Differential vascular effects of aspirin in people with Type 2 diabetes without cardiovascular disease and matched controls without diabetes.

AIM: We investigated whether the effect of low-dose aspirin on endothelium-dependent vasodilation and arterial stiffness in people with Type 2 diabetes is different from a matched control group. We examined acute and chronic effects, and effects over the 24h dosing interval. METHODS: In an open-label parallel group intervention study, we included 21 participants with Type 2 diabetes and 21 age- and sex-matched controls. Endothelium-dependent vasodilation was assessed as the reactive hyperaemia index (lnRHI) measured by peripheral arterial tonometry (EndoPAT® ). Arterial stiffness was assessed as pulse wave velocity (PWV) measured by applanation tonometry (SphygmoCor® ). Measurements were performed prior to aspirin intake and 1h after aspirin administration (75 mg). Participants were then treated for 6 days, and measurements were repeated at 24 h and 1 h after aspirin intake. RESULTS: Baseline lnRHI did not differ between groups. The controls had an immediate increase in lnRHI after the first aspirin tablet. This was not observed in participants with diabetes (difference between groups; P < 0.05). After 1 week, both groups demonstrated increased lnRHI compared with baseline (P < 0.01). In participants with diabetes, lnRHI was significantly lower 24 h after aspirin administration compared with 1 h after administration (P < 0.05). This difference was not observed in controls (P = 0.84, difference between groups; P = 0.12). The effect on PWV did not differ between groups. CONCLUSION: Aspirin had a reduced immediate effect on endothelium-dependent vasodilation in participants with diabetes. Both groups had improved endothelial function after 1 week of treatment. Further, the effect of aspirin on endothelial function may be declining during a 24 h dosing interval in people with Type 2 diabetes. (Clinical Trial Registry No: 2016-000515-32).

Plasma levels of MASP-1, MASP-3 and MAp44 in patients with type 2 diabetes: influence of glycaemic control, body composition and polymorphisms in the MASP1 gene.

Mounting evidence indicates that adverse activation of the complement system plays a role in the development of diabetic vascular complications. Plasma levels of the complement proteins mannan-binding lectin (MBL) and its associated serine proteases (MASP-1 and MASP-2) are elevated in diabetes. We hypothesized that single nucleotide polymorphisms (SNPs) in the MASP1 gene may contribute to altered plasma levels of the belonging gene products; MASP-1, MASP-3 and mannan-binding lectin-associated protein of 44 kDa (MAp44) in patients with type 2 diabetes. To investigate this, we compared plasma levels of MASP-1, MASP-3 and MAp44 in 100 patients with type 2 diabetes and 100 sex- and age-matched controls. Ten carefully selected SNPs were analysed using TaqMan® genotyping assay. Additionally, we included a streptozotocin-induced diabetes mouse model to directly examine the effect of inducing diabetes on MASP-1 levels. MASP-1 levels were significantly higher among patients with type 2 diabetes compared with healthy controls (P = 0·017). Five SNPs (rs874603, rs72549254, rs3774275, rs67143992, rs850312) in the MASP1 gene were associated with plasma levels of MASP-1, MASP-3 and MAp44. In the diabetes mouse model, diabetic mice had significantly higher MASP-1 levels than control mice (P = 0·003). In conclusion, MASP-1 levels were higher among patients with type 2 diabetes and diabetic mice. The mechanism behind this increase remains elusive.

Chronic adrenergic stimulation induces brown adipose tissue differentiation in visceral adipose tissue.

BACKGROUND: Recruitment of brown adipose tissue is a promising strategy to treat obesity and Type 2 diabetes, but the physiological effects of a large amount of metabolically active brown adipose tissue in humans are unknown. CASE REPORT: In the present paper, we report a case of massive brown adipose tissue infiltration of the visceral adipose tissue depot in a person with Type 2 diabetes with a catecholamine-secreting paraganglioma. The patient was evaluated with [18F]-fludeoxyglucose positron emission tomography/computed tomography on three occasions: pre-therapy, during α-blockade and postoperatively. During surgery, biopsies of visceral and subcutaneous adipose tissue were obtained and evaluated for brown adipose tissue. At diagnosis, brown adipose tissue glucose uptake, assessed by [18F]-fludeoxyglucose-positron emission tomography, was massively increased. [18F]-fludeoxyglucose uptake was confined to known locations for brown adipose tissue, with additional uptake in the visceral adipose tissue. As a result of increased thermogenesis, resting energy expenditure was doubled. After surgical removal of the tumour, antidiabetic medicine was no longer needed, despite an 8.2-kg weight gain. CONCLUSION: These results show that human visceral adipose tissue holds an unprecedented potential for brown adipogenic differentiation; however, a detrimental effect on glucose metabolism persisted despite massive brown adipose tissue activity, with a doubling of resting energy expenditure.

