Vagal mediation of corticotropin-releasing-factor-induced increase in insulinemia in lean and genetically obese fa/fa rats

The effects of intracerebroventricular (i.c.v.) administration of corticotropin-releasing factor (CRF) on plasma glucose and insulin levels were investigated in lean Zucker (FA/FA) rats; i.c.v. CRF induced a rapid (within 1 min), marked, but transient increase in insulinemia that was not accompanied by any change in glycemia. At a time when insulinemia already returned toward basal values, glycemia started to increase. The effect of i.c.v. CRF in stimulating plasma insulin levels was dose-dependent and could be blocked by pretreatment of the animals with atropine methylnitrate. Similar results were obtained when studying the acute effects of i.c.v. CRF in genetically obese (fa/fa) rats. Although, in absolute values, the amount of insulin released in response to i.c.v. CRF was higher in obese than in lean animals, it was similar in both groups of rats, when expressed as fold increase over basal insulin levels. In summary, i.c.v. CRF elicits a rapid, vagally mediated stimulatory effect on insulin secretion both in lean and genetically obese fa/fa rats with no qualitative or quantitative difference between the two groups of animals. The site(s) of action of this CRF effect on insulinemia remains to be elucidated.     

Central glucocorticoid regulation of parasympathetic drive to pancreatic B-cells in the obese fa/fa rat

The effects of glucocorticoids on the insulin secretory response to an intravenous glucose load have been studied in lean (Fa/?) and obese fa/fa Zucker rats. The role of parasympathetic drive to the pancreatic B-cells was assessed as that component of the insulin secretory response that was blocked by pretreatment of the rats with intravenous atropine. The insulin secretory response to the glucose load was greater in obese than in lean rats. Atropine significantly reduced basal and stimulated levels of insulin in obese but not in lean rats. Adrenalectomy reduced basal insulin levels and the secretory response in obese but not lean rats and also abolished the atropine-blockable component of the response. Peripheral corticosterone replacement of adrenalectomized fa/fa rats restored the hyperinsulinemia. Chronic infusion of dexamethasone intracerebroventricularly to adrenalectomized fa/fa rats increased basal insulin and the secretory response to glucose and this effect was blocked by atropine. In contrast, intracerebroventricular infusion of obese rats with corticotropin releasing factor reduced basal and stimulated insulin levels. It is concluded that the hypersecretion of insulin in obese fa/fa rats results, at least in part, from a central glucocorticoid-mediated stimulation of vagal drive to the pancreatic B-cells.     

Acute intravenous corticotropin-releasing factor administration: effects on insulin secretion in lean and genetically obese fa/fa rats.

The effect of an i.v. administration of different doses (250, 500, and 1000 pmol) of ovine CRF (oCRF) on plasma glucose and insulin levels in lean and genetically obese fa/fa rats was investigated. In both phenotypes, i.v. CRF promoted a rapid (peak at 1 min) transient doubling of basal insulin levels without a concomitant change in glycemia. The dose-dependency of this early insulin response was bell-shaped in both lean and obese animals, with a maximal response at 500 pmol oCRF. After this early rise in insulinemia, glycemia increased in a dose-dependent manner in both lean and obese rats. It was accompanied by a bell-shaped insulin response in lean rats, while such a response was linear in obese rats. The early transient stimulatory effect of CRF on plasma insulin levels could not be prevented by the prior administration of an anti-CRF serum or the alpha-helical CRF-(9-41) antagonist, although administration of either one of these compounds was effective in preventing the CRF-induced changes in the pituitary-adrenal axis. The effect of CRF on the early insulin response was, however, completely suppressed by an acute cholinergic blockade (i.v. injection of atropine). It is suggested that i.v. CRF administration mimics the reflex, cephalic phase insulin secretion. Such cephalic phase insulin output is known to play a role in oral glucose tolerance and may be of physiopathological importance in the Zucker rat strain.     

Effect of pertussis toxin on islet insulin secretion in obese (fa/fa) Zucker rats.

