epidermal-growth-factor and Hyperinsulinism

We report the case of a 63-year-old obese man with a rapid-onset of widespread acanthosis nigricans (AN) in the setting of having recently initiated treatment with niacin for dyslipidemia. Although obesity and insulin-resistance are risk factors for AN, AN associated with endocrine dysfunction tends to have a more gradual onset and limited involvement. Owing to our patient's age, the rapid onset, and extensive distribution of his eruption, we initially were concerned about paraneoplastic AN. However, an evaluation for a malignant condition was negative. The timing of the onset of our patient's eruption within several months of starting niacin therapy is consistent with niacin-induced AN. Niacin is known to cause rapidly progressive, widespread AN that is reversible upon discontinuation of the medication. We discuss the pathogenesis of AN, which is thought to be the final common manifestation of stimulation of different subtypes of tyrosine kinase receptors by various epidermal growth factors.

Topics: Acanthosis Nigricans; Cardiovascular Diseases; Diagnosis, Differential; Dyslipidemias; Epidermal Growth Factor; Humans; Hyperinsulinism; Hypolipidemic Agents; Insulin Resistance; Male; Middle Aged; Niacin; Obesity; Paraneoplastic Syndromes; Receptor Protein-Tyrosine Kinases

Equine laminitis is a disease of the digital epidermal lamellae typified by epidermal cell proliferation and structural collapse. Most commonly the disease is caused by hyperinsulinemia, although the pathogenesis is incompletely understood. Insulin can activate the epidermal growth factor (EGF) system in other species and the present study tested the hypothesis that upregulation of EGF receptor (EGFR) signalling is a key factor in laminitis pathophysiology. First, we examined lamellar tissue from healthy Standardbred horses and those with induced hyperinsulinemia and laminitis for EGFR distribution and quantity using immunostaining and gene expression, respectively. Phosphorylation of EGFR was also quantified. Next, plasma EGF concentrations were compared in healthy and insulin-infused horses, and in healthy and insulin-dysregulated ponies before and after feeding. The EGFR were localised to the secondary epidermal lamellae, with stronger staining in parabasal, rather than basal, cells. No change in EGFR gene expression occurred with laminitis, although the receptor showed some phosphorylation. No difference was seen in EGF concentrations in horses, but in insulin-dysregulated ponies mean, post-prandial EGF concentrations were almost three times higher than in healthy ponies (274 ± 90 vs. 97.4 ± 20.9 pg/mL, P = 0.05). Although the EGFR does not appear to play a major pathogenic role in hyperinsulinemic laminitis, the significance of increased EGF in insulin-dysregulated ponies deserves further investigation.

Topics: Animals; Epidermal Growth Factor; ErbB Receptors; Foot Diseases; Gene Dosage; Gene Expression Regulation; Hoof and Claw; Horse Diseases; Horses; Hyperinsulinism; Insulin; Phosphorylation

Levels of epidermal growth factor (EGF) in serum were significantly decreased in streptozotocin (STZ)-diabetic mice (446 +/- 168 pg/ml after 1 week and 423 +/- 52 after 4 weeks vs 766 +/- 162 pg/ml in controls, P.002 and less than .001. respectively) and in genetically diabetic ob/ob mice (455 +/- 285 vs 962 +/- 453 pg/ml in nondiabetic ob/+ controls, P.043). The urinary excretion of EGF was significantly increased in STZ mice (104 +/- 53 vs 51 +/- 23 ng/h, P.013) but unchanged in ob/ob mice (33 +/- 9 vs 45 +/- 16 ng/h, P.134). However, when expressed per mg creatinine it was decreased in both cases: in STZ mice to 680 +/- 250 ng/mg at 1 week and 684 +/- 211 at 4 weeks vs 1250 +/- 303 ng/mg in controls (P less than .01); and in the ob/ob mice to 552 +/- 117 vs 1237 +/- 300 ng/mg in ob/+ controls (P less than .01). EGF content of the submandibular glands of STZ mice remained unchanged at 1 week (13.1 +/- 2.9 vs 11.0 +/- 1.8 micrograms/mg protein, P.170) but dropped by 4 weeks (4.7 +/- 1.2 micrograms/mg, P less than .001); in the ob/ob mice it was less than 20% that of controls (2.1 +/- 0.8 vs 12.2 +/- 3.6 micrograms/mg protein). In kidneys, the EGF content was not altered in either ob/ob (524 +/- 50 vs 571 +/- 33 pg/mg protein) or STZ mice (652 +/- 183 vs 665 +/- 80 pg/mg). The preproEGF mRNA level in STZ-treated mice was reduced after 4 weeks in submandibular glands but not in kidneys. The results show that diabetes affects EGF production, utilization and/or excretion in mice and that kidneys are spared from suppression of EGF synthesis that is pronounced in the submandibular glands.

Topics: Animals; Blotting, Northern; Diabetes Mellitus, Experimental; Epidermal Growth Factor; Hyperinsulinism; Kidney; Male; Mice; Mice, Obese; Protein Precursors; Radioimmunoassay; RNA, Messenger; Submandibular Gland