Objective measurements of activity patterns in people with newly diagnosed Type 2 diabetes demonstrate a sedentary lifestyle.

AIMS: To evaluate physical activity in people with newly diagnosed Type 2 diabetes using objective measures. METHODS: We analysed data from a study aimed at assessing carotid femoral pulse wave velocity in which a piezoelectric accelerometer was worn by 100 people with newly diagnosed Type 2 diabetes and by 100 age- and sex-matched control subjects. Differences in physical activity patterns were investigated. RESULTS: Compared with the control group, the people with Type 2 diabetes spent significantly more time engaged in sedentary or lower level activities during the day, with a mean (sd) time of 926 (44) vs 898 (70) min, P < 0.001). This difference remained significant after correction for differences in BMI between the two groups. CONCLUSIONS: Using objective measurements, our findings demonstrate that people with newly diagnosed Type 2 diabetes have a more sedentary lifestyle compared with well-matched controls.

High MBL-expressing genotypes are associated with deterioration in renal function in type 2 diabetes.

Introduction: Accumulating evidence support that mannan-binding lectin (MBL) is a promising prognostic biomarker for risk-stratification of diabetic micro- and macrovascular complications. Serum MBL levels are predominately genetically determined and depend on MBL genotype. However, Type 1 diabetes (T1D) is associated with higher MBL serum levels for a given MBL genotype, but it remains unknown if this is also the case for patients with T2D. In this study, we evaluated the impact of MBL genotypes on renal function trajectories serum MBL levels and compared MBL genotypes in newly diagnosed patients with T2D with age- and sex-matched healthy individuals. Furthermore, we evaluated differences in parameters of insulin resistance within MBL genotypes. Methods: In a cross-sectional study, we included 100 patients who were recently diagnosed with T2D and 100 age- and sex-matched individuals. We measured serum MBL levels, MBL genotype, standard biochemistry, and DEXA, in all participants. A 5-year clinical follow-up study was conducted, followed by 12-year data on follow-up biochemistry and clinical status for the progression to micro- or macroalbuminuria for the patients with T2D. Results: We found similar serum MBL levels and distribution of MBL genotypes between T2D patients and healthy individuals. The serum MBL level for a given MBL genotype did not differ between the groups neither at study entry nor at 5-year follow-up. We found that plasma creatinine increased more rapidly in patients with T2D with the high MBL expression genotype than with the medium/low MBL expression genotype over the 12-year follow-up period (p = 0.029). Serum MBL levels did not correlate with diabetes duration nor with HbA1c. Interestingly, serum MBL was inversely correlated with body fat percentage in individuals with high MBL expression genotypes both at study entry (p=0.0005) and 5-years follow-up (p=0.002). Discussion: Contrary to T1D, T2D is not per se associated with increased MBL serum level for a given MBL genotype or with diabetes duration. Serum MBL was inversely correlated with body fat percentage, and T2D patients with the high MBL expression genotype presented with deterioration of renal function.

Diffusion tensor imaging MR Neurography detects polyneuropathy in type 2 diabetes.

AIM: To evaluate if diffusion-tensor-imaging MR-Neurography (DTI-MRN) can detect lesions of peripheral nerves due to polyneuropathy in patients with type 2 diabetes. METHODS: Ten patients with type 2 diabetes with polyneuropathy (DPN), 10 patients with type 2 diabetes without polyneuropathy (nDPN) as well as 20 healthy controls (HC) were included. DTI-MRN covered proximal (sciatic nerve) and distal regions (tibial nerve) of the lower extremity. Fractional-anisotropy (FA) and diffusivity (mean (MD), axial (AD) and radial (RD)) were calculated and compared to neuropathy severity. Conventional T2-relaxation-time and proton-spin-density data were obtained from a multi-echo SE sequence. Furthermore, we evaluated sensitivity and specificity of DTI-MRN from receiver operating characteristics (ROC). RESULTS: The proximal and distal FA was lowest in patients with DPN compared with nDPN and HC (p < 0.01). Likewise, proximal and distal RD was highest in patients with DPN (p < 0.01). MD and AD were also significantly different though less pronounced. ROC curve analyses of DTI separated nDPN and DPN with area-under-the-curve values ranging from 0.65 to 0.98. T2-relaxation-time and proton-spin-density could not differentiate between nDPN and DPN. CONCLUSION: DTI-MRN accurately detects DPN by lower nerve FA and higher RD. These alterations are likely to reflect both proximal and distal nerve fiber pathology in patients with type 2 diabetes.

