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The distributions of light and tissue oxygenation (S

The University of Rochester's Graduate Experience in Science Education (GESE) course familiarizes biomedical science graduate students interested in pursuing academic career tracks with a fundamental understanding of some of the theory, principles, and concepts of science education. This one-semester elective course provides graduate students with practical teaching and communication skills to help them better relate science content to, and increase their confidence in, their own teaching abilities. The 2-h weekly sessions include an introduction to cognitive hierarchies, learning styles, and multiple intelligences; modeling and coaching some practical aspects of science education pedagogy; lesson-planning skills; an introduction to instructional methods such as case studies and problem-based learning; and use of computer-based instructional technologies. It is hoped that the early development of knowledge and skills about teaching and learning will encourage graduate students to continue their growth as educators throughout their careers. This article summarizes the GESE course and presents evidence on the effectiveness of this course in providing graduate students with information about teaching and learning that they will use throughout their careers.

To compare the efficacy and safety of ciprofloxacin 0.3%/dexamethasone 0.1% (CIP/DEX) otic suspension with that of neomycin 0.35%/polymyxin B 10,000 IU/mL/hydrocortisone 1.0% (N/P/H) otic suspension in patients with acute otitis externa (AOE).Randomized, observer-masked, parallel-group, multicenter study. Patients were randomized to 7 days treatment with either CIP/DEX 3-4 drops twice daily or N/P/H 3-4 drops three times daily.Patients of either sex and older than 1 year, with a clinical diagnosis of mild, moderate, or severe AOE and intact tympanic membranes were recruited to participate.Signs and symptoms of AOE, including ear inflammation, tenderness, edema and discharge (assessed on Days 3, 8 [End-of-Therapy] and 18 [Test-of-Cure]); microbiologic eradication (presumed or documented); and frequency of adverse events.Patients enrolled numbered 468. In culture-positive patients who met the inclusion criteria (N = 396), clinical cure rates at Day 18 were significantly higher with CIP/DEX than with N/P/H (90.9% vs. 83.9%; p = 0.0375), as were microbiologic eradication rates (94.7% vs. 86.0%; p = 0.0057). In addition, the clinical response was significantly better with CIP/DEX than with N/P/H at Days 3 and 18 (p = 0.0279 and p = 0.0321, respectively), as was the reduction in ear inflammation at Day 18 (p = 0.0268). Both preparations were well tolerated in pediatric and adult patients.7 days treatment with CIP/DEX otic suspension administered twice daily is clinically and microbiologically superior to N/P/H otic suspension administered 3 times daily in the treatment of mild to severe AOE, and is equally well tolerated.

Objective. To determine the efficacy and safety of topical ciprofloxacin/dexamethasone otic suspension compared with ofloxacin otic solution in the treatment of acute otitis media with otorrhea through tympanostomy tubes (AOMT) in pediatric patients. Methods. This multicenter, prospective, randomized, observer-masked, parallel-group study was conducted at 39 sites in 599 children aged ≥6 months to 12 years with an AOMT episode of ≤3 weeks’ duration. The mean age of patients was 2.5 years (standard deviation: 2.37 years). Patients received either ciprofloxacin 0.3%/dexamethasone 0.1% otic suspension 4 drops twice daily for 7 days or ofloxacin 0.3% otic solution 5 drops twice daily for 10 days. Clinical signs and symptoms of AOMT were evaluated at clinic visits on days 1 (baseline), 3 (on therapy), 11 (end of therapy), and 18 (test of cure). A patient diary was used to measure time to cessation of otorrhea. Principal pretherapy pathogens included Streptococcus pneumoniae (16.8%), Staphylococcus aureus (13.0%), Pseudomonas aeruginosa (12.7%), Haemophilus influenzae (12.4%), S epidermidis (10.2%), and Moraxella catarrhalis (4.1%). Results. Ciprofloxacin/dexamethasone is superior to ofloxacin for clinical cure (90% vs 78%) and microbiologic success (92% vs 81.8%) at the test-of-cure visit, produces fewer treatment failures (4.4% vs 14.1%), and results in a shorter median time to cessation of otorrhea (4 days vs 6 days). Ciprofloxacin/dexamethasone treatment is also superior to improvement in clinical response by visit, absence of otorrhea by visit, and reduction of otorrhea volume by visit. Both topical otic preparations are safe and well tolerated in pediatric patients. No change in speech recognition threshold or decrease in hearing from baseline, based on audiometric testing, was noted with either regimen. Conclusion. Topical ciprofloxacin/dexamethasone treatment is superior to topical ofloxacin in the treatment of AOMT.

