Autonomic neuropathy and the ventilatory responses of diabetics to progressive hypoxemia and hypercarbia.

To investigate one suggested cause of unexplained deaths of diabetic patients with autonomic neuropathy, ventilatory responses to progressive hypoxemia and to progressive hypercarbia were compared among two groups of diabetic patients, with and without autonomic neuropathy, and a group of normal control subjects. Hypoxemia was induced gradually under isocapnic conditions and the arterial oxygen saturation was reduced to below 75%. In a separate test the end tidal CO2 was increased gradually to 55 mm Hg in subjects who could tolerate this degree of hypercarbia. The ventilatory responses to hypoxemia and to hypercarbia did not differ among groups nor did age, duration of diabetes, or presence of proliferative retinopathy and nephropathy have a significant effect on the ventilatory responses of diabetics. The authors conclude that defective ventilatory responses to hypoxemia or hypercarbia are not associated with the sudden unexplained deaths in diabetics with autonomic neuropathy.

Isolated high serum triiodothyronine levels. Clinical relevance after sodium iodide I 131 therapy.

Ten of 25 thyrotoxic patients treated with sodium iodine I 131 had thyroid function test results that indicated a high triiodothyronine (T3) level, with normal thyroxine (T4) and thyroid-stimulating hormone (TSH) levels, within 15 months of treatment. This pattern was usually transitional and lasted a variable time, eventually leading to euthyroidism, hyperthyroidism, or hypothyroidism. It is concluded that an isolated elevation of T3 levels after radioactive iodine therapy can be associated with any clinical pattern of thyroid function and has no clear prognostic value. No specific treatment is needed for this abnormality.

Clinical resistance to vasopressin. Detection of antibody by hemagglutination.

We describe a patient with hypothalamic diabetes insipidus who after 20 years became refractory to the effect of commercial vasopressin injection. Vasopressin antibodies were measured using a sensitive hemagglutination technique. Resistance was associated with a high titer of antibodies that disappeared once vasopressin therapy was withdrawn and the diabetes insipidus was controlled with chlorpropamide. Antibodies were also measured in four additional patients with diabetes insipidus while they were or were not receiving vasopressin. A patient who had received the drug for only two years already had a substantial titer of antibodies to vasopressin, but in this case the response to the hormone was not impaired.

The young adult with diabetes: impact of the disease on marriage and having children.

To investigate the impact of insulin-dependent diabetes mellitus on marriage and having children we studied 50 young adults (aged 20-35 yr) with onset of the disease less than 20 yr. The subjects studied (37 women and 13 men) included 17 single, 26 married, and 7 divorced/separated diabetic patients. Twenty-two spouses of the 26 married diabetic patients also participated in the study. A 35-item questionnaire was developed with a 4-point Likert scale format for responses and administered separately to the patients and their spouses. None of the young adults in this study had made a conscious decision to remain unmarried, but 14 of 50 had decided not to have children. Onset of diabetes before 9 yr was associated with a significantly higher marriage rate than later onset of diabetes. Although onset of the disease after age 13 yr was more often associated with a decision to remain childless compared with earlier onset, this difference was not significant. Both men and women with diabetes found that the disease had an impact on certain aspects of their marital life, at times leading to friction and causing a financial burden. Whereas spouses were perceived to be very supportive, there was disagreement between young diabetic subjects and their spouses as to the impact of the disease on family activities and finances, the partners with diabetes perceiving a greater effect on these aspects of their lives than did their spouses.

Adolescent diabetes mellitus: parent/child perspectives of the effect of the disease on family and social interactions.

To investigate the perceived effects of adolescent diabetes mellitus on family and social interactions from the children's and parents' perspectives, 50 teenagers with diabetes were studied: 21 from a private practice and 29 from a diabetes camp. Children and parents answered separately a specially prepared questionnaire dealing with daily life situations; the adolescents also responded to the Firo B questionnaire. On corresponding questions agreement between the responses of children and parents varied from as high as 86% to as low as 30%. Questions referring to the effect of diabetes on scholastic performance, concentration, and social life were associated with poor agreement. No correlation was found between the measure of agreement between parents and children on various responses and glycosylated hemoglobin determinations. The adolescents' perspectives were clearly influenced by sex and age of onset of diabetes. Female compared with male adolescents perceived significantly less effect from diabetes on scholastic performance and concentration, and the age of onset of their diabetes affected the measure of agreement with parents. In their responses to the Firo B questionnaire female diabetic adolescents differed significantly from norms in 2 of the 6 subscales measured, unlike male adolescents, whose scores were similar to those of norm groups. Male diabetic adolescents felt the most effect from diabetes on social life, scholastic performance, and concentration when they had developed the disease between 9 and 12 yr of age. Although the parents of this subgroup of adolescents underestimated these feelings, in general, parents of male and female diabetic adolescents perceived more effect from diabetes than their children.