Ambulatory pulse pressure, decreased nocturnal blood pressure reduction and progression of nephropathy in type 2 diabetic patients.

AIMS/HYPOTHESIS: We followed type 2 diabetic patients over a long period to evaluate the predictive value of ambulatory pulse pressure (PP) and decreased nocturnal BP reduction (non-dipping) for nephropathy progression. METHODS: Type 2 diabetic patients (n = 112) were followed for an average of 9.5 (range 0.5-14.5) years. At baseline, all patients underwent 24 h ambulatory BP measurement. Urinary albumin excretion rate was evaluated by three urinary albumin:creatinine ratio measurements at baseline and follow-up. RESULTS: At baseline, patients who subsequently progressed to a more advanced nephropathy stage (n = 35) had reduced diastolic night/day BP variation and higher 24 h systolic BP and PP values; they also had more advanced nephropathy and were more likely to smoke than those with no progression of nephropathy (n = 77). In a Cox regression analysis, independent predictors of nephropathy progression were 24 h PP (p < 0.01), diastolic night:day BP ratio (p = 0.02) and smoking (p = 0.02). The adjusted hazards ratio (95% CI) for each mmHg increment in 24 h PP was 1.04 (1.01-1.07), whereas the adjusted hazards ratio (95% CI) for each 1% increase in diastolic night:day BP ratio was 1.06 (1.01-1.11). Only one of 33 patients (3.0%) with both a diastolic night:day BP ratio and a 24 h PP below the median progressed, whereas 17 of 32 patients (53.1%) with both a diastolic night:day BP ratio and a 24 h PP equal to or above the median progressed to a more advanced nephropathy stage (p < 0.001). CONCLUSIONS/INTERPRETATION: Ambulatory PP, impaired nocturnal BP decline and smoking are strong, independent predictors of nephropathy progression in type 2 diabetic patients.

Ambulatory blood pressure in the transition from normo- to microalbuminuria. A longitudinal study in IDDM patients.

To describe the development in blood pressure (BP) in relation to urinary albumin excretion (UAE) more exactly, 44 initially normoalbuminuric type I diabetic patients and 21 healthy individuals were included in a 3.1-year follow-up study by using ambulatory BP (AMBP) monitoring. Six patients developed microalbuminuria according to accepted criteria (progressors; UAE at follow-up was > 20 micrograms/min). Initial UAE was higher in this group (9.0 x/divided by 1.4 micrograms/min) compared with both the nonprogressors (5.2 x/divided by 1.6 micrograms/min) and the control subjects (3.9 x/divided by 1.6 micrograms/min), P < 0.01. The values were almost identical for initial 24-h AMBP between the progressors and the two other groups. The transition to microalbuminuria (31.7 x/divided by 1.8 micrograms/min) was associated with an increase in 24-h systolic AMBP of 11.5 +/- 8.3 mmHg, which was significantly higher than the increase in the nonprogressors (3.1 +/- 7.7 mmHg) and the control subjects (2.2 +/- 6.1 mmHg, P = 0.02). Significant correlations were detected between development in UAE and development in systolic and diastolic 24-h AMBP (r = 0.39, r = 0.41, P < 0.01). In addition, an increase in UAE, even including increases within the normoalbuminuric range, was always associated with an increase in 24-h AMBP (P < 0.01). Ordinary clinical measurements did not reveal any of these differences or correlations. In conclusion, a close association between increases in UAE and 24-h AMBP emerges in this study. Initial BP was not increased in the progressors.(ABSTRACT TRUNCATED AT 250 WORDS)

Isokinetic muscle strength in long-term IDDM patients in relation to diabetic complications.

