Receptor and postreceptor defects contribute to the insulin resistance in noninsulin-dependent diabetes mellitus.

We have assessed the mechanisms involved in the pathogenesis of the insulin resistance associated with impaired glucose tolerance and Type II diabetes mellitus by exploring, by means of the euglycemic glucose-clamp technique, the in vivo dose-response relationship between serum insulin and the overall rate of glucose disposal in 14 control subjects; 8 subjects with impaired glucose tolerance, and 23 subjects with Type II diabetes. Each subject had at least three studies performed on separate days at insulin infusion rates of 40, 120, 240, 1,200, or 1,800 mU/M2 per min. In the subjects with impaired glucose tolerance, the dose-response curve was shifted to the right (half-maximally effective insulin level 240 vs. 135 microunits/ml for controls), but the maximal rate of glucose disposal remained normal. In patients with Type II diabetes mellitus, the dose-response curve was also shifted to the right, but in addition, there was a posal. This pattern was seen both in the 13 nonobese and the 10 obese diabetic subjects. Among these patients, an inverse linear relationship exists (r = -0.72) so that the higher the fasting glucose level, the lower the maximal glucose disposal rate. Basal rates of hepatic glucose output were 74 +/- 4, 82 +/- 7, 139 +/- 24, and 125 +/- 16 mg/M2 per min for the control subjects, subjects with impaired glucose tolerance, nonobese Type II diabetic subjects, and obese Type II diabetic subjects, respectively. Higher serum insulin levels were required to suppress hepatic glucose output in the subjects with impaired glucose tolerance and Type II diabetics, compared with controls, but hepatic glucose output could be totally suppressed in each study group. We conclude that the mechanisms of insulin resistance in patients with impaired glucose tolerance and in patients with Type II noninsulin-dependent diabetes are complex, and result from heterogeneous causes. (a) In the patients with the mildest disorders of carbohydrate homeostasis (patients with impaired glucose tolerance) the insulin resistance can be accounted for solely on the basis of decreased insulin receptors. (b) In patients with fasting hyperglycemia, insulin resistance is due to both decreased insulin receptors and postreceptor defect in the glucose mechanisms. (c) As the hyperglycemia worsens, the postreceptor defect in peripheral glucose disposal emerges and progressively increases. And (d) no postreceptor defect was detected in any of the patient groups when insulin's ability to suppress hepatic glucose output was measured.

Glucose and insulin responses to oral glucose in overt non-insulin-dependent diabetics with and without the islet cell antibody.

Plasma insulin, glucose, and insulin/glucose responses to a 50-g oral glucose tolerance test (OGTT) were compared in 14 islet cell antibody (ICAb) positive non-insulin-dependent diabetics (NIDDM), 14 matched ICAb negative NIDDM, and 14 ICAb negative nondiabetic controls. Both groups of NIDDM exhibited marked carbohydrate intolerance with insulinopenia. Despite having significantly higher plasma glucose concentrations during the study, the ICAb positive NIDDM had significantly lower insulin levels, and thus lower insulin/glucose ratios, than the ICAb negative NIDDM both in the fasting state and in response to the OGTT. Similarily, ICAb positive NIDDM had higher integrated glucose responses (delta G), lower integrated insulin responses (delta I), and lower delta I/delta G values than ICAb negative NIDDM. Three ICAb negative and seven ICAb positive NIDDM subsequently required insulin treatment. These findings show that ICAb positive NIDDM suffer from a greater disturbance of B-cell function than do matched ICAb negative NIDDM.

The acute and chronic effects of sulfonylurea therapy in type II diabetic subjects.

