Postprandial effects of long-term niacin/laropiprant use on glucose and lipid metabolism and on cardiovascular risk in patients with polycystic ovary syndrome.

AIM: This study investigated the effect of long-term niacin/laropiprant therapy on CV risk and IR in obese women with PCOS. METHODS: In this double-blind randomized placebo-controlled trial, 13 and 12 PCOS women completed a 12 week course of niacin/laropiprant or placebo, respectively. Fasted subjects had an endothelial function test (EndoPat2000) and then consumed a mixed meal with blood sampled postprandially for 6 h before and after intervention. RESULTS: By 12 weeks, niacin/laropiprant lowered low-density lipoprotein cholesterol (LDL-c) (13%) and increased HDL-c (17%). Despite a reduction in fasting triglycerides (21%), the drug had no effect on their postprandial rise (2.69 ± 1.44 vs. 2.49 ± 1.14 mmol/l, p = 0.72). However, following the mixed meal, plasma glucose area under the response curve increased from 13.1 ± 2.9 to 14.0 ± 2.8 mmol/l, p = 0.05, as a consequence of both increased insulin resistance [HOMA-IR: 2.2 (1.2, 4.2) vs. 3.8(1.3, 5.5), p = 0.02] and a reduced acute insulin response to glucose [424 (211, 975) vs. 257(122, 418) pmol/mmol, p = 0.04]. Niacin/laropiprant did not improve RHI (1.97 ± 0.40 vs. 2.05 ± 0.58, p = 0.33) or hsCRP. CONCLUSIONS: In PCOS, niacin/laropiprant had a significant negative impact on postprandial glucose and no improvement in postprandial hypertriglyceridaemia, with at least the former mediated through increased IR and reduced ß-cell function. This data may help explain why the improvement in fasting lipids has not translated into improved CV risk markers in PCOS.

The benefits of oestrogens on postprandial lipid metabolism are lost in post-menopausal women with Type 2 diabetes.

AIMS: Women with Type 2 diabetes appear to lose the protection against cardiovascular disease (CVD) afforded by oestrogens. We examined the effects of oestrogen hormone replacement therapy (HRT) on postprandial clearance of dietary fat in non-diabetic and diabetic post-menopausal women. METHODS: In a cross-sectional study, fasting subjects [HRT+ and HRT- control and diabetic women; Type 2 diabetes (DM) HRT+n = 8, DM HRT-n = 14, control HRT+n = 7, control HRT-n = 11] consumed a meal containing the stable isotope 1,1,1-[13]C-tripalmitin, with blood and breath sampled for 6 and 24 h, respectively, in the postprandial period. RESULTS: In diabetic women, there were no differences between the HRT+ and HRT- groups for any of these parameters. In contrast, in HRT+ compared with HRT- control women, the triglyceride (TG) area under the curve was lower [AUC; HRT+ median (range) 7.7 (4.1, 12.8) mmol/l per 6 h, HRT- 9.7 (3.9, 18.5) mmol/l per 6 h, P < 0.05] and [13]C-palmitic acid in the TG fraction was also lower [HRT+ 23.2 (10.3, 41.3) ng/ml per 6 h, HRT- 47.7 (12.6, 77.2) ng/ml per 6 h, P < 0.05], suggesting the lower postprandial triglyceridaemia associated with HRT in non-diabetic women is because of better chylomicron clearance. CONCLUSIONS: The oestrogen-associated advantage in clearance of dietary lipid we observed in non-diabetic post-menopausal women is not seen in post-menopausal diabetic women. This is likely to promote an atherogenic lipoprotein profile and may contribute to the loss of CVD protection seen in diabetic women.

Relation of skin capillary pressure in patients with insulin-dependent diabetes mellitus to complications and metabolic control.