Neonatal morbidity among infants of diabetic mothers.

While the modern approach to management of diabetic pregnancy has reduced the perinatal mortality significantly, the neonatal morbidity remains high. This study has investigated factors which may account for the persisting high neonatal morbidity when birth trauma has been virtually eliminated and the incidence of respiratory distress syndrome (RDS) considerably reduced. Major congenital malformations emerge not only as the leading cause of perinatal losses but also as an important cause of morbidity. Delivery before 37 weeks increased the incidence of RDS and hypocalcemia, and it is suggested that, when strict metabolic control is used and with the help of facilities to monitor the fetus closely in the last weeks of pregnancy, the number of infants delivered at this early date can be further reduced. The present study also indicates that normoglycemia should also be encouraged on the day of delivery as maternal hyperglycemia at this stage increases the incidence of neonatal hypoglycemia. Jaundice, which very commonly affects newborn infants of diabetic mothers, is influenced by the use of oxytocin for vaginal delivery and by infant overweight (greater than 90th percentile) at birth, factors which are not beyond control. Finally, route of delivery per se may not be important in relation to neonatal morbidity.

Hyperosmolar hyperglycemic nonketotic syndrome. Report of 22 cases and brief review.

In a series of 22 patients with the hyperosmolar hyperglycemic nonketotic syndrome managed during a five-year period in a community hospital setting, 21 patients were known to be diabetic and only six patients were in coma. The overall mortality was 36.3 percent, and seven of the eight deaths were explained by associated nonmetabolic causes. In this study, hyperosmolarity was not related to coma or to final outcome of treatment. Patients were managed with relatively small amounts of fluid, and the type of fluid used did not influence the final outcome.

Graves' ophthalmopathy. An unusual course.

A patient with an unusual course of Graves' ophthalmopathy is presented; serial computed tomographic scanning of the orbits was used to follow the course of the eye disease. Right-sided unilateral ophthalmopathy first developed two years after thyroid ablation with radioactive iodine and was followed by complete resolution two years later. The remission of this patient's eye disease was short-lived; within eight months, unilateral ophthalmopathy affected the left eye, and ophthalmopathy recurred in the right eye a few months later. Current hypotheses do not readily explain the course of this patient's ophthalmopathy.

Lymphocytic interstitial pneumonitis in autoimmune thyroid disease.

Four patients are described who were found to have autoimmune thyroid disease associated with lymphocytic interstitial pneumonitis. The patients were not receiving any medications known to cause lymphocytic interstitial pneumonitis. Their response to steroid therapy and the relapse of their clinical symptoms after steroid withdrawal support an underlying immunologic dysfunction. It is proposed that lymphocytic interstitial pneumonitis may be yet another manifestation of immune dysfunction in autoimmune thyroid disease.

Electrocardiographic finding simulating acute myocardial infarction in a compound metabolic aberration.

A patient with hypokalemic metabolic alkalosis, hypophosphatemia, and hypomagnesemia/hypocalcemia is described. Electrocardiography demonstrated the pattern of acute anterior myocardial infarction. Further evaluation revealed that the patient had not actually had the acute myocardial infarction and that the electrocardiographic change was a mere simulation. The possible role of hypomagnesemia in the pathogenesis of the electrocardiographic change and the interrelation between the metabolic disturbances noted are discussed.

Lipoatrophic diabetes: endocrine dysfunction and the response to control hypertriglyceridemia.

Endocrine function was studied in a 24 year old female with lipoatrophic diabetes (LD). Baseline endocrine studies (serum triglycerides: 2600 mg/dl) demonstrated hyperprolactinemia (serum prolactin 51 ng/ml), increased ACTH levels, absence of suppression of ACTH to a high dose of dexamethasone which suppressed serum cortisol normally and, hyperresponsiveness of TSH to stimulation with TRH. Thyroid hormone levels (total and free fraction) were essentially normal. Major metabolites of thyroid hormone (T3, rT3, 3, 3'-T2, and 3', 5'-T2) were also normal and exhibited a normal response to the administration of L-thyroxine and propylthiouracil. Exchange of 84% of the patient's plasma resulted in a decrease in serum triglycerides (700 mg/dl) which was followed by a rebound to the original level in seven days. After the sixth plasmapheresis serum triglycerides stabilized at less than 1000 mg/dl. Plasmapheresis was associated with the appearance of amenorrhea and galactorrhea; also hypertension and proliferative retinopathy developed during this therapy. Repeat endocrine function studies (serum triglycerides: 700 mg/dl) showed a further rise in serum prolactin (greater than 160 ng/ml), persistence of abnormal ACTH secretion and normalization of TSH responsiveness. Lipoatrophic diabetes is associated with abnormal central endocrine function but appropriate peripheral target gland secretion. A course of plasmapheresis improves the hypertriglyceridemia but not the endocrine dysfunction. In this patient with LD the most important side effect of plasmapheresis was the development of cardiovascular complications.

