Biomedical subjects
Publications and source records attributed to M J MacDonald.
Guidelines for the prescription, initiation, and adjustment of insulin plans in diabetic children are outlined, with an emphasis on patient education and active participation in the treatment regimen. The management of special situations--sick days, surgery, noncompliance, and travel--is also discussed.
The management of complications of insulin therapy, such as lipoatrophy, allergic reactions, insulin resistance, and insulin edema, is outlined. Human and animal insulin preparations currently available in the United States are discussed, highlighting the comparative costs and indications for use.
The use of continuous subcutaneous insulin infusion in diabetic children is physiologically beneficial. However, careful patient selection and appropriate patient education are essential for successful treatment with CSII. The authors provide a comparative analysis of insulin pumps currently on the market. The risks of potential complications of CSII--ketoacidosis, hypoglycemia, and cutaneous problems--are also assessed.
The genetic, viral, and autoimmune factors that may play a role in causing insulin-dependent diabetes are explored. The author presents guidelines for genetic counseling of families with diabetic children. Case histories illustrate various atypical presentations of diabetes in children, and help the clinician in diagnosing and managing the borderline diabetic.
The value of blood glucose testing over urine sugar testing is emphasized, and techniques of self-monitoring of blood glucose in children are presented. Test strips and reflectance meters currently on the market are described and evaluated. Useful suggestions are made for introducing blood glucose testing to children, stressing flexibility in the frequency of testing, at least initially, and proper education in the interpretation of testing results.
As an important aspect of newborn care, the rapid assessment of glucose homeostasis is often accomplished by a glucose oxidase-peroxidase chromagen test strip method, either alone or with a reflectance colorimeter. The precision of these techniques has been established, but few studies have determined accuracy in an intensive care setting. We performed the following study. During the time of routine heelstick blood sampling, the nurses collected 90 complete study sets for glucose analysis from 43 neonates. Dextrostix, Ames Meter, Chemstrip bG, and Stat Tek Meter determinations were performed according to manufacturers' instructions. Concurrent determination of blood glucose level by a glucose analyzer (Beckman) served as a standard for comparison. There was no significant difference in estimation of true blood glucose concentration among the rapid methods tested. The marked variability of results suggests only modest accuracy in estimating whole blood glucose concentration when employed in the routine neonatal clinical setting. These data indicate that the results from rapid blood glucose estimation techniques require confirmation by conventional laboratory methods prior to therapeutic intervention.
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Pancreatic islets contain enzyme activity which catalyzes the phosphorylation by MgATP of cardiac, skeletal, or smooth muscle myosin light chains. The enzyme is activated by calcium (Ka = 10 microM) and calmodulin (Ka = 2 nM) and inhibited by trifluoperazine (Ki = 10 microM), a known inhibitor of calmodulin and of insulin secretion. The enzyme binds to a calmodulin affinity column when Ca2+ is present and is eluted when Ca2+ is omitted. These are the properties of myosin light chain kinase. Since phosphorylation of smooth muscle myosin is necessary for its activation by actin, the kinase may have a key role in coupling stimuli that increase intracellular calcium to the contractile processes involved in insulin secretion.
Homogenates of isolated pancreatic islets contain 40-70 times as much flavin-linked glycerol-3-phosphate dehydrogenase (EC 1.1.99.5) as homogenates of whole pancreas, liver, heart, or skeletal muscle when the activity is assayed with either iodonitrotetrazolium or with dichloroindophenol as an electron acceptor. Intact mitochondria from islets release 3HOH from [2-3H]glycerol phosphate 7 times faster than do skeletal muscle mitochondria. The activity of the cytosolic, NAD-linked, glycerol phosphate dehydrogenase (EC 1.1.1.8) in pancreatic islets is comparable to that of the mitochondrial dehydrogenase so a glycerol phosphate shuttle is possible in pancreatic islets. Diazoxide, an inhibitor of insulin release in vivo and in vitro, inhibits the islet mitochondrial glycerol phosphate dehydrogenase in all three of the assays mentioned above at concentrations that inhibit insulin release and CO2 formation from glucose by isolated pancreatic islets. Diazoxide does not inhibit the dehydrogenase in mitochondria from skeletal muscle, liver, and heart. A slight inhibition in mitochondria from whole pancreas can be accounted for as inhibition of the islet dehydrogenase because no inhibition is observed in mitochondria from pancreas of rats treated with alloxan, an agent that causes diabetes by destroying pancreatic beta cells. The results of this study are compatible with the hypothesis that the mitochondrial glycerol phosphate dehydrogenase has a key role in stimulus-secretion coupling in the pancreatic beta cell during glucose-induced insulin release.