We used isolated islets of lean and obese Zucker rats to determine whether inhibitory pathways mediated by pertussis toxin-sensitive guanyl nucleotide-binding (Gi) proteins contribute to hyperinsulinemia in obese rats. Epinephrine (10(-4) M) and somatostatin (10(-7) M) inhibited insulin secretion by +/- 75% in lean and fa/fa rats. Overnight culture of islets with pertussis toxin (300 ng/ml) enhanced insulin release more in lean (+/- 120%) than obese (+/- 60%) rats. In lean rats incubation of pertussis toxin-treated islets with epinephrine resulted in lower immunoreactive insulin release (p = 0.0005) than pertussis toxin-treated islets without epinephrine. However, in obese rats pertussis toxin treatment reversed this inhibition. Pertussis toxin completely reversed inhibition by somatostatin in both phenotypes. Galanin had no effect on insulin secretion. Cellular cAMP content was similar in lean and obese rats. Inhibitory hormones had no effect on cAMP production. We conclude that islets of obese rats respond normally to inhibitors of insulin release. Reversal of somatostatin-induced inhibition by pertussis toxin indicates normal function of Gi in obese rats. A subtle difference in sensitivity to pertussis toxin between lean and obese islets was noted.     

Dietary conjugated linoleic acid preserves pancreatic function and reduces inflammatory markers in obese, insulin-resistant rats

Pancreatic preservation is an important part of diabetes management that may occur with improved peripheral insulin sensitivity and attenuated low-grade adipose tissue inflammation. The objective of the current study was to determine the response of obese, insulin-resistant fa/fa Zucker rats vs lean controls to dietary conjugated linoleic acid (CLA) supplementation with respect to pancreatic islet size, insulin resistance, and markers of inflammation and adipose glucose uptake. Six-week-old fa/fa and lean Zucker rats (n = 20 per genotype) were fed either a 1.5% CLA mixture or control diet for 8 weeks. Oral glucose tolerance testing was conducted at 7.5 weeks. Fasting serum haptoglobin, insulin, and C-peptide were assayed, and select messenger RNA (mRNA) and protein markers of inflammation and glucose metabolism were measured in adipose and liver tissues. CLA-fed fa/fa Zucker rats had smaller islet cell size, improved oral glucose tolerance and insulinemia, and attenuated serum haptoglobin levels compared with control-fed fa/fa Zucker rats, despite no differences in body weight and a slightly higher visceral adipose mass. CLA did not alter insulin sensitivity or islet size in lean Zucker rats. The CLA-fed fa/fa rats also had greater adipose glucose transporter-4 mRNA and less adipose tumor necrosis factor alpha mRNA and protein compared with control-fed fa/fa rats. In contrast, other markers of inflammation and glucose metabolism including adipose macrophage inflammatory factor, macrophage inflammatory protein-2, and liver pyruvate carboxylase and pyruvate dehydrogenase kinase 4 were not significantly changed. These results suggest that CLA supplementation preserved pancreatic function in conjunction with improved peripheral glucose use and reduced inflammation in fa/fa Zucker rats.     

The effects of gonadectomy on glucose tolerance of genetically obese (fa/fa) rats: influence of sex and genetic background.

In both humans and rodents the occurrence and severity of obesity-associated non-insulin dependent diabetes mellitus (NIDDM) may be influenced by both gonadal hormones and genetic background. Early gonadectomy (at 3-5 days of age) of female and male Wistar diabetic fatty (WDF) rats and of male Zucker rats allowed us to examine these effects in genetically obese rats carrying the fatty (fa) gene. Impairment of glucose tolerance and insulin sensitivity by obesity, and amelioration or exacerbation (in the case of female rats) of this impairment by gonadectomy were assessed by intragastric glucose tolerance tests when the rats reached adulthood. Both glucose tolerance and insulin sensitivity were significantly deranged in obese WDF rats of both sexes and in obese male Zucker rats compared to lean controls of the same sex and strain. Obese male WDF rats were less glucose tolerant and insulin sensitive than were obese male Zucker rats. Glucose intolerance was not ameliorated by castration in lean or obese male WDF or Zucker rats. Insulin sensitivity was significantly improved by castration in obese male rats of both strains, as fasting plasma insulin levels and total areas under the insulin curves were significantly reduced compared to obese sham-operated controls. This effect was greater in the Zucker than in the WDF male rats. Castration significantly decreased the insulin response areas in obese male Zucker rats, but did not alter those of the obese male WDF rats. Ovariectomy did not alter glucose homeostasis of obese female WDF rats.(ABSTRACT TRUNCATED AT 250 WORDS)     

