A model to explore the interaction between muscle insulin resistance and beta-cell dysfunction in the development of type 2 diabetes

Type 2 diabetes is a polygenic disease characterized by defects in both insulin secretion and insulin action. We have previously reported that isolated insulin resistance in muscle by a tissue-specific insulin receptor knockout (MIRKO mouse) is not sufficient to alter glucose homeostasis, whereas beta-cell-specific insulin receptor knockout (betaIRKO) mice manifest severe progressive glucose intolerance due to loss of glucose-stimulated acute-phase insulin release. To explore the interaction between insulin resistance in muscle and altered insulin secretion, we created a double tissue-specific insulin receptor knockout in these tissues. Surprisingly, betaIRKO-MIRKO mice show an improvement rather than a deterioration of glucose tolerance when compared to betaIRKO mice. This is due to improved glucose-stimulated acute insulin release and redistribution of substrates with increased glucose uptake in adipose tissue and liver in vivo, without a significant decrease in muscle glucose uptake. Thus, insulin resistance in muscle leads to improved glucose-stimulated first-phase insulin secretion from beta-cells and shunting of substrates to nonmuscle tissues, collectively leading to improved glucose tolerance. These data suggest that muscle, either via changes in substrate availability or by acting as an endocrine tissue, communicates with and regulates insulin sensitivity in other tissues.     

High-affinity, calcium-stimulated ATPase in brush border membranes of the human term placenta

ATPase activity which is stimulated by submicromolar concentrations of calcium (Ca2+) was identified in human placental microvillous brush border membranes. The high-affinity enzyme has an apparent K0.5 for free Ca2+ of 18.3 +/- 3.7 nM and a Vmax of 233.0 +/- 30.0 nmol/min/mg protein. Studies using trans-1,2-diaminocyclohexane-N,N,N1,N1-tetraacetic acid (CDTA) show that this enzyme requires submicromolar concentrations of Mg2+ for maximal activity, but that it appears to have a low basal activity in the absence of this cation. The high-affinity Ca2+-ATPase was unaffected by up to 100 microM concentrations of vanadate, but was sensitive to trifluoperazine inhibition (I50 less than 50 microM). It was not found to be stimulated by the addition of up to 10 micrograms calmodulin, but this lack of effect may be related to the endogenous calmodulin content of the membrane preparation. A low-affinity, non-specific divalent cation ATPase was also identified in this membrane preparation. In contrast to the high-affinity enzyme, it has an apparent K0.5 for calcium of 99.7 +/- 22.1 microM, and a Vmax of 1.54 +/- 0.17 mumol/min/mg protein. The characteristics of the high-affinity Ca2-ATPase are similar to those of other Ca2+- ATPases known to transport and regulate intracellular calcium concentrations in other tissues. By analogy, we suggest that the high-affinity Ca2+-ATPase described here could play an important role in cellular calcium homeostasis in the human placenta.     

Human placental lipid peroxidation. Some characteristics of the NADPH-supported microsomal reaction

1. The evidence presented in this paper indicates the existence of NADPH-supported lipid peroxidation in human placental microsomes. Thiobarbituric acid assay was used to estimate quantitatively lipid peroxidation. 2. Several biochemical characteristics of the reaction were examined. Maximal lipid peroxidation occurred at pH 7.4 and at a protein concentration of approx. 0.2 mg microsomal protein/ml. The presence of NADPH and chelated iron was required. The reaction was linear up to 5 min and did not exhibit an initial lag phase. 3. Under optimal assay conditions, the rate of lipid peroxidation ranged from 2 to 6 nmol malondialdehyde formed/min/mg protein in different preparations of placental microsomes. 4. Inconclusive results were obtained when assays were performed in the presence of scavengers of reactive oxygen species. 5. Marked inhibition in the malondialdehyde accumulation was observed when phosphate buffer was added to the incubation media. 6. This inhibitory effect appeared to be due to the removal of chelated iron from the system and not due to interference with the electron transport mechanism.     

Potential pitfalls of magnetic resonance imaging in the diagnosis of avascular necrosis

Magnetic resonance (MR) imaging and radionuclide (RN) bone scans were performed in two patients with collagen vascular disease (CVD) to evaluate hip pains. In both patients RN bone scans demonstrated decreased radioactivity in the femoral heads, whereas, MR imaging was normal. Because early changes of avascular necrosis (AVN) frequently present as decreased radioactivity in the femoral head, special attempts were made to detect this decreased activity using pinhole collimator imaging. The diagnosis of AVN was confirmed surgically by venous pressure measurements. Abnormal RN bone scans representing decreased flow due to vasculitis in patients with CVD, may be more sensitive in the diagnosis of AVN before structural changes can be detected on MR studies.     

Cerebral Cavernous Malformations and Pregnancy: Hemorrhage Risk and Influence on Obstetrical Management

BACKGROUND:: Cerebral cavernous malformations are brain vascular malformations associated with intracranial hemorrhage. It is unclear whether pregnancy is a risk factor for hemorrhage, yet there is speculation that it may be. OBJECTIVE:: To compare the risk of clinically significant hemorrhage during pregnancy and nonpregnancy. METHODS:: A total of 186 patients from the University of Toronto Vascular Malformations Study Group were enrolled. The obstetrical history of each patient was collected and matched to their neurological history from the records of the study group. All hemorrhagic events occurring during childbearing years were associated with either a defined pregnancy risk period or nonpregnancy period. Patients were also asked to recall advice that they received from health care professionals regarding risk of hemorrhage in pregnancy. RESULTS:: Among our patient population there were 349 pregnancies (283 live births) and 49 hemorrhages during childbearing years, 3 of which were during pregnancy but none during delivery or within 6 weeks post partum. The hemorrhage rate for pregnant women was 1.15% (95% confidence interval: 0.23-3.35) per person-year and 1.01% (95% confidence interval: 0.75-1.36) per person-year for nonpregnant women. Relative risk of pregnancy was 1.13 (95% confidence interval: 0.34-3.75) (P = .84). Neurosurgeons and obstetricians were the source of most hemorrhage risk advice. The majority of neurosurgeons suggested that the risk was unchanged, but the obstetricians were divided. Four patients never conceived, and 2 others began contraception because of the advice that they received. CONCLUSION:: The risk of intracranial hemorrhage from cerebral cavernous malformations is likely not changed during pregnancy, delivery, or post partum. ABBREVIATIONS:: CCM, cerebral cavernous malformationCI, confidence interval.     

Pellagra in a child–A rare entity

This case has been presented as pellagra, which is very rare in children. Pellagra is due dietary deficiency of niacin. Usually seen in alcoholics, malabsorption syndromes occur very rarely in children. A 11-y-old girl presented with well-defined, hyperpigmented, hyperkeratotic, symmetrical, thick scaly plaques surrounded by erythema on the dorsum of the hands, arms, feet, legs up to knees, and along the sides of the neck. The child was given 100 mg of Nicotinamide. Skin lesions resolved rapidly with the treatment and the child improved.