The various faces of diabetes in the young: changing concepts.

Diabetes included several disorders associated with hyperglycemia. A difference in inheritance between the families of juvenile-onset- and maturity-onset-type diabetics, provides evidence for genetic heterogeneity. Heterogeneity of insulin responses to glucose was foung among nonobese patients with maturity-onset-type diabetes. Prospective studies in young patients have shown that glucose intolerance may not progress for as long as 22 years and that subnormal insulin responses to glucose have not decreased further, up to 12 years. However, patients who progressed to diabetes requiring insulin had insulin responses that were subnormal or below the control mean. None whose insulin responses exceeded this mean have decompensated. Thus, insulin response to glucose has prognostic implications. A tentative classification of diabetes in the young is proposed. There was a significant correlation between muscle capillary basement membrane width and known duration of carbohydrate intolerance.

Feasibility of adjustment of insulin dose by insulin-requiring type II diabetic patients.

Type II (non-insulin-dependent) diabetes accounts for most of the diabetes morbidity and expense, yet no systematic study of the effects of intensification of treatment by such patients who require insulin treatment has been conducted. Therefore, patients were recruited from our diabetes clinics, and by random assignment, experimental and control groups were created (n = 26 and 27, respectively) that were not different at 0 mo regarding 20 demographic, physiological, and treatment variables. Experimental patients practiced an algorithm for adjustment of insulin dosage based on daily prebreakfast capillary blood glucose (CBG) measurements and any symptomatic hypoglycemia. At 2-, 4-, and 6-mo visits, records of CBG measurements were available to the physicians (n = 7), who changed insulin dosages of both groups ad libitum. Feasibility of the experimental treatment is evidenced by study completion by 87% of enrollers, monitoring on 88% of days, accuracy of CBG recording (recorded as percentage of memory meter value, 100.8), weight gain not exceeding that of control subjects, practice of treatment algorithm to effect changes in insulin dosage, modest increase in frequency of mild insulin reactions, and a decrease of glycosylated hemoglobin into the normal range.

A prospective study identifying risk factors for discontinuance of insulin pump therapy.

OBJECTIVE: To identify characteristics of adult patients at baseline associated with duration of subsequent, continuous, subcutaneous infusion of insulin treatment (pump therapy) of type I diabetes. RESEARCH DESIGN AND METHODS: For 6 wk, patients followed a standardized conventional therapy and kept a record of insulin dosages, capillary blood glucose concentrations, and symptomatic hypoglycemia. They were then hospitalized. Additional baseline data were obtained and pump therapy was started. Survival analysis was used to determine the relationship between baseline independent variables or risk factors and duration of pump therapy, which is the dependent variable. RESULTS: Of the 68 participants, 33 (49%) terminated pump therapy after an average of 9.9 mo of treatment. Two models (each P < 0.00005) were developed that exhibited a high degree of consistency. Of the 6 variables, 5 were common to both models (HbA1, autonomic neuropathy, mean amplitude of glycemic excursions, frequency of symptoms of hypoglycemia when blood glucose was < 70 mg/dl, and erythema at injection sites). The sixth variable in model 1 (insulin dosage) was replaced in model 2 by a variable, Adult Self-Efficacy for Diabetes, which was obtained on the 33 more recently enrolled patients; this variable related to patient perceptions of self-care behaviors. CONCLUSIONS: We found that, at baseline, the presence of a high concentration of HbA1 and a low estimation by the patient of their ability to treat the disease portend failure of insulin pump therapy as evidenced by its discontinuation. This effect is accentuated when clinical evidence of autonomic neuropathy is observed. These findings offer guidance in selecting patients with type I diabetes for insulin pump therapy.

The effect of adrenergic receptor blockade on the exercise-induced rise in pancreatic polypeptide in man.

The effect of adrenergic receptor-blocking agents upon plasma levels of human pancreatic polypeptide (hPP), human GH (hGH), immunoreactive insulin, and glucose during graded submaximal exercise was ascertained in six healthy nonobese males. Subjects exercised from 0--27 min on a motor-driven treadmill and received infusions from -10 to 40 min of either 1) saline, 2) saline plus phentolamine (0.5 mg/min; alpha-adrenergic blockade), or 3) propranolol (3 mg) from -10 to -5 min, followed by saline plus propranolol (0.08 mg/min; beta-adrenergic blockade). During saline-exercise, mean plasma hPP rose from a mean (+/-SE) basal level of 45 +/- 11 to 149 +/- 51 pg/ml at 27 min, whereas with phentolamine-exercise, the maximal level reached by mean plasma hPP (305 +/- 28 pg/ml) was significantly greater than that with saline (P less than 0.05). During propranolol-exercise, mean plasma hPP did not rise significantly above the basal level. The incremental area under the hPP curve for phentolamine-exercise also was significantly greater than that for saline-exercise or propranolol-exercise. The changes in plasma hGH during and after saline-exercise correlated with those of hPP, but the effects of phentolamine and propranolol upon exercise-induced increases in hGH were opposite to the effects upon hPP. The exercise-induced fall in immunoreactive insulin was accentuated with propranolol and abolished with phentolamine. It is concluded that 1) submaximal exercise stimulates secretion of hPP and hGH, 2) adrnergic mechanisms participate in exercise-induced increased secretion of hPP (beta-adrenergic stimulation augments secretion and alpha-adrenergic stimulation inhibits secretion), and 3) adrenergic effects which modulate exercise-induced secretion of hPP and insulin are in parallel but are opposite to those that modulate the secretion of hGH.

