Niddm And Ambulatory Bp

The influence of changes in metabolic control

Shift from sulfonulurea to insulin in poorly controlled elderly NIDDM patient improved glycemic control but ambulatory BP after one year was unaffected perhaps due to weight gain [25]. Neither metformin nor glibenclamide affected ambulatory BP in a study of 1 month duration [26] Metformin for 12 weeks improved glycemic control while ambulatory BP was unaffected [27]. Glitazone therapy has reduced both HbAlc and ambulatory BP [28].

Comparison with healthy individuals

Some discrepancies exist. One study has reported an increase in 24-h systolic (but not diastolic) BP in normoalbuminuric diabetic patients [29]. Two studies did not found any difference in 24-h average BP, however the nocturnal reduction of systolic BP was impaired in normoalbuminuric patients [30,31].

If patients (UAE not specified) and healthy subjects were divided into groups with and without hypertension no statistical difference of 24-h BP have been reported [7,32].

The relation to abnormal albuminuria.

No difference in day-time or 24-h BP were noticed between normo- and microalbuminuric patients [29,31,33-36]. In contrast ambulatory BP was reported significantly higher in microalbuminuric patients (90 % males, 50 % non-Caucasians) than in normoalbuminuric patients (71 % males, 28 % non-Caucasians) [37]. In NIDDM both ambulatory and clinic BP correlates with UAE roughly to a similar extent [29,37] although one study using albumin/creatinin ratio reported no correlation [38]. Ambulatory BP is higher in patients with diabetic nephropathy than in normoalbuminuric patients [30,39].

Abnormal diurnal BP pattern (high night BP) are seen in patients with microalbuminuria [31,35,36,39-42] and overt diabetic nephropathy [30,39,41]. As in IDDM this abnormality seems closely linked to the presence of autonomic neuropathy [30,31,43,45].

The time course of ambulatory BP

In patients receiving standard clinical care including antihypertensive medication, 24-h BP was remarkable stable in both normo- and microalbuminuric patients during an observation period of 4.6 years. Individual changes in both systolic and diastolic 24-h BP were related to changes in UAE [45]. The evolution of UAE did not differ between patients with and without abnormal diurnal BP profile at baseline [45].

Non-dipper: Autonomic neuropathy, nephropathy and extra-cellular volume [ECV].

Numerous studies in mixed IDDM and NIDDM populations or unclassified diabetic patients have demonstrated a reduction or (in few patients) even a reversal of the normal nocturnal decline of BP [11-13,46-50] in patients with autonomic neuropathy. Also in homogenous NIDDM diabetic patients several studies demonstrate [30,34,43,51,52] the association between diabetic nephropathy, signs of autonomic neuropathy or both and a blunted diurnal variation of blood pressure. According to two studies increased nocturnal sympathetic activity (rather than expansion of ECV) seems to be involved in reduced nocturnal BP in NIDDM patients with nephropathy [30,51]. However, a physiological defence against nocturnal volume expansion may explain why a lower night level of aldosterone and a higher level of plasma atrial natriuretic peptide have been reported in "non-dippers", who also had more pronounced signs of autonomic neuropathy than "dippers" [51].

Postprandial hypotension is also a phenomenon observed in patients with autonomic neuropathy [53,54].

The relation to insulin resistance and sodium-lithium counter transport

Ambulatory systolic BP (and clinic systolic BP) correlated in one study with glucose disposal rate, but not with fasting insulin level [55]. However, this relation was not confirmed in another study (S Nielsen personal communication) [33]. No relation has been found between ambulatory BP and sodium-lithium counter transport [37].Insulin resistance has in one study been related to reduced nocturnal BP fall [56].

The relation to diabetic retinopathy and to ambulatory pulse pressure A relation between "non-dipping" status and retinopathy has been suggested [45]. Ambulatory pulse pressure is related to macro- and microvascular complications including retinopathy [57]. Ambulatory BP is similar in patients with and without of macular oedema [58].

IDDM AND AMBULATORY BP The influence of diabetes duration

Two cross sectional study reports a reduction of the nocturnal BP fall in long term normoalbuminuric diabetic patients [59,60].

The influence of gender

The well-known BP difference between healthy males and females seems attenuated in IDDM [60-62].

