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Biomedical subjects

R S Clements

Publications and source records attributed to R S Clements.

At least 19 recordsLinked to original sources
PubMed1999

Measuring glycated proteins: clinical and methodological aspects.

The recognition that nonenzymatic glycation, wherein free sugar condenses with certain reactive protein amino groups, is increased in hyperglycemic states has led to improved means for assessing diabetic control through the measurement of concentrations of glycated proteins in the circulation. This article reviews the chemistry, methods for measurement, and clinical relevance of circulating glycated proteins in the management of diabetes.

Animals↗
PubMed1996

Glycated albumin promotes a generalized vasculopathy in the db/db mouse.

Increased protein glycation has been mechanistically linked to accelerated vascular pathobiology in diabetes. Because glycated albumin induces biosynthetic abnormalities in cultured aortic endothelial cells that resemble those associated with macrovascular disease, we sought evidence that increased glycated albumin is operative in the genesis of diabetic vasculopathy in vivo. Plasma concentrations of fibronectin, a sensitive marker of endothelial cell damage, were increased two-fold in diabetic db/db mice compared with their nondiabetic db/m littermates. Treatment with monoclonal antibodies specifically reactive with albumin modified by Amadori glucose adducts normalized fibronectin in diabetic animals despite persistent hyperglycemia. These findings suggest that increased glycated albumin causally contributes to diabetic vasculopathy, and that blocking this influence ameliorates vascular damage.

Aging↗
PubMed1996

Prevention of decline in renal function in the diabetic db/db mouse.

We recently reported that when diabetic db/db mice, which develop glomerular pathology resembling that in human diabetes mellitus, are treated with monoclonal antibodies (A717) that neutralize the effects of excess glycated albumin, there is an amelioration of mesangial expansion, renal overexpression of mRNAs encoding for the extracellular matrix proteins collagen IV and fibronectin and proteinuria. These findings suggested that A717 might also retard the development of compromised renal function in this animal model. To examine this possibility, serum creatinine and blood urea nitrogen (BUN) were measured in diabetic db/db mice and their non-diabetic db/m littermates before and after an 8-week course of treatment with A717 or irrelevant murine immunoglobulin (MIg). Early in the course of diabetes, BUN and serum creatinine concentrations did not significantly differ from those in the db/m littermates, but were significantly increased after 10 weeks of sustained hyperglycaemia. Treatment of db/db mice with A717 prevented the rise in creatinine and attenuated the elevation in BUN. A717 also prevented the decrease in creatinine clearance observed in diabetic compared with non-diabetic animals (2.2 +/- 0.8 vs 4.1 +/- 0.3 vs 5.0 +/- 1.1 ml/h in db/db vs db/db-A717 vs db/m, respectively). MIg did not alter the change in renal function with time in db/db mice. Taken together with our previous results, the present findings indicate that the diabetic db/db mouse develops changes in renal function and structure that parallel the course of human diabetic nephropathy in nature and chronology and demonstrate, for the first time, that therapy directed against increased glycated albumin can prevent the decline in renal function in this rodent model of genetic diabetes.

Analysis of Variance↗
PubMed1991

Dosage accuracy of self-mixed vs premixed insulin.

The accuracy of patients and health care professionals in drawing up the components of a split-mix insulin regimen and of premixed insulin at three dosages (30 units, 10 units, and 5 units) was assessed with both 30-U and 100-U syringes. Both patients and professionals were inaccurate with both syringes. At low doses tested and with both syringes, patients and professionals showed greater accuracy with premixed insulin than with self-mixed insulin. Errors in drawing up insulin involved errors mainly in the ratio rather than the total volume of insulin drawn. Accuracy improved with higher doses of insulin. The patients' perception of their skill level in drawing up and mixing insulin correlated with the objective measurements of their skill. The improved accuracy in dosing with premixed insulin might explain the previously observed improved glycemic control in patients taking premixed insulin.

Adult↗
PubMed1988

Factors associated with discontinuation of continuous subcutaneous insulin infusion.

Fifty-five patients who had been started on continuous subcutaneous insulin infusion (CSII) more than 1 year previously were surveyed to determine the difference between those who had continued and those who had discontinued CSII. These retrospective results were used to determine characteristics that predict a suitable candidate for CSII which could be tested in a future prospective study and would guide our clinical choice of candidates for CSII. Twenty patients had discontinued CSII (Group D) and 35 patients had continued CSII (Group C). Group D contained younger patients, more likely to be women who had had a shorter duration of diabetes, more frequent antecedent episodes of diabetic ketoacidosis (DKA), and more frequent doctor visits. The major rationale for starting CSII in Group D was poor control with keotacidosis whereas Group C started CSII for poor control with hypoglycemia. The reasons for stopping CSII in Group D were interference with lifestyle (40%), needle site abcesses (40%), psychological rejection (10%), and poor insulin absorption (10%). Group D patients had a significantly higher incidence of psychological rejection of CSII, dermatological problems, and needle site abcesses. For patients in Group D, glycosylated hemoglobin levels during CSII were similar to those prior to CSII. Group C patients had improved glycosylated hemoglobin levels and were more satisfied with CSII despite a slightly higher incidence of pump runaway. Group C patients had a trend toward more frequent hypoglycemia while on CSII; however, in patients who had reported severe hypoglycemia before starting CSII, there was a significant decline in the frequency of severe hypoglycemia.(ABSTRACT TRUNCATED AT 250 WORDS)

Abscess↗
PubMed1988

Paradoxical organ-specific adaptations to streptozotocin diabetes mellitus in adult rats.