Ciclosporin-induced noninsulin-receiving remissions in insulin-dependent diabetes mellitus are associated with enhancement of beta-cell function. Patients in remission show virtually no insulin responses to parenteral glucose, contrasting with substantial responses to mixed meals, indicating effects of nonglucose nutrients and/or enteroinsular mechanisms. Remission is associated with normal insulin sensitivity; loss of insulin sensitivity can lead to relapse. The risks of the treatment call for studies with lower doses, and it is argued that a continuing search for immunomodulatory interventions that enhance and preserve the clinical remission-phase characteristics should be pursued.

The effect of secretin on forearm metabolism (muscle compartment) was examined in the presence of low and high concentrations of insulin. Continuous infusions (30 min. duration) of secretin 12 ng/min. (SEC), insulin 160 ng/min. (INS) or these doses of insulin and secretin together (INS + SEC) were delivered into the brachial arteries of normal volunteers. SEC alone was without significant effect on forearm metabolism. INS as previously reported, stimulated glucose and potassium uptake and inhibited the output of some amino acids from the deep venous bed. The two hormones together (INS + SEC) increased maximum lactate (p less than 0.025) and alanine output (p less than 0.005) beyond that observed with INS alone. A marked calcium output occurred (p less than 0.001) with the combined infusion which was not observed with either hormone alone. Potassium metabolism with INS + SEC was similar to that observed with INS alone. These results suggest that these two hormones, acting in concert, stimulate glycolysis and net calcium efflux. This joint action of insulin and secretin may have a physiological role in the immediate postprandial period.

The effects of general and extradural anaesthesia on glucose tolerance and plasma cortisol concentration in the surgical patient were assessed. Normal glucose tolerance and insulin release were observed under extradural anaesthesia, whereas general anaesthesia produced decreases in both glucose tolerance and insulin release. The plasma cortisol concentration was increased in both groups. These results indicate possible nutritional advantages in conducting surgery under extradural anaesthesia.

As part of a multicenter trial, 70 individuals with insulin-dependent diabetes were randomized to either conventional insulin therapy (CIT) or continuous subcutaneous insulin infusion (CSII). In order to standardize patient selection in the six participating centers, one of the eligibility criteria was the demonstration that each patient had no residual endogenous insulin secretion as assessed by plasma C-peptide determinations. The patients were of average (± SEM) age of 33.0 ± 1.6 yr, had had diabetes for a mean (±SEM) duration of 17.4 ± 1.1 yr, and had both fasting and postglucagon stimulation C-peptide values of

Responses of plasma immunoreactive gastric inhibitory polypep-tide (IRGIP) to oral triglycéride or galactose were compared in normal and mildly diabetic (non-insulin-dependent) subjects. After triglyceride the responses of IRGIP were similar, but after galactose those of the diabetics were slightly exaggerated. Both stimuli evoked increments of plasma immunoreactive glucagon (IRG) in diabetics but not in normal subjects. Plasma immunoreactive insulin (IRI) did not change. In normal subjects given oral triglyceride or galactose followed by intravenous (I.V.) glucose the early-phase response of plasma IRI was enhanced and glucose tolerance improved. In the diabet-ics, oral triglyceride did not affect insulin release or glucose tolerance after I. V. glucose; oral galactose elicited a slight increase of insulin release without improving glucose tolerance. In the diabetics the rise in plasma IRG after ingestion of triglyceride or galactose was maintained after I. V. glucose. It is concluded that endogenous GIP is insulinotropic and that there is partial resistance to this action in diabetes. The results were compatible with feedback inhibition of GIP secretion by insulin and with the suggestion that the rise of plasma IRG associated with secretion of GIP in diabetics may be due to the glucagono-tropic action of this peptide.