Contribution of hyperinsulinemia to modulation of lipoprotein lipase activity in the obese Zucker rat

This study was designed to assess the contribution of hyperinsulinemia to the maintenance of high adipose and low muscle lipoprotein lipase (LPL) activity in the obese Zucker fa/fa rat. Insulinemia in obese Zucker rats was reduced for 4 days with a single injection of low-dose streptozotocin (STZ). Saline-injected intact obese (obese-INT) and STZ-injected obese (obese-STZ) rats were compared with a lean Fa/? reference group. LPL activity was assessed after a 12-hour fast, with or without a 1-hour refeeding period. Fasting serum insulin levels were 17-fold higher in obese-INT versus lean rats and were reduced to 60% of obese-INT levels in obese-STZ animals. In the postprandial state, serum insulin levels remained low in obese-STZ rats and were similar to the values in lean animals, whereas insulinemia increased in the obese-INT group to 18-fold the levels in lean rats. Serum glucose, nonesterified fatty acid (NEFA), and triglyceride levels, which were higher in obese-INT versus lean rats, were further increased in the obese-STZ group. Tissue weights of obese rats were unaffected by STZ treatment. Fasting LPL specific activity was higher in white adipose tissue ([WAT] +87%) and brown adipose tissue ([BAT] +167%) of obese-INT versus lean rats. Reducing the insulinemia in obese-STZ rats reduced fasting enzyme activity to the levels in lean animals in both WAT and BAT. Insulinemia and adipose LPL activity were positively correlated in the fasted state. Acute food intake increased WAT LPL activity in lean animals, but not in obese animals. Soleus LPL activity was lower in obese-INT compared with lean rats and was further decreased in obese-STZ animals. Heart LPL was decreased only in obese-STZ rats compared with the lean group. LPL in muscle tissue was not correlated with insulinemia, but an inverse relationship was found between serum NEFA levels and enzyme activity. It is concluded that in the obese Zucker rat, hyperinsulinemia is responsible for the maintenance of elevated basal LPL activity in adipose tissue independently of fat mass, whereas muscle enzyme activity appears to be more strongly and inversely related to the availability or tissue utilization of lipid substrates.     

The parasympathetic nervous system and glucocorticoid-mediated hyperinsulinaemia in the genetically obese (fa/fa) Zucker rat

Lean (Fa/-) and genetically obese (fa/fa) Zucker rats were adrenalectomized at 18 days of age (3 days before weaning) before the onset of hyperinsulinaemia. At 40-41 days of age, basal and glucose-stimulated insulin concentrations did not differ significantly between lean and obese rats. Plasma insulin and glucose concentrations were higher in both phenotypes 24 h after administration of corticosterone (2.0 mg at 12-h intervals). Corticosterone-treated obese rats had higher basal and glucose-stimulated insulin levels than similarly treated lean animals, although plasma glucose concentrations did not differ between phenotypes. The basal plasma insulin concentration of obese rats treated with corticosterone for 24 h was reduced 15, 30 and 45 min after injection of atropine (0.3 mg) without any significant change in the plasma glucose level. Injection of atropine (0.3 mg) 20 min before a glucose load prevented the greater increment in plasma insulin concentration of corticosterone-treated obese rats compared with similarly treated lean animals. Atropine administration (0.3 mg) to intact obese rats at 40 days of age reduced, but did not abolish, their hyperinsulinaemia compared with intact lean animals. It is concluded that (1) pre-weaning adrenalectomy prevents the development of hyperinsulinaemia in genetically obese rats, (2) corticosterone replacement for only 24 h restores the hyperinsulinaemia of obese rats, (3) the differential effects of corticosterone on insulin secretion by lean and obese rats are mediated by the parasympathetic nervous system and (4) the parasympathetic nervous system contributes to, but is not the only cause of, hyperinsulinaemia in intact obese rats.     

