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Biomedical subjects

M J Prince

Publications and source records attributed to M J Prince.

At least 55 records · Page 3Linked to original sources
PubMed1988

Metabolic effects of hydrochlorothiazide and enalapril during treatment of the hypertensive diabetic patient. Enalapril for hypertensive diabetics.

To determine the effect of enalapril maleate and low-dose hydrochlorothiazide therapy on blood pressure and glucose and lipid homeostasis in hypertensive type II diabetic patients, we treated nine of these patients sequentially with placebo, hydrochlorothiazide (25 mg/d with supplemental potassium chloride), and enalapril (10 to 20 mg/d). Sitting blood pressure fell significantly and to comparable levels with both hydrochlorothiazide and enalapril monotherapy. Enalapril monotherapy was associated with a slight, but not significant, fall in fasting blood glucose levels and with a significant fall in hemoglobin A1c levels. This improved glucose homeostasis could not be explained satisfactorily by changes in peripheral insulin sensitivity or hepatic glucose output, determined with the euglycemic clamp technique, or by changes in fasting serum insulin levels or monocyte insulin binding. In these low doses, hydrochlorothiazide did not worsen glucose homeostasis. Serum total cholesterol levels were significantly lower with enalapril therapy than with hydrochlorothiazide therapy or with placebo, and serum high-density lipoprotein cholesterol and triglyceride levels did not change significantly with either treatment. Thus, by providing effective blood pressure control and beneficial metabolic effects, enalapril therapy appears ideal for treatment of hypertension in diabetic patients. Similarly, low-dose hydrochlorothiazide therapy appears to have fewer metabolic complications in these patients and is, therefore, a logical alternative to substitute for, or add to, enalapril therapy.

Adult↗
PubMed1987

Hyperinsulinemia and hyperandrogenemia: in vivo androgen response to insulin infusion.

The plasma androgen responses to multiple-dose insulin infusions were determined in six normal females, four normal males, five obese females, and in three females with severe insulin resistance, hirsutism, and acanthosis nigricans. During the insulin infusions, the plasma glucose concentrations were maintained at 85 +/- 1 mg/dL by variable infusions of dextrose. Plasma androstenedione was augmented by 27-39% at physiologic insulin concentrations in the normal subjects and the obese group, and by 25% at hyperinsulinemic levels in the insulin-resistant group with acanthosis nigricans. The increased androstenedione concentrations achieved in the normal females and obese females were similar to the hyperandrogenemic levels seen in the acanthotic subjects in the basal state. Plasma cortisol also increased in all groups from 19% in normal females to 135% in obese females during the insulin infusions, but these changes did not reach statistical significance. These studies suggest that hyperinsulinemia may play a pathogenic role in the hyperandrogenemia of polycystic ovarian disease.

Acanthosis Nigricans↗
PubMed1986

Insulin resistance with acanthosis nigricans: the roles of obesity and androgen excess.

The roles of hyperandrogenemia and obesity in the syndrome of severe insulin resistance with acanthosis nigricans were evaluated in studies of 11 females with this condition. Our results in these subjects were compared to evaluations of control subjects matched for degree of androgen excess or obesity. Fasting insulin levels were 3-, 5-, and 15-fold higher in the obese (OB), hyperandrogenemic (HO), and acanthosis nigricans (AN) groups, respectively, when compared to normal females. Responsiveness to a standard bolus of exogenous insulin was 78% of normal in the OB group, 40% of normal in the HO group, and 30% of normal in the AN group. Insulin binding to monocytes from both the OB group, and the HO group was modestly diminished primarily due to decreased receptor number. As a group, AN subjects when compared to either normal or weight-matched controls, demonstrated a significant decrease in monocyte insulin binding predominantly due to a decrease in receptor number. However, two patients in the AN group had normal insulin binding suggesting a postreceptor mechanism for the insulin resistance in at least some of these subjects. In vivo glucose utilization insulin dose response curves were determined in 3 acanthotic subjects using the euglycemic clamp technique. All 3 of these subjects had a right shift of the curve and diminished maximal utilization, consistent with combined receptor and postreceptor defects in insulin action. In evaluating the relationship between hyperandrogenemia, insulin resistance, and acanthosis nigricans, significant correlations among basal levels of plasma insulin, and both testosterone and androstenedione were demonstrated.(ABSTRACT TRUNCATED AT 250 WORDS)