Gastric inhibitory polypeptide (GIP) is insulinotropic and is released after ingestion of glucose in normal man. Changes in plasma immunoreactive gastric inhibitory polypeptide (IRGIP) were therefore studied during a 50-gm. oral glucose tolerance test in 10 normal subjects and 20 subjects with maturity-onset diabetes mellitus. The diabetics were nonobese and treated by diet alone; they exhibited exaggerated increments of plasma IRGIP in association with delayed and diminished peak increases in plasma immunoreactive insulin, suggesting relative failure of the beta-cell response to GIP. The diabetic subjects also showed a paradoxk rise in mean plasma immunoreactive glucagon, with a peak coinciding with that of plasma IRGIP. It is suggested that the defective beta-cell response may lead to diminished feedback inhibition of GIP secretion by insulin in diabetes mellitus and that the glucagonotropic action of GIP may be expressed under these conditions.

Control of glycemia by means of continuous subcutaneous infusion of insulin (CSII) was examined in insulin-dependent diabetes mellitus (IDDM). A battery-powered portable infusion pump was employed to deliver insulin at a constant basal rate designed to maintain plasma glucose within the normal range in the postabsorptive state, and empirically determined supplementary infusions of insulin were delivered before meals by the same system with the objective of maintaining excursions of plasma glucose within the normal range during absorption of a meal. The effects of CSII were compared with those of optimized conventional treatment using twice daily injections of mixed intermediate-acting and crystalline insulins in the same groups of volunteers in short term (1 wk) studies in hospital and in longer term (1 to 7 mo) studies with unrestricted activity under normal conditions after leaving hospital. The control of glycemia obtained with CSII in hospital was closely approximated by optimized conventional treatment under these conditions. In studies in hospital, continued infusion of insulin by the CSII program at basal rates with omission of meals and with vigorous exercise did not result in hypoglycemia. Abrupt cessation of CSII for 12 h overnight resulted in moderate ketoacidosis, which was rapidly corrected on resumption of insulin infusion. After the subjects were discharged from hospital, their mean postabsorptive plasma glucose concentrations and mean excursions of plasma glucose after ingestion of meals were maintained within normal limits with CSII but not with optimized conventional therapy. The control of glycemia with CSII was associated with significant reduction of daily dose of insulin by comparison with conventional treatment. During CSII, plasma free immunoreactive insulin (IRI) concentrations were in the normal range in the postabsorptive state. The supplementary doses of insulin before meals with the CSII program were shown to be essential for control of glycemia and were associated with dose-related increments of plasma free IRI, which were detectable within 15 min of delivery, rose to peaks at between 60 and 90 min, and declined to baseline at between 3 and 4 h. It is concluded that the management of IDDM by CSII is effective and safe and provides normalization of mean diurnal plasma glucose concentration through prolonged unrestricted activities under everyday conditions. The treatment can be maintained by the unaided subject and permits the undertaking of long term studies of its effects on the complications of diabetes mellitus.

Continuous subcutaneous insulin infusion (CSII) has been compared with conventional insulin injection treatment (CIT) supplemented by self-monitoring of capillary blood glucose (SMBG) in 18 nonobese adults with insulin-dependent diabetes mellitus (IDDM). Mean daily insulin dosage and rates of hypoglycemia were similar during CSII (duration of treatment 36 ± 2 wk mean ± SE) and CIT (31 ± 1.6 wk). On the basis of fasting C-peptide concentrations and postintravenous glucagon increments of < 0.1 pmol/ml, subjects were classified C-peptide negative (CP NEG) (N = 11), or C-peptide positive (CP POS) (N = 7). Relative to CIT, CP NEG subjects on CSII had significant decreases in premeal/bedtime and postmeal plasma glucose concentrations and glycosylated hemoglobin (percent of total). CP POS patients during each of CSII and CIT showed glycemic responses equivalent to those of CP NEG patients on CSII. In neither group could results be explained on the basis of improved beta cell function. Thus, therapeutic advantage of CSII was not apparent in IDDM adults retaining significant C-peptide activity.