Gastric inhibitory polypeptide and hyperinsulinemia in the Zucker (fa/fa) rat: a developmental study

The role of the gut hormone GIP (gastric inhibitory polypeptide; glucose-dependent insulinotropic polypeptide) in the development of hyperinsulinemia of pre-obese (fa/fa) Zucker rats was investigated. Plasma GIP levels were compared in lean and fa/fa pups from 21 to 35 days of age. The onset of both basal and glucose-stimulated hyperinsulinemia was studied. Possible causal roles for glucose, GIP and acetylcholine in hyperinsulinemia were investigated in the isolated perfused pancreas preparation. Immunocytochemical studies of pancreatic islets were also carried out. Glucose-stimulated hyperinsulinemia was present in fa/fa rats at 21 days of age but fasting hyperinsulinemia did not become apparent until 35 days of age. At no time did plasma GIP levels differ between lean and fa/fa rats. Immunocytochemical analysis of the pancreas revealed enlarged islets in fa/fa rats from 7 days of age onward. In the in vitro perfused pancreas of 21 day old fa/fa pups the insulin response was not different from that of lean controls in the presence of glucose (300 mg/dl) plus GIP or acetylcholine. An increased pancreatic insulin response to glucose (300 mg/dl or 80 mg/dl) plus GIP in fa/fa compared to lean animals was observed at 35 days of age. These data suggest that defects in the beta-cell response to GIP become apparent at 35 days of age in fa/fa rats resulting in a loss of the glucose threshold for the insulinotropic action of GIP and onset of fasting hyperinsulinemia in vivo. Causal factors for glucose-stimulated hyperinsulinemia at 21 days of age appear to be complex and not easily replicated in in vitro experiments.     

Correlation between pancreatic islet uncoupling protein-2 (UCP2) mRNA concentration and insulin status in rats

Hypothesizing that UCP2 may influence insulin secretion by modifying the ATP/ADP ratio within pancreatic islets, we have investigated the expression of intraislet UCP2 gene in rats showing insulin oversecretion (non-diabetic Zucker fa/fa obese rats, glucose-infused Wistar rats) or insulin undersecretion (fasting and mildly diabetic rats). We found that in Zucker fa/fa obese rats, hyperinsulinemia (1222+/-98 pmol/l vs. 128+/-22 pmol/l in lean Zucker rats) was accompanied by a significant increase in UCP2 mRNA levels. In rat submitted to a 5 day infusion with glucose, hyperinsulinemia (1126+/-101 pmol/l vs. 215+/-25 pmol/l in Wistar control rats), coincided with an enhanced intraislet UCP2 gene expression, whereas a 8h or a 2 day-infusion did not induce significant changes in UCP2 mRNA expression. In rats made hypoinsulinemic and mildly diabetic by the injection of a low dose of streptozotocin, and in 4-day-fasting rats (plasma insulin 28+/-5 pmol/l) UCP2 gene expression was sharply decreased. A 3-day-fast was ineffective. The data show the existence of a time-dependent correlation between islet mRNA UCP2 and insulin that may be interpreted as an adaptative response to prolonged insulin excess.     

Physiological difference between obese (fa/fa) Zucker rats and lean Zucker rats concerning adiponectin

Obese (fa/fa) Zucker rat is a spontaneous genetic obesity model and, by comparison with lean Zucker rat, exhibits hyperphagia, hyperinsulinemia, and hyperlipidemia. The aim of this study was to examine the physiological difference concerning adiponectin between obese (fa/fa) Zucker rats and control lean Zucker rats. We therefore measured plasma adiponectin level and analyzed adiponectin and adiponectin receptor 1 mRNA expression in retroperitoneal white adipose tissue (RT WAT), brown adipose tissue (BAT), liver, and soleus muscle. We also examined the tissue mRNA expression of peroxisome proliferator-activated receptor alpha (PPAR alpha), PPAR delta, and PPAR gamma, which regulate adiponectin expression sensitivity to a PPAR gamma agonist shown by brown adipocytes from obese (fa/fa) Zucker rats and lean Zucker rats, by measuring adiponectin release from these cells. Plasma adiponectin levels of obese (fa/fa) Zucker rats were significantly higher than those of lean Zucker rats. Adiponectin mRNA expression levels in RT WAT were lower in obese (fa/fa) Zucker rats than in lean Zucker rats, but those in BAT were higher. Adiponectin receptor 1 expression levels in RT WAT, BAT, and liver of obese (fa/fa) Zucker rats were lower than in lean Zucker rats. The expression level of PPAR alpha, PPAR delta, and PPAR gamma in BAT was lower in obese (fa/fa) Zucker rats than in lean Zucker rats. Moreover, the PPAR gamma agonist increased adiponectin release only from the brown adipocytes isolated from lean Zucker rats. It is the conclusive difference between obese (fa/fa) Zucker rats and lean Zucker rats that plasma adiponectin levels of obese (fa/fa) Zucker rats are significantly higher than those of lean Zucker rats. Moreover, we clarified that mRNA expression level of adiponectin receptor 1 in RT WAT, BAT, and liver of obese (fa/fa) Zucker rats is low despite high plasma adiponectin level, and low expression of PPARs in BAT leads to less sensibility of adiponectin release from brown adipocytes to a PPAR gamma agonist in obese (fa/fa) Zucker rats.     