Acanthosis Nigricans↗
PubMed1986

Acanthosis nigricans and obesity: acquired and intrinsic defects in insulin action.

Six obese, severely acanthotic females were evaluated for insulin resistance by an oral glucose tolerance test, intravenous insulin tolerance test, and insulin binding to freshly isolated monocytes, as well as studies of cultured skin fibroblasts. After baseline studies were obtained, the acanthotic subjects were maintained for 14 days on a 500 calorie diet, and the evaluations were repeated. Initial evaluation demonstrated normal glucose tolerance, but marked fasting hyperinsulinemia (57 +/- 5 microU/mL) and dramatically blunted response to exogenous insulin (KITT, 2.0%/min) when compared with five nonacanthotic weight-matched controls (insulin, 15 +/- 2 microU/mL; KITT, 5.2%/min). Monocyte insulin binding for the acanthotic group (0.251 +/- 0.050%/10(6) cells) was only 56% of the binding seen in the obese controls (0.447 +/- 0.108%). After the acanthotic females dieted for 14 days, their hyperinsulinemia and monocyte insulin binding improved, but failed to normalize. The response to exogenous insulin was unchanged and remained drastically blunted. In contrast to the normal insulin binding found in the cultured fibroblasts from the nonacanthotic obese controls, insulin binding to fibroblasts from the acanthotic group was decreased by 40%, suggesting that an intrinsic defect in insulin binding was present. Thus, we conclude that this cohort of acanthotic obese females are considerably more insulin-resistant than nonacanthotic weight-matched females. Furthermore, these studies suggest that the severe insulin resistance results from a combination of an acquired defect related to obesity and an inherent cellular defect in insulin action at, or beyond, the receptor.

Acanthosis Nigricans↗
PubMed1986

Insulin receptor proliferation: a mechanism for tumor-associated hypoglycemia.

A 30-yr-old man was found to have intractable hypoglycemia associated with colon carcinoma metastatic to the liver. Analysis of glucose requirements before death revealed a level of glucose turnover in excess of 12.9 mg/kg X min, consistent with maximally stimulated whole body glucose utilization. This high level of glucose turnover was present at a time when plasma immunoreactive insulin was very low. Insulin binding was measured in freshly isolated circulating mononuclear cells before death and in plasma membranes prepared from several tissues obtained at autopsy. A 3- to 5-fold increase in insulin receptor number was found in the mononuclear cells and liver and muscle plasma membranes. In contrast, skin fibroblasts maintained in tissue culture demonstrated no increase in insulin binding, thus suggesting that the increase in insulin receptors in freshly isolated tissues was acquired rather than intrinsic. Antibodies directed against the insulin receptor were not present. The patient's serum concentration of insulin-like growth factor I was low, but the serum level of nonsuppressible insulin-like protein was elevated. Serum bioassayable insulin-like activity was decreased. Based on tumor bulk at autopsy and in vitro analysis of glucose transport by his tumor cells maintained in monolayer tissue culture, it was estimated that his tumor could directly account for less than one third of the whole body glucose requirement. These data suggest that the increased tissue utilization of glucose in this hypoglycemic patient was caused by proliferation of insulin receptors in liver and muscle induced by his nonislet cell tumor through an unknown humoral mechanism(s).

Adenocarcinoma↗
PubMed1986

Functional characteristics of decreased insulin receptors on fibroblasts obtained from a subject with severe insulin resistance and acanthosis nigricans.

