Prospects for the treatment of obesity.
Explore the source record for details and available documents.
Appetite Depressants↗
Biomedical subjects
J Proietto
Publications and source records attributed to J Proietto.
Cyclic AMP acutely stimulates translocation of the major insulin-regulatable glucose transporter GLUT4.
Facilitated glucose transport across plasma membranes is mediated by a family of transporters (GLUT1-GLUT5) that have different tissue distributions and Km values for transport. It has been shown that insulin stimulates glucose transport in fat and muscle tissues by causing the redistribution of one of these proteins (GLUT4) from inside the cell to the plasma membrane. Previous studies have shown that agents that change cAMP levels are able to modulate glucose transport in fat cells. The aim of this study was to investigate the mechanisms responsible for modulation of glucose transport by cAMP. 2-Deoxyglucose transport and insulin-regulatable glucose transporter (GLUT4) immunoreactivity in plasma and low density microsomal membranes were measured in adipocytes incubated for 30 min with insulin or dibutyryl-cAMP (Bt2cAMP). Low concentrations of Bt2cAMP (10 microM) increased 2-deoxyglucose uptake by translocating GLUT4 from low density microsomal membranes to the plasma membranes. Bt2cAMP at 1000 microM inhibited glucose transport below basal but further increased translocation of GLUT4. The effect of Bt2cAMP on translocation was additive to that of 7 nM insulin. We conclude that in rat adipocytes, Bt2cAMP acutely translocates GLUT4 but inhibits its activity to transport glucose.
Adipose Tissue↗
A high-fat diet worsens metabolic control in streptozotocin-treated rats by increasing hepatic glucose production.
The aim of this study was to determine the mechanism by which a high-fat diet exacerbates the diabetes produced by a low dose of streptozotocin (STZ). The glucose clamp technique was used to determine hepatic glucose production (HGP) and the disappearance rate (Rd) of glucose, basally and during insulin infusions of 1.0 and 3.0 mU/kg/min in control of STZ-treated rats fed either a low-fat or high-fat diet. Fasting plasma glucose in the high fat-STZ (HFS) group was significantly higher than in any of the other groups: low fat-STZ (LFS), high-fat controls (HFC), or low-fat controls (LFC) (18.1 +/- 1.6 v 8.1 +/- 0.8 mmol/L, P less than .001; 6.0 +/- 0.2 mmol/L, P less than .001; 5.4 +/- 0.1 mmol/L, P less than .001, respectively). Basal HGP was markedly higher in the HFS group compared with each of the other three groups (98.8 +/- 5.9 v 61.4 +/- 3.7, P less than .001; 42.9 +/- 1.6, P less than .001; 39.6 +/- 1.3 mumol/kg/min, P less than .001; HFS v LFS, HFC, and LFC, respectively). Following insulin infusion, no differences were observed in HGP between the LFC and LFS groups at either insulin dose. However, HGP was not suppressed to control levels in either of the high-fat diet groups, and this defect was more marked in the HFS group. It is concluded that a high-fat diet exacerbates mild STZ diabetes primarily by increasing HGP.
Animals↗
Identification of early metabolic defects in diabetes-prone Australian aborigines.
The aim of the present study was to identify in young, diabetes-prone subjects the early abnormalities which may predispose to the development of type 2 diabetes. We studied 10 full-blood Australian Aborigines all of whom had a family history of diabetes and who were from an urbanised community with a high prevalence of this disorder. They were compared to 10 age- and body-mass-index-matched Caucasian controls with no family history of diabetes. Glucose kinetics were measured basally and following an oral glucose load. Fasting plasma glucose was equal in the two groups, but 2 h following the 75 g glucose load, the Aboriginal subjects had higher glycaemia than the controls (P less than 0.01). Insulinaemia was higher in the Aborigines both basally and following the glucose drink (P less than 0.05). Despite the hyperinsulinaemia, hepatic glucose production was higher in the Aboriginal subjects (P less than 0.01), while metabolic clearance rate was lower. It is concluded that in young Australian Aborigines with a strong family history of type 2 diabetes, both hepatic and peripheral insulin resistance are early abnormalities.
Administration, Oral↗
Reversal of a neurologic paraneoplastic syndrome with octreotide (Sandostatin) in a patient with glucagonoma.
A 69-year-old woman with classic glucagonoma syndrome had associated progressive neurologic disease manifest as dementia, ataxia, optic atrophy, and lower limb weakness. Visual evoked responses (VERs) were absent bilaterally. After an attempt at resection was unsuccessful, therapy was started with somatostatin analogue (Sandostatin, SMS 201-995). Over the ensuing 3 months, there was a decrease in the plasma glucagon level, resolution of the rash, weight gain, reversal of the dementia, and an improvement in coordination and limb weakness. Subsequent VERs revealed bilateral delayed responses.