The isokinetic muscle strength in 56 IDDM patients with > 20 years of diabetes duration and in their individually sex-, age-, weight-, and height-matched control subjects was assessed. Peak torque of foot dorsal and plantar flexion and knee and wrist extension and flexion was measured. The neuropathic condition was assessed by a neurological disability score, a neuropathy symptom score, nerve conduction studies, and quantitative sensory examination. All results were summed to obtain a neuropathy rank-sum score for each patient. According to their renal albumin excretion, the patients were classified to have normo-, micro-, or macroalbuminuria. In addition, according to their retinal status, patients were classified as having no, simple, or proliferative retinopathy. The IDDM patients had a 21% reduction of muscle strength of both ankle dorsal (P < 1 x 10(-4)) and plantar flexors (P < 0.01), compared with control subjects. A 16% reduction of knee extensors (P < 0.005) and a 17% reduction of knee flexors (P < 0.01) was found. In contrast, muscle strength in wrist flexors and extensors was not significantly reduced (10 and 11%, respectively [NS]). In patients with the most severe weakness, muscle strength of the calf muscles was only 50% of the expected performance. Correlations were found between the neuropathy rank-sum score and the muscle strength of ankle dorsal (r = -0.66, P < 1 x 10(-7)) and plantar flexors (r = -0.51, P < 0.0005), knee extensors (r = -0.51, P < 0.0005) and flexors (r = -0.44, P < 0.005), and wrist flexors (r = -0.41, P < 0.005). No correlation was found for wrist extensors (r = 0). Neither were there any relationships between muscle strength at the ankle and knee and the degree of albuminuria or retinopathy. In conclusion, motor performance is substantially impaired in long-term IDDM patients, and the weakness is related to the presence of neuropathy but not to albuminuria or retinopathy per se.

Increased QTc dispersion is related to blunted circadian blood pressure variation in normoalbuminuric type 1 diabetic patients.

A reduced nocturnal fall in blood pressure (BP) and increased QT dispersion both predict an increased risk of cardiovascular events in diabetic as well as nondiabetic subjects. The relationship between these two parameters remains unclear. The role of diabetic autonomic neuropathy in both QT dispersion and circadian BP variation has been proposed, but data have been conflicting. The aim of the present study was to describe associations between QT dispersion and circadian BP variation as well as autonomic function in type 1 diabetic patients. In 106 normoalbuminuric (urinary albumin excretion <20 microg/min) normotensive patients, we performed 24-h ambulatory BP (Spacelabs 90207) and short-term (three times in 5 min) power spectral analysis of RR interval oscillations, as well as cardiovascular reflex tests (deep breathing test, postural heart rate, and BP response). No patient had received (or had earlier received) antihypertensive or other medical treatment apart from insulin. In a resting 12-lead electrocardiogram, the QT interval was measured by the tangent method in all leads with well-defined T-waves. The measurement was made by one observer blinded to other data. The QT interval was corrected for heart rate using Bazett's formula. The QTc dispersion was defined as the difference between the maximum and the minimum QTc interval in any of the 12 leads. When comparing patients with QTc dispersion below and above the median (43 ms), the latter had significantly higher night BP (114/67 vs. 109/62 mmHg, P < 0.003/P < 0.001), whereas day BP was comparable (129/81 vs. 127/79 mmHg). Diurnal BP variation was blunted in the group with QTc dispersion >43 ms with significantly higher night/day ratio, both for systolic (88.8 vs. 86.2%, P < 0.01) and diastolic (83.1 vs. 79.5%, P < 0.01) BP. The association between QTc dispersion and diastolic night BP persisted after controlling for potential confounders such as sex, age, duration of diabetes, urinary albumin excretion, and HbA1c. Power spectral analysis suggested an altered sympathovagal balance in patients with QTc dispersion above the median (ratio of low-frequency/high-frequency power: 1.0 vs. 0.85, P < 0.01). In normoalbuminuric type 1 diabetic patients, increased QTc dispersion is associated with reduced nocturnal fall in BP and an altered sympathovagal balance. This coexistence may be operative in the ability of these parameters to predict cardiovascular events.

Characteristics and prognosis of normoalbuminuric type 1 diabetic patients.

Intervention in type 1 diabetic patients with increased urinary albumin excretion (UAE) represents a great step forward in modern diabetology. At the moment, the consensus calls for antihypertensive treatment in normotensive type 1 diabetic patients with persistent microalbuminuria. However, recent data indicate that substantial pathophysiological changes have already taken place at the microalbuminuric stage. Thus, prevention of progression from normo- to microalbuminuria would be a major clinical turning point. A considerable number of potential risk factors for progression to microalbuminuria have been proposed, among which are blood pressure elevation and disturbancies in circadian blood pressure variation. We performed 24-h ambulatory blood pressure (AMBP) monitoring in 115 normoalbuminuric (UAE < 20 micrograms/min) patients, along with performing an assessment of circadian blood pressure and heart rate (HR) variation and a short-term power spectral analysis of RR interval oscillations. Patients with UAE above the median had significantly higher systolic and diastolic AMBP compared to the low normoalbuminuric group. The difference in blood pressure between the two groups was most pronounced for the night blood pressure (P < 0.01 and 0.02). A positive correlation between UAE and circadian variation (described as diastolic night/day ratio) was present--that is, the higher the normoalbuminuria, the more blunted the night/day ratio. The patients characterized by a combination of high-normal UAE and blunted circadian variation also proved to have significantly higher HbA1c values, higher 24-h mean arterial blood pressure, and lower vagal activity. In conclusion, high-normal UAE, poor metabolic control, and cigarette smoking are at present the only established risk factors for progression from normo- to microalbuminuria. However, new data emphasizes the close relation between blood pressure and albumin excretion. Pathophysiological abnormalities (poorer glycemic control, higher blood pressure, and attenuated vagal activity) tend to cluster in patients characterized by high-normal UAE and blunted circadian variation of blood pressures, and this patient group might constitute a putative high-risk group.

