Belinda Brooks

TBI or not TBI: that is the question. Is it better to measure toe pressure than ankle pressure in diabetic patients?

Aims Measurement of ankle blood pressure is a simple method of assessing lower limb arterial blood supply. However, its use in diabetes has been questioned due to the presence of medial artery calcification. Measurement of toe blood pressure has been advocated as an alternative but it is technically more difficult. The aim of this study was to obtain information to guide clinicians as to when pressure measurements should be taken at the toe.

Augmentation of central arterial pressure in Type 2 diabetes

Aims  Aortic systolic blood pressure has been shown to be augmented in Type 1 diabetes, indicative of more rapid pulse wave reflection due to increased arterial stiffness. This abnormality is more pronounced in diabetic males. The aim of this study was to examine the effects of diabetes on augmentation of aortic systolic pressure in subjects with Type 2 diabetes.

Diastolic dysfunction and abnormalities of the microcirculation in type 2 diabetes.

Aim:  Diabetic cardiomyopathy is an increasingly recognized entity. The pathogenic factors that may contribute to its development, especially the earliest changes of diastolic dysfunction (DD), have not been clearly defined. Microvessel dysfunction and upregulation of profibrotic growth factors have been described as possible causes. The aim of this study was therefore to determine whether microvascular dysfunction and/or upregulation of the profibrotic connective tissue growth factor (CTGF) are associated with subclinical DD in subjects with type 2 diabetes.

Very low calorie diet (VLCD): A useful alternative in the treatment of the obese NIDDM patient

Conventional treatment of obese noninsulin dependent diabetes mellitus (NIDDM) patients is often unsatisfactory. In this study the efficacy of Modifast, a commercial very low calorie diet (VLCD), was evaluated in a population of obese poorly controlled NIDDM patients. The mechanisms of action of VLCD in these patients were also studied by comparing: (i) Plasma insulin and glucose profiles after a VLCD and an isocaloric mixed meal and (ii) plasma amino acid levels, both at baseline and after four weeks of VLCD treatment. A total of 14 obese NIDDM patients (M/F 7/7. median body mass index (BMI) 38.7 kg-2, interquartile range (IQ) 34.7-46.5 kg-2, waist circumference 116 cm, IQ 106-139 cm, insulin treated 7/14) with poor diabetic control (HbA1c 8.6%, IQ 7.8-10%) were studied. Patients were given a VLCD (425 kcal/day) for 12 weeks. At baseline, VLCD and isocaloric meal tests were performed on consecutive mornings. Fasting plasma amino acid levels were also determined at baseline and after 4 weeks of VLCD treatment. Weight, waist circumference, HbA1c, blood pressure, fasting plasma insulin, total cholesterol and triglyceride levels all fell significantly following VLCD treatment. Insulin therapy was able to be ceased in the seven insulin treated patients. Oral hypoglycaemic agent dosage fell from a median of eight (IQ 6-12) to two (IQ 0-8) tablets per day (P = 0.03) in patients initially on this form of therapy. Insulin secretion was higher after VLCD than isocaloric meal (P = 0.04). Fasting plasma alanine level fell from 512.0 (IQ 412.0-563.0) to 374.0 (IQ 342-472.0) mumol/l (P = 0.04) following VLCD treatment. In conclusion, the short term use of a VLCD is very effective in rapidly improving glycaemic control and promoting substantial weight loss in obese NIDDM patients. Moreover, a VLCD diet increases insulin secretion and reduces substrate for gluconeogenesis. Thus, VLCD treatment may improve glycaemic control by factors more than caloric restriction alone.

