Effect of adrenalectomy on the development of a pancreatic islet lesion in fa/fa rats

Abstract

Summary Adrenalectomy prevents development of obesity and hyperinsulinaemia in obese (fa/fa)Zucker rats, thereby implicating the hypothalamopituitary-adrenal axis in the pathogenesis of obesity. In this study glucose-induced insulin secretion and glucokinase activity were investigated in isolated islets from adrenalectomized and control obese and lean female rats. Islets from control fa/fa rats were more sensitive to glucose with a half-maximal effective concentration (ECs0) of 6.1 + 2.0 mmol. 1-1 compared with 10.6 + 2.7 mmol. 1-1 for adrenalectomized fa/fa rat islets. Adrenalectomy did not alter the islet sensitivity to glucose in the lean rats (ECs0 of 9.4+1.5mmo1.1-1 and 9.3+2.0mmo1-1-1 for adrenalectomized and control lean rats respectively). Mannoheptulose did not inhibit insulin secretion from control obese rats; however at concentrations of 1.0 mmol 9 1-1 or more it significantly inhibited glucose-induced insulin secretion in adrenalectomized obese and lean, and control lean rat islets (p < 0.05).In adrenalectomized fa/fa islets the glucokinase K m was increased twofold compared with the control fa/fa rats (9.5 + 1.5 mmol. 1-1 vs 5.0 + 1.5 mmol. 1-1, respectively), but there was no significant change in glucokinase K m in the lean rat islets after adrenalectomy. Mannoheptulose (10 mmol. 1-1) caused a significant reduction in glucose phosphorylation in disrupted islets of adrenalectomized fa/fa and lean, and of control lean rats, but not of control fa/fa rats. These data demonstrate that development of abnormal regulation of glycolysis in pancreatic islet beta cells offa/ fa rats, as indicated by the insulin response to mannoheptulose and glucokinase activity, is dependent on an intact hypothalamo-pituitary-adrenal axis. [Diabetologia (1996) 39: 190-198] Key words Insulin secretion, mannoheptulose, adrenalectomy, glucokinase, hypothalamo-pituitary-adrenal axis, islets of Langerhans.Hyperinsulinaemia is a characteristic of human obesity and the genetically transmitted obesity syndromes Abbreviations: ADX, Adrenalectomy/adrenalectomized; CRH, corticotrophin releasing hormone; DMEM, Dulbecco's modified Eagle's medium; ECs0; half-maximal effective concentration; HPA, hypothalamo-pituitary-adrenal; MH, mannoheptulose; Hepes, 4-(2-hydroxyethyl)-l-piperazineethane sulphonic acid.high-carbohydrate diet plays a significant role in the development of obesity and hyperinsulinaemia in these rats [2]. Increased sensitivity to glucose of the pancreatic beta cells of fa/fa rats in both the preobese [3][4][5] and adult stages [6][7][8][9] is observed. This increased response offa/fa rats to glucose stimulation might be related to changes in the primary glucose sensing mechanisms of the pancreatic islet beta cells because sensitivity to other stimulants is not different from that observed in lean rats [9].Glucokinase, for which there is growing evidence as the primary pancreatic beta-cell glucose sensor [10], is reported to have increased sensitivity to glucose in fa/fa rat isolated islets [11]. The activity of glucoki...

Uncoupling Protein 2 and Islet Function

“…However, it becomes more difficult to reconcile an increase in ␤-cell UCP2 with the fasting hyperinsulinemia observed in obese and obese-diabetic rodents such as fa/fa and ZDF rats. This hypersecretion of insulin has been shown to be dependent on mitochondrial ATP production and K ATP channel inactivation (57) and may be related to altered kinetics of glucokinase or other metabolic enzymes (58), which strongly depends on the deranged hypothalamopituitary-adrenal axis in genetically obese rodent models (59). The increase in overall metabolism is sufficient to induce K ATP channel closure at lower than normal glucose (60).…”

Interactions between effects of adrenalectomy and diet on insulin secretion in fa/fa Zucker rats

“…and tap water ad libitum prior to surgery. Rats were either bilaterally adrenalectomized (ADX) or sham-operated (SH) through a ventral incision after anesthesia with a mixture 2 mL of sodium pentobarbital (65 mg/ ml) and 2 mL diazepam (5 mg/mL) in 6 mL of saline (0.9% NaCl) (Kibenge and Chan 1996). After surgery the animals were housed individually, in an artificially lit room with a 12 h dark : light cycle at a temperature of 22-25°C.…”

“…Mannoheptulose (1-100 mM) was added to islet samples in media containing 16.5 mM glucose and all samples were then statically incubated for 90 min at 37°C (95% air-5% CO 2 , saturated with water vapour). Although culture conditions may alter insulin secretion patterns, our previous work demonstrated that the effects of ADX persisted in 24 h cultured islets (Kibenge and Chan 1996). Insulin release and islet insulin content were measured as previously described by Chan et al (1993).…”

“…Our recent study demonstrated that adrenalectomy (ADX) normalized B-cell glucose sensitivity, glucokinase kinetics, and mannoheptulose sensitivity in fa/fa rats (Kibenge and Chan 1996), implicating the hypothalamo-pituitary-adrenal axis as a regulator of GK function. The actions of ADX on islet biochemistry are likely caused by decreased vagal tone (Stubbs and York 1991) but may also be influenced by changes in food intake or other metabolic effects of ADX (Rohner-Jeanrenaud et al 1983;Vander Tuig et al 1984).…”

“…We hypothesized that post-surgical feeding of an elevated fat diet would negate the benefits of ADX on B-cell function in obese fa/fa rats. This idea was based on: (i) the importance of lipids in the regulation of B-cell function (Prentki and Corkey 1996), (ii) the ability of ADX to normalize several insulin secretion parameters in prepubertal fa/fa rats (Kibenge and Chan 1996), and iii) the observation that ADX reduced plasma TG (Castonguay et al 1986). The results were compared with those from control (sham-operated) rats fed a diet with elevated fat content.…”