Although sulfonylurea agents have been used in the clinical management of type II diabetes (non-insulin-dependent diabetes mellitus, NIDDM) for over two decades, the mechanisms responsible for their hypoglycemic action remain controversial. We have quantitated glycemic control, endogenous insulin secretion in response to mixed meals, adipocyte insulin binding, insulin-mediated peripheral glucose disposal, and basal hepatic glucose output in 17 type II diabetic subjects before and after 3 mo of therapy with the second-generation, sulfonylurea compound glyburide in an attempt to identify the factors responsible for the clinical response to the drug. In addition, 9 subjects were treated for an additional 15 mo to see if the response to the drug changed with time. The mean fasting serum glucose level fell from an initial value of 264 +/- 17 mg/dl to 178 +/- 16 mg/dl after 3 mo of drug therapy. Endogenous insulin secretion increased in all subjects, but the increase was most marked in those subjects who continued to exhibit fasting hyperglycemia (fasting serum glucose greater than 175 mg/dl) after 3 mo of therapy. Adipocyte insulin binding was unchanged after 3 mo of therapy, while the maximal rate of peripheral glucose disposal was increased by 23%, indicating enhancement of peripheral insulin action at a postreceptor site(s). Basal hepatic glucose output showed a significant correlation with the fasting serum glucose level both before and after therapy (r = 0.86, P less than 0.001) and fell from 141 +/- 12 mg/m2/min before therapy to 107 +/- 11 mg/m2/min after 3 mo of therapy.(ABSTRACT TRUNCATED AT 250 WORDS)

In vivo deactivation of peripheral, hepatic, and pancreatic insulin action in man.

The in vivo deactivation of insulin action has been studied in 10 lean, nondiabetic subjects using a modification of the euglycemic glucose clamp technique. Following cessation of 40- and 120-mU/m2/min insulin infusions, the serum insulin levels fell to one-half their initial values (mean +/- SE) of 126 +/- 7 and 350 +/- 14 microunits/ml in 7 +/- 1 and 8 +/- 1 min, respectively. The mean incremental glucose disposal rates (IGDR) fell more slowly following discontinuation of the 40- and 120-mU/m2/min insulin infusions, so that the time required for the IGDRs to fall to one-half their initial values (D50 IGDR) were were 42 +/- 5 and 78 +/- 1 min, respectively. Mean hepatic glucose output was totally suppressed during the 40- and 120-mU/m2/min insulin infusions, remained completely suppressed following cessation of the infusions for 50 and 80 mi, and subsequently returned to basal levels. The times required for the HGOs to return to one-half their basal levels (R50 HGO) were 59 +/- 8 and 119 +/- 6 min, respectively. The times required for insulin action to decrease to one-half the initial values in the periphery (D50 IGDR) and in the liver (R50 HGO) were correlated with the preceding steady-state glucose disposal rates in individual subjects (r = 0.75, P less than 0.001 and r = 0.58, P less than 0.05, respectively). The suppression of endogenous insulin secretion by exogenous insulin infusions was also studied in 4 subjects during a total of 5 euglycemic glucose clamps; the mean basal serum C-peptide level was 0.67 +/- 0.24 pmol/ml before administration of the exogenous insulin, fell to 0.34 +/- 0.17 pmol/ml during the steady-state phase of the study, and remained suppressed throughout the duration of the deactivation phase of the glucose clamp. Residual pancreatic insulin secretory capacity was demonstrated by a rise in the serum C-peptide level to 1.77 +/- 0.50 pmol/ml at 120 min following a standardized meal given at the conclusion of the deactivation phase of the glucose clamp. These results demonstrate that the deactivation of insulin action in the periphery, liver, and pancreas lags behind the disappearance of insulin from the plasma. The mechanisms responsible for this lag in in vivo deactivation are not known for certain, but may include slower clearance of insulin form tissue compartments than form the plasma, the necessity for the target tissues to generate specific deactivation signals, or a slow rate of decay of saturable steps in the cellular activation process.

Pancreatic islet-cell antibodies in diabetes mellitus correlated with the duration and type of diabetes, coexistent autoimmune disease, and HLA type.