The rates of incorporation in vitro of glucose carbons into carbon dioxide and glyceride-glycerol and fatty acids by specimens of omental adipose tissue obtained from patients undergoing elective surgery were studied in the absence and presence of insulin. The basal (absence of insulin) activity for each parameter of glucose metabolism in the individual specimens correlated significantly with the insulin-stimulated increments. The glucose metabolism of specimens of subcutaneous adipose tissue, obtained under local anesthesia from normal volunteers in the fasting state and after ingestion of a standard breakfast, was also studied. In the absence of added insulin the incorporation of the glucose carbons into glyceride-fatty acids was consistently greater in specimens obtained after feeding, but incorporation into carbon dioxide and glyceride-glycerol was not significantly increased. In the presence of maximally effective amounts of insulin, there was no significant difference between the elevated rates of incorporation of glucose carbons into carbon dioxide and glyceride-glycerol and fatty acids between the specimens obtained before and after feeding. It was concluded that feeding did not enhance the maximal capacity for lipogenesis in adipose tissue. The modest increase in glyceride-fatty acid production in specimens obtained after feeding was probably due to effects of endogenous insulin. A hypothetical rate of lipogenesis from glucose derived from these data suggests that the production of fatty acids from glucose in human adult adipose tissue occurs on a very small scale relative to the intake of carbohydrate in normal man.

To examine the effects of long-term elevation of plasma gastric inhibitory polypeptide (GIP), the responses to parenteral (PA) or enteral (EA) alimentation were studied in consciousrats with duodenal and venous cannulae. A weight-maintaining liquid diet (84% as glucose, 16% as amino acids) was infused at a constant rate for 6 days by either route, and daily blood samples were taken. A subset of animals receiving PA also received porcine GIP with the infusate (PA plus GIP; plateau plasma immunoreactive GIP, IRGIP, 610 ± 120 pg/ml). With PA, plasma IRGIPdid not change from basal levels, whereas with EA IRGIP rose to virtual plateau levels (mean 530 ±110 pg/ml). In the steady state, plasma immunoreactive insulin (IRI) was significantly lower with EA (mean, 153 ± 5 μU/ml) than with PA (mean, 226 ± 15 μU/ml), which in turn was lower than with PA plus GIP (mean, 375 ± 23 μU/ml, P < 0.001 by ANOVA). A similar ranking of plasma glucose levels occurred in the steady state, with means of 113 ± 7 (EA), 126 ± 3 (PA), and 184 ± 9 (PA plus GIP) mg/dl (P < 0.001 by ANOVA). To assess the response to transient hyperglycemia in the steady state, an intravenous glucose bolus was given to each group on the fifth day. Peak plasma IRI levels did not differ among the three groups; however, the glucose disappearance rate was significantly slower with PA plus GIP compared with either EA or PA. Assuming that porcine GIP did not stimulate glucose production, this peptide appeared to induce hyperinsulinemia with insulin resistance during parenteral alimentation. The contrasting features of relatively low glucose and insulin levels during enteral alimentation associated with high levels of endogenous IRGIP in the blood suggest either (1) that the findings depend on variations of GIP or its actions in the different species, or (2) that mechanisms originating in the intestine act to preserve insulin sensitivity during absorption of nutrients from the gut under physiologic conditions.

In 68 newly diagnosed patients with insulin-dependent diabetes mellitus (IDDM) whose treatment included cyclosporin (CyA) the prevalence and mean titre of islet cell cytoplasmic antibodies (ICA) fell faster than they did in the 56 who received only insulin. However, in the CyA-treated patients the prevalence or titre of ICA at diagnosis did not correlate with beta-cell function as measured by glucagon-stimulated C-peptide levels; improvement and recovery of beta-cell function after 30 days of CyA therapy occurred despite the continued presence of ICA; and CyA-induced remission of IDDM (ie, glucagon stimulated plasma C-peptide levels greater than 0.6 pmol/ml) was not predicted by nor coincident with disappearance of ICA. Therefore, although CyA therapy was associated with a higher than expected frequency of remission and faster disappearance of ICA, the two observations were not temporally and may not be causally related. ICA should not be used to identify the target population for or to predict response to immunosuppressive therapy. The contribution of ICA to the pathogenesis of beta-cell destruction in IDDM needs serious re-examination.