In a patient with severe insulin resistance and acanthosis nigricans, a decrease in the number of insulin receptors has been found on freshly isolated monocytes and cultured fibroblasts compatible with a primary or genetic decrease in cell-surface insulin receptors. To determine the functional characteristics of the remaining receptors on these cells, insulin-stimulated glucose uptake, insulin internalization, and insulin-induced receptor loss were evaluated in monolayer fibroblasts obtained from this subject. Maximal insulin stimulation of 2-deoxyglucose was markedly blunted, compatible with abnormal insulin responsiveness due to a functional impairment of the remaining receptors. In the presence of chloroquine, the acanthotic subject's fibroblasts internalized more insulin per available receptor compared with the normal cell line, suggesting an accelerated rate of insulin internalization. When the rate of insulin internalization was more directly determined by assessing the rate of appearance of acid-resistant, cell-associated radioactivity at 37 degrees C, a similar increase in insulin internalization rate was evident. When downregulation was assessed, insulin's ability to induce receptor loss in the acanthotic subject's cell line was augmented. Thus, a primary or genetic decrease in insulin receptors on cultured fibroblasts from a patient with acanthosis nigricans and insulin resistance is associated with functional impairment of the remaining receptors leading to significant alterations in ligand processing and subsequent insulin action.

Acanthosis Nigricans↗
PubMed1985

Obesity, acanthosis nigricans, insulin resistance, and hyperandrogenemia: pediatric perspective and natural history.

We studied the syndrome of acanthosis nigricans, obesity, insulin resistance, and hyperandrogenemia in 22 patients. Although isolated case reports in adolescents have appeared, this syndrome has not received full recognition as a pediatric entity. Our patients (17 girls, five boys) had a mean weight 5.7 SD above the mean for age, although mean height was only 0.5 SD above the mean for age. All patients had acanthosis nigricans. Their insulin resistance was significantly greater than that in a control group with comparable obesity. Fasting insulin concentration was 5.25 microU/ml in lean controls, 19.6 microU/ml in obese controls, and 49.8 microU/ml in study patients (P less than 0.002). Mean glucose disappearance rate during an insulin tolerance test was 6.7%/min in lean controls, 5.19%/min in obese controls, and 2.35%/min in study patients (P less than 0.02). After menarche, mean plasma testosterone concentration was 106 ng/dl, compared with less than 50 ng/dl in all lean and obese control patients. Data derived from our series of patients lead us to conclude that (1) this is a genetic syndrome, although the exact mode of inheritance is unclear; (2) the natural history of the syndrome invariably begins with the onset of obesity, followed by acanthosis nigricans that worsens with progressive weight gain; (3) acanthosis nigricans is thus a marker for hyperinsulinemia, which occurs before hyperandrogenemia; (4) hyperandrogenemia occurs only after menarche. Identification of this syndrome should permit monitoring for the development of hyperandrogenemia during puberty and determination of other affected family members.

Acanthosis Nigricans↗
PubMed1983

Insulin resistance in noninsulin-dependent diabetes mellitus: impact of sulfonylurea agents in vivo and in vitro.

The insulin resistance associated with NIDDM appears to be caused by decreased insulin binding in conjunction with a significant postreceptor defect in insulin action. In the untreated state, the postreceptor defect appears to be the predominant lesion and the magnitude of this postreceptor defect appears to correlate directly with the degree of fasting hyperglycemia in individual patients. In vitro studies using isolated adipocytes suggest that the postreceptor defect in insulin action resides at the level of the glucose transport system. Insulin treatment ameliorates the postreceptor defect in insulin action which suggests that it is an acquired defect secondary to some aspect of the altered metabolic state. Therapy with the second-generation sulfonylurea compound glyburide enhances overall insulin responsiveness without altering insulin binding. Prevailing insulin levels are increased markedly during glyburide therapy but do not correlate with the clinical response, which suggests that the improvement in target tissue insulin action is the critical determinant in terms of the clinical response to the drug. In vitro studies utilizing cultured human fibroblasts indicate that glyburide increases the number of cell-surface insulin receptors and opposes insulin-mediated down-regulation.