In a study of 972 patients with diabetes mellitus, humoral pancreatic islet-cell antibodies (I.C.Ab.) were detected in highest prevalence in insulin-treated diabetics with (38 per cent) and without (22 per cent) associated overt organ-specific autoimmune disease (A.I.D.) where consideration was not given to the duration of diabetes. They were also detected in 8 per cent of diabetics treated with oral hypoglycemic agents (O.H.A.), but not in diabetics requiring diet alone and in only 0.5 per cent of 434 control subjects. Six per cent of 522 patients with overt organ-specific A.I.D. but not diagnosed to be diabetic had I.C.Ab.s. I.C.Ab.s were present in the sera of 2 per cent of 157 first-degree relatives of I.C.Ab.-positive subjects. In insulin-treated diabetics and, to a lesser extent, in diabetics not requiring insulin, the prevalence of humoral I.C.Ab. was strongly dependent of the duration of the diabetes, being 60 per cent during the first year from diagnosis in the insulin-treated group and falling to 20 per cent at two to five years and to 5 per cent at 10-20 years. The prevalence of I.C.Ab. in insulin-treated diabetics showed no correlation with the patient's age at the time of testing when the duration of diabetes was taken into account. Diabetics who did not require insulin for treatment but who were I.C.Ab.-positive showed a significant tendency to subsequently require insulin and to have a higher prevalence of other autoantibodies than insulin-independent diabetics who were I.C.Ab.-negative. Persistence of I.C.Ab. for more than five years from diagnosis of diabetes was associated with coexistent overt organ-specific A.I.D. and with HLA-B8, A1, and A1 + B8.

Lack of in vivo insulin resistance in controlled insulin-dependent, type I, diabetic patients.

Although type I diabetic patients are clearly insulin deficient, it is unclear whether they have normal in vivo sensitivity to insulin. Recent studies which suggested that insulin resistance is a common feature of insulin-dependent diabetics have not taken into account their degree of metabolic control or the presence of circulating antibodies. In the present study, we performed multiple euglycemic glucose clamp studies to construct insulin dose-response curves in 5 well controlled and 5 poorly controlled type I diabetic patients and 21 age-matched normal subjects. Each study was performed on a separate day at insulin infusion rates of 15, 40, 120, 240, or 1200 mU/M2 X min. During the 40 and 120 mU/M2 X min infusions, steady state insulin levels of 96 +/- 8 (+/- SE) and 285 +/- 27 microU/ml respectively, were achieved within 25 min in normal subjects. In contrast, diabetic subjects did not achieve steady state insulin levels (62 +/- 8 and 212 +/- 16 microU/ml) until 90 min of infusion, and insulin antibodies were detectable in the serum of all these patients. The dose-response curve for insulin stimulation of glucose disposal in well controlled diabetic subjects was comparable to that in normal subjects, with half-maximally effective insulin levels of 84 microU/ml in the diabetic patients compared to 70 microU/ml in normal subjects and virtually identical maximal rates of glucose disposal (433 +/- 11 vs. 411 +/- 17 mg/M2 X min in controls). In contrast, the dose-response curve for poorly controlled diabetic subjects was significantly right-shifted (half-maximally effective insulin level, 112 microU/ml), with marked reduction in the maximal glucose disposal rate (324 +/- 25 vs. 411 +/- 17 mg/M2 X min in normal subjects). Basal hepatic glucose output was increased in both poorly controlled and well controlled type I diabetic patients (132 +/- 7 and 101 +/- 16 mg/M2 X min, respectively) compared to normal subjects (76 +/- 7 mg/M2 X min). However, during each insulin infusion, hepatic glucose output was virtually 100% suppressed in all 3 groups.(ABSTRACT TRUNCATED AT 400 WORDS)

Prevalence of subclinical thyroid failure in insulin-dependent diabetes.