Administration of ascorbic acid and an aldose reductase inhibitor (Tolrestat) in diabetes : Effect on urinary albumin excretion

The important role of ascorbic acid (AA) as an anti-oxidant is particularly relevant in diabetes mellitus where plasma concentrations of AA are reduced. This study was conducted to evaluate the effects of treatment with AA or an aldose reductase inhibitor, tolrestat, on AA metabolism and urinary albumin excretion in diabetes. Blood and urine samples were collected at 0, 3, 6, 9, and 12 months from 20 diabetic subjects who were randomized into two groups to receive either oral AA 500 mg twice daily or placebo. Systolic and diastolic blood pressures, HbA1c, plasma lipids, urinary albumin, and total glycosaminoglycan excretion were measured at all time points, and heparan sulphate (glycosaminoglycan) was measured at 0 and 12 months. The same parameters, as well as urinary AA excretion, were determined at 0 and 3 months for 16 diabetes subjects receiving 200 mg tolrestat/day. AA treatment increased plasma AA (ANOVA, F ratio = 12.1, p = 0.004) and reduced albumin excretion rate (AER) after 9 months (ANOVA, F ratio = 3.2, p = 0.03), but did not change the other parameters measured. Tolrestat lowered plasma AA (Wilcoxon’s signed-rank test, p < 0.05), but did not change AER or the other parameters measured. The ability of AA treatment to decrease AER may be related to changes in extracellular matrix or improvement in oxidative defence mechanism. Unlike the rat model of diabetes, inhibition of aldose reductase did not normalize plasma AA or AER in humans. In fact, tolrestat reduced the plasma AA concentration, a phenomenon which may be due to increased utilization of AA. Dietary supplementation of AA in diabetic subjects may have long-term benefits in attenuating the progression of diabetic complications.

Serum MMP-7 is increased in diabetic renal disease and diabetic diastolic dysfunction

Circulating matrix metalloproteinase (MMP) levels may correlate with diabetic complications. Whether they are changed in early diabetic cardiomyopathy is not known and was examined in this study. TIMP-1 and collagen degradation products were also measured. Results from subjects with and without diastolic dysfunction were compared with those obtained for patients with varying stages of diabetic renal disease. Patients with type 2 diabetes with or without diastolic dysfunction with varying degrees of renal disease were recruited for this study. Age-matched non-diabetic subjects served as controls. MMPs (-1, -3 and -7) and TIMP-1 were measured by ELISA, MMP-2 and -9 by zymography and collagen degradation products by radioimmunoassay. Differences in the pattern of MMPs/TIMPs and collagen degradation products were observed. The most consistent change was in totalMMP-7, which was increased in those with diastolic dysfunction and those with macroalbuminuria. MMP-7 correlated with cardiac function (p<0.05 vs control, in those with diastolic dysfunction), and renal filtration function (p<0.05 vs control). In summary, we have identified novel relationships between serum MMP-7 and diabetic complications specifically in renal disease and in diastolic dysfunction. How increased circulating MMP-7 is associated with these diabetic microvascular complications and the significance of these findings will require prospective studies.

Endothelial and neural regulation of skin microvascular blood flow in patients with diabetic peripheral neuropathy: effect of treatment with the isoform-specific protein kinase C β inhibitor, ruboxistaurin

PURPOSE This article aims to study the effects of ruboxistaurin (RBX) on skin microvascular blood flow (SkBF) and evaluate the relationship between endothelial and neural control of SkBF in patients with diabetic peripheral neuropathy (DPN). METHODS We studied 11 placebo- and 9 RBX (32 mg/day)-treated patients who participated in a 1-year, double-masked, randomized, Phase 3 study of RBX for treatment of DPN sensory symptoms. Patients had type 1 or type 2 diabetes, a detectable sural sensory nerve action potential, and Neuropathy Total Symptom Score-6 (NTSS-6) >6 points. SkBF was measured by laser Doppler velocimetry, combined with iontophoresis of acetylcholine and sodium nitroprusside, at baseline, 3 months, and 1 year. Sensory symptoms and electrophysiology were also evaluated during the study. The relationship between endothelial and neural control of SkBF at baseline was assessed using linear regression. RESULTS No significant differences (RBX vs. placebo) were demonstrable for post-iontophoresis SkBF [fold increase from basal state (1 year): endothelium-dependent, 3.6 vs. 8.6; endothelium-independent, 3.7 vs. 2.0; C fiber-mediated, 1.7 vs. 2.0; P>.05] or sensory symptoms [NTSS-6 total score (1 year): 7.7 vs. 6.0 points; P=.4]. There were also no significant between-group differences in nerve conduction parameters, except for placebo peroneal nerve conduction velocity, which demonstrated a statistically significant improvement of unknown clinical importance (Z=2.1; P=.034). At baseline, C fiber-mediated vasodilatation correlated well with endothelium-dependent vasodilation (r=.7, P<.01) but not with endothelium-independent vasodilatation (r=-.1, P=.7). CONCLUSIONS RBX demonstrated no effect on SkBF or sensory symptoms after 1 year in this cohort. The correlation between C fiber-mediated and endothelium-dependent SkBF at baseline suggests that improving endothelial function could affect the microcirculation not only locally but also via the neurovascular arcade.