Out of 524 tumours of the ovary seen over a 20 year period, the diagnosis was that of a thecal tumour in 14 cases. In addition to the symptoms common to all ovarian tumours, in 7 cases there was metrorrhagia, including 4 post-menopausal. Vaginal cytology after the menopause was abnormally young in 6 cases. In 7 cases out of 13 the endometrium was hyperplasic. In only 5 cases were urinary oestrogen levels increased. At operation, the tumour was bilateral in 3 cases and ascites was present in 4. Histological findings were as follows: 6 thecomas, 4 fibro-thecomas, 1 luteinised thecal tumour, 3 tumours with granular cells and 1 case associated with a Brenner tumour. Two of these "mixed tumours" were malignant, with a fatal outcome. All the others were cured by operation. In young women in whom conservative procedures were used there were 4 subsequent pregnancies. The following questions were posed: The coexistence of ascites with tumours totally free of secretory cells (3 cases); The existence in true thecal tumours of signs of hyperoestrogenism (5 out of 6) whilst fibro-thecomas are not associated with any abnormal production of oestrogen.

The results of epidemiological and clinical studies of diabetes in man and of studies of experimental diabetes in animals provide strong evidence: (1) that insulin-dependent diabetes mellitus is due to absolute or severe deficiency of insulin; (2) that replacement treatment with insulin is potentially capable of normalizing the metabolic abnormalities; and (3) that normalization of the metabolic abnormalities can be expected to prevent or ameliorate the complications of the disease. However, consideration of the problems involved in replacement treatment with insulin raises practical and physiological questions regarding the appropriate patterns and routes of delivery of the hormone. Studies with glucose-controlled automatic infusion systems delivering into systemic or portal vessels point to the question whether the homeostatic mechanism can be viewed as one dominated by the responses of the endocrine pancreas to glucose. Nevertheless, empirical studies with non-glucose-controlled portable programmed infusion systems delivering insulin by intravenous, subcutaneous, or intraperitoneal routes have suggested that these techniques can produce near-normoglycemia under everyday conditions in a high proportion of insulin-dependent diabetic subjects. The blood levels of biologically active insulin resulting from these treatments are not higher, and may be lower, than those with conventional depot injection therapy. It appears also that the results of intensive depot injection therapy making use of 3 or 4 injections day-1 of crystalline and intermediate-acting insulins can approximate the effects of insulin infusion treatment. It is argued that the intensive insulin treatment regimens with continuous or intermittent use of the subcutaneous route of delivery can be viewed as options in the management of insulin-dependent diabetes mellitus when adequate supervision and monitoring is available, and that clinical systems fulfilling these conditions must be provided.

The binding of 125I-insulin was determined using erythrocytes obtained from 11 subjects with Type I diabetes mellitus treated with continuous subcutaneous infusions of insulin for 1 year or more. The binding characteristics were compared to those for erythrocytes isolated from 12 normal subjects and 10 subjects with Type I diabetes mellitus treated with conventional daily injections of insulin. The total binding of 125I-insulin, receptor concentration, and high and low affinity binding constants were estimated using washed erythrocytes obtained from fasted subjects. The mean total specific binding for subjects treated with continuous subcutaneous infusion did not differ from that for conventionally treated diabetic subjects but was slightly lower than that for normal subjects at p less than 0.05. Receptor concentration did not vary significantly between the groups. High and low affinity binding constants were slightly lower in the group treated with continuous subcutaneous infusion. Both basal and diurnal plasma levels of free immunoreactive insulin were slightly but significantly elevated in both groups of diabetic subjects compared to that in normal subjects. Thus, in spite of the greater biological effectiveness of the continuous insulin infusion program in terms of glycemic control, the insulin-binding parameters, as well as the estimates of plasma free immunoreactive insulin levels, are consistent with modest and comparable degrees of hyperinsulinemia with both treatments.

Previous work has shown enhanced aggregation and thromboxane synthesis by platelets from diabetic subjects. We have compared thromboxane synthesis by platelets from normal subjects with that of platelets from two groups of insulin-dependent diabetic patients: one group receiving conventional depot insulin therapy and the other continuous subcutaneous insulin infusions. Thromboxane synthesis was significantly higher with platelets from the conventionally-treated diabetic patients than that observed for control subjects. Patients on continuous insulin infusions were similar to control subjects. This group of patients also had better control of glycemia. The effect on thromboxane production might be related to normalization of plasma lipids which occurs with continuous infusion insulin therapy.

