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Biomedical subjects

M J MacDonald

Publications and source records attributed to M J MacDonald.

At least 91 records · Page 5Linked to original sources
PubMed1991

Correlation of glycosylated hemoglobin measured by affinity vs ion exchange chromatography with mean blood sugar in pediatric IDDM patients.

Affinity chromatography provides a more specific estimate of glycosylated hemoglobin (GlyHb) than does ion exchange chromatography (HbA1). However, whether GlyHb correlates closer than HbA1 with mean blood glucose has not been established. GlyHb and HbA1 were measured in pediatric IDDM patients attending a clinic (n = 285 visits) over a one year period and correlated with the mean of a patient's blood glucose measurements from records of home blood glucose monitoring. Mean GlyHb was higher than mean HbA1 (10.8% vs 9.6%) as was its standard deviation (2.2% vs 1.5%). While both GlyHb (r = 0.75) and HbA1 (r = 0.65) were strongly correlated with estimates of mean blood glucose, the correlation with GlyHb was significantly stronger than with HbA1 for the entire spectrum of metabolic control (P = 0.03), as well as for a segregated group of 'poorly controlled' patients with mean blood glucose greater than 150 mg/dl (P = 0.04). The results suggest that GlyHb is more accurate than HbA1 for estimating metabolic control and that GlyHb shows greater discriminating power than HbA1, especially at high concentrations of blood sugar. The mean blood glucose can be estimated from the equation: mean blood glucose (mg/dl) = (11.3 x GlyHb) + 32.

Adolescent↗
PubMed1991

Reinforcing breath carbon monoxide reductions in chronic obstructive pulmonary disease.

Chronic Obstructive Pulmonary Disease (COPD) usually results from tobacco smoking. Smoking cessation slows COPD's progression, but few have studied anti-smoking treatments in COPD. In 3-month trials we paid lottery tickets during daily home visits to still-smoking COPD patients for reductions in breath carbon monoxide (CO), a measure of smoke intake. In our first protocol experimental patients received 0-3 tickets per day, depending upon the extent of CO reduction below pre-treatment baselines; yoked controls received the same number of tickets, but not contingent on CO. The protocol produced no change. In a second study patients were assigned a post-baseline quit-date, received nicotine gum, and were paid up to 5 tickets per night, but only for CO less than 10 parts per million (ppm). CO fell sharply as the intervention began, but gradually rose again. A third protocol added special reinforcement schedules for those who did not quit or relapsed (up to 20 tickets per night for CO less than 10 ppm). Daily CO concentrations fell from 27.1 parts per million (baseline mean) to 12.7 (intervention mean), but rapid increases followed the intervention. Few patients stopped smoking, but CO and cigarettes used per day significantly fell during Studies 2 and 3. Post-hoc analysis suggested only a small effect from gum.

Breath Tests↗
PubMed1991

Quinone reductase enzyme activity in pancreatic islets.

A water-soluble quinone, coenzyme Q0 (CoQ0), was shown to stimulate insulin release, and dicumarol, an inhibitor of quinone reductase, inhibited glucose-induced insulin release in pancreatic islets. Since this suggested that quinone reductase might play some role in physiological insulin release, this enzyme was characterized in islets. More than 90% of the total activity was located in the cytosol, but the specific enzyme activity was highest in the microsomal fraction. The relative rates of activity with various substrates (CoQ0 approximately equal to durohydroquinone greater than menadione greater than duroquinone greater than CoQ6 = CoQ10 greater than ferricyanide) were similar to those described previously for quinone reductase from liver Dicumarol, chlorpromazine, and T3 were much more potent inhibitors of the enzyme when NADPH was the coenzyme than when NADH was the coenzyme. Dicumarol was the most potent inhibitor. The enzyme was not inhibited by rotenone. Islets ranked second to liver in quinone reductase activity, but the activity in islets was much closer to that found in all other tissues examined. Quinone reductase may play a role in insulin secretion.

Animals↗
PubMed1990

High activity of mitochondrial glycerol phosphate dehydrogenase in insulinomas and carcinoid and other tumors of the amine precursor uptake decarboxylation system.