Albuminuria and 24-h ambulatory blood pressure in normoalbuminuric and microalbuminuric NIDDM patients. A longitudinal study.

OBJECTIVE: To assess the long-term relationships between 24-h ambulatory blood pressure (AMBP), urinary albumin excretion (UAE) rate, and metabolic control in non-insulin-dependent diabetes mellitus (NIDDM) patients with normo- and microalbuminuria. RESEARCH DESIGN AND METHODS: We conducted a prospective study of 23 NIDDM patients (11 with normoalbuminuria and 12 with microalbuminuria) receiving standard clinical care, including antihypertensive treatment, attending the outpatient clinic and 8 healthy control subjects. Twenty-four-hour AMBP and UAE were measured synchronously in addition to fasting plasma glucose, HbA1c, and serum creatinine at baseline and after 4.6 (4.2-5.1) years [mean (range)]. RESULTS: Baseline systolic, but not diastolic, 24-h AMBP was significantly higher in diabetic patients compared with control subjects (146/80 [16/11] vs. 133/78 [9/9] mmHg, P < 0.05), but was similar in normoalbuminuric (143/81 [11/11] mmHg) and microalbuminuric (148/80 [20/10] mmHg) patients during strict blood pressure control. The annual increase in 24-h AMBP was equivalent in diabetic patients (0.6/-0.2 [2.6/1.5] mmHg/year) and control subjects (0.7/0.2 [1.2/1.4] mmHg/year, NS) and not significantly different from zero. Overall UAE did not change in control subjects (5.6 [1.6] vs. 4.4 [1.9]) (geometric mean [antilog SD]) or in the normoalbuminuric (8.7 [1.7] vs. 11.3 [3.0] micrograms/min) and microalbuminuric (35.7 [2.1] vs. 34.5 [3.2] micrograms/min) patients. In diabetic patients, the annual change in UAE correlated significantly with the annual change in the systolic (r = 0.61, P < 0.002) and diastolic (r = 0.54, P < 0.008) 24-h AMBP. In microalbuminuric patients, only the annual increase in systolic 24-h AMBP correlated significantly with the annual change in UAE (r = 0.71, P = 0.010), whereas in the normoalbuminuric patients, only the annual increase in diastolic 24-h AMBP and the annual change in UAE were significantly correlated (r = 0.66, P = 0.026). In a stepwise multiple linear regression analysis, the annual progression in albuminuria in NIDDM patients was significantly determined by increases in systolic (parameter estimate 0.018, SE 0.006, P < 0.008) as well as in diastolic 24-h AMBP (parameter estimate 0.026, SE 0.011, P < 0.033). CONCLUSIONS: In an outpatient clinical setting, 24-h AMBP is similar in NIDDM patients with normo- and microalbuminuria. Alterations in both 24-h AMBP and UAE are on average moderate and equivalent compared with those in healthy control subjects. Although the average change in albuminuria is small, a progression in albuminuria relates to increments in both systolic and diastolic 24-h AMBP.

Determinants of 24-h blood pressure in IDDM patients.

OBJECTIVE: To assess the influence of basic clinical data on ambulatory blood pressure (AMBP) in insulin-dependent diabetes mellitus (IDDM) patients and to evaluate the reproducibility of the method. RESEARCH DESIGN AND METHODS: AMBP was measured in 66 IDDM patients with urinary albumin excretion (UAE) < 20 micrograms/min and in 53 healthy subjects. Determinants of AMBP were identified in a stepwise multiple regression model. In addition, 14 diabetic patients were monitored on two days of the same type, and 14 patients were monitored on one work day and one day off. RESULTS: In healthy subjects, sex was the most important determinant of 24-h blood pressure (BP), whereas UAE and age were the main covariates in diabetes patients. The male-female difference in 24-h diastolic BP (dBP) was 5.6 mmHg lower in diabetic patients than in healthy control subjects (P < 0.05). In patients with long diabetes duration, nighttime dBP (69 +/- 7 mmHg) was higher than in patients with medium diabetes duration (63 +/- 8 mmHg, P < 0.05; after matching for age and sex). Daytime dBP was 5 mmHg higher on a work day than on a day off (P < 0.02). Standard deviation of the difference for repeated measurement of 24-h systolic/diastolic BP in the same subject was 5.7/2.5 mmHg. CONCLUSIONS: The male-female difference in 24-h dBP was attenuated in diabetes. The influence of UAE on AMBP was noticed even in normoalbuminuric diabetic patients. Standardized AMBP was highly reproducible.

