessel endothelial cells.21Insulin also increases the uptake and esterification of

lipoprotein cholesterol by VSMCs and decreases its deesterification and release by these cells.1425Insulin

resistance and hyperinsulinemia may also promote atherosclerosis by retarding the fibrinolytic

process.121314Insulin stimulates PAI-1 production,12and there is a strong relation between plasma insulin levelsand fibrinogen and PAI-1 levels.1213Both insulin and IGF-1 appear to function as progression factors or

cofactors and promote the proliferative properties of several cytokines, including tumor necrosis

factor.1424Thus, elevated circulating levels of insulin, as exist in type II diabetes in many patients with essentialhypertension, may contribute directly or in conjunction with IGF to the accelerated atherosclerosis associated

with these conditions.Role of Hyperglycemia in the Vascular Abnormalities Associated With Diabetes andHypertensionChronic hyperglycemia may exacerbate the vascular disease associated with diabetes mellitus and

hypertension.30At high concentrations glucose has a direct, toxic effect (independent of osmolality) on vascular

endothelial cells.192021This toxic effect may lead to decreased endothelium-mediated vascular relaxation,

increased vasoconstriction, promotion of VSMC hyperplasia, vascular remodeling, and atherosclerotic

events.1430High glucose concentrations, as seen in the diabetic hyperglycemic state, have been shown to induce

the overexpression of fibronectin and collagen IV in cultured human vascular endothelial cells.32Increased

expression of fibronectin and collagen IV further contributes to endothelial cell dysfunction. Fibronectin is a

glycoprotein with a critical role in cell matrix interactions,32and its overexpression may contribute to both

diabetic vascular disease30and thickening of the glomerular basement membrane and mesangial hyperplasia.32Hyperglycemia also accelerates the formation of nonenzymatic advanced glycosylation products, which

accumulate in vascular tissue33(Table 4). There are a number of sites where nonenzymatic protein

glycosylation can affect key processes in atherogenesis and vascular remodeling. Indeed, a close association has

been noted between the accumulation of increased levels of AGE and vascular disease.33Glycosylation of

collagen results in increased rigidity and decreased responsiveness to collagenase (proteinase digestion) .33There

is also abnormal covalent cross-linking and an enhanced ability to bind nonglycosylated proteins, such as LDL,

albumin, and immunoglobulins. Lipoprotein binding to glycosylated collagen may not only prolong its intimal

residence time but also enhance its susceptibility to oxidation within the arterial intima.33View this table:

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Table 4.
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Potential Vascular Effects of Nonenzymatic Protein Glycosylation in Diabetes Associated With Hypertension

A membrane-associated macrophage receptor that specifically recognizes proteins to which AGE are bound has

been identified.33The binding of these proteins to macrophage receptors induces the synthesis and secretion of

tumor necrosis factor and interleukin-1.33These cytokines in turn stimulate other cells to increase protein

synthesis and to proliferate.33AGE proteins also increase platelet-derived growth factor secretion, enhance

endothelial cell permeability, and are chemotactic for blood monocytes.33Apolipoproteins and LDL are

glycosylated, and this process leads to enhanced cholesterol ester synthesis and accumulation in macrophages

and impaired degradation and release.33Thus, prolonged hyperglycemia may result in enhanced production of

extracellular matrix and in proliferation of VSMCs as a result of an increase in the number of highly cross-

linked proteins with AGE, with resulting vascular hypertrophy and remodeling. The fact that chronic

hyperglycemia is associated with decreased elasticity of vascular arterial wall connective tissue and elevated

pulse pressures may be related in part to AGE.3033

Several other mechanisms associated with chronic hyperglycemia may also contribute to the hypertension

frequently accompanying diabetes mellitus. For example, elevated glucose levels have been reported to increase

VSMC [Ca2+]i,34which could result in increased vascular tone.21430Glucose can be extracted by renal proximal

tubule cells by an active process in which sodium and glucose cotransporters are involved. Hyperglycemia

results in hyperfiltration of glucose, which in turn stimulates the proximal tubular sodium-glucose

cotransporter.35This process is insulin independent and rapidly operative, as elevated proximal tubular cell

sodium concentration and increased Na

+

,K

+

-ATPase activity occur within days of inducing hyperglycemia.