The activity of the mitochondrial glycerol phosphate dehydrogenase (EC 1.1.99.5), the enzyme unique to the glycerol phosphate hydrogen shuttle, was measured in normal human tissues and tumors and compared with the activity of succinate dehydrogenase, another enzyme that transfers electrons to ubiquinone at site II of the electron transport chain. Six of 7 insulinomas and 10 of 12 carcinoid tumors showed high glycerol phosphate dehydrogenase activity. The activity was also increased in 3 of 4 gastrinomas, 2 paraganglionomas, 1 of 4 thyroid nodules, and 1 parathyroid tumor. These tissues belong to the amine precursor uptake decarboxylation system. The activity of glycerol phosphate dehydrogenase was generally unremarkable in non-amine precursor uptake decarboxylation system tumors and in normal tissues studied. However, 1 of 2 breast carcinomas, 1 submandibular tumor, and 2 of 3 melanomas were enriched in glycerol phosphate dehydrogenase activity. In general, succinate dehydrogenase activity exceeded that of glycerol phosphate dehydrogenase in all tissues except some of the tissues in which glycerol phosphate dehydrogenase activity was high. Normal tissues, such as the pancreatic beta-cell, which aerobically metabolize glucose rapidly utilize the glycerol phosphate shuttle to oxidize the large amount of NADH formed from glucose metabolism in the cytosol. Whether this is the reason for the enriched activity of the glycerol phosphate dehydrogenase in certain amine precursor uptake decarboxylation system tumors is unknown.

APUD Cells↗
PubMed1990

Insulin release in pancreatic islets by a glycolytic and a Krebs cycle intermediate: contrasting patterns of glyceraldehyde phosphate and succinate.

Glyceraldehyde phosphate, a glycolytic intermediate, and succinic acid (as its methyl ester to make it permeable to the cell), a citric acid cycle intermediate, were the only glucose metabolites of many recently tested that stimulated insulin release. The effects of these two "new" insulin secretagogues on several pancreatic islet parameters were compared. Glyceraldehyde phosphate stimulated all of the insulin it released during the first 5 min after islets were exposed to it, and its maximum effect on calcium uptake was observed at 5 min. Monomethyl succinate stimulated insulin release mostly during the last 30 min of a 1-h incubation and its maximum effect on calcium uptake was at 60 min after it was applied to islets. Monomethyl succinate-induced insulin release, but not glyceraldehyde phosphate-induced insulin release, was inhibited by metabolic inhibitors (antimycin A, rotenone, cyanide, FCCP, fluoride, and iodoacetamide). This is consistent with the idea that monomethyl succinate is hydrolyzed to succinate which is metabolized intramitochondrially. The effects of glyceraldehyde suggest that glucose signals the first phase of insulin release by an agonist-like mechanism that originates in the cytosol and requires minimal energy. The effects of monomethyl succinate suggest that the signal for the second phase of glucose-induced insulin release originates in the mitochondrion and requires a large amount of energy.

Animals↗
PubMed1990

Novel effects of insulin secretagogues on capacitation of insulin release and survival of cultured pancreatic islets.

Agents that stimulate insulin release from fresh pancreatic islets were tested for their ability to capacitate pancreatic islets to secrete insulin and to support beta-cell survival in tissue culture. Capacitation was defined as the ability to release insulin after 24 h in culture in the presence of an insulinotropic concentration of a secretagogue. Viable islets that lose glucose-induced insulin release gradually regain it during culture for 24 h in 20 mM glucose. Survival was defined as the ability to regain glucose-induced insulin release. To measure insulin release after culture, islets were incubated with various secretagogues in Krebs-Ringer buffer for 1 h. Examples of the diverse patterns of responses included the following. Glucose was the only secretagogue that capacitated glucose-induced release. Leucine-, leucine plus glutamine-, and glyceraldehyde-induced release remained capacitated after culture with no secretagogue. Culture at high glucose completely inhibited leucine-induced release. Culture at low glucose (1 mM) or at both high leucine and glutamine abolished glucose-induced release. Only leucine and glutamine capacitated monomethyl succinate-induced release. All agents including subinsulinotropic glucose (1 mM), except D-glyceraldehyde, permitted islet survival. Thus the metabolic pathways for initiation, capacitation, and survival are not identical between and within secretagogues. There is a reciprocal relationship between leucine and glucose with respect to capacitation. Capacitation follows a time course, which suggests that it is regulated by enzyme induction.

Animals↗
PubMed1990

Elusive proximal signals of beta-cells for insulin secretion.

