Changes in cognitive and social functioning of diabetic patients following initiation of insulin infusion therapy.

Functional health outcomes resulting from intensive insulin regimens may differ depending upon the age of the diabetic patient. This study tested the hypothesis that health functioning is poorer for younger insulin-dependent diabetic (IDDM) patients following a change to the insulin infusion pump regimen, with progressive improvements occurring in functional health status at higher age levels. Thirty IDDM patients aged 10-47 years were administered health status instruments prior to changing to the new regimen, and again six months later. The instruments assessed physical, cognitive, psychological, and social health functioning. When compared at six months to an age-matched control group on conventional insulin therapy, declines in social activities were found for younger insulin pump patients, with improvements occurring linearly as age increased. Lower performance levels were also found for the younger patients in Conceptual Quotient (CQ), an indicator of cognitive functional status, with progressive improvements with age through the early 30s. However, corresponding declines in function occurred at the oldest age levels. Adaptation to an intensive diabetes regimen appears to be more difficult at younger and older age levels.

Acute complications associated with the use of insulin infusion pumps.

Because insulin pump therapy is capable of providing insulin both at a slow continuous basal rate and in boluses, it more closely approximates physiologic insulin secretion than is possible with other methods of insulin administration. However, several short-comings are specifically related to the way insulin is delivered by pumps. These include increased risk of diabetic ketoacidosis and increased likelihood of infection at injection sites. The risk of hypoglycemic coma is apparently no greater with pump therapy than with conventional injections. Health professionals using pump therapy need a good working knowledge of the technical details as well as of the risks and benefits, and must be prepared to provide comprehensive training to their patients, particularly in the practice of frequent self-monitoring of blood glucose levels.

Flocculation and loss of potency of human NPH insulin.

In late 1986, several vials of Humulin N (NPH human insulin, recombinant DNA origin) came to our attention because of a clumped, white coating on the inside of the vials. To determine the frequency of this phenomenon, we surveyed 100 consecutive patients who used Humulin N. Ten patients had encountered 21 vials of flocculated insulin in the previous 12 mo, reflecting an incidence of 1 per 72 vials. Insulin drawn from affected vials was markedly reduced in potency: 20.9 +/- 3.4 U/ml vs. the labeled potency of 100 U/ml. Several patients reporting flocculated insulin, including one hospitalized with ketoacidosis, experienced unusual and unexplained elevation in blood glucose concentration for several days before flocculation was observed. Patients who use NPH human insulin should be aware of this phenomenon and carefully inspect their vials for evidence of insulin precipitation before each injection.

Factors related to discontinuation of continuous subcutaneous insulin-infusion therapy.

To determine the factors related to discontinuation of continuous subcutaneous insulin-infusion (CSII) therapy in patients with insulin-dependent diabetes mellitus, we analyzed clinical data from a group of 177 patients followed for up to 5 yr. Fifty-one (29%) of the patients made a decision to terminate CSII during the study. Of the clinical characteristics present before the onset of treatment with an insulin pump, the most important variable to predict a future decision to terminate CSII was pregnancy, followed by female gender. In addition, there was a greater percentage of smokers, single or divorced patients, and patients with a history of treatment for mental illness in the dropout group, although none of these differences was statistically significant. There was no correlation between discontinuation of CSII and age, duration of diabetes, or prepump concentrations of HbA1c. Events occurring during CSII were also analyzed for predictive value. Patients who discontinued CSII had a higher incidence of ketoacidosis and a lower incidence of hypoglycemic coma while using a pump. The most common reason reported by patients for terminating CSII therapy, cited by 24 (47%) of the 51, was discomfort, irritation, or infection at the infusion site.

Malfunction of continuous subcutaneous insulin infusion systems: a one-year prospective study of 127 patients.

Malfunction of portable continuous subcutaneous insulin infusion (CSII) systems may result in either ketoacidosis or serious hypoglycemia. To determine the types and frequencies of infusion system failure and the resulting clinical consequences, we recorded their occurrences in a 1-yr prospective study of 127 patients who were using insulin infusion pumps in a clinical practice setting. Of the 127 patients, 109 (86%) experienced at least one infusion system failure during the study. Most of the infusion system failures (96%) occurred in the syringe, infusion tube and connections, or subcutaneous infusion site. Virtually all malfunctions resulted in interruption of insulin flow, and most were associated with temporary loss of diabetes control. Equipment malfunction was documented in 6 of 7 patients who used insulin pumps and were treated in our hospital for diabetic ketoacidosis during the study. Pump "runaway" was not observed. We conclude that infusion system malfunction resulting in interruption of insulin flow is a common occurrence, is often associated with temporary hyperglycemia, and may account for some of the increased incidence of diabetic ketoacidosis previously described in these patients.

