In a diabetic liver transplant recipient, immunosuppressed with FK 506, a severe digestive moniliasis required treatment with the antifungal imidazole derivative fluconazole. This was followed by a brisk rise in serum creatinine levels, which returned promptly to baseline when this combination was stopped. Serial measurements of FK 506 concentrations in plasma showed excessive areas under the 24 h time-concentration curve and trough levels during the concomitant intake of imidazole antifungals and FK 506. Eighteen months later, this patient presents with normal renal function. Antifungal imidazole derivatives inhibit the P 450 cytochrome enzyme system and may thus decrease the catabolism of FK 506. Meticulous monitoring of FK 506 trough levels and dosage adaptation are compulsory when concomitant treatment with such a drug is unavoidable. The same is true for cyclosporine in auto-immune diabetic patients receiving cyclosporine A.

Circadian Rhythm↗

PubMedDate not supplied

Course of pancreatic beta cell destruction in prediabetic NOD mice: a histomorphometric evaluation.

The course of pancreatic beta cell destruction during the prediabetic period of autoimmune diabetic syndromes is not precisely known. We have analyzed the course of insulitis (n = 140) and the beta cell and lymphocytic volume densities by morphometric methods (n = 80) in NOD mice aged 6 to 45 weeks. In the absence of diabetes the mean beta cell density was only slightly reduced with age: 0.64 +/- 0.04% glandular tissue (mean SEM; n = 12) in 6 wk-old mice, 0.52 +/- 0.06% in 45 wk-old mice (n = 12; ns). However, a minority of pancreases were free of insulitis or showed isolated periinsulitis at the end of the 45-wk follow-up period. Invasive insulitis (i.e. mononuclear cells invading the islet area) was detected in 60-85% of mice from the 12th week on. In non overtly diabetic mice, beta cell density was reduced only when insulitis was invasive in more than 40% of islets: 0.30 +/- 0.03%, (n = 11) vs 0.59 +/- 0.04% (n = 34) in moderately invasive insulitis (p < 0.05). These mice had significant metabolic abnormalities. In diabetic mice, the beta cell density was markedly decreased: 0.02 +/- 0.01% (n = 7; p < 0.001). On the whole, a lymphocytic infiltrate affecting less than 50% of the islet volume was compatible with a normal beta cell density. Beyond this 50% lymphocytic infiltration threshold, beta cell density was tightly and negatively related to the lymphocytic volume density.(ABSTRACT TRUNCATED AT 250 WORDS)

Aging↗

PubMedDate not supplied

[Diabetes and autoimmune polyendocrine disorders: practical aspects].

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Autoimmune Diseases↗

PubMedDate not supplied

Pentamidine-induced dysglycaemia: experimental models in the rat.

In order to analyse further the pathophysiology of pentamidine effects on blood glucose regulation, the following experimental models were established in rats: impairment of the renal function, bile duct ligation, inhibition of the P450 cytochrome enzyme system. In otherwise intact rats, 7.5 mg/day pentamidine was well tolerated whereas doses of 15 mg/day induced severe, relapsing and eventually lethal hypoglycaemia within a few days. Induction of a renal insufficiency of graded severity by treatment with gentamycin, subtotal nephrectomy and total bilateral nephrectomy resulted in repetitive, severe (sometimes lethal) hypoglycaemia, alternating with hyperglycaemia, glucosuria and ketonuria in pentamidine-treated rats (7.5 mg/d). No long-standing insulin-dependent diabetes was observed. In the dysglycemic animals, plasma insulin levels were inappropriate to the concomitant glycaemia; no stimulation was obtained by i.v. glucose. Glucagon levels were higher than normal, suppressible by i.v. glucose, responsive to IV arginine and to hypoglycaemia. Dysglycemic events were more frequent and marked in the rats with the most severe renal functional derangement. They were more frequent in the rats treated with pentamidine mesylate than in those treated with the isethionate salt. Control uremic rats (free of pentamidine) remained euglycaemic. The islets of Langerhans displayed severe vascular congestion and degranulation and necrosis of the B cells, while the non B cells (and particularly the A cells) were intact. Exocrine pancreatitis was occasionally observed in the most severely uremic rats. In contrast with uremic rats, neither surgical ligation of choledocus, nor treatment by P450 cytochrome inhibitors (particularly ketoconazole) precipitated dysglycaemia in the pentamidine-treated rats. These experimental data: 1) strengthen the concept of inappropriate insulin release from pentamidine-lesioned islet B cells due to pentamidine accumulation; 2) indicate a predominant role for renal insufficiency in determining the accumulation of this drug; 3) emphasize the clinical importance of renal insufficiency as a risk factor for pentamidine-induced dysglycaemia. Association with ketoconazole does not appear to be a risk factor.

Animals↗