Decreased insulin binding to pancreatic islets of genetically obese (fa/fa) rats

Binding of insulin and insulin secretion were studied in isolated pancreatic islets of homozygous obese fa/fa rats, their lean littermates (Fa/?) and Wistar rats. Despite normoglycemia fa/fa rats exhibit hyperinsulinemia. Glucose-induced insulin secretion from pancreatic islets in vitro was increased by more than 50% in fa/fa rats compared with islets of lean littermates and normal Wistar rats when calculated per microgram islet protein. Exogenous insulin inhibited glucose (16.7 mM)-induced insulin secretion in islets of either of these rats, and maximum inhibition was rather the same (secretion was reduced by 62.3-65.6%). However, the EC50 (half-maximal effective concentration) for inhibition was increased in fa/fa rats being 1.4 +/- 0.1 nM compared with 0.6 +/- 0.2 and 0.5 +/- 0.2 nM in lean littermates and Wistar rats, respectively (P less than 0.05 vs. fa/fa rats). Islets of fa/fa rats found 24% less [125I]insulin (P less than 0.01) than islets of lean littermates and of Wistar rats. Scatchard analysis of data of displacement of [125I]insulin binding by native insulin showed 2 binding sites; a decrease in the number of high affinity insulin binding sites (Bmax) from 4.2 +/- 1.3 and 4.7 +/- 1.6 fmol/mg protein to 2.6 +/- 0.7 fmol/mg protein was calculated when islets of lean littermates and normal Wistar rats were compared to islets of fa/fa rats. The Kd of the high affinity binding site was not changed (0.77 +/- 0.06, 0.78 +/- 0.11 and 0.61 +/- 0.14 nM, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)     

Tissue and isoform-selective activation of protein kinase C in insulin-resistant obese Zucker rats - effects of feeding.

The mechanisms of insulin resistance in the obese Zucker rat have not been clearly established but increased diacylglycerol-protein kinase C (DAG-PKC) signalling has been associated with decreased glucose utilisation in states of insulin resistance and non-insulin-dependent diabetes mellitus. The purpose of this study was to characterise tissue- and isoform-selective differences in DAG-PKC signalling in insulin-sensitive tissues from obese Zucker rats, and to assess the effects of feeding on DAG-PKC pathways. Groups of male obese (fa/fa, n=24) and lean (fa/-, n=24) Zucker rats were studied after baseline measurements of fasting serum glucose, triglycerides, insulin and oral glucose tolerance tests. Liver, epididymal fat and soleus muscle samples were obtained from fed and overnight-fasted rats for measurements of DAG, PKC activity and individual PKC isoforms in cytosol and membrane fractions. Obese rats were heavier (488+/-7 vs 315+/-9 g) with fasting hyperglycaemia (10.5+/-0.8 vs 7.7+/-0.1 mM) and hyperinsulinaemia (7167+/-363 vs 251+/-62 pM) relative to lean controls. In fasted rats, PKC activity in the membrane fraction of liver was significantly higher in the obese group (174+/-16 vs 108+/-12 pmol/min/mg protein, P<0.05) but there were no differences in muscle and fat. The fed state was associated with increased DAG levels and threefold higher PKC activity in muscle tissue of obese rats, and increased expression of the major muscle isoforms, PKC-theta and PKC-epsilon: e.g. PKC activity in the membrane fraction of muscle from obese animals was 283+/-42 (fed) vs 107+/-20 pmol/min/mg protein (fasting) compared with 197+/-27 (fed) and 154+/-21 pmol/min/mg protein (fasting) in lean rats. In conclusion, hepatic PKC activity is higher in obese rats under basal fasting conditions and feeding-induced activation of DAG-PKC signalling occurs selectively in muscle of obese (fa/fa) rats due to increased DAG-mediated activation and/or synthesis of PKC-theta and PKC-epsilon. These changes in PKC are likely to exacerbate the hyperglycaemia and hypertriglyceridaemia associated with obesity-induced diabetes.     