BACKGROUND: Microvascular disease is a major problem in patients with diabetes mellitus. It has been suggested that diabetic microangiopathy may result from an increase in capillary blood flow and capillary hypertension, but direct evidence of capillary hypertension in such patients is lacking. METHODS: We measured capillary pressure at the summit of the capillary loop by direct microcannulation of skin nail-fold capillaries and a dynamic method of pressure measurement in 29 patients with insulin-dependent (Type I) diabetes and 29 normal subjects matched for age and sex. Among the diabetic patients, 7 had had diabetes for less than one year, 12 had incipient nephropathy (albumin excretion, 20 to 200 micrograms per minute), and 10 had overt nephropathy (albumin excretion, greater than 200 micrograms per minute). In addition, seven patients with no evidence of nephropathy were studied before and after three months of improved glycemic control. RESULTS: The median capillary pressure in the diabetic patients was 20.4 mm Hg (range, 13.6 to 25.3), as compared with 16.7 mm Hg (range, 12.8 to 22.8; P less than 0.001) in the normal subjects. The values were higher in each subgroup of diabetic patients than in the corresponding group of normal subjects, but the values did not differ among the three subgroups of diabetic patients. In the seven patients who were studied before and after three months of improved glycemic control, the median capillary pressure fell from 20.0 mm Hg (range, 18.5 to 21.7) to 17.8 mm Hg (range, 14.1 to 20.3; P = 0.02). CONCLUSIONS: Nail-fold capillary hypertension may develop early in the course of diabetes, before the emergence of microvascular disease, and may be influenced by changes in metabolic control.

Microvascular hemodynamics in hypertension and diabetes.

Microvascular damage occurs in both diabetes and hypertension and hypertension is a risk factor for diabetic microangiopathy. In both conditions, indirect evidence suggests that capillary pressure might be raised. A servonulling pressure measuring technique has been used in conjunction with direct micropuncture of finger nailfold capillaries to determine capillary pressure dynamically. In patients with essential hypertension, capillary pressure is raised compared to matched normotensive controls. In insulin-dependent diabetic patients, capillary pressure is also raised, to a degree that correlates with recent diabetic control. In a pilot study of hypertensive diabetic patients, elevated capillary pressure has been normalized using an angiotensin-converting enzyme inhibitor. Manipulation of microvascular hemodynamics in diabetes and hypertension may provide a means of protecting against the microvascular complications of these two conditions.

Effect of an increase in systemic blood pressure on nailfold capillary pressure in humans.

Moderate autoregulation of capillary pressure occurs during changes in arterial and/or venous pressure in animals. Whether an increase in systemic blood pressure is transmitted to capillaries in humans is unknown. Eight healthy volunteers performed isometric handgrip exercise (30% of maximum) while nailfold capillary pressure (CP) and digital arterial blood pressure (DBP) were measured in the contralateral hand. CP was measured for 40 s before exercise and 40-100 s during exercise. Only experiments with no change in pipette position and no artifactual changes in flow were accepted. Basal DBP was stable [91.5 +/- 12.7 mmHg (-40 to -20 s basal) and 91.3 +/- 11.8 mmHg (-20 to 0 s basal)], and isometric exercise increased DBP [100.4 +/- 13.9 mmHg (0-20 s exercise) and 103.1 +/- 15.3 mmHg (20-40 s exercise); P < 0.05]. CP was unchanged during the first 40 s of exercise [18.9 +/- 4.9 mmHg (-40 to 20 s basal), 18.9 +/- 5.2 mmHg (-20 to 0 s basal), 18.4 +/- 4.7 mmHg (0-20 s exercise), and 18.3 +/- 5.3 mmHg (20-40 s exercise)] and remained unchanged for up to 100 s (n = 5), despite a continued elevation of DBP. These data suggest that protective mechanisms minimize the transmission of increases in systemic blood pressure to the capillary bed in humans.

Capillary pressure, pulse pressure amplitude, and pressure waveform in healthy volunteers.

The influence of gender, local temperature, and systemic blood pressure on human capillary pressure is unknown. Finger nail fold capillary pressure was therefore directly measured in 74 healthy supine volunteers (40 female) at midaxillary level. Capillary pressure was lower in women than in men (15.9 +/- 3.0 vs. 18.2 +/- 2.3 mmHg; P = 0.001), particularly in premenopausal women, but was not related to systolic, diastolic, or mean blood pressure. Capillary pulse pressure amplitude was related to skin temperature, an effect more marked in women (P = 0.003). There was a significant association between skin temperature and the time taken for the systolic pressure rise to reach the capillary, in women only (r = -0.69, P < 0.001). Increasing age reduced the high-frequency waves in the pressure waveform [2nd harmonic percentage of fundamental: r = -0.52 and P = 0.002 (women), r = -0.52 and P = 0.004 (men)]. Thus mean capillary pressure and the pressure waveform may be influenced by gender, age, and skin temperature, illustrating the necessity to adequately match control groups during assessments of capillary pressure pathophysiology.