The beta-cell is unique because its major agonists, i.e., insulin secretagogues, undergo metabolism instead of interacting with a receptor. This perspectives presents the hypothesis that the first part of a metabolic signal of a secretagogue is specific to the secretagogue and the beta-cell and can be envisioned as proximal. The second part, which occurs after transduction to more universal signaling mechanisms, is viewed as distal. Distal signaling and exocytosis in the beta-cell operate the same as in other cells. Aerobic glycolysis is required for glucose-induced insulin release. Because glyceraldehyde, which enters metabolism at the triose phosphates in the glycolytic pathway, is a potent insulin secretagogue but pyruvate, which is metabolized in the mitochondrion, is not an insulin secretagogue, the proximal signal for glucose-induced insulin release originates with an interaction between the central part of the glycolytic pathway and mitochondrial metabolism. The proximal message in leucine-induced insulin release originates with leucine allosterically activating glutamate dehydrogenase, which activates endogenous glutamate metabolism, and by the metabolism of leucine itself. The methyl ester of succinate is a potent experimental insulin secretagogue. It is puzzling why the glucose signal requires the interplay of glycolysis and mitochondrial metabolism, whereas the signals from leucine and succinate originate entirely from within the mitochondrion. Leucine-induced insulin release is suppressed and glucose-induced insulin release is activated in islets cultured at a high concentration of glucose. Conversely, leucine-induced insulin release is activated and glucose-induced insulin release is suppressed in islets cultured at low glucose.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

Kinetic advantages of hetero-enzyme complexes with glutamate dehydrogenase and the alpha-ketoglutarate dehydrogenase complex.

We have found previously (Fahien, L.A., Kmiotek, E.H., MacDonald, M. J., Fibich, B., and Mandic, M. (1988) J. Biol. Chem. 263, 10687-10697) that glutamate-malate oxidation can be enhanced by cooperative binding of mitochondrial aspartate aminotransferase and malate dehydrogenase to the alpha-ketoglutarate dehydrogenase complex. The present results demonstrate that glutamate dehydrogenase, which forms binary complexes with these enzymes, adds to this ternary complex and thereby increases binding of the other enzymes. Kinetic evidence for direct transfer of alpha-ketoglutarate and NADH, within these complexes, has been obtained by measuring steady-state rates of E2 when most of the substrate or coenzyme is bound to the aminotransferase or glutamate dehydrogenase (E1). Rates significantly greater than those which can be accounted for by the concentration of free ligand, calculated from the measured values of the E1-ligand dissociation constants, require that the E1-ligand complex serve as a substrate for E2 (Srivastava, D. K., and Bernhard, S. A. (1986) Curr. Tops. Cell Regul. 28, 1-68). By this criterion, NADH is transferred directly from glutamate dehydrogenase to malate dehydrogenase and alpha-ketoglutarate is channeled from the aminotransferase to both glutamate dehydrogenase and the alpha-ketoglutarate dehydrogenase complex. Similar evidence indicates that GTP bound to an allosteric site on glutamate dehydrogenase functions as a substrate for succinic thiokinase. The potential physiological advantages to channeling of activators and inhibitors as well as substrates within multienzyme complexes organized around the alpha-ketoglutarate dehydrogenase complex are discussed.

Animals↗
PubMed1989

Activation of the cellular proto-oncogene product p21Ras by addition of a myristylation signal.

The 21-kD proteins encoded by ras oncogenes (p21Ras) are modified covalently by a palmitate attached to a cysteine residue near the carboxyl terminus. Changing cysteine at position 186 to serine in oncogenic forms produces a nonpalmitylated protein that fails to associate with membranes and does not transform NIH 3T3 cells. Nonpalmitylated p21Ras derivatives were constructed that contained myristic acid at their amino termini to determine if a different form of lipid modification could restore either membrane association or transforming activity. An activated p21Ras, altered in this way, exhibited both efficient membrane association and full transforming activity. Surprisingly, myristylated forms of normal cellular Ras were also transforming. This demonstrates that Ras must bind to membranes in order to transmit a signal for transformation, but that either myristate or palmitate can perform this role. However, the normal function of cellular Ras is diverted to transformation by myristate and therefore must be regulated ordinarily by some unique property of palmitate that myristate does not mimic. Myristylation thus represents a novel mechanism by which Ras can become transforming.