Pancreatic hypersensitivity to glucose by young obese Zucker rats (fa/fa)

Insulin secretory response to glucose was investigated in 5- to 6-week-old male Zucker obese (fa/fa) and lean (Fa/Fa) rats using a pancreatic perfusion procedure. Blood glucose response to fasting was studied in lean and obese animals over 24 hours. Plasma glucose was slightly elevated in pentobarbital-anesthetized obese rats. However, plasma insulin was 4.6 times greater than that of leans. A hypoglycemic glucose stimulus (75 mg/dL) caused pancreata from obese animals to release 6 times more insulin than lean animals. Stimuli of 125 mg/dL (normoglycemic) and 600 mg/dL (hyperglycemic) caused hypersecretion of 8 and 5 times, respectively. Hypersecretion was not accounted for solely by the twofold increase in pancreatic insulin content. Obese animals had steeper decreases in plasma glucose than lean controls during seven to 13 hours of fasting. Hypersecretion by pancreata from young obese rats to physiological levels of glucose may result in hyperphagia in order to maintain normoglycemia.     

Functional characterization of alpha-adrenoceptors on pancreatic islets of fa/fa Zucker rats.

Recently, a defect in pertussis toxin-independent actions of epinephrine on pancreatic B-cells of fa/fa Zucker rats was reported (Cawthorn and Chan (1991) Mol. Cell. Endocrinol. 75, 197-204). We now report studies of islet alpha 2-adrenoceptor function of fa/fa rats. Insulin and cAMP production by islets of obese rats were both inhibited by the alpha 2-adrenoceptor agonist clonidine. Calculated pD2 values for clonidine were 9.57 +/- 0.59 and 9.43 +/- 0.33 for lean and fa/fa rat islets, respectively. Yohimbine reversed clonidine effects equipotently in lean and obese rat islets (pA2 values of 7.48 +/- 0.57 vs 7.43 +/- 0.58). Unexpectedly, the alpha 1-antagonist prazosin stimulated insulin secretion from islets of obese but not lean rats. Functional characteristics of the alpha-adrenoceptors on fa/fa islets are thus similar to those recently designated alpha 2B. Altered expression of alpha-adrenoceptors on pancreatic islets of fa/fa rats may contribute to changes in the pertussis toxin-independent pathway of epinephrine action previously observed.     

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.     

Reduction of carbohydrate-induced hypertriglyceridemia in (fa,fa) “Zucker” rats by the α-glucosidase inhibitor acarbose (BAY g 5421)

Inhibition of carbohydrate digestion by the α-glucosidase inhibitor acarbose (BAY g 5421) reduces carbohydrate-induced postprandial blood glucose increase and insulin secretion. As a consequence, in feeding experiments sucrose-induced hyperinsulinemia and hypertriglyceridemia in genetically obese (fa,fa) “Zucker” rats were dose-dependently reduced by addition of acarbose to the diet (15–80 mg/100 g feed). The body weight gain was dose-dependently reduced. In short-term experiments with a fat-free diet acarbose not only prevented serum triglyceride and free fatty acid increase in spite of lowered insulin concentrations but also decreased their concentrations below the values obtained on standard feed. Under these conditions there were no significant effects on body weight. Hypertriglyceridemia induced by i.v. injection of the lipoprotein lipase inhibitor Triton WR 1339 was reduced without affecting body weight in “Zucker” rats after 3 days on a fat-free diet supplemented with acarbose. The triglyceride increase was even lower than in animals kept on standard feed. The data demonstrate that acarbose reduces sucrose-induced hypertriglyceridemia in (fa,fa) “Zucker” rats by diminishing VLDL production and/or secretion rather than by increasing VLDL removal from the blood.     

