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Biomedical subjects

I G Fantus

Publications and source records attributed to I G Fantus.

43 records · Page 3Linked to original sources
PubMed1986

Glucose intolerance in Friedreich's ataxia: association with insulin resistance and decreased insulin binding.

Friedreich's Ataxia (FA) is a neurologic disorder associated with a high prevalence of diabetes mellitus. To assess insulin secretion and insulin resistance, glucose and insulin responses to oral glucose and insulin binding to circulating monocytes and dextran gradient fractionated and unfractionated red blood cells (RBCs) were compared in 11 subjects with FA to 11 age-matched controls. Glucose and insulin responses were elevated from one to three hours after oral glucose in FA. The mean corrected insulin responses were not different while peripheral insulin activity (A) was significantly decreased (1.38 +/- 0.22 v 0.77 +/- 0.16, control v FA, P less than 0.025) indicating the presence of insulin resistance. A significant correlation between the degree of insulin resistance (A) and duration of neurologic symptoms was found (r = .65. P less than 0.025). Resistance to exogenous insulin was confirmed in ten subjects with FA by intravenous insulin tolerance tests (KITT, %/min, 6.25 +/- 0.90 v 3.93 +/- 0.61, P less than .05). Both FA and control groups showed highest insulin binding to fraction A (youngest) RBCs, but no difference was observed between the two groups. However, insulin binding to monocytes was significantly decreased in subjects with FA (% specific binding/10(7) cells/mL, 6.37 +/- 0.71 v 4.51 +/- 0.39, P less than 0.05, control v FA). This was associated with a decrease in apparent receptor affinity. We conclude that FA is associated with insulin resistance, which increases with the duration of neurologic impairment. The insulin binding to monocytes suggests that the insulin resistance may be partially explained by a receptor defect.

Adolescent↗
PubMed1986

Mechanism of action of metformin: insulin receptor and postreceptor effects in vitro and in vivo.

Metformin (Met) is a biguanide oral hypoglycemic agent used in the treatment of noninsulin-dependent diabetes mellitus (NIDDM). To define whether the glucose-lowering effects are mediated via alterations of insulin receptors, the effects of Met in vitro in rat adipocytes and in vivo in patients with poorly controlled NIDDM were studied. In vitro exposure of rat adipose tissue to metformin for 20 h resulted in a significant increase in insulin binding (mean +/- SEM percent specific [125I]insulin bound per 10(5) adipocytes: control, 1.35 +/- 0.13; Met, 1.69 +/- 0.18; P less than 0.02). No change occurred after 2 h of exposure or less. In contrast, after only 1 h of preincubation. Met alone stimulated [U-14C]glucose oxidation by 58 +/- 15.5% (P less than 0.01). Met did not stimulate glucose oxidation in the presence of a high insulin concentration. For the in vivo studies, oral glucose tolerance tests and monocyte [125I]insulin binding assays were performed before and after 7 days of Met treatment (2 g/day) in 18 patients with poorly controlled NIDDM. All patients responded to Met with a decrease in fasting and postglucose plasma glucose concentrations, but no change in insulin concentrations [pre-Met vs. post-Met: fasting plasma glucose, 210 +/- 10 vs. 157 +/- 11 mg/dl (P less than 0.001); fasting plasma insulin, 20.3 +/- 3.1 vs. 18.4 +/- 2.0 microU/ml]. When insulin binding was examined, 8 patients with decreased binding each responded to Met with a 50% or greater increase (group 1), while 10 patients with normal binding had no increase after treatment (group 2). However, both groups had similar lowering of glucose concentrations [fasting plasma glucose: group 1, 205 +/- 19 vs. 153 +/- 20 (P less than 0.001); group 2, 214 +/- 11 vs. 160 +/- 13 (P less than 0.001)]. We conclude that 1) Met has an acute insulin-like effect in vitro independent of its ability to increase insulin binding; 2) Met acts in vivo predominantly at a postreceptor site to lower plasma glucose; 3) the glucose-lowering effect is independent of pretreatment insulin binding status; and 4) the increase in insulin binding after Met treatment in patients with NIDDM and low insulin binding occurs without changes in insulin concentrations.

Adipose Tissue↗
PubMed1982

Mechanism of glucocorticoid-induced increase in insulin receptors of cultured human lymphocytes.

Glucocorticoids increase the number of insulin receptors in cultured human lymphocytes. This effect is specific for the insulin receptor as growth hormone receptor concentration decreases. The effect is time-dependent, dose-dependent over the physiologic concentration range of glucocorticoid, reversible, and appears to be mediated via specific glucocorticoid receptors. Protein synthesis and glycosylation are required as the effect is inhibited by actinomycin D, puromycin, cycloheximide, and tunicamycin. Isolated solubilized plasma membranes, as well as solubilized whole cells from glucocorticoid-treated lymphocytes, show the same increase in insulin receptors as do intact cells. The glucocorticoid-induced receptors are immunologically indistinguishable from control when precipitated by anti-receptor antibody. Glucocorticoids do not stabilize existing receptors since the degradation rate of receptors is actually increased. Regulation of the insulin receptor by insulin is independent of the steroid effect. However, there is a right-ward shift of the dose-response curve for "down regulation" by insulin in the presence of glucocorticoid. We conclude that glucocorticoids increase the number of insulin receptors in cultured human lymphocytes by increasing the synthesis of new receptors. This represents the first induction of insulin receptor synthesis by a pharmacologic agent.