Elevated ambulatory blood pressure in microalbuminuric IDDM patients is inversely associated with renal plasma flow. A compensatory mechanism?

OBJECTIVE: To evaluate the relationship between renal function, ambulatory blood pressure (AMBP), and glycemic control in microalbuminuric IDDM patients compared with normoalbuminuric patients. RESEARCH DESIGN AND METHODS: Nineteen male patients (age 33 +/- 6 years) with slight microalbuminuria (UAE 20-70 micrograms/min) were compared with 19 normoalbuminuric (UAE < 15 micrograms/min) age-matched (33 +/- 6 years) male patients. Through constant infusion technique, 125I-iothalamate marked the glomerular filtration rate (GFR), and 131I-hippuran marked effective renal plasma flow (RPF). AMBP was measured by oscillometric technique (Spacelabs 90202). RESULTS: The microalbuminuric group had higher daytime systolic AMBP (132 +/- 11 vs. 125 +/- 7 mmHg, P < 0.05) and a poorer glycemic control (HbA1c 9.5 +/- 1.5 vs. 8.2 +/- 1.3%, P < 0.01). GFR (135 +/- 22 and 135 +/- 17 ml/min) and RPF (598 +/- 112 and 542 +/- 98 ml/min) were similar in the two groups. In the microalbuminuric group, daytime systolic AMBP was inversely correlated to both RPF (r = -0.77, P < 0.005) and GFR (r = -0.53, P = 0.02). HbA1c and GFR correlated positively in the microalbuminuric group (r = 0.47, P < 0.04). In contrast, the normoalbuminuric patients exhibited no such associations. CONCLUSIONS: IDDM patients with moderate microalbuminuria have elevated AMBP and a strong negative association between AMBP and RPF. This leaves several possibilities of interpretation. Primary blood pressure increase (of unknown origin) may induce morphological changes leading to reduction in renal function. Alternatively, blood pressure increase early in the course of incipient nephropathy may represent a compensatory mechanism, initially aiming at preservation of renal function, but later becoming maladaptive.

Effect of meal frequency on blood glucose, insulin, and free fatty acids in NIDDM subjects.

OBJECTIVE: We studied the effects of meal frequency on blood glucose, serum insulin, and FFAs in 12 NIDDM subjects. RESEARCH DESIGN AND METHODS: Subjects were assigned in random order to two 8-hr observation periods after an overnight fast. They received isocaloric diets with similar composition either as six small or as two large meals. At the end of each study period, an IVGTT was given. RESULTS: Two large meals induced an 84% greater maximum amplitude of glucose excursions than six small meals (6.1 +/- 0.5 vs. 3.3 +/- 0.5 mM, P < 0.005) and higher insulin responses (P < 0.03). The Kg response to an IVGTT did not differ in the two situations. The average FFA level was lowest in response to frequent meals (P < 0.02). CONCLUSIONS: A higher meal frequency acutely subdues glucose excursions and reduces insulin and FFA levels during the daytime in older NIDDM subjects.

Multicenter evaluation of the Micral-Test II test strip, an immunologic rapid test for the detection of microalbuminuria.

OBJECTIVE: To assess the performance of the Micral-Test II immunologic test strip for the detection of microalbuminuria, a multicenter evaluation in eight European study sites was performed. RESEARCH DESIGN AND METHODS: Using both the Micral-Test II test strip and the routine method for the determination of albumin concentration, we investigated 2,228 urine samples from diabetic patients. Additionally, interperson variability, color stability, and possible interfering factors (temperature, pH, leucocyturia, erythrocyturia, and drugs) were tested. RESULTS: For a cutoff concentration of 20 mg/l with respect to the routine methods, a sensitivity of 96.7% and a specificity of 71% were calculated for the Micral-Test II test strip. The negative predictive value was 0.95, and the positive predictive value was 0.78, with a prevalence of positive samples (laboratory method) of 52%. The interperson variability of color interpretation showed 93% concordant readings. The interference study showed an influence of oxytetracycline, leading to higher readings. There was no interference from pH. A sample temperature of < 10 degrees C led to lower readings. In the case of samples with massive leucocyturia and erythrocyturia that may delete the chromatographic process, waiting an additional 1-2 min is needed before reading. CONCLUSIONS: The results of the multicenter evaluation show that the Micral-Test II test strip permits an immediate and reliable semiquantitative determination of low albumin concentrations in urine samples with an almost user-independent color interpretation.