Insulin, proinsulin, glucagon and gastrin in pancreatic tumors and in plasma of patients with organic hyperinsulinism.

Insulin, proinsulin, glucagon and gastrin were determined in extracts of tumors of 27 patients with pancreatic islet cell neoplasia of pancreas, in one patient with nesidioblastosis, in extracts of uninvolved portions of the pancreas in 11 of the tumor patients and of 15 control pancreases. Mean insulin concentration in solitary adenomas and in adenomas of patients with adenomatosis was higher than in control pancreases; however, in all but 1 patient the insulin concentration in neoplastic islet tissue was lower than in islet tissue of control pancreas, assuming islet volume is 1% of pancreas. The percentage of proinsulin was elevated in 52% of tumors. Adenoma insulin content correlated with increments of plasma insulin after tolbutamide administration. Insulin and proinsulin concentrations in pancreas uninvolved by tumor were not suppressed. Fasting plasma glucagon was elevated in patients with islet cell adenomatosis and in patients with islet cell carcinoma some of whom had multiple endocrine adenomatosis. The mean concentration of glucagon in tumors was lower than in control pancreases. Elevated concentration of gastrin was found in some adenomas. The data indicate: 1) insulin-secreting islet cell tumors have decreased storage capacity for insulin, 2) elevated concentration of proinsulin in tumors may be due to decreased capacity to store insulin and in some to decreased conversion of proinsulin to insulin as well, 3) tolbutamide stimulates the exaggerated release of a relatively constant fraction of insulin stored in adenomas. 4) solitary adenomas may contain excess amounts of pancreatic hormones in addition to insulin, 5) elevated plasma glucagon in patients with organic hyperinsulinism may indicate malignancy, microadenomatosis or multiple endocrine adenoma syndrome, and 6) chronic hyperinsulinism and hypoglycemia due to adenoma do not suppress insulin and proinsulin content of uninvolved pancreas.

Effect of age on fasting plasma levels of pancreatic hormones in man.

The effect of age and adiposity on fasting plasma levels of pancreatic polypeptide (HPP), glucagon (IRG), insulin (IRI) and glucose was examined in 263 healthy subjects between the ages of 20-69 yr. Mean plasma levels of hPP rose continuously from the third through the seventh decades. Mean plasma levels of IRG rose within the third and fourth decades but failed to rise further thereafter. Mean plasma levels of IRI did not change with age. Mean plasma levels of glucose rose by approximately 2 mg/dl . decade. The correlations of age with hPP, IRG, glucose, and adiposity were 0.47, 0.35, 0.25 (all P less than 0.01) and 0.15 (P less than 0.05), respectively. When adjustments were made for adiposity, the correlations of age with hPP, IRG, and glucose remained. Adiposity correlated with IRI, IRG, and glucose but when age correction was made, only the correlation of adiposity with IRI persisted. We conclude that: 1) age has a significant effect on fasting plasma levels of hPP and IRG; 2) the patterns of the age-related changes in hPP and IRG are not the same, suggesting that there are differences in the mechanism(s) by which age influences plasma levels of these two pancreatic hormones; and 3) age should be considered in the interpretation of fasting plasma levels of hPP and IRG.

Sex difference in the sensitivity of the human pancreatic polypeptide cell to autonomic nervous stimulation in man.

We have examined the plasma human pancreatic polypeptide (hPP) response to beta-adrenergic (infusion of epinephrine-phentolamine), vagal cholinergic, (insulin-hypoglycemia), and extravagal cholinergic (secretion infusion) stimulation in healthy, nonobese, age-matched males and females. beta-Adrenergic stimulation caused a rise in plasma hPP concentration in males that was 6 times that of females, whereas there were no differences between the sexes in the mean responses of pulse rate, systolic and diastolic blood pressure, or in plasma concentrations of glucose, insulin, and glucagon. Extravagal cholinergic stimulation caused increases of hPP secretion that were similar in males and females. Insulin-induced hypoglycemia was the most efficacious stimulus, and caused a similar rise in hPP response in males and females. Thus, in males there is greater sensitivity of the hPP cell to beta-adrenergic stimulation than females. The plasma hPP responses appear to be a more sensitive, discriminating index of adrenergic autonomic function than cardiovascular and other pancreatic hormonal responses.