Long-term metabolic control with insulin pump therapy. Report of experience with 127 patients.

To determine the long-term efficacy of insulin-pump therapy, we analyzed trends in glycosylated hemoglobin concentrations in 127 patients with Type I diabetes using insulin pumps for periods ranging from 13 to 47 months. In the first year of pump therapy the average glycosylated hemoglobin concentration improved in 83 per cent of the patients, as compared with the value before pump therapy. Although only 11 of the 127 subjects had normal glycosylated hemoglobin values before pump therapy, 33 had a normal average value during the first full year of pump use (P = 0.0001). This favorable trend persisted for the three-year duration of the study. Seventeen of the 19 patients who subsequently discontinued insulin-pump therapy had improved glycosylated hemoglobin values during the period of pump use. Eleven of the 19 patients remained available for follow-up study; the glycosylated hemoglobin concentration became worse in 7 when they returned to conventional treatment. We conclude that the improvement in metabolic control repeatedly demonstrated in short-term studies with the insulin pump can be maintained for a period of years.

Complications of insulin pump therapy: the effect of insulin preparation.

Complications of insulin infusion pump therapy include ketoacidosis related to interruption of insulin delivery and infected infusion sites. To determine if the type of insulin used in insulin pumps is a factor influencing these complications, we compared the occurrence of inflammation and infection at infusion sites and obstruction of infusion tubing in a 6-mo crossover study of 28 patients using two different insulin preparations. The use of buffered purified pork insulin was associated with less infusion site inflammation (P = 0.0039) and infusion set obstruction (P = 0.0215) than use of unbuffered beef-pork insulin. Infected infusion sites occurred less often with buffered pure pork insulin than with unbuffered beef-pork insulin, but the difference was not statistically significant. We conclude that the type of insulin selected for use in insulin pumps influences the occurrence of adverse reactions to insulin pump therapy: buffered purified pork insulin is associated with less infusion site inflammation and infusion set obstruction than unbuffered beef-pork insulin.

Acute complications associated with insulin infusion pump therapy. Report of experience with 161 patients.

We determined the frequency of acute complications associated with insulin pump therapy in 161 insulin-dependent patients followed up for a total of 2,978 patient-months. Diabetes control improved substantively with pump therapy, but 42% of the patients experienced one or more acute complications while using insulin pumps. Infected infusion sites, ketoacidosis, and hypoglycemic coma occurred once in every 27, 78, and 175 patient-months, respectively. More patients experienced ketoacidosis after the onset of pump therapy than in an equivalent interval immediately before the onset of pump therapy. Ketoacidosis also occurred in more patients using pump therapy than in a comparison group of 165 patients receiving conventional insulin injections surveyed during an equivalent period. The frequency of hypoglycemic coma was not significantly changed by pump therapy.

Clinical use of the insulin infusion pump in 100 patients with type I diabetes.

We investigated the efficacy of insulin-pump therapy in insulin-dependent diabetics, aged 18 to 69 years, by comparing the metabolic control achieved in 100 patients using this technique with that previously obtained by conventional insulin therapy. Patients were followed during pump therapy for as long as 15 months. Fasting and nonfasting blood glucose levels (mean +/- S.E.M.) decreased from 201 +/- 6 and 213 +/- 6 mg per deciliter (11.2 +/- 0.3 and 11.8 +/- 0.3 mmol per liter), respectively, to 158 +/- 5 and 145 +/- 3 mg per deciliter (8.77 +/- 0.3 and 8.05 +/- 0.2 mmol per liter) after one month of pump therapy (P less than 0.001). Ninety-three patients had improved blood sugar control; 71 per cent had a mean blood sugar concentration of 150 mg per deciliter (8.3 mmol per liter) or less after six months. Glycosylated hemoglobin values became normal in 44 per cent of 88 patients who had follow-up determinations. In over 500 patient-months there were four episodes of ketoacidosis and five episodes of serious hypoglycemia. Three patients abandoned pump therapy. We conclude that insulin-pump therapy is acceptable to patients and that it can be successfully applied to clinical practice and large-scale research studies.

Hypothalamic function in men with hypogonadotrophic hypogonadism.