Assessment of blood pressure in patients with Type 2 diabetes: comparison between home blood pressure monitoring, clinic blood pressure measurement and 24-h ambulatory blood pressure monitoring.

AIMS: To compare a home blood pressure (BP) monitoring device and clinic BP measurement with 24-h ambulatory BP monitoring in patients with Type 2 diabetes mellitus (DM). METHODS: Fifty-five patients with type 2 DM had BP measured at three consecutive visits to the DM clinic by nurses using a stethoscope and mercury sphygmomanometer (CBP). Twenty-four-hour ambulatory BP was measured using a Spacelabs 90207 automatic cuff-oscillometric device (ABPM). Subjects were then instructed in how to use a Boots HEM 732B semiautomatic cuff-oscillometric home BP monitoring device and measured BP at home on three specified occasions on each of 4 consecutive days at varying times (HBPM). RESULTS: Correlations between HBPM and ABPM were r = 0.88, P < 0.001 for systolic BP and r = 0.76, P < 0.001 for diastolic BP, with correlations between CBP and ABPM being systolic r = 0.59, P < 0.001, diastolic r = 0.47, P < 0.001. HBPM agreed with ABPM more closely compared with CBP (CBP +10.9/+3.8 (95% confidence intervals (CI) 6.9, 14.8/1.6, 6.1) vs. HBPM +8.2/+3.7 (95% CI 6.0, 10.3/2.0, 5.4)). The sensitivity, specificity and positive predictive value of HBPM in detecting hypertension were 100%, 79% and 90%, respectively, compared with CBP (85%, 46% and 58%, respectively). CONCLUSIONS: In patients with Type 2 DM, home BP monitoring is superior to clinic BP measurement, when compared with 24-h ambulatory BP, and allows better detection of hypertension. It would be a rational addition to the annual review process. Diabet. Med. 18, 431-437 (2001)

Posturally induced vasoconstriction in diabetes mellitus.

In healthy subjects, standing elicits a reduction in blood flow to the skin of the foot. In adults with insulin dependent diabetes this posturally induced response is deficient, resulting in capillary hypertension when the foot is in the dependent position (that is, below heart level). Such functional abnormalities of the microcirculation in diabetes may precede any evidence of clinically detectable microangiopathy. This study investigates the posturally induced change in blood flow to the skin of the foot in prepubertal and postpubertal patients with insulin dependent diabetes. Laser Doppler fluximetry was used to assess the postural change in blood flow at the pulp of the great toe. Postural vasoconstriction (dependent flux value/supine flux value x 100) was greater after puberty in normal subjects (median (range) 60.4 (7.0-164.9)% prepubertal v 20.5 (5.9-101.0)% postpubertal). Prepubertal children with diabetes did not differ from their healthy peers (69.8 (7.2-192.7)% with diabetes v 60.4 (7.0-164.9)% controls); however postpubertal children with diabetes had a significantly impaired postural vasoconstriction (40.6 (7.9-140.2)% with diabetes v 20.5 (5.9-101.7)% controls). Abnormalities in the normal reduction of blood flow on standing occurred in young postpubertal children with diabetes, most of whom were free of complications.

Impaired microvascular hyperaemic response in children with diabetes mellitus.

Clinically detectable microvascular complications of diabetes are uncommon in children with diabetes especially in the prepubertal group. It is unclear whether subtle functional abnormalities of the microcirculation occur in children without evidence of clinical microangiopathy and in particular whether abnormalities can be demonstrated in children before puberty. The maximum hyperaemic response to direct local heating (44 degrees C) of the foot skin was measured by laser Doppler fluximetry in 50 diabetic and 50 non-diabetic children. An impaired hyperaemic response occurred in the diabetic children compared with control children (diabetic 1.25 (95% CI 1.13-1.37) V; control 1.74 (1.60-1.88) V; p less than 0.001) and was significantly related to duration of diabetes but not to long-term blood glucose control. The impaired response was also present in prepubertal diabetic children (diabetic 1.37 (1.16-1.58) V; control 1.89 (1.67-2.12) V; p less than 0.001). Systolic and diastolic blood pressure were significantly raised in the prepubertal diabetic children. These data suggest that a functional abnormality of the microcirculation occurs in children with diabetes in the absence of clinically detectable microangiopathy, and even before puberty.