Animals↗
PubMed1989

Glyceraldehyde phosphate: an insulin secretagogue with possible effects on inositol phosphate formation in pancreatic islets.

The insulinotropic action of glucose, the most potent physiologic insulin secretagogue, involves its metabolism. However, no glucose metabolite has ever been identified as a key intermediate. We tested the abilities of a number of glucose metabolites to stimulate insulin release from pancreatic islets. Of all of these metabolites, glyceraldehyde 3-phosphate was the most potent insulin secretagogue. In numerous experiments over 3 years, insulin release by 4 mM glyceraldehyde phosphate ranged from 50 to 200% of that initiated by 16.7 mM glucose--a near-maximal insulin stimulus. At concentrations of 1 and 4 mM, glyceraldehyde phosphate was even more potent than the known secretagogues glucose and glyceraldehyde. Glucose metabolites were also tested for their ability to stimulate inositol tris-, bis-, and monophosphate formation by permeabilized islets. Only glyceraldehyde phosphate stimulated inositol phosphate formation and this stimulation occurred at concentrations of glyceraldehyde phosphate which could be present in the beta cell under physiologic conditions (K0.5 = 25 microM). The current results are consistent with the idea that glyceraldehyde phosphate is a key insulinotropic glucose metabolite that might act directly (or rather directly via a receptor) on the phospholipase C that forms inositol trisphosphate in the plasma membrane.

Animals↗
PubMed1989

Autoimmune thyroid phenomena are not evidence for human lymphocyte antigen-genetic heterogeneity in insulin-dependent diabetes.

It is well established that there is genetic heterogeneity between a human lymphocyte antigen (HLA)-DR3-associated allele and an HLA-DR4-associated allele in insulin-dependent diabetes mellitus (IDDM). Equally well established are the association of DR3 with Graves' disease and other autoimmune disorders in nondiabetics and the increased prevalence of autoimmune thyroid disease in IDDM. Perhaps in large part because of these facts, it has been postulated that there are two major forms of classical IDDM--one form characterized by coexistent autoimmune disease, such as autoimmune thyroid disease which is associated with DR3, and another form not associated with additional autoimmune disorders, which is associated with DR4. Several studies have repudiated the idea of specific clinical findings in IDDM being associated exclusively with DR4. However, the DR3-thyroid association in IDDM has not been investigated carefully. Therefore, in order to study this putative association, we divided a group of diabetic children into overlapping subgroups based on thyroid enlargement, antithyroid microsomal antibodies, acquired hypothyroidism, and no evidence of thyroid disease. The distributions of HLA-DR3 and -DR4 among these subgroups did not differ from each other; nor did the distribution of the HLA alleles differ from those of randomly selected IDDM individuals. These results suggest that thyroid autoimmunity in IDDM is part of the IDDM "syndrome" and is associated with DR3 and DR4 to the same extent that IDDM without thyroid disease is associated with these two antigens. Thus, although genetic studies are consistent with the heterogeneity between DR3 and DR4 in IDDM, there is no HLA-thyroid disease association to support this heterogeneity.

Diabetes Mellitus, Type 1↗
PubMed1989

Activation of ras oncogenes in chemically transformed BALB/MK-2 mouse keratinocytes.

BALB/MK-2 cells are an epidermal growth factor (EGF)-dependent cell line derived from BALB/c mouse epidermis that can undergo terminal differentiation under appropriate conditions. Previous studies have shown that transformation of these cells by retroviral oncogenes relieves the EGF requirement while blocking the terminal differentiation program. In this report we show that BALB/MK-2 cells are sensitive to transformation by the chemical carcinogens dimethylbenz[a]anthracene (DMBA), 3-methylcholanthrene (MCA), and N-methyl-N'-nitro-N'-nitroso-guanidine (MNNG). BALB/MK-2 cells transformed by these carcinogens proliferate in the absence of EGF and do not undergo terminal differentiation in response to calcium. However, the cells retain their anchorage growth dependence and are nontumorigenic in nude mice. NIH 3T3 transfection analysis showed that the endogenous Ha-ras gene had been activated in both DMBA- and MNNG-transformed cells and the Ki-ras gene had been activated in the MCA-transformed cells. Additionally, non-ras transforming activity was detected in some MNNG-transformed BALB/MK-2 cells. Thus, the BALB/MK-2 cell line provides a reproducible in vitro assay system for chemical transformation of epithelial cells and for identification of oncogene activations associated with changes in growth control and differentiation.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1989

Does glyceraldehyde enter pancreatic islet metabolism via both the triokinase and the glyceraldehyde phosphate dehydrogenase reactions? A study of these enzymes in islets.