A study was made of the distribution of primary thyroid failure, indicated by a raised serum TSH concentration, in 605 (294 males and 311 females) insulin-dependent (type I) diabetics, aged 21-84 yr, not previously suspected of having thyroid disease. The prevalence of a raised serum TSH concentration in females of all ages (17%) was significantly greater (P less than 0.0005) than that in males (6.1%) and increased with increasing age at onset of diabetes (P less than 0.05) and age at time of study (P less than 0.001) in females but not in males. There was no significant difference in the duration of diabetes when comparing patients with normal and raised serum TSH concentrations. The prevalence of a raised TSH concentration in late-onset insulin-dependent diabetics was no greater in patients requiring insulin within 3 months of diagnosis of diabetes than in those exhibiting secondary sulfonylurea failure, who required insulin more than 3 months after diagnosis. In type I diabetes, the prevalence of subclinical primary thyroid failure is considerably greater than has previously been suspected, with female late-onset insulin-dependent diabetics being at the greatest risk.

Successful long-term kidney-pancreas transplants in diabetic patients with high C-peptide levels.

BACKGROUND: Pancreas transplants are rarely done in type 2 (noninsulin dependent) diabetic patients. Most researchers believe that in type 2 diabetic patients, peripheral insulin resistance plays a central role and also is associated with relative insulin deficiency or an insulin secretory defect. This suggests that in patients receiving transplants, the new beta cells will be overstimulated, leading to beta cell "exhaustion" and graft failure. METHODS: Early in our experience, simultaneous pancreas-kidney transplant candidates were selected using only clinical criteria for type 1 diabetes, i.e., early onset of diabetes and rapid onset of insulin use. Pretransplant sera were available for C-peptide analysis in 70 of 94 of those patients. Forty-four percent (31/70) were African American (AA). RESULTS: Thirteen patients (12 AA) with a nonfasting C-peptide level >1.37 ng/ml were identified. In these patients with high C-peptide levels, pancreas and kidney survival rates were 10O%. The results did not differ statistically from the low C-peptide group (< or =1.37 ng/ ml). There were no differences between patient and pancreas-kidney survival rates when the patients were separated into AA and non-AA groups. The follow-up was 1-89 months, with a mean of 45.5 months. CONCLUSIONS: Long-term pancreas graft function is attainable and beta cell "exhaustion" does not occur in patients with high preoperative C-peptide (>1.37 ng/ ml) levels. AA and non-AA patients have equivalent long-term patient, kidney, and pancreas-kidney graft survival rates.

Prednisolone metasulphobenzoate foam retention enemas suppress the hypothalamo-pituitary-adrenal axis.

BACKGROUND: Corticosteroid enemas represent effective treatment for ulcerative proctitis, but absorption into the systemic circulation may have undesirable metabolic consequences. Prednisolone metasulphobenzoate, a lipophobic corticosteroid derivative, is designed to be absorbed poorly through the recto-sigmoid mucosa, but the effects of foam enema preparations upon the hypothalamo-pituitary-adrenal axis have not been examined. METHODS: Nine patients suffering from active ulcerative proctitis underwent four weeks of therapy with prednisolone metasulphobenzoate foam enemas. The hypothalamo-pituitary-adrenal axis, defined using the modified single-dose metyrapone test, glucose homeostasis and lipid profiles were studied before and after treatment. RESULTS: The hypothalamo-pituitary-adrenal axis was significantly depressed after the treatment period; mean stimulated plasma cortisol concentration fell from 384 +/- 244 (s.d.) to 288 +/- 252 nmol/L, P < 0.02; stimulated mean plasma 11-deoxycortisol concentration fell from 677 +/- 333 to 407 +/- 326 nmol/L, P < 0.01. Mean fasting plasma glucose, insulin, C-peptide, fructosamine and triglyceride concentration were unchanged, whilst the mean serum cholesterol concentrations rose from 5.6 +/- 1.1 to 6.0 +/- 1.2 mmol/L (not significant). CONCLUSION: Prednisolone metasulphobenzoate foam enemas have significant systemic and endocrine metabolic effects, which could assume importance with long-term therapy.

Collagen shields exacerbate ulceration of alkali-burned rabbit corneas.