Diabetes Mellitus↗
PubMed1982

Hyperphosphatemic tumoral calcinosis: association with elevation of serum 1,25-dihydroxycholecalciferol concentrations.

Seven siblings with hyperphosphatemic tumoral calcinosis were studied using metabolic measures. Serum phosphorus and 1, 25-dihydroxycholecalciferol concentrations were significantly increased and serum parathyroid hormone and 25-hydroxycholecalciferol concentrations were significantly decreased in these subjects. Metabolic balance studies done in three of the siblings showed positive calcium and phosphorus balances, reflected by increased gastrointestinal absorption and decreased renal excretion. These data suggest that a hereditary abnormality of vitamin D metabolism may be present in patients with hyperphosphatemic tumoral calcinosis. Failure of the normal feedback mechanism regulating the 25-hydroxy-1-alpha-hydroxylase enzyme is suggested as the major cause. Although this defect could lead to many of the metabolic abnormalities seen in these patients, the overall contribution of altered vitamin D metabolism to the pathogenesis of tumoral calcinosis is not fully understood.

Adolescent↗
PubMed1981

Regulation of insulin receptors in cultured human fibroblasts.

The ability of insulin to regulate its own receptor was investigated in cultured human fibroblasts. Physiological insulin concentrations led to a loss of insulin receptors, and this process was dependent on cellular energy and ongoing protein synthesis. The insulin concentration primarily affected the rate of receptor loss rather than the eventual cellular receptor concentration. Studies of receptor regeneration revealed that the absolute rate of insertion of new or recycled receptors into the plasma membrane was constant and independent of the amount of proceeding receptor loss or the time over which receptor loss occurred. These results are compatible with the concept that insulin-induced receptor loss in cultured human fibroblasts is a self-limited process mediated by an endocytotic internalization pathway which is dependent on new protein synthesis. Receptor regeneration is a distinct cellular process dependent on ongoing protein synthesis and does not imply represent the absence of ongoing receptor loss.

Cells, Cultured↗
PubMed1981

Insulin binding, internalization, and insulin receptor regulation in fibroblasts from type II, non-insulin-dependent diabetic subjects.

The ability of insulin to bind, internalize, and regulate its own receptor was investigated in cultured human fibroblasts obtained from 8 normal subjects and 8 patients with type II, non-insulin-dependent diabetes mellitus (NIDDM). The ability of the cells from the two groups to bind insulin was the same, and Scatchard analysis demonstrated identical curvilinear plots. When cells were incubated at 37 degrees C with the lysosomotropic agent, chloroquine, and 125I-insulin, the drug led to a marked, but comparable, increase in cell-associated radioactivity in both control and diabetic fibroblasts (236 and 245% increase, respectively). Insulin pretreatment leads to a loss of insulin receptors in cultured human fibroblasts and preincubation with insulin led to a comparable dose-dependent decrease in subsequent insulin binding in both normal and diabetic fibroblasts. Scatchard analysis demonstrated that this decrease in binding was entirely due to a decrease in receptor number with no change in receptor affinity. These data demonstrate normal insulin binding, insulin internalization, and insulin-mediated receptor loss in fibroblasts from patients with with NIDDM, and these cells are several generations removed form the in vivo milieu. Thus, these results provide direct evidence that the well-known decrease in insulin binding in freshly isolated cells from patients with NIDDM, and these cells are several generations removed from the in vivo milieu. Thus, these results provide direct evidence that the well-known decrease in insulin binding in freshly isolated cells form patients with NIDDM is a reflection of environmental factors rather than an intrinsic (genetic) cellular abnormality.