Dysregulation of glucose transport in hearts of genetically obese (fa/fa) Rats

Overall D-glucose metabolism and 3-0-methylglucose transport were measured in the perfused heart preparation of lean and genetically obese (fa/fa) rats. Absolute values of basal and insulin-stimulated glucose metabolism were decreased in hearts of 15-week-old obese rats when compared to lean age-matched controls. Basal and maximally stimulated (i.e., by the combined addition of insulin and increasing perfusion pressure) 3-0-methylglucose transport was normal in hearts from young obese rats (5-week-old). However, when only one stimulus was used (insulin or increasing perfusion pressure alone), 3-0-methylglucose transport was stimulated to values that were lower than those of lean rats. Basal 3-0-methylglucose transport was four times lower in hearts from older obese rats (15-week-old) than in lean ones of the same age. At this age, stimulation of 3-0-methylglucose transport by insulin alone, by increasing perfusion pressure alone or by the combination of both stimuli, reached values in obese rats that were only half those of lean animals. It is concluded that: (a) in the early phase of the syndrome, the basal glucose transport system in hearts of obese rats is normal, but its response to stimulation becomes abnormal and; (b) at a later phase of obesity, the glucose transport system becomes abnormal even under basal conditions and its responsiveness to various stimuli is markedly impaired.     

Insulin resistance in the heart: studies on isolated cardiocytes of genetically obese Zucker rats

Isolated cardiac myocytes from lean and genetically obese (fa/fa) Zucker rats were used to study cellular alterations related to the obesity syndrome in this tissue. Scatchard analysis of insulin binding data suggested a reduction in the number of low affinity sites in cells from obese rats; in contrast, an unaltered high affinity segment with Kd values of 5.7 +/- 0.6 and 4.5 +/- 0.7 X 10(-10) mol/liter (n = 4) in lean and obese rats, respectively, has been observed. Insulin internalization, as estimated from the amount of increased cell-associated radioactivity in chloroquine-treated cells, was decreased by 70% from 12.8 fmol insulin/10(6) cells X 120 min in lean rats to 3.8 fmol/10(6) cells X 120 min in obese rats. Determinations of initial velocities of 3-O-methylglucose influx were used for assessing glucose transport activity. Basal activity of the glucose transport system was reduced in cells from obese animals. This was found to be due to a decreased maximum velocity of the carrier with corresponding values of 69.8 +/- 5.2 and 38.3 +/- 3.2 nmol/10 sec X 10(6) cells (n = 3) in cardiocytes from lean and obese rats, respectively. Glucose transport exhibited an unaltered sensitivity toward stimulation by insulin, but an impaired responsiveness in cardiocytes from obese rats. The data suggest involvement of both receptor and postreceptor defects in the development of an insulin-resistant state in cardiac muscle.     

Atherogenesis in two strains of obese rats. The fatty Zucker and LA/N-corpulent

Two strains of obese rats, the fatty Zucker and the LA/N-corpulent have been compared at 6 months age for the presence of vascular and myocardial disease. Both strains, when obese, exhibit a VLDL hyperlipidemia with elevated triglycerides and moderate elevations of plasma cholesterol concentrations compared to the lean rats of the same strain. The hyperlipidemia is more modest in the fatty Zucker than the corpulent LA/N, and the serum lipid concentrations of the lean Zucker are lower than those of the lean LA/N. Apolipoprotein concentrations were similar and elevated in the two obese genotypes compared to the lean genotypes which were also similar to each other. Male and female obese animals of both strains exhibited hyperinsulinemia under fasting conditions and after oral glucose, with obese male LA/N rats exhibiting the most severe hyperinsulinemia. Glucose tolerance was impaired in obese LA/N animals but was normal in lean rats of both strains and fatty Zucker rats of both sexes. The glucose intolerance observed in obese LA/N animals was more severe in the male than in the female rats. Unlike the corpulent rat, which develops atherosclerotic lesions, the fatty Zucker shows no evidence of advanced vascular lesions on scanning electron microscopy. The fatty Zucker also does not develop the myocardial lesions that are frequent in the male corpulent LA/N rat. It is suggested that the initiation of the atherogenic process is dependent upon elevated insulin levels or transient hyperglycemia. Development of the advanced lesions appears to require the presence of hyperlipidemia.