Adult male Fisher rats injected with streptozotocin (Stz) to produce diabetes mellitus demonstrated a significant loss of total body weight associated with adipose and muscle tissue wasting. Paradoxically, intestinal mass and length were increased in Stz-treated rats despite catabolism of other tissues. Concomitant with increased intestinal mass, food and water intake increased significantly in Stz-diabetic animals. Renal weight was not reduced despite the fall in total body weight. It is proposed that the adult Stz-diabetic rat responds to a loss of available insulin by polyphagia, polydipsia, and catabolism of adipose and muscle tissue and that a large percentage of available synthetic fuel is devoted to the production of additional intestinal tissue.

Adaptation, Physiological↗
PubMed1988

Prevention of the complications of diabetes.

Until drugs that will prevent metabolic derangements that cause the complications of diabetes have been developed, the best approach to their prevention is control: of hyperglycemia, of hypertension, of obesity, and of smoking. Intensive insulin therapy, although demonstrably effective, must be approached with caution because hypoglycemia is a potentially life-endangering threat. Conversely, a Danish study has demonstrated a decrease in hypoglycemic episodes with intensive insulin therapy (Parving HH. Personal communication, 1988). With this in mind, it may be essential to bring blood glucose levels into a reasonable range shortly after the diagnosis of diabetes mellitus has been made. Insulin therapy is required for type I diabetic patients, and it may also be an appropriate therapy for all type II patients who do not become rapidly normoglycemic following diet and oral sulfonylurea treatment. Some physicians believe that a frontal "attack" of a split-mixed program of insulin therapy when type II diabetes is diagnosed is of psychologic as well as physiologic benefit, impressing the patient with the importance of control and vigilance. Compliance to rigid dietary change is notoriously unsuccessful, and the "trial-and-failure" approach, often ending in insulin therapy in any case, may not be the most effective. The advent of easy-to-use blood glucose monitoring devices and convenient and discreet insulin delivery systems has made maintenance of glycemic control less difficult for the insulin-using patient. New antihypertensive agents, lipid-reducing drugs, and second-generation sulfonylureas that do not affect the quality of life are now available and should be used in the person with diabetes as necessary.(ABSTRACT TRUNCATED AT 250 WORDS)

Diabetic Angiopathies↗
PubMed1987

Rapid insulin initiation in non-insulin-dependent diabetes mellitus.

Three insulin-initiation regimens were compared in 43 severely hyperglycemic non-insulin-dependent diabetic patients: a "standard" regimen (Lente insulin once daily), a "rapid" regimen (a mixture of regular and Lente insulins twice daily), and a "rapid/intravenous" regimen (the "rapid" regimen preceded by overnight intravenous infusion of regular insulin). The mean serum glucose level fell more rapidly in both groups receiving "rapid" regimens, reaching less than 200 mg/dl in 3.0 days with the "rapid" regimen compared with 5.9 days with the "standard" regimen (p less than 0.005). Duration of hospitalization was similarly reduced (6.4 versus 9.9 days, p less than 0.0001) as was the cost of hospitalization. In contrast to the "rapid" regimens, symptomatic hypoglycemia was common and adequate glycemic control was rare with the "standard" regimen. Thus, rapid initiation of insulin therapy with 0.5 to 0.6 units/kg per day of a mixture of regular and intermediate-acting insulins given twice daily is effective, safe, and reduces the cost of hospitalization in patients with non-insulin-dependent diabetes mellitus who require insulin treatment.

Adult↗
PubMed1987

Effect of insulin therapy on lipoproteins in non-insulin dependent diabetes mellitus (NIDDM).