The influence of short term changes in metabolic control

This question has so far never been addressed by well designed intervention studies employing ambulatory BP. Clinic BP has been reported lower after short term improvement of diabetic control by insulin pumps (24-h insulin dose unchanged) [63]. Intra-arterial BP (10-h day time average) was also reduced after improved glycemic control achieved by increasing insulin dose in most patients [64]. No significant change in clinic BP was observed in a study where poor metabolic control was obtained by reducing insulin dose [65].

Recently it has been suggested that intensive insulin therapy by hyperinsulinemia (1.0 U/kg) is associated with high night blood pressure [66]. However, it has convincingly been demonstrated that tight blood glucose control obtained by normal insulin doses (0.6 U/kg) by no means affects the normal nocturnal blood pressure reduction [67].

The influence of smoking and type of day (work day/day-off)

We have compared ambulatory BP in 16 normoalbuminuric smokers and non-smokers without hypertension. Systolic BP was slightly higher (3mmHg day time, 5 mmHg night time) in smokers, but this failed to reach statistical significance [68]. In a larger study encompassing 24 normoalbuminuric smokers and non-smokers diastolic day and night BP was significantly higher (3.9 and 3.5 mmHg respectively) in smokers. In addition a dose response relationship was demonstrated [69]. Notably, this effect of smoking in diabetic individuals contrast the well known finding of a lower night BP in non-diabetic smokers [68,70]. Smoking does not affect the night/day ratio of BP in diabetes [68,69,71].

Day-time BP is significantly lower (5 mmHg) on a day off than on a work day [60].

Comparison with healthy individuals

Most studies [72-77], but not all [61,78,79] agree that day-time BP is comparable between normoalbuminuric diabetic patients and healthy subjects. Since ambulatory BP is higher in normoalbuminuric females than in healthy females [60,61], the result of a comparison between a diabetic and a control population depends on the sex distribution. Also the majority of investigators found no difference in the diurnal BP profile [72,73,76-79,80,81] In contrast two studies have reported a slightly reduced nocturnal BP fall [61,74,82] and one study has surprisingly described a much higher night/day ratio of BP in normoalbuminuric patients [75].

Recently ambulatory BP was compared in normoalbuminuric IDDM patients and healthy controls (n=55 in each group) [61]. In contrast to previous comparison [72] (n=34 in each group) a slightly but significantly higher ambulatory BP was observed in diabetic patients. This may be explained by a higher proportion of women (42% vs. 29% in the previous study) and partly by increased statistical power due to the larger number of patients. Ambulatory BP (24h and day) was higher in diabetic women than in control women but no difference (for 24h and day time) was observed between diabetic men and control men. The night dip in BP was similar in diabetic and control women but a reduced night dip was reported for diabetic men compared with control men. Diastolic night dip in BP correlated in the total diabetic population with indices of autonomic neuropathy [61].

With this exception, the diversities are minor and may be explained by varying diabetes duration or proportion of males/females. Thus, as a rule normoalbuminuric patients have a 24-h BP profile very similar to healthy control subjects (Fig 1).

Figure 1. Twenty-four hour profile of mean systolic and diastolic BP for type 1 diabetic patients and healthy controls. Diabetic patients with nephropathy and without antihypertensive treatment (n=13, filled triangles), microalbuminuric patients (n=26, open triangles), normoalbuminuric patients (n=26, open circles) and healthy individuals (n=26, filled circles). From [90] with permission.

The relation to abnormal albuminuria

This subject has been reviewed [83]. Ambulatory BP is significantly higher and the diurnal BP pattern is abnormal in consecutively studied patients compared with healthy controls [84]. This largely depends on abnormal albuminuria present in some of the patients [84]. Ambulatory BP is significantly increased in microalbuminuric as compared with normoalbuminuric patients [72,85-87]. In some studies day-time BP were only numerically but not statistically significantly higher in microalbuminuric patients [81,82,88,89]. This is probably due to lower number of microalbuminuric patients in these studies. The night/day ratio of diastolic BP is significantly higher in microalbuminuric patients than in healthy individuals [90] and night/day ratio for normoalbuminuric patients is in between [19,90]. If the comparison between


2400 0400 0800 1200 1600 2000 2400

Clock time micro- and normoalbuminuric patients is restricted to patients in good metabolic control and without any signs of autonomic neuropathy day time BP is still elevated in microalbuminuric patients [77]. Ambulatory BP correlates more closely with UAE than clinic BP [72,73,77,78,88](Table 1). This is probably due to the multiplicity of measurements rather than their quality as true ambulatory values.

Table 1 Correlations between blood pressure and urinary albumin excretion in combined normo-and microalbuminuric type 1 diabetic patients.