35

Theresultant sodium retention caused by hyperglycemia can help explain the increased total exchangeable sodium

seen in diabetic hypertensive patients.114


Metabolic Abnormalities and Renal Glomerular Disease: Analogy toVascular Atherosclerosis

Pathophysiological changes of diabetic nephropathy are histologically different from those of other types of

renal disease.13637In humans, mesangial expansion leads to the earliest lesions seen in IDDM.38In experimental

studies the earliest pathological change is an increase in the thickness of the glomerular basement membrane;usually the volume of the glomerulus is increased compared with that of nondiabetic subjects. Subsequently, the

amount of matrix in the mesangium increases, and in some patients this mesangial expansion can progress to

increasingly more severe diffuse or nodular glomerulosclerosis.

36

Basement membranes are specialized regionsof extracellular matrix composed of type IV collagen, laminin, entactin/nidogen, and proteoglycans, which

together form a complex meshlike structure.37Sievelike permselectivity is one important function of basement

membrane that may be gradually lost in diabetes mellitus, with associated progressively increasingproteinuria.37Nonenzymatic glycosylation of long-lived proteins, such as the basement membrane components

type IV collagen and laminin, and cross-link formation of these components appear to lead to modification of

basement membrane ultrastructure and loss of permselectivity.37AGE can also have important influences on

renal mesangium. AGE binding to mesangial cells can lead to a significant increase in fibronectin and several

other mesangial structural proteins.37AGE binding to mesangial AGE receptors can lead to an increase in

basement membrane collagen as well.37Thus, hyperglycemia clearly contributes to the development of diabetic

nephropathy.36

Mesangial cells share many properties with VSMCs. They are known to contract in response to vasoactive

agents such as angiotensin II, vasopressive platelet-activating factor, and endothelin-1.119394041Contraction of

mesangial cells is important because the mesangium binds together capillary loops; contraction of themesangium thus can alter capillary flow, pressures, or both. The mesangial cell synthesizes several growthfactors that may act in an autocrine/paracrine fashion. These include IGF-1, platelet-derived growth factor,

platelet-activating factor, endothelin, prostanoids, and interleukin-1. Thus, the mesangial cell has supportive,

filtrative, and synthetic functions. The glomerular endothelial cell is separated from the mesangial cell of the

kidney only by its basement membrane; passage of substances between these two cells is easily accomplished.

Substances elaborated by the endothelium affect mesangial cell growth contraction and protein synthesis. For

example, endothelin-1 increases growth and extracellular matrix production by mesangial cells. Endothelium-derived relaxing factor and vasodilator prostaglandins inhibit mesangial cell growth and

contraction.39Furthermore, increased local production of growth factors by stimulated endothelial and

inflammatory cells can result in mesangial expansion. For example, endothelial damage can result in platelet

activation, with release of platelet-derived growth factor and other growth factors that can also enhance

mesangial cell proliferation and matrix overproduction.1939

Mesangial cell abnormalities typically appear after 5 to 15 years of clinical diabetes in individuals with type Idisease.363738The most common abnormality observed by light microscopy is diffuse intercapillary sclerosis

due to expansion of the mesangium. Nodular intercapillary sclerosis is seen in approximately 25% of patients
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with diabetic nephropathy.363738The pathophysiological alterations that occur with focal and diffuse

glomerulosclerosis are similar to those that occur in vascular glomerulosclerosis, with mesangial cell changes

paralleling those in VSMCs, including proliferation, hypertrophy, foam cell accumulation, appearance of

extracellular matrix material, deposits of amorphous debris, and evolving sclerosis. The observed mesangial

expansion is primarily related to mesangial cell hypertrophy and an accumulation of mesangial cell matrix. A

number of hormones have been demonstrated to alter mesangial cell growth in vitro, but only angiotensin II and

vasopressin have been clearly demonstrated to promote hypertrophy,19

36

37

38

which is more prominent inglomerulosclerosis than is proliferation. This may help explain why ACE inhibitors have been shown to slow

the progression of glomerulosclerosis in both type I and type II diabetic patients.4243Diabetic nephropathy has become the leading cause of end-stage renal disease in the United