Circulating dipeptidyl peptidase-4 activity correlates with measures of hepatocyte apoptosis and fibrosis in non-alcoholic fatty liver disease in type 2 diabetes mellitus and obesity: A dual cohort cross-sectional study.

Intrahepatic expression of dipeptidyl peptidase‐4 (DPP4), and circulating DPP4 (cDPP4) levels and its enzymatic activity, are increased in non‐alcoholic fatty liver disease (NAFLD) and in type 2 diabetes mellitus and/or obesity. DPP4 has been implicated as a causative factor in NAFLD progression but few studies have examined associations between cDPP4 activity and NAFLD severity in humans. This study aimed to examine the relationship of cDPP4 activity with measures of liver disease severity in NAFLD in subjects with diabetes and/or obesity.

Alterations in Monocyte CD16 in Association with Diabetes Complications

Monocytes express many cell surface markers indicative of their inflammatory and activation status. Whether these markers are affected by diabetes and its complications is not known and was investigated in this study. Blood was obtained from 22 nondiabetic and 43 diabetic subjects with a duration of diabetes >10 years, including 25 without and 18 with clinically significant complications. The number of CD45+CD14+ monocytes and the percentage expressing the proinflammatory marker CD16 were determined by flow cytometry. Other markers of monocyte activation and expression of chemokine receptors were also examined. The relationship between monocyte CD16 and clinical data, selected cytokines, and chemokines was also investigated. Diabetes had no effect on total white cell number but increased monocyte number. Diabetes also significantly decreased the number of CD16+ monocytes but only in those with diabetic complications. Other markers of monocyte activation status and chemokine receptors were not affected by diabetes or complications status. Diabetes induced plasma proinflammatory cytokines and they were lower in diabetic subjects with complications compared to those without complications. These results suggest that the circulating monocyte phenotype is altered by diabetic complications status. These changes may be causally related to and could potentially be used to predict susceptibility to diabetic complications.

Detection and characterisation of microcirculatory abnormalities in the skin of diabetic patients with microvascular complications

The aim of this study was to characterise microvascular blood flow in the skin and to compare it with biomarkers of endothelial dysfunction and tissue inflammation in patients with type 2 diabetes with (n=20) or without (n=20) microvascular complications and 20 control subjects. Microvascular function was measured by laser Doppler velocimetry in combination with iontophoresis of acetylcholine (ACh) and sodium nitroprusside (SNP). Blood was collected for measurement of biomarkers including plasminogen activator inhibitor-1 (PAI-1), soluble intercellular adhesion molecule (sICAM), soluble vascular cell adhesion molecule (sVCAM) and high-sensitivity C-reactive protein (hsCRP). Both ACh and SNP responses fall progressively with the development of diabetes and microvascular complications. For the total cohort, there was a significant overall correlation between ACh and SNP response (r=0.7, p<0.0001), and this relationship was particularly strong in those with microvascular complications. There was a trend towards higher hsCRP levels across the three groups, but no difference in other biomarkers. Abnormalities of microvascular blood flow are evident in diabetes and become more marked with the development of microvascular complications. This relationship was similar to that shown by the marker of inflammation (hsCRP), but stronger than that pertaining to biomarkers of endothelial function. As both ACh and SNP responses are attenuated, the disturbance is not characteristic of endothelial dysfunction alone.