Biomedical subjects

Marc S Rendell

Publications and source records attributed to Marc S Rendell.

6 recordsLinked to original sources

PubMed2006

Targeting postprandial hyperglycemia.

In healthy individuals, blood glucose levels in the fasting state are maintained by the continuous basal-level insulin secretion. After a meal, the rise in postprandial glucose (PPG) is controlled by the rapid pancreatic release of insulin, stimulated by both glucose and the intestinal production of the incretins glucose-dependent insulinotropic polypeptide and glucagon-like peptide 1. In diabetic individuals, postprandial insulin secretion is insufficient to suppress an excessive rise in PPG. There is increasing evidence that elevated PPG exerts a more deleterious effect on the vascular system than elevation of fasting plasma glucose. In particular, individuals with normal fasting plasma glucose but impaired glucose tolerance have significantly increased risk of cardiovascular events. With the recognition of the importance of PPG and the availability of new pharmacologic options, management of diabetes will shift to greater attention to PPG levels. The prototype for such an approach is in the treatment of gestational diabetes and diabetic pregnancies where PPG is the primary target of efforts at glycemic control. These efforts have been extremely successful in improving the outlook for diabetic pregnant women. There are many approaches to reduction of PPG; dietary management and promotion of exercise are very effective. Sulfonylureas, meglitinides, metformin, thiazolidinediones, and disaccharidase inhibitors all counteract PPG elevation. The development of glucagon-like peptide 1 agonists such as exendin and dipeptidyl peptidase IV inhibitors such as vildagliptin offers a new approach to suppression of PPG elevation. New semisynthetic insulin analogues permit a more aggressive response to postprandial glucose elevation, with lower risk of hypoglycemia, than with regular insulin. Inhaled insulin also has a rapid onset of action and offers benefits in PPG control. It is proposed that an aggressive treatment approach focusing on PPG, similar to the current standards for diabetic pregancies, be directed at individuals with diabetes and impaired glucose tolerance.

Cardiovascular Diseases↗

PubMed2005

Manifestations of cutaneous diabetic microangiopathy.

The etiologies of a variety of skin conditions associated with diabetes have not been fully explained. One possible etiological factor is diabetic microangiopathy, which is known to affect the eyes and kidneys in patients with diabetes. There are many mechanisms by which diabetes may cause microangiopathy. These include excess sorbitol formation, increased glycation end products, oxidative damage, and protein kinase C overactivity. All of these processes occur in the skin, and the existence of a cutaneous diabetic microangiopathy has been well demonstrated. These microangiopathic changes are associated with abnormalities of skin perfusion. Because the skin plays a thermoregulatory role, there is significant capillary redundancy in normal skin. In diabetic patients, loss of capillaries is associated with a decrease in perfusion reserve. This lost reserve is demonstrable under stressed conditions, such as thermal stimulation. The associated failure of microvascular perfusion to meet the requirements of skin metabolism may result in diverse skin lesions in patients with diabetes. Many skin conditions peculiar to diabetes are fairly rare. Necrobiosis lipoidica diabeticorum (NLD) and diabetic bullae occur very infrequently as compared with diabetic retinopathy and nephropathy. Conversely, there is a correlation between diabetic microvascular disease and NLD. This correlation also exists with more common skin conditions, such as diabetic dermopathy. This relationship suggests that diabetic microangiopathy may contribute to these conditions even if it is not primarily causal. Clinically, the major significance of diabetic cutaneous microangiopathy is seen in skin ulceration which is very common and has a major impact on diabetic patients. Many factors contribute to the development of diabetic foot ulcers. Neuropathy, decreased large vessel perfusion, increased susceptibility to infection, and altered biomechanics all play a role, but there is no doubt that inadequate small blood vessel perfusion is a major cause of the inability to heal small wounds that eventually results in ulcer formation. The accessibility of skin capillaries makes cutaneous diabetic microangiopathy an attractive model for research on the evolution of microvascular disease in diabetic patients.

Aldehyde Reductase↗

PubMed2004

Depressed ventilatory reflexes after capsaicin challenge in streptozotocin-treated rats.

Diabetic sensory neuropathy is an affliction that decreases sensory perception in a number of organ systems. Although little is known of its pulmonary effects certain diabetic patients have reduced airway reactivity to cold air and elevated cough threshold to irritant inhalation, reflexes reported to be mediated by pulmonary C-fibers. Therefore we studied the effects the selective C-fiber activator capsaicin (0.01% aerosol, 30 s) on variables of ventilation using a whole-body plethysmograph in age-matched rats treated with streptozotocin (STZ) or its vehicle at 6 and 12 weeks after treatment. Body weight increased and plasma glucose and glycosylated hemoglobin were stable in vehicle-treated rats. In STZ-treated rats body weight decreased and plasma glucose and glycosylated hemoglobin increased. Capsaicin challenge decreased tidal volume, respiratory rate and therefore minute ventilation in non-treated and vehicle-treated rats. However capsaicin challenge increased tidal volume thereby altering minute ventilation in STZ-treated rats. Specific airway resistance increased in both groups after capsaicin challenge. Changes in ventilation in response to capsaicin challenge in STZ-treated rats may involve C-fiber sensory neuropathy.

Analysis of Variance↗

PubMed2002

Skin blood flow response in the rat model of wound healing: expression of vasoactive factors.