Thirty patients with NIDDM and severe hyperglycemia (fasting plasma glucose greater than 200 mg/dl) were initiated on insulin therapy. Lipoprotein concentrations were measured by the Vertical Autoprofile procedure before insulin therapy and 1, 3, 6 and 26 weeks after insulin initiation. Patients were divided into 4 phenotypes based on their pretreatment lipoprotein profile: HyperVLDL (elevated VLDL), HyperLDL (elevated LDL), HyperVLDL-LDL (elevated VLDL and LDL), and non-hyperlipidemic. There were no differences in the initial fasting plasma glucose, Hgb Alc, or fasting free insulin concentrations between the groups. Both the HyperVLDL and HyperLDL groups had significantly lower HDL-C concentrations that the non-hyperlipidemic group and the HyperVLDL-LDL group had significantly higher IDL-C than any of the other groups. Insulin therapy resulted in similar decreases in fasting plasma glucose and increases in fasting free insulin concentrations in all 4 groups. HDL-C increased in all 4 groups. The most marked improvements in HDL-C were seen in the non-hyperlipidemic (+37%) and HyperLDL (+42%) groups while the HyperVLDL group had only an 18% increase. VLDL-C fell in all groups but in the HyperVLDL group it fell dramatically to almost normal levels within the first week, whereas it took 6 weeks for the HyperVLDL-LDL group to reach its VLDL-C nadir and this was still significantly higher than normal. LDL-C improved modestly in only the HyperLDL patients after 6 weeks of insulin therapy. There were no statistically significant changes in either the IDL-C or Lp(a)-C in any of the groups during insulin therapy. The changes in HDL-C and IDL-C were negatively correlated with the fasting plasma glucose and Hgb Alc but not with the free insulin concentration. We conclude that: 1) Insulin therapy can cause dramatic improvements in HDL-C and VLDL-C while it has only a mild suppressive effect on LDL-C and no statistically significant effect on IDL-C or Lp(a)-C. The degree of improvement in the lipid profiles varied considerably between the different lipid phenotypes. 2) The hyperlipidemic phenotypes seen in these patients appear to be determined primarily by factors other than the degree of hyperglycemia and hypoinsulinemia.

Blood Glucose↗
PubMed1987

Diminished flare response in neuropathic diabetic patients. Comparison of effects of substance P, histamine, and capsaicin.

The flare response in skin largely depends on an intact primary sensory fiber, the C-fiber. We measured the flare response to the intradermal injection of substance P, histamine, and capsaicin in control subjects and in diabetic patients with and without clinically obvious polyneuropathy. The neuropathic diabetic patients had a reduced flare response to substance P, histamine, and capsaicin, compared with control and nonneuropathic diabetic subjects. The smaller flare response in the neuropathic diabetics after capsaicin administration suggested a dysfunction of the peripheral component of the C-fiber. Alternatively, dysfunction of the mast cell or vascular reactivity may contribute to the diminished flare. Because C-fibers participate in nociception in addition to the flare response, the findings of this study, by a method that permits a quantifiable measurement of the function of peripheral sensory neurons in diabetic subjects, has potential usefulness in evaluating sensory neuropathy in diabetic patients.

Capsaicin↗
PubMed1986

New therapies for the chronic complications of older diabetic patients.

Recently, four biochemical mechanisms have been implicated in the pathogenesis of certain late complications of diabetes mellitus. All of these mechanisms (altered polyol pathway activity, disrupted myo-inositol metabolism, increased vascular permeability, and increased nonenzymatic glycosylation of proteins) are activated by exposure of tissues to hyperglycemia. There is evidence to suggest that the development of retinopathy, nephropathy, and neuropathy is directly related to the level of glycemia in patients with diabetes mellitus. Whether strict glycemic control will prevent or reverse diabetic complications is the subject of the Diabetes Control and Complications Trial. Until the results of that study are reported, and until euglycemia can be achieved in all diabetic patients, the search will continue for other pharmacologic agents that might prevent the development of complications. Therapies that are currently under investigation include administration of aldose reductase inhibitors and supplementation of dietary myo-inositol. It is too early to conclude whether such therapies will prove useful in the prevention or reversal of diabetic complications.

Aged↗
PubMed1986

The polyol pathway. A historical review.

Polyhydric alcohols (polyols) are widely distributed in nature, and the enzymes of the polyol pathway (aldose reductase and sorbitol dehydrogenase) are present in many mammalian tissues. The function of this pathway remains a mystery. A primary role for the pathway in the pathogenesis of 'sugar cataract' was provided by a number of experimental observations and in the 1960s the 'osmotic hypothesis' was propounded. This hypothesis also had implications for the pathogenesis of diabetic neuropathy. However, in the 1970s doubts were raised about the validity of the hypothesis, culminating in experiments which suggested that abnormalities in myo-inositol metabolism in nerve and lens were more closely related to the glucose-induced functional changes in these tissues than was the polyol pathway. Nevertheless, increased activity of the polyol pathway must still be regarded as an instigator of the biochemical abnormalities that lead to damage of lens and nerve in diabetes mellitus.

Animals↗
PubMed1985

Complications of diabetes. Prevalence, detection, current treatment, and prognosis.

The late complications associated with diabetes mellitus affect the eye (retinopathy and cataract), the kidney (diabetic glomerulosclerosis), the nerves (mononeuropathies, distal symmetric polyneuropathy, and autonomic neuropathy), and the large blood vessels (coronary artery, cerebrovascular, and peripheral vascular disease). With the exception of large blood vessel disease, evidence in animals and humans has suggested that the development of diabetes-associated complications is related to metabolic abnormalities associated with hyperglycemia. Although the exact mechanism by which hyperglycemia causes damage in individual tissues is unknown, a number of potentially pathogenic mechanisms have been proposed. These include increased activity of the polyol pathway, disturbance in the metabolism of myo-inositol and its phospholipid derivatives, abnormal permeability of the small blood vessels, and excessive glycosylation of various proteins. With the introduction of potent aldose reductase inhibitors, the role of increased activity of the polyol pathway (and related abnormalities in myo-inositol metabolism) in the pathogenesis of diabetes-associated complications can be clarified.

Adult↗