Glyceraldehyde has been known to be an insulin secretagogue for more than 15 years. It has been (reasonably) assumed that glyceraldehyde enters the glycolytic pathway via its phosphorylation by ATP to form glyceraldehyde phosphate, a reaction catalyzed by the enzyme triokinase, and that subsequent metabolism is identical to that of glucose. glucose. However, up to now there have been no studies verifying the presence of triokinase in the pancreatic beta cell. We report here that (1) the activity of triokinase in pancreatic islets is very low, indicating that the activity is intrinsically low and/or the enzyme was rapidly inactivated during the preparation of tissue for assay; (2) the activity is much lower than glucose phosphorylating activity (hexokinase plus glucokinase) in islets, even though glyceraldehyde is a more efficient insulin secretagogue than glucose; (3) glyceraldehyde phosphate dehydrogenase from pancreatic islets can use glyceraldehyde as a substrate in place of glyceraldehyde phosphate (the Vmax of glyceraldehyde phosphate dehydrogenase from islets when glyceraldehyde is the substrate is 20-fold that of triokinase when glyceraldehyde is the substrate); and (4) the Km of glyceraldehyde phosphate dehydrogenase with respect to glyceraldehyde (4.8 mM) is similar to the concentration of glyceraldehyde that gives one-half maximal rates of insulin release from pancreatic islets, whereas the Km of triokinase with respect to glyceraldehyde is much lower (less than 50 microM). These data suggest that besides stimulating insulin release in islets via its entering metabolism by phosphorylation to glyceraldehyde phosphate in the triokinase reaction, glyceraldehyde could be phosphorylated by Pi in the glyceraldehyde phosphate dehydrogenase reaction to form glycerate 1-phosphate which is probably unmetabolizable in islets. The second reaction could drastically increase the NADH/NAD ratio in islets without providing substrates for hydrogen shuttles that reoxidize cytosolic NADH. Since an increased NAD(P)H/NAD(P) ratio is believed to be a key part of the signal for insulin release, such a mechanism would explain the potent insulinotropism of glyceraldehyde in short-term experiments. In addition, the formation of unmetabolizable acids may explain the toxic effects of long-term exposure of islets to glyceraldehyde and why glyceraldehyde causes the beta cell to become acidic, whereas glucose does not.

Animals↗
PubMed1989

Effect of esters of succinic acid and other citric acid cycle intermediates on insulin release and inositol phosphate formation by pancreatic islets.

Esters of carboxylic acids are permeable to cells and once inside the cell are hydrolyzed to carboxylic acids. Methyl and ethyl esters of succinate and other citric acid cycle intermediates were tested to find out whether they are insulin secretagogues. Monomethyl succinate stimulated insulin release from pancreatic islets in a concentration-dependent manner with maximal release attained at a concentration of 10 mM. Dimethyl succinate (10 mM) was as effective as monomethyl succinate, but pyruvate methyl ester, monoethyl succinate, and dimethyl fumarate were ineffective as primary secretagogues. However, dimethyl fumarate potentiated both leucine- and leucine-plus-glutamine-induced insulin release. Glucose, leucine, leucine plus glutamine, and monomethyl succinate increased inositol tris-, bis- and monophosphate formation in pancreatic islets and antimycin A inhibited this formation. Since mitochondrial metabolism is probably essential for glucose-induced insulin release and the metabolism of succinate and leucine (without or with glutamine) involves mitochondrial respiration exclusively, these results might indicate that mitochondrial metabolism generates conditions or factors that are transmitted to the cytosol to increase inositol trisphosphate formation and thus calcium mobilization and insulin release. Since succinate is believed to enter metabolism at site II of the mitochondrial respiratory chain, it is interesting that rotenone, an inhibitor of NADH dehydrogenase and site I of the respiratory chain, was a potent inhibitor of monomethyl succinate-induced insulin released. Rotenone also inhibited leucine (plus or minus glutamine)-induced insulin release. These results indicate that beta cell metabolism of monomethyl succinate and leucine, like glucose, influences dehydrogenases that produce NADH.