OBJECTIVE: To determine the impact of collagen shields on ulceration of rabbit corneas after alkali burn. METHODS: After a 60-second 2N sodium hydroxide burn to rabbit corneas, 24-hour collagen shields were placed on the corneas daily for 21 days; control corneas did not receive collagen shields. The extent of corneal ulceration was documented daily for 21 days by slit-lamp examination of treated and control eyes. Three separate studies were performed using collagen shields from two commercial sources. RESULTS: In the three studies, corneas in the collagen shield-treated eyes began to ulcerate sooner than those in the control group; the corneas in collagen shield-treated eyes also began to perforate sooner. At 21 days after alkali injury, the mean (+/- SE) corneal ulceration score in the collagen shield-treated rabbits was 4.1 +/- 0.17 (descemetocele formation) compared with 2.7 +/- 0.28 (midstromal ulceration) in controls. This difference was significant at P < .005. CONCLUSION: Collagen shield treatment results in marked acceleration of corneal ulceration and perforation after alkali injury.

Serum alpha 2-macroglobulin levels in diabetes.

Serum alpha 2-macroglobulin levels have been determined in diabetic patients by quantitative radial immunodiffusion and compared with those observed in age- and sex-matched controls. In addition, the results in diabetics have been analysed with respect to such variables as the age and sex of the patient, the duration of disease, treatment, control, and the occurrence of retinopathy or nephropathy. The alpha 2-macroglobulin levels in diabetic patients were found to be significantly higher than in age- and sex-matched controls, thus confirming previous observations. However, these differences were most apparent in the more extreme age groups. Multiple regression analysis also revealed that the only variables contributing significantly to the regression apart from age and sex were control and retinopathy.

Platelet and coagulation factors in proliferative diabetic retinopathy.

Plasma beta-thromboglobulin, platelet factor 4, fibrinogen, fibrinopeptide A, antithrombin III, factor VIII related antigen, alpha 2-macroglobulin, platelet count, and total glycosylated haemoglobin were measured in three well matched groups of subjects: non-diabetic controls, diabetics without retinopathy, and diabetics with proliferative retinopathy. beta-thromboglobulin and platelet factor 4 concentrations were significantly higher in the diabetics with retinopathy than in the controls and platelet factor 4 was also increased in the diabetics without retinopathy compared with controls. Fibrinogen concentration was raised in diabetics without retinopathy compared with controls, diabetics with retinopathy compared with controls, and diabetics with retinopathy compared with those without. Fibrinopeptide A concentration did not differ significantly between groups. Antithrombin III levels were increased in diabetics with retinopathy compared with controls, and in diabetics with retinopathy compared with those without. Factor VIII related antigen values were higher in both the diabetic groups when compared with the controls. Fibrinopeptide A concentration correlated with both beta-thromboglobulin and platelet factor 4 in each of the three groups. Haemostatic abnormalities in diabetes have been shown, although a hypercoagulable state has not been confirmed. These changes in platelet and coagulation function may be secondary to the development of microvascular disease and their role in the pathogenesis of retinopathy remains uncertain.

Effect of a glucosidase inhibitor on the metabolic response of diabetic rats to a high carbohydrate diet, consisting of starch and sucrose, or glucose.

The metabolic consequences of the addition of Bay-g-5421 to a diet whose caloric value included 67% carbohydrate, comprising wheat starch (diet A), equal quantities of wheat starch and sucrose (diet B) or glucose (diet C) were studied in lean diabetic and non-diabetic rats. BAY-g-5421 led to a significant (30%) reduction in daily food intake of diabetic and non-diabetic rats fed diets A and B, respectively. In diabetic rats fed diets A and B with Bay-g-5421, daily urinary glucose was diminished ten-fold, while the post-prandial plasma glucose excursions were almost halved. Serum cholesterol, but not triglyceride concentrations, were reduced after five days, by the addition of BAY-g-5421 to diets A or B in non-diabetic rats, and in diabetic rats when the animals fed diets A and B were combined. BAY-g-5421 did not significantly after the food intake, urinary glucose excretion, post-prandial plasma glucose excursions nor serum lipids in diabetic and non-diabetic rats fed diet C. These findings illustrate the therapeutic potential of BAY-g-5421 as an adjunct to the dietary management of diabetes mellitus.