Adipose Tissue↗
PubMed1980

Direct in vitro effect of a sulfonylurea to increase human fibroblast insulin receptors.

We have studied the effects of the oral sulfonylurea agent glyburide to modulate insulin receptors on nontransformed human fibroblasts in tissue culture. When glyburide was added to monolayers of human fibroblasts, a dose-dependent increase in the number of cell surface receptors was observed with a maximum effect (19% increase) seen at 1 microgram/ml glyburide. Insulin can induce a loss of insulin receptors in these cells, and when fibroblasts are exposed to 100 ng/ml insulin for 6 h, approximately 60% of the initial complement of cell surface receptors are lost. When the process of insulin-induced receptor loss (or down regulation) was studied in the presence of glyburide, the drug exerted a marked inhibitory effect on this regulatory process. Thus, glyburide inhibited insulin-induced receptor loss in a dose-dependent fashion, and the maximally effective drug concentration (1 microgram/ml) inhibited 34% of the receptor loss. These studies demonstrate a direct in vitro effect of this oral hypoglycemic agent to increase the number of cell surface insulin receptors or prevent their loss, presumably by slowing the rate of receptor internalization. These findings may explain the well known extrapancreatic effect of sulfonylurea agents to improve insulin-mediated tissue glucose metabolism.

Dose-Response Relationship, Drug↗
PubMed1980

Tumoral calcinosis: scintigraphic studies of an affected family.

Tumoral calcinosis is a rare, familial ectopic calcification syndrome associated with hyperphosphataemia. A family in which seven of 13 siblings had demonstrable, clinical, radiological and pathological findings of tumoral calcinosis was evaluated. The purposes were to compare the efficacy of bone scintiscans with serum phosphorus determination in detecting subclinical disease early in asymptomatic siblings and to assess therapeutic results in affected family members following initiation of phosphate depletion therapy. History, physical examination, serum calcium, serum phosphorus and bone scintiscans were performed in 12 of 13 siblings. All the affected siblings had markedly elevated serum phosphorus levels and abnormal bone scintiscans while the unaffected siblings had normal serum phosphorus levels and normal bone scintiscans. All the siblings, affected and unaffected, were normocalcaemic. After initiation of phosphate depletion therapy, gross changes in the appearance of lesions were detected on bone scintiscans. Serum phosphorus levels likewise showed a modest decline, although still remaining in the hyperphosphataemic range. In conclusion, bone scintiscans and serum phosphorus determinations are equally sensitive in detecting subclinical disease. However, the scintiscans are helpful in assessing not only the extent of the disease, but also whole-body and regional changes following any therapeutic interventions.

Adolescent↗
PubMed1979

Cutaneous manifestations of tumoral calcinosis.

We have followed up a large family in which seven members have tumoral calcinosis. One girl had the skin lesions of localized calcinosis cutis apart from the typical subcutaneous deposits of calcium. Like most persons with tumoral calcinosis, our patient had normal serum calcium concentrations; however, the serum phosphorus levels were greatly elevated. The familial occurrence and elevated serum phosphorus levels suggest the possibility of some as yet undefined, heritable metabolic defect as the underlying cause. The occurrence of tumoral calcinosis with localized calcinosis cutis is a rare association, and there has been only one other reported case to our knowledge. This report describes our patient and offers a brief discussion of tumoral calcinosis. The therapeutic response to the phosphate depletion regimen and topical steroids was disappointing in our case.

Calcinosis↗
PubMed1976

The role of serum nonsuppressible insulin-like activity (NSILA) in compensatory renal growth.

The nonsuppressible insulin-like activity (NSILA) of serum is defined as the insulin-like activity measured in insulin bioassays that is not suppressed by addition of insulin antiserum. The major part of serum NSILA is attributable to a 90,000 mol wt trace protein which has been recently purified. This study was designed to evaluate the role of serum NSILA in compensatory renal growth (CRG).

Adrenocorticotropic Hormone↗