Multiple endocrine neoplasia type I: assessment of laboratory tests to screen for the gene in a large kindred.

We measured multiple components of serum or plasma in 221 members of a kindred with familial multiple endocrine neoplasia type 1 (FMEN1). The kindred showed typical features of FMEN1; the FMEN1 gene could be traced through 7 generations with 74 members identifiable as gene carriers. Between family screening in 1981 and completion of our study in 1985, we identified 16 previously unscreened members as carriers of the FMEN1 gene. The earliest age at diagnosis of FMEN1 was 17. The tests with the greatest yield of abnormal results among carriers of the FMEN1 gene were albumin-adjusted calcium, PTH, gastrin, and (in females) prolactin. The following tests provided little or no use in identifying carriers: prolactin (in males), pancreatic polypeptide, glucagon, glicentin, insulin, growth hormone, motilin, and somatostatin. Primary hyperparathyroidism was the commonest expression of the FMEN1 gene; the gene penetrance for this trait increased from near 0% before age 15 to near 100% after age 40. It appeared prior to development of serious morbidity from hypergastrinemia or hyperprolactinemia. All 42 co-operating members who were alive and expressing the FMEN1 gene in 1984 showed active or treated primary hyperparathyroidism. Primary hypergastrinemia had a prevalence below half of that for primary hyperparathyroidism at all ages and was not diagnosed in the absence of primary hyperparathyroidism. Primary hyperprolactinemia was still less prevalent than primary hypergastrinemia. It was limited almost exclusively to females.

Quality of life activities associated with adherence to insulin infusion pump therapy in the treatment of insulin dependent diabetes mellitus.

The impact of continuous subcutaneous insulin infusion (CSII) pump therapy on patients' activities of daily living and the prevalence of acute complications were examined in order to characterize patients' experience while on CSII, and to ascertain whether any of these factors could be associated with continued use of CSII. Fifty-one of 55 patients (93%) identified as initiating CSII in our medical center patient population completed retrospective surveys; 37 individuals (73%) were still using pumps and 14 individuals (27%) had discontinued pump use. CSII appeared to affect the quality of daily activities only modestly, neither improving nor interfering with many activities to any great degree. Activities associated with greatest improvements were eating, working, traveling, sleeping, and exercising. Results of logit analyses adjusting for duration of pump therapy indicated that the prevalence of six different acute complications (skin infections at the needle site, mild insulin reactions, more severe insulin reactions requiring assistance, hypoglycemic coma, asymptomatic hypoglycemia, and ketoacidosis) was not statistically associated with patients' decisions to continue or to stop CSII. In contrast, significant differences (p less than 0.05) between the groups continuing and discontinuing CSII were found in 11 of 18 activities of daily living. In general, patients continuing CSII, in contrast to those discontinuing CSII, found that many of their activities were improved significantly during pump therapy. There were few differences between groups in the degree to which CSII was perceived to interfere with daily activities. However, those continuing CSII found it significantly less necessary to take the pump off while doing some activities than did those discontinuing CSII.(ABSTRACT TRUNCATED AT 250 WORDS)

Secretion of pancreatic polypeptide in man in response to beef ingestion is mediated in part by an extravagal cholinergic mechanism.

The effect of atropine, a muscarinic cholinergic blocking agent, on the response of plasma pancreatic polypeptide (hPP) to the ingestion of beef was investigated. Six healthy subjects ingested 250 g broiled ground beef on three occasions. After beef ingestion alone, the expected biphasic plasma hPP response was observed. On the two other occasions atropine (intravenous bolus followed by infusion) was begun either at 4 or 60 min after the beginning of beef ingestion so as to coincide with the early (first) and late (second) phases of hPP response to beef ingestion. On both occasions plasma hPP concentrations returned rapidly to baseline. Mean integrated incremental hPP responses in the absence of atropine were 9.1 +/- 3.4 ng min ml-1 for the first phase (0-40 min) and 29.7 +/- 5.7 ng min ml-1 for the second phase (60-180 min); with atropine at 4 min, respective responses were 0.8 +/- 0.9 and -1.0 +/- 1.3 ng min ml,-1 and with atropine at 60 min they were 10.6 +/- 5.0 and 1.3 +/- 1.6 ng min ml.-1 After atropine administration, the half-time of disappearance of hPP from the circulation was 4-6 min, suggesting the complete cessation of stimulated hPP secretion. We conclude that the mechanisms of both the early and late phases of beef meal-stimulated release of hPP involve muscarinic cholinergic-neural transmission. The portion of the second (late) phase response which has been shown to persist after truncal vagotomy must be mediated by a cholinergic mechanism which is extravagal in character.