To study the interrelationships of phosphoenolpyruvate carboxykinase and glyceroneogenesis in adipose tissue, investigations with two effectors of the hepatic carboxykinase, Fe2+ and Mn2+, and two inhibitors of the enzyme and of gluconeogenesis in liver, quinolinic acid and 3-mercaptopicolinic acid, were carried out. Incubating adipose tissue cytosol with 30 microM Fe2+ or 100 microM Mn2+ prior to assaying for phosphoenolpyruvate carboxykinase activity doubled the enzyme activity. Inhibition of the enzyme by quinolinate alone was minimal. Adding 30 microM Fe2+ to the cytosol decreased the K0.5 (concentration that gives 50% inhibition) for quinolinate to 0.4 mM and the K0.5 for mercaptopicolinate from 200 to 14 microM. Activating the enzyme with 100 microM Mn2+ did not lower the K0.5 values and adding 500 microM Mn2+ to the cytosol completely interfered with the enhancement of inhibition induced by Fe2+. Each inhibitor interfered with 14C incorporation into glyceride glycerol from labeled pyruvate, alanine and lactate in suspensions of adipocytes. Adding 1 mM Mn2+ to the adipocyte suspension almost completely prevented the inhibition of pyruvate and alanine incorporation into glyceride glycerol, but adding the Mn2+ or 250 microM Fe2+ to the adipocytes in the absence of inhibitors did not enhance glyceride glycerol formation. Adding 250 microM Fe2+ to the adipocytes did not enhance inhibition of lipid synthesis by mercaptopicolinate or quinolinate. Mercaptopicolinate did not inhibit glyceride glycerol, fatty acid, total lipid or CO2 production from glucose. The lack of activation of glyceride glycerol synthesis by added Fe2+ or Mn2+, the lack of enhancement of pyridine carboxylate inhibition by Fe2+ and the interference with inhibition by Mn2+ are compatible with the idea that a transition metal ion similar to Fe2+, if not Fe2+ itself, is available to, or loosely bound to, the adipose tissue carboxykinase in vivo. Taken together with the results of previous work which showed ferroactivator (a cytosol protein necessary for Fe2+ activation of the carboxykinase) to be present in adipose tissue, the present results indicate that the control of the adipose tissue carboxykinase may be similar to the enzyme in liver. Fatty acid synthesis was also diminished by the inhibitors, albeit to a lesser extent than was glyceride glycerol formation. It is hypothesized that this was secondary to decreased esterification caused by the lack of glycerol 3-phosphate from inhibition of the carboxykinase. Decreased esterification would lead to a build-up of fatty acyl CoA which inhibits fatty acid synthesis.
The distributions of HLA-A, -B, -C and -D antigens in 38 black American insulin-dependent juvenile diabetics were studied. Antigens A1, A2, B8 and Cw3 were slightly increased, but the corrected probability values were not statistically significant. As determined by mixed lymphocyte culture, the frequency of Dw3 was 89% in the juvenile diabetics and that of Dw4 was 42% in comparison with 14 and 8%, respectively, in the controls. The relative risks for juvenile diabetes were 52 for Dw3 (p = 10(-8) and 9 for Dw4 (p = 10(-6). Dw2 was significantly decreased in the diabetics (p equals 0.008). All of these deviations in A, B, C and D locus specificities have been previously reported by others in white juvenile diabetics. Because there are white genes in the American black gene pool and juvenile diabetes is rare in blacks in western Africa, many cases of juvenile diabetes in American blacks could be the result of genes ultimately derived from the white genes. This hypothesis is supported by the similar HLA associations in juvenile diabetes in the black and white ethnic groups.
The flavin contents of pancreatic islets and acinar tissue, whole pancreas, and liver of the rat were measured fluorometrically. Spectrofluorometric scanning of extracts of islets proved that they contained flavins. The spectra showed excitation peaks at approximately 370 and 445 nm and an emission peak at 530 nm; these values are identical to those of authentic flavins. Pancreatic islets contained 3 times as much flavin as whole pancreas or acinar tissue and 20% more than liver. Forty-six percent of the total islet flavin was in the cytosolic compartment compared with about only 11--12% in whole pancreas or liver. The results raise the question of whether islet cytosol contains a flavin-requiring enzyme important for hormone release.
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