Hansen et al [72]

Moore et al [78]

Benhamou et al [73]

Lurbe et al [88]


Three overnight collections

One 24h collection

Three overnight collections

Three 24h collections


Normo (n=34) Micro (n=34)

Normo (n=27) Micro (n=11)

Normo (n=23) Micro (n=12)

Normo (n=34) Micro (n=11)

UAE vs. clinic BP (auscultatory)

r=0.21, NS (systolic)


r=-0.01, NS (systolic)

r=0.19, NS (MAP)

UAE vs day time BP

r=0.45, p<0.05 (systolic)


r=0.17, NS (systolic)

r=0.035, p<0.05 (MAP)

UAE vs. night time BP

r=0.53, p<0.00001 (systolic)

r=0.38, p<0.05 (systolic)

r=0.60, p<0.01 (MAP)

UAE vs. 24h BP

r=0.49, p<0.0001 (systolic)

(systolic) r=0.60, p<0.01 (diastolic)

r=0.29, NS (systolic)

Ambulatory BP is further increased in patients with overt diabetic nephropathy [90] (Fig 1) and the circadian variation of BP is severely disturbed in patients with advanced diabetic nephropathy [82,90,91] (Fig 2).

The transition from normo- to microalbuminuria

In a recent study 40 initially normoalbuminuric patients were reinvestigated with ambulatory BP monitoring and measurement of UAE after a mean period of 3 years [92]. Six patients progressed to microalbuminuria and their baseline UAE (9.7 ^g min-1) was statistically significantly higher than baseline UAE in non-progressors (5.5 ^g min-1). Importantly, no difference was noticed between 24-h ambulatory BP at baseline in progressors (124/74 mmHg) and non-progressors (124/75 mmHg). However, the rise in UAE even to low microalbuminuria (31.7 ^g min-1) were accompanied with an increase in 24-h ambulatory BP (12/5 mmHg) which was statistically higher than the increase in non-progressors (4/2 mmHg). No statistically significant changes were seen if these changes were evaluated from the average of three clinic BP measurements at baseline and at follow up [92]. The diastolic night/day ratio at baseline was significantly higher in progressors (0.88) than in non-progressors (0.81), but no further increase was found in progressors during follow-up and the overlap between the two groups was large.


D1 D2 D3 D4

Figure 2. Individual night/day ratio for diastolic BP in healthy individuals and type 1 diabetic patients. C= control subjects (n=26), D1= normoalbuminuric patients (n=26), D2= microalbuminuric patients (n=26), D3= patients with diabetic nephropathy without antihypertensive treatment (n=13), D4= patients with diabetic nephropathy with antihypertensive treatment. From [90] with permission.

In a recent study Lurbe et al. argue that increased night BP in normoalbuminuric patients precedes progression to microalbuminuria [93]. The study has been debated [94]: Urinary albumin excretion measured at every 3 months visits was surprisingly stable during the period of 27 months from the first (11.6 ± 8.5 mg/24h) to the final (16.8 ± 10.3 mg/24h) evaluation in patients who developed microalbuminuria ( > 30 mg/24h) at the following two visits. The night/day ratio of systolic BP was similar at the first evaluation in the group who developed microalbuminuria (0.89) and in the group who persisted normoalbuminuric (0.89). The frequency of microalbuminuria (21.9 %) in patients with an abnormal BP at the first evaluation did not differ significantly


from the frequency of microalbuminuria (16.3 %) in patients with normal diurnal BP variation. This finding implies that ambulatory BP measured approximately two years before progression to microalbuminuria cannot foresee this event. The final ambulatory BP performed just (approx 6 months) before the patients fulfilled the criteria for microalbuminuria showed high night BP. This information is of limited in clinical practice. At this late stage of progression to microalbuminuria the demonstration of elevated night BP is compatible with a parallel progression of the kidney disease and increase in night BP.

In a cross sectional study of normoalbuminuric patients the 24-h BP were significantly higher in patients with "high" normal UAE than in patients with "low" normal UAE [95,96]. Similar results have been reported in a study comparing "high" normoalbuminuric patients with healthy individuals [97].

These results support the idea that rise in UAE and ambulatory BP cannot be separated even in the very early phase of diabetic nephropathy.

