Recognizing factitious hypoglycemia in the family practice setting.

BACKGROUND: Factitious hypoglycemia is a deliberate attempt to induce a low serum glucose level using either insulin or oral hypoglycemic agents. Sulfonylurea-induced hypoglycemia is more common than incidents of insulin abuse, and hypoglycemia caused by these oral agents is biochemically indistinguishable from insulinoma. METHODS: We describe a case of factitious hypoglycemia resulting from insulin abuse in an adult diabetic patient, review the essentials of glucose homeostasis, and describe diagnostic tests that allow a differential diagnosis. RESULTS AND CONCLUSION: Factitious hypoglycemia is associated with a higher incidence of suicide, depression, and personality disorders. Insulin-induced hypoglycemia can be detected by an insulin to C-peptide ratio that is greater than 1.0. In the absence of proof to the contrary, insulinoma should be considered the cause of hypoglycemia until another diagnosis is established. The generally poor prognosis for patients with factitious hypoglycemia underscores the importance of early recognition of factitious disorders.

The acid instability of myelin. A model for myelin degeneration in multiple sclerosis.

Electron micrographs of samples of bovine spinal cord which have been briefly acidified (10 mM lactate buffer, pH 5.5, 25 degrees C, 15 minutes) prior to being fixed for EM examination, reveal extensive vesicular disruption of the myelin lamellae; micrographs of control samples incubated under identical conditions at pH 7.0, show normal compact lamellae. Culture of thioglycollate-elicited rat peritoneal macrophages in the presence of derivatized, non-ingestible, bovine CNS material results in the secretion of lactic acid and the acidification of the culture medium to levels which are comparable to those which cause lamellae disruption in the tissue slices. Because of the sensitivity of the myelin lamellae to an acidic microenvironment, it is suggested that a local hyperlactemia, with the resulting decrease in interstitial pH, may be a major pathological process in cell-mediated inflammatory demyelination. Antihyperlactemics may therefore provide a new therapeutic approach to minimizing myelin degeneration in multiple sclerosis and in other CNS disorders characterized by inflammatory demyelination.

Purification and kinetic mechanism of S-adenosylmethionine: myelin basic protein methyltransferase from bovine brain.

The enzyme S-adenosylmethionine (AdoMet): myelin basic protein (MBP) methyltransferase was purified 250-fold from bovine brain with an overall yield of 130%, relative to crude supernatant. The purification involves acid-base and (NH4)2SO4 precipitation, chromatography over Sephadex G-100 and DEAE-cellulose, followed by preparative isoelectric focusing. The enzyme has a pI of 5.60 +/- 0.05, and the Mr is estimated to be between 71,000 (from SDS/polyacrylamide-gel electrophoresis) and 74,500 (from gel filtration). The enzyme is stable at 37 degrees C for over 2 h, is stable frozen and does not require metal ions or reductants. The enzyme shows a high specificity for MBP and does not accept polyarginine as a substrate; F1 histone is methylated at 37% of the rate of MBP. Methylation occurs on an arginine residue in a single h.p.l.c.-resolvable peptide from the tryptic cleavage of MBP. Simple saturation kinetics are observed with respect to both substrates, with Km values of 18 microM and 32 microM for MBP and AdoMet respectively. The simplest kinetic mechanism that is consistent with the data requires ordered rapid-equilibrium binding, with AdoMet as the first substrate. The enzyme isolated in this work is different, both physically and kinetically, from the histone-specific arginine methyltransferases described by other workers. A new, simple, assay system for the methylation of MBP is described.

Mechanism of the interaction between myelin basic protein and the myelin membrane; the role of arginine methylation.

The addition of solutions of bovine myelin basic protein to suspensions of unilamellar vesicles prepared from whole myelin suspensions results in the rapid equilibrium association of the vesicles into dimers, followed by time-dependent aggregation reactions. Other cationic proteins also induce the dimerization of the vesicles and equilibrium constants for dimer formation are obtained for bovine myelin basic protein, lysozyme, polyhistidine and myelin basic protein from carp, which differs from the bovine protein in that it contains no methylarginine residues. The bovine protein is more efficient at inducing dimer formation than the carp protein by approximately 0.93 kcal/mole; the carp protein is approximately as effective as the other cationic proteins examined. Complete methylation of the bovine MBP by AdoMet:MBP methyltransferase increases the interaction between MBP and the membrane by approximately 0.13 kcal/mole, consistent with the suggestion that a large portion of the free energy difference between the carp and bovine proteins arises from favorable interactions involving the methylarginine residues.

Time dependence of the methylation of myelin basic protein from bovine brain; evidence for protein-methylarginine demethylation.

In the presence of excess S-adenosylmethionine (AdoMet), the extent of methylation of myelin basic protein (MBP) by partially purified AdoMet:MBP methyltransferase is a non-linear function of time, reaching a limiting value as available MBP is depleted and then decreasing monotonically. This decrease is not caused by proteolytic cleavage of MBP nor by effects related to substrate or product instability under the incubation conditions and is not observed in heat-inactivated samples. S-Adenosylhomocysteine is not required for the demethylation to occur, and with purified enzyme, the decrease is not observed. The data strongly suggest that the decrease in methyl content represents an enzyme-catalyzed demethylation reaction. This would represent the first report of an enzyme which catalyzes protein-methylarginine demethylation.