The effect of cyclosporine (Cyclosporin A) on insulin binding to erythrocytes was investigated in Type 1 diabetes mellitus of recent onset. The subjects were drawn from a pilot study (The Canadian Open Study on the effects of immunosuppression with Cyclosporine in Type 1 Diabetes Mellitus) in which 50% of the patients demonstrated remission during one year of cyclosporine administration. Specific binding of 125I-insulin was examined before and after 3, 6, or 12 months of cyclosporine in different groups of patients. Those who maintained target control of blood glucose without exogenous insulin for two or more weeks were designated non-insulin requiring. Basal and intravenous glucagon-stimulated immunoreactive plasma C-peptide rose in all groups but to higher levels in non-insulin requiring groups. Insulin binding at tracer concentration, reflecting the number of insulin receptors, was initially normal but tended to decrease with duration of cyclosporine administration. This decrease was significant especially in groups which remained insulin-requiring throughout the study. The affinity of erythrocyte receptors was assessed by determining the insulin concentration required for 50% inhibition of 125I-insulin binding, the ID50. These values suggested that the affinity of insulin receptors was not affected in subjects attaining non-insulin requiring remission; however, in subjects remaining dependent on exogenous insulin, receptor affinity appeared to be adversely affected. Even in subjects who demonstrated complete remission, affinity was decreased during periods of dependence on exogenous insulin. After discontinuation of cyclosporine for one month or more, the mean daily insulin dosage increased and plasma C-peptide decreased. Insulin binding at tracer concentration was not affected but the apparent affinity was decreased after withdrawal of cyclosporine. These results suggest that insulin action at the receptor may be affected by the administration of cyclosporine. The number of insulin receptors appears to be decreased but whether this effect has an impact on insulin sensitivity remains to be seen. Receptor affinity appears to be affected mainly by exogenous insulin. Thus immunosuppression with cyclosporine in newly diagnosed Type 1 diabetes mellitus may have a modest adverse effect on insulin receptors; whether the benefits of cyclosporine treatment outweigh this risk is difficult to assess.

Eighteen lean adult volunteers with insulin-requiring diabetes mellitus attempted to achieve normoglycemia using continuous subcutaneous insulin infusion (CSII) or conventional insulin therapy (CIT) in a randomized crossover trial of 68 +/- 2.5 weeks (mean +/- SEM) duration. As reported (Diabetes Care 8: 447-55, 1985) the group with absent to low beta-cell function (C-peptide negative, n = 11) attained mean post-absorptive normoglycemia only during CSII vs CIT (p less than 0.05). Only following CSII was this without change in post-absorptive serum triglyceride concentrations (-4 +/- 5.6 vs 12 +/- 4.7 mg/dl; -0.04 +/- 0.6 vs 0.14 +/- 0.05 mM, p less than 0.05) or body weight (0.01 +/- 0.02 vs 0.05 +/- 0.01 kg/week, p less than 0.05). In the group with glucagon stimulated serum C-peptide 100-400 pmol/L (C-peptide positive) responses to CSII or CIT were equal. As total daily insulin dosage (0.05 +/- 0.04 U/kg/day) was the same under all conditions, to explain the efficacy of CSII, glucoregulatory hormone responses were examined. Pre- and post-test breakfast serum free immunoreactive insulin and plasma glucagon concentrations were essentially unaffected by C-peptide or treatment status. Erythrocyte 125I-insulin binding was decreased in the C-peptide negative group only during CSII (8.6 +/- 0.5 vs 10.1 +/- 0.7%, p less than 0.005); C-peptide positive group receptor binding was consistently low (8.2 +/- 0.8, 8.4 +/- 0.9%). During CIT using intermediate-acting insulin post-lunch peripheral venous insulin failed to rise (p less than 0.05), but in the C-peptide positive group, on the basis of C-peptide responses to breakfast an undetected rise and fall of portal venous insulin was assumed to coincide with each meal. Thus, only during CIT in the C-peptide negative group, which received on average 6.4/wk/subject fewer pre-meal regular insulin boluses (p less than 0.01), was the frequency of meal-related change in portal insulinemia decreased. Consistent meal-related fluctuations in portal insulinemia inherent in CSII hepatocytes sensitized by a post-receptor mechanism to the suppressive effects of insulin on glucose output and thus were indirectly responsible for the observed improvement in glycemic control and lipid metabolism in the C-peptide negative group.