No deleterious effects of tight blood glucose control on 24-hour ambulatory blood pressure in normoalbuminuric insulin-dependent diabetes mellitus patients.

Intensive therapy aiming at near normalization of glucose levels effectively delays the onset and slows the progression of complications in insulin-dependent diabetes mellitus (IDDM) and is recommended in most patients. However, in a recent report, intensive insulin treatment was found to be associated with deleterious effects on nocturnal blood pressure (BP), the proposed mechanisms being subclinical nocturnal hypoglycemia or hyperinsulinemia. The aim of the present study was to evaluate the association between glycemic control, insulin dose, and 24-h ambulatory BP (AMBP) in a group of well-characterized IDDM patients. Twenty-four-h AMBP was measured in 123 normoalbuminuric [urinary albumin excretion (UAE) < 20 microg/min] IDDM patients using an oscillometric technique (SpaceLabs 90207) with readings at 20-min intervals. UAE was measured by RIA and expressed as geometric mean of three overnight collections made within 1 week. Tobacco use and level of physical activity was assessed by questionnaire. HbA1c was determined by high-pressure liquid chromatography (nondiabetic range, 4.4-6.4%), and patients were stratified into quartiles according to HbA1c levels. Mean HbA1c values in the four groups were 7.0% (n = 31), 8.0% (n = 31), 8.6% (n = 31), and 9.7% (n = 30). The groups were comparable regarding age, gender, diabetes duration, body mass index, UAE, smoking status, and physical activity. AMBP levels were almost identical in the HbA1c quartiles with night values of (increasing HbA1c order): 110/63, 112/66, 112/66, and 113/65 mm Hg (P = 0.69/P = 0.32). There was no association between tight glucose control and higher nocturnal BP or a more blunted circadian BP variation. On the contrary, a weak positive correlation between night to day ratios of mean arterial BP and HbA1c values was found (r = 0.26, P = 0.005), i.e. blunted circadian BP variation is most frequent in patients with high HbA1c values. Neither did we find doses of insulin to be associated with night BP (r = 0.04, P = 0.68). Tight blood glucose control is not associated with deleterious effects on 24-h AMBP in normoalbuminuric IDDM patients. Intensive therapy can be implemented without concerns of inducing high nocturnal BP and accelerating diabetic complications.

Increased plasma concentrations of osteoprotegerin in type 2 diabetic patients with microvascular complications.

OBJECTIVE: Osteoprotegerin (OPG) is a newly identified inhibitor of bone resorption. Recent studies indicate that OPG also acts as an important regulatory molecule in the vasculature. Plasma levels of OPG seem to be elevated in subjects with diabetes as well as in non-diabetic subjects with cardiovascular disease. The aim of the present study was to examine the association between plasma OPG levels and microvascular complications and glycemic control in patients with type 2 diabetes. DESIGN AND METHODS: Four groups of 20 subjects in each, individually matched for age and gender, were included in the study: (i) subjects with normal glucose tolerance (NGT); (ii) subjects with impaired glucose tolerance (IGT); (iii) type 2 diabetic patients without retinopathy; and (iv) type 2 diabetic patients with diabetic maculopathy (DMa). Plasma concentration of OPG was measured in duplicate by a sandwich ELISA method. Furthermore, fundus photography, flourescein angiography, and measurements of urinary albumin excretion rate (RIA) were performed. RESULTS: Plasma OPG was significantly higher in diabetic (iii+iv) than in NGT (i) subjects (3.04+/-0.15 vs 2.54+/-0.16 ng/ml, P<0.05). Plasma OPG was significantly higher in the DMa (iv) group than in the NGT (i) group (3.25+/-0.23 vs 2.54+/-0.16 ng/ml, P=0.01). Moreover, plasma OPG was significantly higher (3.61+/-0.36 ng/ml) in the group of diabetic subjects with both microalbuminuria and DMa (n=7) than in the NGT (i) (2.54+/-0.16 ng/ml, P<0.01), IGT (ii) (2.82+/-0.21 ng/ml, P<0.05), and no retinopathy (iii) groups (2.83+/-0.20 ng/ml, P<0.05). CONCLUSIONS: We found increased levels of OPG in plasma from diabetic patients with microvascular complications. This finding indicates that OPG may be involved in the development of vascular dysfunction in diabetes [corrected].