BACKGROUND: Although the microvascular blood flow response to wounding is predominantly vasodilation at skin sites with nutritive capillary perfusion (NUTR), there is a significant vasoconstrictive response at sites with high arteriovenous perfusion (AV). There may be a difference between NUTR and AV sites in the vasoactive factors which mediate the blood flow response to wounding. We measured the levels of mRNA expression of several potential mediators of the blood flow response to assess this possible difference. MATERIALS AND METHODS: We measured skin blood flow at wounds placed at the back, a NUTR site, and at the paw, an AV site, in 12 Wistar Kyoto rats. Measurements were performed at baseline and then at 7 days post wounding. There was a significant increase in blood flow at back wound sites, with a rise from 4.1 +/- 0.3 ml/min/100 g to 9.8 +/- 1.9 ml/min/100 g. At the undisturbed wound perimeter, outside the zone of granulation tissue, flow rose to 7.3 +/- 1.1 ml/min/100 g. At the paw wound site, Day 0 flow was 8.8 +/- 0.8 ml/min/100 g. At 7 days, there was a significant decrease in flow at wound center to 5.5 +/- 0.5 ml/min/100 g. We measured the levels of inducible nitric oxide synthetase (iNOS), endothelin, endothelin receptor, vascular endothelial growth factor (VEGF), and keratinocyte growth factor (KGF) gene mRNAs using reverse transcriptase PCR. RESULTS: There was a 10-fold increase in NOS mRNA in granulation tissue of both wounds on Day 7. There was a lesser but still substantial increase in the wound perimeter tissue. Levels of endothelin mRNA in the wound and wound perimeter were significantly lower at the paw than at the back. At baseline, the level of endothelin receptor B (ETrB) mRNA was greater at the back than at the paw. Wounding resulted in a substantial increase in EtrB mRNA levels in granulation tissue, reaching the same level at the back and paw wounds. There was also a substantial rise in EtrB mRNA levels at the paw wound perimeter, so that there was a reversal of the baseline condition, with paw levels actually surpassing the levels at the back perimeter. CONCLUSIONS: Thus, we have found significant changes in mediators both of vasoconstriction and vasodilation affecting the healing wound. These changes affect NUTR and AV sites in different ways. These results demonstrate the complexity of the regulatory processes controlling microvascular blood flow in wound healing.

Animals↗

PubMedDate not supplied

Combination therapy with pioglitazone plus metformin or sulfonylurea in patients with Type 2 diabetes: influence of prior antidiabetic drug regimen.

PURPOSE: To evaluate two trials of combination therapy, pioglitazone together with metformin or sulfonylurea, for Type 2 diabetes mellitus and to examine how pretrial antidiabetic therapies may have influenced the results. SUBJECTS AND METHODS: The results of two published trials that examine combination therapy, pioglitazone plus metformin or pioglitazone plus sulfonylurea were analyzed. A post hoc analysis was performed in which patients from both of these trials were subdivided on the basis of their oral antidiabetic therapy before enrollment into the trials. Those subsets receiving pretrial therapy with a sulfonylurea plus metformin - and discontinuing one of the agents before randomization - were compared to those receiving only one of the agents before enrollment. RESULTS: Patients in the combination pioglitazone (30 mg/day) plus metformin therapy arm of one trial, who entered with stable metformin monotherapy, experienced a significant decrease in glycosylated hemoglobin (HbA(1C)) levels during the 16-week course of the trial (-1.0+/-0.1 [mean+/-S.E.] percentage points; P<.05). In contrast, those in the same arm of the trial whose pretrial therapy included metformin plus a sulfonylurea - and who discontinued the sulfonylurea before enrollment - experienced no significant change in HbA(1C) levels (0.2+/-0.2 percentage points; P>.05). The difference between groups was significant (P<.001). Patients in the combination pioglitazone (15 or 30 mg/day) plus sulfonylurea therapy arm of the other trial, who entered the trial on stable sulfonylurea monotherapy, experienced significant decreases in HbA(1C) levels (-1.0+/-0.1 and -1.4+/-0.1 percentage points, respectively, for the 15- and 30-mg pioglitazone arms; P<.05). Those in the same arm whose pretrial therapy included sulfonylurea plus metformin - and who discontinued the metformin before enrollment - experienced no significant change in HbA(1C) levels. Differences between the groups separated on the basis of pretrial antidiabetic regimen were significant (P<.001). CONCLUSIONS: The efficacy of pioglitazone as an add-on in combination therapy (with metformin or a sulfonylurea) is likely to be greater than in previous reports, because those trial results were influenced by treatment regimens used by a portion of the patients before enrollment. Trials of oral hypoglycemic agents must be carefully constructed to consider the effects of agents given prior to the trial.

Administration, Oral↗

PubMedDate not supplied

Effect of cilostazol in patients with intermittent claudication: a randomized, double-blind, placebo-controlled study.

A multicenter, double-blind, randomized, placebo-controlled, parallel study was conducted to compare the efficacy and safety of cilostazol 100 mg and 50 mg, both administered twice daily, with that of placebo in patients with moderately severe intermittent claudication (IC) secondary to peripheral arterial disease.A total of 394 subjects 40 years of age or older with chronic, stable, symptomatic IC received cilostazol 100 mg twice daily, 50 mg twice daily, or placebo for 24 weeks. Subjects receiving cilostazol 100 mg twice daily experienced a 21% net improvement in maximal walking distance (MWD)compared with placebo subjects (p = 0.0003) and a 22% net improvement in distance walked to the onset of symptoms (PFWD) (p = 0.0015). Subjects who received cilostazol 50 mg twice daily also benefited from therapy, but not to a statistically significant degree (7% and 11% improvement in MWD and PFWD, respectively). Quality-of-life and functional status assessments corroborated these objective results. Cilostazol, in particular 100 mg twice daily, significantly improves symptoms in patients with IC.

Adult↗