Glycosylated hemoglobin and its temporal relationship to plasma glucose in non-insulin dependent (type 2) diabetes mellitus.

Total glycosylated hemoglobin (HbAI) and random plasma glucose were measured at monthly intervals for 6 mo in 33 non-insulin dependent (type 2) diabetics. The mean HbAI and mean plasma glucose in individual patients over the 6 mo showed a close correlation (p less than 0.001). A significantly higher HbAI (p less than 0.001) for a given plasma glucose was seen in those patients receiving combined chlorpropamide and metformin therapy (n = 14) than in those receiving chlorpropamide alone (n = 19). For each patient correlation coefficients were calculated between plasma glucose and HbAI with time lags of 0.1 and 2 mo. The coefficients with no time lag showed a significant tendency to be positive (p less than 0.01) whereas those with time lags of 1 or 2 mo were not significant. A constant proportional variability of both HbAI and plasma glucose over time was demonstrated, the mean coefficient of variation for HbAI being 8.4 +/- 2.7% and for plasma glucose 22.3 +/- 9.7%. We conclude that HbAI provides an index of plasma glucose control, not during the preceding few months as was previously thought but, during the previous few weeks. In terms of variability from month to month a single HbAI determination was equivalent to approximately the mean of 3 single plasma glucose values.

The prothoracicotropic hormone (PTTH) of the commercial silkmoth, Bombyx mori, in the CNS of the tobacco hornworm, Manduca sexta.

Immunocytochemistry revealed that a Bombyx mori prothoracicotropic hormone (PTTH)-like peptide is expressed by the Manduca sexta big PTTH-producing neurons, the lateral neurosecretory cell group III (L-NSC III). Independent PCR of genomic DNA and a L-NSC III cDNA library yielded products with 99% sequence similarity to the cDNA encoding Bombyx PTTH. This similarity necessitated evaluation of the relationship between Manduca big PTTH and Bombyx PTTH by 1) bioassay of IEF separated Manduca PTTH and 2) direct assessment of Bombyx PTTH biological activity with Manduca prothoracic glands. Together, these studies indicate that Bombyx PTTH and Manduca PTTH are different peptides expressed by the L-NSC III. The possible physiological significance of a Bombyx PTTH-like peptide in Manduca and its coexpression with Manduca big PTTH by the L-NSC III are discussed.

Immunoaffinity purification of the neuropeptide prothoracicotropic hormone from Manduca sexta.

The prothoracicotropic hormones (PTTH) are cerebral peptides that control insect postembryonic development by stimulating the prothoracic glands to synthesize ecdysteroids. Using immunoaffinity chromatography and SDS-PAGE, a 25.5 kDa big PTTH has been purified from Manduca sexta. Based upon SDS-PAGE and Western blot analysis, the native form of big PTTH appears to be a dimer with monomers of 16.5 kDa. Four HPLC-separated fragments of this acidic peptide were sequenced and exhibited no sequence similarity with Bombyx mori PTTH. In agreement with this finding, the basic Bombyx PTTH had no PTTH bioactivity in Manduca. One sequenced fragment of the Manduca PTTH is approximately 70% similar to the vertebrate cellular retinoid binding proteins, suggesting these binding proteins may be present in insects.

HLA antigens and other risk factors in the development of retinopathy in type 1 diabetes.