Non-dipper: Autonomic neuropathy, nephropathy and extracellular volume (ECV)

In IDDM the presence of autonomic neuropathy is clearly associated with impaired reduction of night BP [10,98,99]. Autonomic neuropathy and diabetic nephropathy are closely associated [100-103]. Their relative role for the abnormal diurnal variation in blood pressure is therefore difficult to ascertain. However, the literature gives no examples of a group of IDDM patients with blunted diurnal variation of BP without concomitant signs of autonomic neuropathy either by formal test [98,99] or by increased heart rate [72]. Indeed autonomic dysfunction can be documented even in "high" normoalbuminuric patients if refined test (spectral analysis of heart rate variability) is employed [96]. In contrast an impaired reduction of night BP and increased heart rate is seen in long term diabetic patients who are stricly normoalbuminuric [59,60].

Naturally the question of a possible causative role of autonomic neuropathy for the development of diabetic nephropathy has arisen [104,105]. The link could be a higher night BP, which is more readily transmitted to the glomeruli because of renal vasodilation. Alternatively early autonomic dysfunction may just be part of a syndrome indicative of later diabetic complications in patients with suboptimal glycemic control [96,106]. A retrospective study in patients with diabetic nephropathy has described a faster decline of renal function in patients with a "non-dipping" BP profile compared with "dippers" [107]. However there was no baseline or follow-up measurement of ambulatory BP, which was measured at one time point only during a 6-year observation period. Since renal function was already reduced in "non-dippers" at the time when the ambulatory BP measurement was performed it is not possible to postulate a cause/effect relationship.

Expanded ECV has been described even in normoalbuminuric "non-dippers"[108]. Two lines of evidence suggest that homeostasis of ECV is associated with elevated night BP in particular in patients abnormal albuminuria. First plasma aldosteron is reported significantly lower in "non-dipping" patients with incipient diabetic nephropathy, which could be interpreted as a defence again fluid retention [109]. Second, in patients with overt diabetic nephropathy, elevated nocturnal BP is associated with expansion of ECV This may reflect the result of a nocturnal shift of fluid from the interstitial to the intravascular space [110]. This view has been challenged by a study, which did not find any association between elevated night BP and ECV in IDDM patients with nephropathy [111].

Increased QTc dispersion is associated with high night BP in normoalbuminuric patients. The pathophysiological link is unclarified but may involve both autonomic dysfunction and left ventricular hypertrophy [112].

The relation to glomerular filtration rate (GFR) and renal strucure.

A negative correlation between ambulatory BP and GFR has been described in microalbuminuric patients [78,113]. Non dippers with microalbuminuria or overt nephropathy seems not to have a reduced GFR [109-111]. One study in normoalbuminuric patients reported a higher night BP and expanded ECV (23 litre) in patients with glomerular hyperfiltration compared with the group with normofiltration (19 litre) [108]. Despite similar methods (Cr EDTA single shot) ECV is found inexplicable high in this latter study [108] compared with the two previously mentioned studies dealing with nephropathy (14 litre) [108,111]. In adolescents who have had performed a kidney biopsy the nocturnal BP (and heart rate) correlated with basal membrane thickness. This is further indirect support for the hypothesis that early autonomic dysfunction and related high (night) BP could be causative related to ultrastructural renal damage [114].

The relation to diabetic retinopathy

Elevated night BP is reported in patients with more advanced signs of diabetic retinopathy. Importantly this association was described in strictly normoalbuminuric patients excluding the confounding effect of diabetic kidney disease [115].

Predisposition to hypertension and diabetic nephropathy

The controversy of predisposition to hypertension and development of diabetic nephropathy has recently been addressed by performing ambulatory BP in parents of IDDM patients with and without diabetic nephropathy [116]. The 24h BP was almost identical among the two groups of parents without antihypertensive medication (126/76 vs. 126/74 mmHg respectively, NS). The frequency of hypertension defined as use of antihypertensive medication or a 24h BP > 135/85 mmHg was significantly higher in parents of patients with nephropathy (57%) than in parents of patients without nephropathy (41%).

Relation to pregnancy

Ambulatory BP monitoring has been applied to both non-diabetic [117] (several publications) and diabetic pregnant women with purpose of early identification of patients at risk for developing preeclampsia [118]. So far only microalbuminuria can predict this event in diabetes [119].

Diabetes 2

Diabetes 2

Diabetes is a disease that affects the way your body uses food. Normally, your body converts sugars, starches and other foods into a form of sugar called glucose. Your body uses glucose for fuel. The cells receive the glucose through the bloodstream. They then use insulin a hormone made by the pancreas to absorb the glucose, convert it into energy, and either use it or store it for later use. Learn more...

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