States.2363738Hypertension is acknowledged to be a major risk factor in the progression of diabetic renal

disease.2Diabetic nephropathy, defined as the appearance of proteinuria, elevated arterial BP, and diminished

GFR, will develop in as many as 40% of IDDM patients .2363738In patients with the onset of diabetes at an early

age, renal disease is an important contributor to mortality, accounting for up to 31% of all deaths .2363738Renal

disease also complicates NIDDM in adults and contributes significantly to morbidity and mortality in thisgroup.236A smaller percentage of patients with NIDDM develop renal disease, and the incidence of end-stage

renal disease is strongly related to the duration of diabetes. However, more than 50% of diabetic end-stage renal

disease is associated with NIDDM because this form of diabetes constitutes more than 90% of diabetic

patients.236

In both types of diabetes mellitus the appearance of clinically detectable proteinuria (>200 g/min of urinaryalbumin excretion) signals the onset of the relentless progression of diabetic nephropathy, which is typicallyfollowed by deterioration to end-stage renal disease.2363738Currently, it is believed that diabetic nephropathy

develops as a result of the interplay of the metabolic abnormalities inherent to diabetes (eg, hyperglycemia) and

hemodynamic abnormalities of the renal microcirculation that result in progressive structural and functional

glomerular abnormalities.363738


Treatment of Hypertension in Patients with Diabetes Mellitus

General Goals of TherapyNo large, population-based, randomized trials of hypertension treatment in diabetic patients have been

conducted. Nevertheless, as proposed by a recent consensus statement,2the goal of treating hypertension in

diabetic patients should be to prevent death and disability associated with high BP. In addition, other reversiblerisk factors for cardiovascular disease need to be addressed. For example, target-organ involvement should be

considered when a treatment plan is being formulated. The major focus of clinical and investigative efforts has

been on retarding the progression of diabetic nephropathy (see below) and to a lesser extent reducing

cardiovascular morbidity and mortality. The diagnosis of hypertension should be based on multiple BP

measurements obtained in a standardized fashion on at least three occasions. Supine, sitting, and standing BPs

should be measured in all diabetic patients. Automated ambulatory BP monitoring may be especially helpful in

the diabetic patient for evaluating BP control over a 24-hour period to document the absence of the usual

nocturnal fall in BP in diabetes (especially with autonomic dysfunction or nephropathy). Ambulatory BP

monitoring may also be useful in documenting episodic hypertension, orthostatic hypotension, or resistant

hypertension, which are relatively common in diabetic individuals with accompanying hypertension.2What Is the BP Goal in Diabetics With Hypertension?Although the optimal BP level during antihypertensive treatment in patients with diabetic nephropathy has not

been defined, a review of the relationship between the rate of fall in GFR and the BP level duringantihypertensive treatments suggests that we should strive for lower goal BP than recommended by current

guidelines.244First, the benefit of reducing BP has been demonstrated most clearly when treatment is instituted

before GFR is markedly reduced.44This emphasizes the concept that efforts to reduce BP should begin before

serum creatinine is elevated. Second, the best results apparently have been achieved by reducing BP below

conventionally accepted levels.244Indeed, the smallest decline in renal function is found in patients with BP

levels around 130/85 mm Hg, a level that is readily attainable during treatment in incipient diabetic nephropathy

before the decline in GFR has started. This is also the goal of BP attainment recommended in a recent

consensus244(Fig 2).
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Figure 2.Chart shows suggested approach to hypertension therapy in diabetic individuals. Treatment goal is to maintain

BP at less than 130/85 mm Hg. Diabetic renal disease, autonomic dysfunction, and adverse effects on glucose

and lipid metabolism must be considered before the course of therapeutic intervention is chosen. (Adapted from

Reference 22with modification.)

