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Nephropathy may develop in patients with type 1 diabetes because poor glycemic control produces effects that eventually lead to glomerular scarring and renal failure. The worse and more prolonged the hyperglycemia, the greater the risk of diabetic nephropathy. In patients with type 2 diabetes, hyperglycemia, as well as insulin resistance and generalized vascular disease, is involved in the pathogenesis of nephropathy. The glomerular changes of early diabetic nephropathy can be identified only by renal biopsy or by testing for microalbuminuria. Once macroalbuminuria occurs (albumin excretion rate, > 300 mg/day), usually after type 1 diabetes has been present for 10 to 15 postpubertal years, end-stage renal disease is almost inevitable. However, aggressive control of hypertension in diabetic patients without microalbuminuria helps avoid nephropathy, and tight glycemic control in those with microalbuminuria can avoid or delay its onset. Even when macroalbuminuria is present, treatment can prolong renal function. Aggressive antihypertensive therapy, especially with ACE inhibitors, can reduce renal decline by half. Avoiding circumstances that may damage the kidneys (e.g., use of radiocontrast materials or nephrotoxic drugs, dehydration, hyperlipidemia, urinary tract infection, buildup of AGEs) is critical. Some treatment methods are controversial (dietary protein restriction) or still under investigation (use of injected or oral heparin) but may help delay renal transplantation or dialysis.

GH, an important growth-promoting and metabolic hormone, exerts its biological effects by interacting with cell surface GH receptors (GHRs). The GHR is a single membrane-spanning protein that binds GH via its extracellular domain. The high affinity GH-binding protein (GHBP), which corresponds to a soluble form of the GHR extracellular domain, carries a substantial fraction of the GH in the circulation of various species and probably has a role in modulation of the hormone's bioavailability. Although in rodents, it is believed that the GHBP is largely derived by translation of an alternatively spliced GHR messenger RNA, in humans and rabbits, proteolytic cleavage of the membrane-anchored receptor releases the GHR extracellular domain, which is believed to thereby become the GHBP. In this study, we used human IM-9 lymphocytes and GHR antibodies to study this proteolytic shedding of the GHBP. As determined by immunoblotting with anti-GHR cytoplasmic domain serum, addition of phorbol 12-myristate 13-acetate (PMA; 1 microg/ml) to serum-starved cells led to rapid loss (roughly 60% decline after 1 h; t(1/2) = approximately 5 min) of mature GHRs (115-140 kDa) from either total cell or detergent-soluble extracts. Loss of full-length GHRs was accompanied by accumulation of four proteins (65-68 kDa), each reactive with the cytoplasmically directed antiserum. The pattern of appearance of these GHR ctyoplasmic domain proteins, the electrophoretic and immunological characteristics of which are similar to those of a recombinant rabbit GHR mutant that lacks the extracellular domain, was such that progressively faster migrating forms were evident between 5-60 min of PMA exposure. Treatment with N-ethylmaleimide (NEM; 5 mM), an agent known to cause GHBP shedding from IM-9 cells, promoted a similar rapid loss of full-length GHRs and an accumulation of GHR cytoplasmic domain remnant proteins. PMA-induced, but not NEM-induced, GHR proteolysis was blocked by the protein kinase C inhibitor, GF109203X. Both PMA- and NEM-induced receptor proteolysis were, however, inhibited by the metalloprotease inhibitor, Immunex Compound 3 (minimum effective concentration, 10 microM). Notably, PMA and NEM also promoted shedding of GHBP into the conditioned medium of the cells, as determined by a chromatographic [125I]human GH binding assay; this GHBP shedding was also inhibited by Immunex Compound 3. These results strongly implicate a member(s) of the metalloprotease family as a potential GHBP-generating enzyme.

Objective: To describe the clinical features of giant-cell granulomatous hypophysitis and to report on the results of corticosteroid treatment., Methods: A case of giant-cell granulomatous hypophysitis is presented, and the pertinent literature is reviewed., Results: A 41-year-old woman with anterior pituitary dysfunction had a pituitary mass that was 18 by 16 by 13 mm by magnetic resonance imaging. The pituitary stalk was thickened and enhanced after intravenous administration of gadolinium. A biopsy specimen that was obtained at transsphenoidal pituitary exploration revealed that the patient had giant-cell granulomatous hypophysitis, a rare inflammatory pituitary disorder. High-dose corticosteroid therapy failed to reverse her anterior pituitary dysfunction., Conclusion: The coincidence of a contrast-enhancing pituitary mass with a thickened pituitary stalk and the awareness of the rare occurrence of endocrine inactive tumors in women of childbearing age should suggest an inflammatory pituitary condition. Such lesions should also be suspected in otherwise healthy young women with hypopituitarism and no evidence of hormone hypersecretion. On the basis of the literature and our experience, corticosteroid treatment does not seem to improve anterior pituitary function.

Diabetic ketoacidosis is a preventable condition that usually has a satisfactory outcome. However, the potential for a poor outcome and even death demands early and aggressive treatment. Insulin administration, rehydration, and electrolyte replacement are the mainstays of treatment. A search for the underlying cause is also a priority if recurrences are to be avoided.