Binding, Competitive↗
PubMed1981

The effect of glucocorticoids on the insulin receptor: an in vivo and in vitro study.

We have studied the effect of glucocorticoid exposure on the insulin receptor of short term cultures of human lymphocytes (IM-9 cells) and the effect of short term administration of these agents to normal volunteers. When cultured human lymphocytes were exposed to 10(-5) M hydrocortisone for 18 h at 37 C, insulin binding increased due to an increase in the number of receptors per cell. The effect had appropriate specificity in terms of concentration and type of steroid used. By contrast, hGH binding to these cells was decreased under similar circumstances of incubation, due to a decrease in the number of hGH receptors per cell. When prednisone (40 mg/day) was given to normal subjects for 3 days, a moderate state of insulin resistance was induced characterized by a modest increase in blood glucose and a more pronounced increase in plasma insulin concentration. Under these circumstances there was no change in tracer insulin binding to peripheral monocytes nor changes in the concentration of insulin necessary to inhibit binding by 50%, the number of receptors per cell or the affinity of the receptor. We conclude that glucocorticoids increase insulin binding in vitro in cultured human lymphocytes but that competing influences in vivo such as increasing circulating insulin concentration, redistribution of cell types in the circulation, and possibly other influences prevent these changes from occurring in circulating monocytes. These findings emphasize the complexity of studying the effects of pharmacological agents on hormone binding.

Blood Glucose↗
PubMed1976

Unstable angina pectoris.

Unstable angina is a syndrome which comprises a spectrum of symptomatic manifestations of coronary artery disease which lies between stable angina pectoris and acute myocardial infarction. Patients fall into three groups: angina of recent onset (4 weeks), angina of changing pattern, and angina occurring at rest (longer than 15 minutes). The syndrome may presage acute myocardial infarction or sudden death, or may itself be the manifestation of a myocardial infarction. The pathophysiology may involve primary cardiac events or extracardiac precipitating factors, and does not appear to be the consequence of a particular anatomic pattern of coronary artery disease. Pain may occur as a result of regional reduction of coronary flow to pressure-dependent areas of myocardium during states of increased myocardial oxygen demand. Persisting ischemia leads to infarction via a series of events which may include myocardial edema formation, increased beta-sympathetic tone, and others which have been experimentally modified by interventions designed to limit infarct size. Although the incidence of acute myocardial infarction and death was high in early studies, in recent reports acute infarction occurs in under 15.5 per cent and death in under 2 per cent. Patients at high risk are those pain persists with bed rest, and those with preceding stable angina pectoris or myocardial infarction. Prognostic differences among Groups 1, 2, and 3 may exist but cannot be assessed from available studies. Studies of the management of unstable angina have generally been uncontrolled. Hospitalization, bed rest, and short- and long-acting nitrates are generally employed in Groups 2 and 3 patients and the marked reduction in myocardial infarction rates from early to recent studies tends to support these approaches. Anticoagulants are less used now than formerly. Propranolol can produce a significant reduction of myocardial oxygen consumption and may redirect coronary flow to ischemic areas. The drug has effectively controlled pain in several studies and is now widely used to manage unstable angina. Aortocoronary bypass surgery has been extensively employed but there is only one preliminary report of a controlled study available. The role of surgery is not yet defined. The optimal approach to therapy may eventually involve the use of medical therapy, including beta-blockade to stabilize patients, with delayed semielective coronary angiography and surgery in those who respond. Emergency angiography and surgery might then be reserved for the high-risk group of patients whose pain persists during optimal medical therapy.

Angina Pectoris↗
PubMedDate not supplied

Modulation of insulin action by vanadate: evidence of a role for phosphotyrosine phosphatase activity to alter cellular signaling.

UNLABELLED: A number of vanadium compounds (vanadate, vanadyl sulfate, metavanadate) have insulin-mimicking actions both in vitro and in vivo. They have multiple biological effects in cultured cells and interact directly with various enzymes. The inhibitory action on phosphoprotein tyrosine phosphatases (PTPs) and enhancement of cellular tyrosine phosphorylation appear to be the most relevant to explain the ability to mimic insulin. We demonstrated that in rat adipocytes both acute insulin effects, e.g. stimulation of IGF-II and transferrin binding and a chronic effect, insulin receptor downregulation, were stimulated by vanadate. Vanadate also enhanced insulin binding, particularly at very low insulin concentrations, associated with increased receptor affinity. This resulted in increased adipocyte insulin sensitivity. Finally vanadate augmented the extent of activation of the insulin receptor kinase by submaximal insulin concentrations. This was associated with a prolongation of the insulin biological response, lipogenesis, after removal of hormone. IN CONCLUSION: in rat adipocytes vanadate promotes insulin action by three mechanisms, 1) a direct insulin-mimetic action, 2) an enhancement of insulin sensitivity and 3) a prolongation of insulin biological response. These data suggest that PTP inhibitors have potential as useful therapeutic agents in insulin-resistant and relatively insulin-deficient forms of diabetes mellitus.

Adipocytes↗