Release of human pancreatic polypeptide and gastrin in response to intraduodenal stimuli: a case report.

A recent clinical case afforded an opportunity to study the effects of duodenal stimulation on plasma human pancreatic polypeptide and gastrin concentrations, independent of gastric stimulation. A distension stimulus was provided by rapid injection of 100 ml of water and saline via a T-tube into an isolated duodenal afferent limb. In a third experiment, the saline contained 200 pg/ml of heptadecapeptide human gastrin. Within 2 min after each injection, a rapid rise in circulating human pancreatic polypeptide levels appeared that fell promptly towards basal thereafter. Injections of 100 ml of Flexical, a supplemental tube feeding, resulted in a biphasic human pancreatic polypeptide response, the initial peak comparable to that seen following distension with water, saline, or saline containing gastrin, and a second peak of much greater magnitude and duration followed the initial peak. Plasma gastrin concentrations were not influenced following any of the stimuli. Duodenal distension alone may induce an early transient increase in plasma human pancreatic polypeptide concentrations, while intraduodenal nutrients per se may induce a later increment of greater magnitude and duration.

Delayed vaccination does not improve antibody responses in splenectomized rats experiencing hypovolemic shock.

Delayed vaccination after splenectomy has been shown to increase the antibody response in normotensive rats. The purpose of this experiment was to study the effect of timing of vaccination on antibody responses in rats undergoing splenectomy and experiencing hypovolemic shock. Sixty male Sprague-Dawley rats weighing 250 to 400 g underwent either a sham abdominal surgery or splenectomy after a 30-minute period of controlled hypovolemic shock. All rats then received pneumococcal vaccinations one day, 7 days, or 28 days postoperatively. Antibody levels were determined by enzyme-linked immunosorbent assay 3 weeks after vaccination. Results were compared by analysis of variance. Animals vaccinated one day postoperatively had similar or higher antibody responses than did rats receiving delayed vaccinations after 7 or 28 days. These results were similar for immunoglobulins G and M and more importantly were consistent for animals undergoing splenectomy and sham operations. Delayed vaccinations failed to improve antibody responses when hypovolemic shock preceded splenectomy. We propose that this is the result of complex cytokine responses to hypovolemic shock. These responses have been studied extensively in the setting of septic shock but not in the setting of hypovolemic or hemorrhagic shock.

Improved antibody responses to delayed pneumococcal vaccination in splenectomized rats.

Pneumococcal vaccination following splenectomy is widely used as prophylaxis against overwhelming postsplenectomy infection. There remains controversy however, over the timing of vaccination. We hypothesized that delaying vaccination would increase the antibody response. Pneumococcal vaccinations were given at designated intervals to rats that had undergone either a sham abdominal surgery or splenectomy. Sixty male Sprague-Dawley rats, 250 to 400 g, were divided into three groups for vaccination: I, 1 day postoperatively; II, 7 days postoperatively; and III, 28 days postsplenectomy/sham. Serum antibody levels were then determined by enzyme-linked immunosorbent assay at 5 and 21 days after vaccination. Immunoglobulin (Ig) levels after delayed vaccination at 1 week postoperatively and 1 month postoperatively were significantly higher than levels from rats vaccinated 1 day postoperatively. IgM levels after vaccinations 1 week and 1 month postoperatively were also significantly higher than levels of rats vaccinated 1 day postoperatively (P < 0.05 for both IgG and IgM). On the basis of these results, we conclude that delaying vaccination after splenectomy enhances antibody responses.

Effectiveness of a foot care education program on attitudes and behaviors of staff nurses.

The purpose of this study was to determine differences in nurse attitude and clinical practice following a foot care education program. In a survey completed after the program, 23 nurses reported that they had less difficulty touching a smelly foot (p less than .02), that they would be less bothered by a foot with an odor (p less than .03), that they would have less difficulty touching an unsightly foot depicted in a slide (p less than .03), and that they felt less anger at patients who don't follow recommendations (p less than .03). The nurses also expressed more belief that patients quickly forget important information (p less than .03) and that if patients knew the effects of their poor health habits they would change (p less than .02). Ninety-one percent of the RN sample reported that their foot assessment and care practices had changed as a result of the program.