Factors possibly influencing the development of diabetic retinopathy were studied in 112 randomly selected type 1 diabetics having no or minimal retinopathy (group A) and in 82 type 1 diabetics with known severe diabetic retinopathy. The latter comprised those with severe background retinopathy (group B, n = 17) and those having proliferative retinopathy without (group C, n = 38) and with group D, n = 27) diabetic nephropathy. Nonretinopaths (group A) were of similar sex ratio, body weight, and age at diagnosis of diabetes but had been diabetic longer (p less than 0.001) and were thus older (p less than 0.001) than retinopaths (groups B-D). The distribution of HLA antigens of the A, B, and C loci was similar in nonretinopaths and retinopaths with the exception that HLA B7 showed a reduced (p less than 0.05) prevalence in the retinopaths (6% versus 17%) and was singularly underrepresented in group D, where no patients had this antigen. Mean postprandial plasma glucose and HbA1 concentrations were higher (p less than 0.01 and p less than 0.001) and cigarette smoking was more prevalent (p less than 0.01) in the retinopathy groups B-D than in group A. Systolic and diastolic blood pressures were similar in groups A-C, with higher (p less than 0.001) values only in group D. There was no association between insulin antibody binding in the serum or measurable plasma C-peptide immunoreactivity and retinopathy status. The risk of development of diabetic retinopathy in type 1 diabetes may be related to HLA-associated genetic factors and to cigarette smoking.

Circulating tissue-type plasminogen activator and plasminogen activator inhibitor type 1 in proliferative diabetic retinopathy: a pilot study.

Several haemostatic abnormalities are associated with proliferative diabetic retinopathy. While abnormalities in plasma fibrinolytic activity have been described in diabetic retinopathy, platelets (a rich source of plasminogen activator inhibitor type 1, PAI-1) have received little attention. As a result, little is known about the fibrinolytic potential of circulating whole blood in diabetic retinopathy. The concentrations of tissue-type plasminogen activator (t-PA) and of its fast-acting inhibitor. PAI-1 were measured in plasma from eight patients with type 1 diabetes complicated by proliferative retinopathy, and from eight patients with type 1 diabetes and background or no retinopathy, matched for age, sex and duration of diabetes. The concentration of PAI-1 in platelets was also measured. The ratio of t-PTA to PAI-1 in plasma was significantly higher in patients with proliferative retinopathy than in those without (0.66 vs. 0.37, p < 0.02). The average quantity of PAI-1 per platelet was significantly lower in the group with proliferative retinopathy (0.33 vs. 0.50 ng/10(6) platelets, p < 0.02). These data suggest that among patients with type 1 diabetes, total circulating fibrinolytic potential is higher in those with proliferative retinopathy.

Modulation of chicken plaque-forming cells by serotonin and dopamine.

Serotonin (5-hydroxytryptamine, 5-HT) and dopamine (DA) are endogenous components of the central nervous and endocrine systems of the chicken. To determine the effects of these monoamines on antibody-mediated immunity. New Hampshire chickens of Line UNH 105 were injected intravenously with 5-HT (100 micrograms/kg of body weight) and DA (1 mg/kg of body weight). One milliliter of a 5% SRBC suspension was injected intravenously 30 min later. Both IgM and IgG splenic plaque-forming cells were assayed 5 days after antigen injection. For in vitro studies, spleen lymphocytes from SRBC-primed chicks were incubated with DA and 5-HT followed by quantitation of IgM and IgG plaque-forming cells. The in vivo incubation of splenic lymphocytes with specific antagonists was used to ascertain the presence of monoamine receptors on lymphocytes. The 5-HT significantly enhanced IgM plaque-forming cells compared with controls following in vivo [550 +/- 85 (SE) cells/10(6) splenic lymphocytes versus 359 +/- 44] but not in vitro exposure. The IgG plaque-forming cells were not affected by 5-HT. The DA significantly suppressed IgM plaque-forming cells responses following in vivo (284 +/- 46 versus 499 +/- 66) and in vitro (254 +/- 57 versus 451 +/- 51) exposure. Significant suppression of IgG plaque-forming cells was found in vivo (287 +/- 40 versus 462 +/- 75) and in vitro (153 +/- 36 versus 371 +/- 81) following treatment. Specific DA antagonists, apomorphine and metoclopramide, did not alleviate the in vitro suppressive effect of DA.

Acute myelocytic leukaemia presenting as anergic pulmonary tuberculosis.

This case report describes a patient with anergic pulmonary tuberculosis who presented with pyrexia of unknown origin and vasculitis. He did not exhibit any pulmonary symptoms at his initial presentation and developed acute myelocytic leukaemia, a recognised association, during the subsequent course of his illness.