In a group of 55 insulin-dependent diabetic patients with early diabetic retinopathy, microaneurysm counts from fluorescein angiograms were related to the level and severity of retinopathy derived by grading eight standard stereo color photographs as used in the Early Treatment of Retinopathy Study (ETDRS). All patients were studied at 0, 8, and 24 months. Significant correlations were present between both "definite" and "possible" microaneurysm count and retinopathy level of the eye studied and the mean retinopathy level of the two eyes, at all three time intervals, (P less than 0.05-less than 0.001). Similarly, there were significant correlations between microaneurysm counts and severity of the following lesions: microaneurysms and haemorrhages, cotton-wool spots (P less than 0.05-less than 0.001); to a lesser degree, severity of hard exudates (P less than 0.1-less than 0.001) and intraretinal microvascular abnormalities (P not significant-less than 0.001). There was no correlation between microaneurysm count and venous abnormalities (as at no time were there more than 11 eyes with any venous abnormality). We conclude that microaneurysm counts from fluorescein angiograms accurately reflect the severity of important signs in early diabetic retinopathy.

In this brief review of regulatory function of gastroenteropancreatic peptides in control of intermediary metabolism in normal and diabetic states, with and without mediation by insulin and/or glucagon, a variety of possible mechanisms have been described. It is apparent that the pharmacologic actions of the peptides identified in various locations provide models for multiple routes of delivery and modes of action of effectors in this control system. Examples already exist of each of the hypothetical mechanisms illustrated in the scheme in Figure 4. It is clear that a great deal of study will be necessary in identification of the active agents and assessment of their importance in the physiology of intermediary metabolism. With respect to the possible pathophysiologic roles of regulatory peptides of the gastroenteropancreatic system other than insulin and glucagon, a number of considerations of Type I and Type II diabetes have been raised. The balance of the evidence suggests that Type I diabetes may be viewed as an insulin deficiency syndrome, so that physiological replacement with insulin may be expected to result in correction of the metabolic abnormalities. Nevertheless, the difficulty of physiologic replacement treatment, which may call for portal delivery of insulin, is well recognized, and abnormalities secondary to insulin deficiency even in "well-treated" Type I diabetes may be compounded by the effects of gastroenteropancreatic peptides other than insulin, exerted through the various mechanisms discussed. In Type II diabetes mellitus, current understanding of the pathophysiology is much less complete and no convincing description of the etiology exists. The various metabolic actions of the gastroenteropancreatic peptides, and their interactions with other endocrine, paracrine and nervous regulatory mechanisms, represent a dauntingly complex control system. The elucidation of this system can provide fertile ground for the development and testing of hypotheses for the pathophysiology of disordered metabolism in Type II diabetes mellitus.

Effects of intravenous (IV) infusion of secretin during IV infusion of glucose were examined in normal men. Secretin was administered according to three schedules: with each schedule a comparable priming dose was delivered in the first minute, but this was followed by a maintained (120 min) infusion of secretin at a relatively high rate, or by maintained infusion at one-third that rate, or by brief (15 min) infusion at the lower rate. The lower infusion rate produced increments in secretin in the blood within the range attainable during endogenous secretion. By comparison with effects of glucose alone each secretin infusion enhanced the increments of immunoreactive insulin in the blood. Enhancement of the early release (0–5 min) of insulin was similar with each type of secretin infusion, but the integrated changes in insulin levels through the total infusion period were related to the total doses of secretin. With each dose of secretin glucose tolerance was improved but the three mean glucose curves observed during infusions of secretin were not distinguishable from one another in spite of widely different integrated insulin responses. Secretin did not modify suppression of immunoreactive glucagon or free fatty acids in the blood during hyperglycemia. The results suggest that the effect of continuous administration of secretin on glucose tolerance is not simply related to its integrated insulinotropic action. It is suggested that the effect may be highly dependent on enhancement of insulin secretion early in the response to glycemia, or that it may be due to effects of secretin on glucose production or disposal which are not mediated by insulin.