Effects of smoking on 24-h ambulatory blood pressure and autonomic function in normoalbuminuric insulin-dependent diabetes mellitus patients.

Smoking is an important risk factor for the development and progression of diabetic nephropathy. The mechanisms by which smoking increases albuminuria and promotes nephropathy are unknown. Considering the acute pressor effect of smoking and the close association between blood pressure elevation and development of diabetic nephropathy, blood pressure increase might be implicated in the association between smoking and diabetic nephropathy. However, among nondiabetics, smokers have repeatedly been found to have lower blood pressure than nonsmokers. This is possibly mediated by an autonomic adjustment to sustained sympathetic stimulation by nicotine. Impaired modulation of the sympathovagal activity has been described in diabetes. In diabetic patients, the effect of smoking on blood pressure and autonomic function remains unclarified. We examined 24-h ambulatory blood pressure (oscillometric technique) and autonomic function (short-term power spectral analysis as well as conventional tests) in 24 smokers and 24 nonsmokers matched for sex, age, and diabetes duration. All patients were normoalbuminuric insulin-dependent diabetes mellitus patients. Smoking status was assessed by questionnaire with confirmatory determinations of urinary cotinine. Diabetic smokers had significantly higher 24-h mean arterial blood pressure (94+/-6.7 mm Hg compared to diabetic nonsmokers 90+/-5.8 mm Hg, P = .04) including higher diastolic nighttime blood pressure (68+/-7.3 mm Hg v 64+/-5.2 mm Hg, P = .03). Smokers also had significantly higher 24-h heart rate (80+/-7.2 compared to 72+/-9.2 beats/min, P < .001). In addition, smoking was associated with significantly reduced short-term RR interval variability (supine low frequency component) (5.45+/-1.29 ln ms2 in smokers compared to 6.31+/-1.11 ln ms2 in nonsmokers, P < .02), as well as reduced brake index (33.5+/-14.5 in smokers v 42.1+/-16.0 in nonsmokers, P < .05). Diabetic smokers have significantly higher 24-h blood pressure compared to diabetic nonsmokers. This finding, contrasting the effect of smoking among nondiabetics, is possibly mediated by coexisting abnormal postural responses in autonomic cardiac regulation in diabetic smokers. Blood pressure elevation, persisting throughout 24 h, might be operative in the association between smoking and development of diabetic nephropathy.

Effects of oral glucose on systemic glucose metabolism during hyperinsulinemic hypoglycemia in normal man.

The widespread use of oral glucose in the treatment of hypoglycemia is mainly empirically based, and little is known about the time lag and subsequent magnitude of effects following its administration. To define the systemic impact and time course of effects following oral glucose during hypoglycemia, we investigated 7 healthy young men twice. On both occasions, a 6-hour hyperinsulinemic (1.5 mU/kg/min)-hypoglycemic clamp was performed to ensure similar plasma glucose profiles during a stepwise decrease toward a nadir less than 50 mg/100 mL after 3 hours. On the first occasion, subjects ingested 40 g glucose and 4 g 3-ortho-methylglucose ([3-OMG] to trace glucose absorption) dissolved in 400 mL tap water after 3.5 hours. The second examination was identical except for the omission of 40 g oral glucose, and glucose levels were clamped at hypoglycemic concentrations similar to those recorded on the first examination. Plasma glucose curves were superimposable, and all participants reached a nadir less than 50 mg/100 mL. Similar increases in growth hormone (GH) and glucagon were observed in both situations. The glucose infusion rates (GIRs) were lower after oral glucose, with the difference starting after 5 to 10 minutes, being statistically significant after 20 minutes, and reaching a maximum of 8.5 +/- 1.6 mg/kg/min after 40 minutes. Circulating 3-OMG increased after 20 minutes. In both situations, infusion of insulin resulted in insulin levels of approximately 150 microU/mL and a suppression of C-peptide levels from 2.0 to 1.1 nmol/L (P < .01). After glucose ingestion, both serum C-peptide and glucagon-like peptide-1 (GLP-1) increased (C-peptide from 1.1 +/- 0.05 to 1.4 +/- 0.05 nmol/L and GLP-1 from 3.2 +/- 0.8 to 18.1 +/- 3.3 pmol/L), in contrast to the situation without oral glucose (P < .05). Isotopically determined glucose turnover was similar. In conclusion, our data suggest that oral glucose affects systemic glucose metabolism rapidly after 5 to 10 minutes. Quantitatively, the immediate impact is relatively small, with the gross impact observed after approximately 40 minutes. Future studies aiming to identify therapeutic oral agents with prompt effect seem warranted.