Diabetes and thyroid disease during pregnancy.

In a prospective study of 100 consecutive diabetic pregnancies, 1 was complicated by hyperthyroidism and 4 by hypothyroidism. The association of hypothyroidism with diabetes mellitus merits special attention as this combination of diseases affected 4 of 20 (20%) White's class D and F diabetics. Hydramnios and/or spontaneous premature labor were features of diabetic pregnancies complicated by compensated hypothyroidism. Delayed diagnosis of hypothyroidism may have contributed to the fatal congenital malformations in one of these fetuses, but the remaining infants survived, including 1 infant suffering from severe respiratory distress syndrome (RDS).

Abnormalities of fuel metabolism in the polycystic ovary syndrome.

To investigate the metabolic effects of medroxyprogesterone acetate, carbohydrate and lipid metabolism in women with polycystic ovary syndrome was evaluated before and after long-term therapy with this drug. The effects of suppression of pituitary gonadotropins and ovarian sex steroids were correlated with the response to an oral glucose load and with a serum lipid profile. Twenty of 25 women with polycystic ovary syndrome weighted more than 150% of their ideal body weight. None of the patients had fasting hyperglycemia. Fasting and peak serum insulin responses to glucose were abnormally high in most patients with polycystic ovary syndrome. Fasting serum insulin had a significant positive correlation with percent ideal body weight (r = .7, P less than .01). High density lipoprotein cholesterol was low in all patients studied, whereas total cholesterol and serum triglyceride levels were normal. Therapy with medroxyprogesterone acetate did not affect body weight, glucose tolerance, or serum lipids. The correlations between serum testosterone and high-density lipoprotein cholesterol or insulin levels were not significant (P greater than .1). The authors conclude that medroxyprogesterone acetate does not affect the metabolic syndrome of obesity, hyperinsulinemia, and decreased high-density lipoprotein cholesterol that is commonly seen in patients with polycystic ovary syndrome.

Sex steroid levels during treatment of endometriosis.

Ovarian endocrine function in endometriosis was studied in 19 women before, during, and after treatment with danazol. Striking abnormalities were seen during treatment. Serum estradiol (E2) and testosterone (T) levels increased markedly, while follicle-stimulating hormone (FSH), luteinizing hormone (LH), and prolactin were unaffected. Direct interference of danazol in the assays for E2 and T was excluded by in vitro experiments. The most likely explanation for the isolated alterations in peripheral hormone levels is that danazol affects the carrier proteins in the circulation. However, other explanations are also possible and cannot be excluded at this stage.

Teaching medical students in ambulatory settings in departments of internal medicine.

Clinical training in ambulatory settings is an increasingly prominent topic in medical education, but most descriptions of internal medicine programs in the literature concern training for residents. The authors undertook a survey of departments of internal medicine to obtain and assess information about requirements for ambulatory clinical experiences for medical students. The results show that few departments (24% of the 101 departments responding) required ambulatory care experiences for undergraduates. Most of the required programs had a goal of broad exposure to ambulatory-patient problems; almost none had special educational interventions to complement students' care of patients. The experiences that were incorporated into the clerkship in a single block of time were more favorably rated than the experiences that occurred intermittently throughout the clerkship. Inability to provide continuity-of-care experience was an important concern of the departments. Most programs had logistical problems, the most serious and frequently cited being the lack of faculty time for teaching. The authors raise concerns about the educational effectiveness of many existing programs and, given the problems with faculty involvement, about the long-term viability of these programs.

Effect of premixed nph and regular insulin on glucose control and health-related quality of life in patients with type 2 diabetes mellitus.