Aged↗
Dexamethasone-induced increase in the rate of appearance in plasma of gut-derived glucose following an oral glucose load in rats.
Glucocorticoids are known to impair oral glucose tolerance and to induce insulin resistance. It has also been reported that glucocorticoids stimulate absorption of glucose, water, and electrolytes from the gut. The aim of the present study was to determine if dexamethasone treatment increased the rate of appearance in plasma of gut-derived glucose. Glucose turnover was measured following an oral glucose load in chronically catheterized, nonstressed rats treated for 96 hours with either normal saline (n = 14) or dexamethasone (5 micrograms twice daily intravenously [IV] (n = 10). Dexamethasone-treated rats had mild glucose intolerance and higher insulin levels than control rats. Total glucose turnover was increased at all time points following the glucose drink in the dexamethasone-treated rats, as was the rate of appearance of gut-derived glucose (154 +/- 25 v 321 +/- 62 mg/45 min; P = .018). It is concluded that in rats, dexamethasone treatment increases the rate of appearance in plasma of orally administered glucose.
Administration, Oral↗
The aetiology of non-insulin-dependent diabetes mellitus: is abnormal suppression of hepatic gluconeogenesis the primary event?
Despite intensive research effort, the aetiology of non-insulin dependent diabetes mellitus remains unknown. In this disorder, hyperglycaemia results from three defects: impaired suppression of hepatic glucose production; reduced peripheral clearance of glucose; and impaired glucose-mediated insulin secretion. It has been proposed that reduced peripheral glucose clearance is the primary or inherited defect and that hyperinsulinaemia secondary to this eventually leads to beta cell exhaustion and impaired insulin secretion. Other authors have proposed that the initial defect is an abnormality in the first phase of insulin secretion. In this paper it is proposed that the primary abnormality is failure of hepatic gluconeogenesis to suppress adequately and that the resulting excess glucose flux results in peripheral insulin resistance and in a defect of glucose-mediated insulin secretion. This hypothesis is supported by recent data showing the glucose per se can induce defects in insulin action and insulin secretion.
Diabetes Mellitus, Type 2↗
Evolution of insulin resistance in New Zealand obese mice.
The etiology of non-insulin-dependent diabetes mellitus (NIDDM) is not known. Hyperglycemia is due to increased hepatic glucose production (HGP), decreased glucose uptake, and impaired insulin secretion. It is unknown if these defects are coinherited or if one precedes and causes the others. The aim of this study was to determine the earliest defects in the evolution of the syndrome in the New Zealand obese (NZO) mouse, a polygenic model of NIDDM. NZO and control NZC mice were studied at 4-5 and 20 wk of age. Glucose turnover and glucose uptake in individual tissues were measured basally and during a hyperinsulinemic clamp. First-phase insulin secretion was measured after an intravenous glucose load. HGP was higher in the NZO mice both basally and during the clamp at both ages. At 4-5 wk of age, there was evidence of insulin insensitivity in brown adipose tissue, soleus, diaphragm, red quadriceps, and red gastrocnemius but not in heart, white quadriceps, and white gastrocnemius. In 20-wk-old mice, insulin responsiveness was decreased in white and brown adipose tissue and soleus muscle but not in heart, diaphragm, red and white quadriceps, and red and white gastrocnemius. First-phase insulin secretion (percentage rise above basal) 3 min after the glucose bolus was impaired in NZO mice at both ages. We conclude that hepatic glucose overproduction, brown adipose tissue and skeletal muscle insulin resistance, and impaired first-phase insulin secretion are all early abnormalities in the NZO mouse.
Adipose Tissue↗
Evolution of dexamethasone-induced insulin resistance in rats.
Glucocorticoids are known to cause insulin resistance and glucose intolerance. Although there have been many studies investigating the mechanism of this effect, several aspects remain to be clarified. The aim of this study was to investigate the evolution and sites of insulin resistance in dexamethasone-treated rats. To achieve this, chronically catheterized nonstressed rats had glucose kinetics measured during an oral glucose tolerance test by means of a double isotope technique. Studies were performed after 6, 48, or 96 h of dexamethasone administration (10 micrograms.rat-1.day-1) and were compared with control rats not treated with the steroid. Total hepatic glucose production (HGP) was increased in the 6-h (166 +/- 8.3, P less than 0.05) and 48-h (198 +/- 21, P less than 0.03) treated groups but not in the 96-h treated rats (140 +/- 8, P = 0.99) compared with the controls (141 +/- 8 mg/55 min). This increased HGP was despite the presence of higher insulin levels in the steroid-treated rats (1,220 +/- 115, P less than 0.09; 1,732 +/- 197, P less than 0.005; 1,567 +/- 107, P less than 0.001 in 6-, 48-, and 96-h treated rats, respectively, compared with 937 +/- 99 mU.l-1 x 55 min-1 in control rats). The metabolic clearance rate of glucose was higher in the dexamethasone-treated rats (200 +/- 14, P less than 0.07; 227 +/- 18, P less than 0.01; 227 +/- 17, P less than 0.01 in 6-, 48-, and 96-h groups, respectively, compared with 165 +/- 10 ml/55 min in control rats).(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Estimation of glucose kinetics following an oral glucose load. Methods and applications.