Animals↗
PubMed1989

A rapid ELISA for measuring insulin in a large number of research samples.

An enzyme-linked immunosorbent assay (ELISA) for insulin was developed. Anti-insulin antibody was bound to the bottom of 96-well microtiter plates. Insulin conjugated to beta-galactosidase was used as a label and methyl umbilliferyl beta-D galactoside was used as an enzyme substrate. To estimate insulin, relative fluorescence was measured with a fluorescent microtiter plate reader. Unknowns from an insulin release experiment yielded results comparable to those obtained with our enzyme-immunoassay (EIA) and a conventional radioimmunoassay (RIA). The insulin ELISA is suitable for research purposes in which samples contain solutions of physiological salts and albumin, but not for samples containing serum. The insulin ELISA is as sensitive as the insulin RIA and has several advantages over the standard insulin RIA. These include (1) avoidance of hazards and inconvenience of handling radioactivity, (2) not requiring a separate test tube for each sample, (3) stability of the enzyme-labeled insulin (greater than 18 months), (4) short time period required for the assay (less than 6 hours), and (5) the possibility of long-term storage (at least 3 months) of antibody-coated microtiter plates.

Animals↗
PubMed1989

Activation of cellular p21ras by myristoylation.

p21ras is palmitoylated on a cysteine residue near the C-terminus. Changing Cys-186 to Ser in oncogenic forms produces a non-palmitoylated protein that fails to associate with membranes and does not transform NIH 3T3 cells. To examine whether palmitate acts in a general way to increase ras protein hydrophobicity, or is involved in more specific interactions between p21ras and membranes, we constructed genes that encode non-palmitoylated ras proteins containing myristic acid at their N-termini. Myristoylated, activated ras, without palmitate (61Leu/186Ser) exhibited both efficient membrane association and full transforming activity. Unexpectedly, we found that myristoylated forms of normal cellular ras were also potently transforming. Myristoylated c-ras retained the high GTP binding and GTPase characteristic of the cellular protein and, moreover, bound predominantly GDP in vivo. This implied that it continued to interact with GAP (GTPase-activating protein). While the membrane binding induced by myristate permitted transformation, only palmitate produced a normal (non-transforming) association of ras with membranes and must therefore regulate ras function by some unique property that myristate does not mimic. Myristoylation thus represents a novel mechanism by which the ras proto-oncogene protein can become transforming.

Acylation↗
PubMed1989

Epidemiology of insulin dependent diabetes before age 20 in Wisconsin, with particular reference to seasonality.

Physicians in the State of Wisconsin were contacted by mail and asked to report all cases of diabetes in patients under 20 yr diagnosed between 1 July 1982 and 30 June 1984 in order to study factors associated with seasonality in insulin-dependent diabetes mellitus (IDDM). Wisconsin's population is fairly homogeneous and is primarily middle socioeconomic class, small-town or rural, and of northern European Caucasian descent. The incidence of IDDM in winter was higher than in summer during the first year of the study, similarly to results of other studies. However, there was no significant winter peak in diagnosis during the second year. When monthly incidence rates from both years were combined, the increased evidence of IDDM in winter vs. summer was evident in males, but not in females. There appeared to be a spike in the number of new cases of IDDM in the first year of the study which was more evident in males. Such a spike is consistent with spikes in the incidence of IDDM occurring about the same time in Europe and in North America. The percentage of patients with antibody titres to Coxsackie virus and mycoplasma pneumoniae diagnosed during the first winter's peak were equal to those in nondiabetic controls. The distributions of HLA DR types of patients diagnosed in winter were no different from diabetics diagnosed in other seasons. The distribution of HLA DR types (5% DR2, 55% DR3, 82% DR4 and 38% DR3DR4) were similar to those of other groups of Caucasian subjects with IDDM. Also similarly to other studies of IDDM, 14% of the patients had thyroid microsomal antibody titers. The results of this study support the previously-advanced idea that winter might precipitate overt carbohydrate intolerance in individuals in whom insulin cell destruction is already well established (Diabetes, 36, 265-268, 1987). If this is true, studies of seasonality in IDDM might not be informative about the causation of IDDM.

Adolescent↗