OBJECTIVE: To compare the effect of the addition of regular insulin as a premixed 70/30 insulin to the treatment regimen of patients with type 2 diabetes who had used NPH insulin alone relative to overall glycemic control (postprandial blood glucose), patient satisfaction, and health-related quality of life. METHODS: We studied 90 patients with type 2 diabetes in a 10-week, randomized, double-blind, crossover trial involving 9 clinical investigators. Patients previously treated with NPH insulin alone were transferred to 30% regular insulin added to 70% NPH as a premixed insulin (70/30) administered twice daily. Patients in one sequence group received NPH insulin twice daily for 4 weeks followed by 70/30 insulin for 4 weeks; in the second sequence group, the order was reversed. RESULTS: The magnitude of the 1.5- and 2-hour postprandial glucose excursion was reduced with 70/30 insulin in comparison with NPH insulin, and patients treated with 70/30 insulin experienced fewer hypoglycemic events than with NPH insulin. With regard to health-related quality of life, patients treated with 70/30 insulin rated their physical functioning as better; rated their ability to be spontaneous, follow the meal plan, and interact socially to be less difficult; and had less fear of hypoglycemia and perceived their diabetes to be better controlled than when treated with NPH insulin alone. CONCLUSION: In patients with type 2 diabetes mellitus, premixed 70/30 insulin improved postprandial glycemic control and health-related quality of life without increasing the frequency of hypoglycemic events and without any additional cost.

[Long-term efficacy of dapagliflozin in patients with type 2 diabetes mellitus receiving high doses of insulin]. / Langzeitwirkung von Dapagliflozin bei Typ-2-Diabetikern unter hoch dosierter Insulintherapie.

BACKGROUND: Dapagliflozin, a selective inhibitor of sodium-glucose cotransporter 2, may improve glycemic control with a lower dose of insulin and attenuate the associated weight gain in patients with inadequate control despite high doses of insulin. OBJECTIVE: To evaluate the efficacy and safety of adding dapagliflozin therapy in patients whose type 2 diabetes mellitus is inadequately controlled with insulin with or without oral antidiabetic drugs. DESIGN: A 24-week, randomized, placebo-controlled, multicenter trial followed by a 24-week extension period. An additional 56-week extension period is ongoing. (ClinicalTrials.gov registration number: NCT00673231). SETTING: 126 centers in Europe and North America from 30 April 2008 to 19 November 2009. PATIENTS: 808 patients with inadequately controlled type 2 diabetes mellitus receiving at least 30 U of insulin daily, with or without up to 2 oral antidiabetic drugs. INTERVENTION: Patients were randomly assigned in a 1:1:1:1 ratio and allocated with a computer-generated scheme to receive placebo or 2.5, 5, or 10 mg of dapagliflozin, once daily, for 48 weeks. MEASUREMENTS: The primary outcome was change in hemoglobin A1c from baseline to 24 weeks. Secondary outcomes included changes in body weight, insulin dose, and fasting plasma glucose level at 24 weeks and during the 24-week extension period. Adverse events were evaluated throughout both 24-week periods. RESULTS: 800 patients were analyzed. After 24 weeks, mean hemoglobin A1c decreased by 0.79 % to 0.96 % with dapagliflozin compared with 0.39 % with placebo (mean difference, -0.40 % [95 % CI, -0.54 % to -0.25 %] in the 2.5-mg group, -0.49 % [CI, -0.65 % to -0.34 %] in the 5-mg group, and -0.57 % [CI, -0.72 % to -0.42 %] in the 10-mg group). Daily insulin dose decreased by 0.63 to 1.95 U with dapagliflozin and increased by 5.65 U with placebo (mean difference, -7.60 U [CI, -10.32 to -4.87 U] in the 2.5-mg group, -6.28 U [CI, -8.99 to -3.58 U] in the 5-mg group, and -6.82 U [CI, -9.56 to -4.09 U] in the 10-mg group). Body weight decreased by 0.92 to 1.61 kg with dapagliflozin and increased by 0.43 kg with placebo (mean differences, -1.35 kg [CI, -1.90 to -0.80 kg] in the 2.5-mg group, -1.42 kg [CI, -1.97 to -0.88 kg] in the 5-mg group, and -2.04 kg [CI, -2.59 to -1.48 kg] in the 10-mg group). These effects were maintained at 48 weeks. Compared with the placebo group, patients in the pooled dapagliflozin groups had a higher rate of hypoglycemic episodes (56.6 % vs. 51.8 %), events suggesting genital infection (9.0 % vs. 2.5 %), and events suggesting urinary tract infection (9.7 % vs. 5.1 %). LIMITATION: Insulin doses were not titrated to target, and the study was not designed to evaluate long-term safety. CONCLUSION: Dapagliflozin improves glycemic control, stabilizes insulin dosing, and reduces weight without increasing major hypoglycemic episodes in patients with inadequately controlled type 2 diabetes mellitus.