The measurement of glucose kinetics using glucose tracers is well established and validated. Several models of the glucose system have been proposed. In this review, two of these models will be described and their application to the measurement of glucose kinetics during an oral glucose tolerance test discussed. Examples of the applications of this method will be given illustrating the type of questions that can be addressed using this approach.
Blood Glucose↗
The effects of islet activating protein on oral glucose tolerance in the genetically obese fa/fa rat.
When tested in insulin-deficient animal models of diabetes, islet activating protein (IAP) has been shown to increase the secretion of insulin and to improve glucose intolerance. The genetically obese fa/fa rat is an animal model of impaired oral glucose tolerance that does not have reduced insulin secretion. In this model IAP treatment increases basal insulin levels, resulting in lower basal glycemia. However, glucose tolerance following an oral glucose load was worsened by IAP. This was found to be due to an exaggerated stimulation of hepatic glucose production (HGP) following glucose, a defect that is already present in the absence of IAP. IAP has been reported to inhibit (by ADP ribosylation) the inhibitory regulatory protein (Ni) of adenylate cyclase. It is therefore suggested that the increased HGP following oral glucose in fa/fa rats either in the absence or in the presence of IAP treatment may result from a cAMP-mediated mechanism. A beta adrenergic activation or a stimulation of glucagon output could therefore be potential candidates responsible for glucose intolerance in obese fa/fa rats.
Adenylate Cyclase Toxin↗
Taste-induced changes in plasma insulin and glucose turnover in lean and genetically obese rats.
Cephalic-phase insulin release (CPIR) and the changes in glucose turnover induced by saccharin ingestion were studied in freely moving lean and genetically obese fa/fa rats equipped with chronic catheters for blood sampling. Six-hour-fasted lean and obese rats were trained to drink 1 ml sodium saccharin (0.15%) or 1 ml glucose (70%), and blood samples were taken before and after the stimuli. As early as 1-1.5 min poststimulus, there was a significant increase in CPIR in lean and obese rats. The amplitude of the CPIR induced either by saccharin or by glucose in the obese rats was significantly higher than it was in the lean rats. The effect of saccharin ingestion on the hepatic glucose production (HGP) and the rate of glucose disappearance (Rd) was studied in 6-h-fasted lean and obese rats, under non-steady-state conditions, according to a method previously validated. Saccharin ingestion produced a significant increase in HGP and Rd in lean and obese rats compared with basal values. The saccharin-induced increments in HGP and Rd were higher in the obese than in the lean animals. We conclude that saccharin (through taste) appears to elicit parasympathetic (insulin release) and sympathetic (HGP increase) reflexes in lean and obese rats. These taste-induced changes in plasma insulin and glucose turnover are exaggerated in the obese rats and may participate in obesity and in insulin resistance of the overall syndrome.
Animals↗
Non-steady-state measurement of glucose turnover in rats by using a one-compartment model.
One of the tracer methods often employed to measure glucose turnover in the non-steady state uses the one compartment model of Steele (Ann. NY Acad Sci 1959). However, this model gives adequate results when it is assumed that only a fraction of the glucose pool takes part in rapid changes of glucose specific activity, thereby being necessary to use a correction factor called the "pool fraction." The aim of this study was to experimentally determine the best pool fraction needed in the rat for the calculation of glucose turnover using a one-compartment model. This is important as no data are available so far in this widely used species. For this purpose, glucose turnover was measured in anesthetized lean and genetically obese fa/fa rats, using two different experimental designs. In all conditions, the error in estimating the total rate of glucose appearance was lowest when 0.5 was used as the pool fraction. The error was greater with an increase and a decrease in the pool fraction value. It is concluded that in the rat the one-compartment model measures changes in glucose turnover with reasonable accuracy in non-steady-state conditions and that a pool fraction of 0.5 gives the best results.
Animals↗
Role of the oropharynx in regulation of glycemia.