To determine whether hypothalamic function is normal in patients with idiopathic gonadotrophin deficiency, nine men with this syndrome were studied. Water conservation after overnight dehydration, thermoregulatory response to a cold (10 degrees C) environmental stress and prolactin secretion following chlorpromazine stimulation were investigated. In response to dehydration, maximal urinary osmolality was 1058 +/- 135 mOsm/kg (mean +/- SD) and no patient showed further increase after exogenous vasopressin administration. The patients responded to the cold stimulus by vigorous shivering and maintained their core body temperatures. Basal concentrations of prolactin which were 12.7 +/- 4.6 ng/ml increased by 15 ng/ml following Thyrotrophin-releasing hormone in six of seven men tested, indicating normal pituitary reserve. Prolactin concentrations doubled in seven of eight men who received chlorpromazine. All responses were indistinguishable from those of normal men. While a diminished secretion of gonadotrophin releasing hormone by the hypothalamus remains the most plausible cause of idiopathic gonadotrophin deficiency, our data indicate that the associated functions tested are intact in men with this syndrome.

Delayed pituitary hormone response to LRF and TRF in patients with anorexia nervosa and with secondary amenorrhea associated with simple weight loss.

The qualitative and quantitative responses of LRF-induced LH and FSH release and TRF-induced TSH and Prolactin (PRL) release were evaluated in 21 patients with anorexia nervosa, 19 patients with secondary amenorrhea associated with simple weight loss (SWL) who did not fulfill the psychologic criteria for anorexia nervosa, and 7 normal women in the early follicular phase of the menstrual cycle. Basal plasma LH and FSH were significantly lower in the anorexia nervosa group compared to the SWL group and normals (P less than 0.05). The LRF-induced integrated LH responses, however, were the same in the 3 groups and the integrated FSH responses were greater in the underweight groups when compared to normal. The time of the peak LH response (mean+/-SE) was signifantly delayed (P less than 0.01) in both the anorexia nervosa (49 +/- 6.1 min) and SWL (28 +/- 2.5 min) groups when compared to normal (17 +/- 2.3 min). The time of the FSH response was significantly delayed (P less than 0.05) in anorexia nervosa (95 +/- 9.6 min) when compared to normals (35 +/0 7.9 min) and SWL patients (62 +/- 11.7 min). Normal basal TSH and PRL and normal peak TSH and PRL responses to TRF were found in anorexia nervosa. The time of the TSH and PRL peak (56+/-8.9 and 36+/-3.6 min,, respectively) in anorexia nervosa was significantly later than normal (26 +/- 1.7 and 36 +/- 3.6 min respectively) (P less than 0.01). It is concluded that despite normal quantitative response to releasing hormones, there are abnormally delayed responses in both anorexia nervosa and SWL patients. The SWL responses were intermediate between those of the anorexia nervosa group and normals. The constellation of normal quantitative but abnormal kinetic LRF and TRF responses supports the hypothesis that the endocrine changes seen in anorexia nervosa are consistent with hypothalamic dysfunction.

Regulation of FSH secretion: use of hydroxyurea to deplete germinal epithelium.

Hydroxyurea, a chemotherapeutic agent that prevents mitosis by inhibiting DNA synthesis, was administered to adult male rats for 70 days. Plasma FSH and LH showed no systematic trend although severe germinal cell depletion was produced. These data suggest that the cell(s) of the seminiferous tubule involved in FSH regulation must be either the type A spermatogonium or the Sertoli cell.

Metabolism of 125 I-luteinizing hormone-releasing hormone.

PIP: With the use of prepared iodine-125-monoiodo-LH-RH, the disappearance rates of LH-RH (luteinizing hormone-releasing hormone) in man and in the rat were investigated, as well as the distribution of LH-RH in the rat. After 10 microcuries of iodine-125-LH-RH were injected as an iv bolus into 3 male volunteers, blood samples from the opposite arm were obtained through an indwelling venous catheter at 2, 5, 8, 11, 15, 20, 30, 45, and 60 minutes postinjection and at 6 and 24 hours postinjection. To describe the disappearance curve a 3-term exponential equation was necessary and sufficient. The ranges of the t1/2s for the first, second, and third components were 2-4 minutes, 30-55 minutes, and starting at more than 10 hours. The initial distribution space was 3-4.7 1 or 37-47 ml/kg body weight. Similar procedures in the rat (45) resulted in an equation with 2 exponentials, with the ranges of the t1/2s for the first and second components being 5-10 minutes and 150-600 minutes. In both man and rat the distribution volume approximated estimated plasma volume. Following the injection of iodine-125-LH-RH in the rat, pituitary radioactivity increased, as expected, reaching a maximum tissue/serum ratio of 1.5 at 90 minutes. 2 iodinated oligomers of LH-RH were found to have different disappearance rates and distributions in the rat than did iodine-125-LHrh. the disappearance rate of iodine-125-LH-RH in this study is consistent with values for other small peptide hormones.^ieng