Nonpharmacological Therapy in Diabetic Hypertensive PatientsLifestyle modifications may serve as definitive therapy for mild hypertension in diabetic patients or as an

adjunct to pharmacological therapy to lower the number and dose of antihypertensive drugs.2The dietrecommended by the American Diabetes Association, which is low in calories and fat, high in carbohydrate and

soluble fiber, and moderately low in protein, has been reported to lower BP in diabetic patients .2Moderate salt

restriction reduces systolic BP, which is often inordinately elevated in diabetic patients.2Weight reduction is

important, particularly in type II diabetics, and improves glucose tolerance as well as reducing BP.28For

example, for each 10-lb weight reduction, systolic and diastolic pressures can be expected to decrease by 10 and

5 mm Hg, respectively.28Moderate but regular aerobic exercise improves glycemic and lipemic control andhelps with weight reduction.

Results of the Diabetes Control and Complications Trial (DCCT),45a 7-year study of more than 1440 patients,

demonstrated that intensive insulin therapy reduced the occurrence of microalbuminuria by 39% and that of

albuminuria by 54%. In addition, intensified therapy patients had lower rates of serious retinopathy requiring

photocoagulation, lower rates of decreased visual acuity, and fewer cases of nephropathy. Similar results were

reported from a study designed to test the hypothesis that optimized glycemic control in type I diabetic

recipients of renal allografts will prevent or delay diabetic renal lesions in the allograft.46This study was a

prospective, controlled, and randomized trial of glycemic control in an inception cohort (ie, all patients were at

stage 0 for diabetic renal lesions in the graft when randomized to the trial) of type I diabetic renal allograft

recipients. The experimental group had maximized glycemic control, and the standard group received standard

clinical diabetic care. Patients underwent baseline (before transplant) and 5-year posttransplant allograftbiopsies. More than a twofold increase in the volume fraction of mesangial matrix per glomerulus occurred, as

well as a threefold increase in arteriolar hyalinosis, greater widening of the glomerular basement membrane, and

increase of volume fraction of the total mesangium in the patients receiving standard treatment compared with

those with maximized glycemic control. This trial indicates a causal relationship between hyperglycemia and an

important lesion of diabetic nephropathy, mesangial matrix expansion, in renal allografts transplanted into

diabetic recipients. In summary, newly available data suggest that aggressive control of blood sugar in the veryearly stages of this disease process can provide significant protection against its development.

Prospective clinical trials in type I diabetic patients with overt nephropathy4748showed that even with moderate

protein restriction, renal function is stabilized in diabetic nephropathy. Although both studies were limited to

diabetic patients with overt nephropathy, it has been suggested that dietary protein restriction will produce even

better results if implemented during the early stages of diabetic nephropathy. In recognition of these data, the

American Diabetes Association has recommended that dietary protein be restricted to 0.8 g/kg body wt per day

in all patients with diabetes other than children and pregnant or lactating women. It is still unclear to what extent

dietary protein intake needs to be restricted to obtain maximal effects on delaying the progression of renal

disease, but without producing metabolic side effects or malnutrition. For most diabetic patients, restricting

dietary protein to 0.8 g/kg body wt per day would constitute a significant but practical reduction of their usual
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protein intake and would be likely to have a beneficial effect. Patients are also more likely to adhere to

moderately protein-restricted diets than to more drastic restrictions.

BP Control and Progression of Diabetic NephropathyHypertension invariably complicates the course of patients with diabetic nephropathy. Of the 35% to 40% of

either IDDM or NIDDM patients who ultimately develop nephropathy, all at some time in their natural history

will be hypertensive.2Numerous clinical trials of both IDDM and NIDDM hypertensive patients with

nephropathy have assessed diverse forms of BP-lowering therapy on the progression of renal dis

hipertnsi dm

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