Previous studies have demonstrated that reflexes originating from the oral cavity at the start of food intake are necessary to ensure a normal glucose tolerance. In our experiment, the underlying mechanisms of these reflexes were studied in conscious, freely moving rats bearing chronic catheters. A double-isotope technique was used to measure, under non-steady-state conditions, rates of total glucose appearance (total Ra), total glucose disappearance (Rd), gut glucose absorption (gut Ra), hepatic glucose production (HGP), and the metabolic clearance rate of glucose (MCRg). In random order, 1 wk apart, rats either spontaneously drank 1 ml of a 60% glucose solution or were given the same dose into the stomach via a chronic gastric catheter. Glycemia and insulinemia were lower when glucose was taken orally than when the same amount of the substrate was administered intragastrically. Total Ra after glucose administration was the same in both groups throughout the experiment. Despite lower insulin and glucose values, the increase in Rd was initially higher in the oral group than in the intragastric group. This was accompanied by initial higher MCRg values in the oral group than in animals that received the glucose load directly into their stomachs. We conclude that a series of reflexes elicited by oral glucose ingestion improve glucose tolerance by increasing the efficiency of glucose disposal in the early stages after a glucose load, with a smaller amount of insulin released.
Animals↗
Mechanism of abnormal oral glucose tolerance of genetically obese fa/fa rats.
The genetically obese fa/fa rat is glucose intolerant when tested in a conscious state after the spontaneous ingestion of a glucose solution. The aim of this study was to investigate the mechanism(s) underlying the abnormal oral glucose tolerance test of obese animals with the non-steady-state measurement of glucose turnover proposed by Steele et al. in 1968. Our results show that the total rate of glucose appearance is enhanced in obese compared with lean animals. This abnormality is not due to an increased gut glucose absorption but to a lack of suppression and even a transient stimulation of hepatic glucose production after the ingestion of glucose. The rate of glucose utilization by the obese animals is somewhat increased compared with controls or unchanged when expressed as glucose metabolic clearance rate, thus excluding this parameter from the factors contributing to the observed glucose intolerance. The results obtained with genetically obese rats agree with those reported for type II diabetes in humans. The observed defect of the obese group could be related to an abnormal regulation of insulin counterregulatory hormone(s) or of hepatic innervation as well as to other defects of hepatic glycogen handling.
Animals↗
Control of glycogen phosphorylase interconversion by phorbol esters, diacylglycerols, Ca2+ and hormones in isolated rat hepatocytes.
In isolated rat hepatocytes: phosphorylase activation by the ionophore A23187 was enhanced in the presence of tumour-promoting phorbol esters and 1,2- (but not 1,3-) diacylglycerols (dioleoyl- and oleoylacetyl-glycerol), with a similar dose-dependency; the activation of phosphorylase by phenylephrine (1 microM) (but not by vasopressin or glucagon) was inhibited both by tumour-promoting phorbol esters and diacylglycerols, but with a different dose-dependency: complete inhibition was achieved with concentrations of phorbol esters two orders of magnitude lower than those of diacylglycerol; binding of the alpha 1-adrenergic antagonist [3H]prazosin and its displacement by unlabelled prazosin was not significantly affected in the presence of the phorbol esters. The possible involvement of protein kinase C in the control of phosphorylase interconversion is discussed.
Animals↗
Tumour-promoting phorbol esters increase basal and inhibit insulin-stimulated lipogenesis in rat adipocytes without decreasing insulin binding.
In isolated rat adipocytes, tumour-promoting phorbol esters caused (1) dose-dependent stimulation of lipogenesis in the absence of insulin and (2) inhibition of the lipogenic effect of submaximal concentrations of insulin, but without affecting insulin binding. The possible involvement of protein kinase C in insulin action is discussed.
Adipose Tissue↗
Hyperinsulinaemia and insulin insensitivity: studies in subjects with insulinoma.
Hepatic glucose turnover, peripheral insulin sensitivity and insulin receptor binding were measured in four subjects with insulinoma before and 3 months after surgical resection of the insulinoma. Basal hepatic glucose production, quantitated employing a primed constant infusion of tritiated glucose, was low pre-operatively (5.2 +/- 1.7 mumol X kg-1 X min-1) but returned to normal post-operatively (14.9 +/- 2.8; normal subjects 13.9 +/- 0.8 mumol X kg-1 X min-1). Paired euglycaemic dose-response curves were developed for each subject. Insulin sensitivity, expressed as a right shift of the dose-response curve (ED50), was low pre- and post-operatively. However, insulin responsiveness (Vmax) remained normal (pre-operatively 13.9 +/- 2.2, post-operatively 13.8 +/- 0.8, normal subjects 16.7 +/- 0.8 ml X kg-1 X min-1). There was no consistent pattern in monocyte or erythrocyte receptor binding before or after surgery. These data suggest that the chronic hyperinsulinaemia causes suppression of hepatic glucose production, and a state of insulin insensitivity which appears to be due to a post-receptor defect.
Adenoma, Islet Cell↗