Hedonic eating in Prader-Willi syndrome is associated with blunted PYY secretion.

Hedonic and homeostatic hunger represent two different forms of eating: just for pleasure or following energy deprivation, respectively. Consumption of food for pleasure was reported to be associated with increased circulating levels of both the orexigenic peptide ghrelin and some specific endocannabinoids in normal-weight subjects and patients with morbid obesity. To date, the effects of palatable food on these mediators in Prader-Willi syndrome (PWS) are still unknown. To explore the role of some gastrointestinal orexigenic and anorexigenic peptides and endocannabinoids (and some related congeners) in chocolate consumption, we measured changes in circulating levels of ghrelin, cholecystokinin (CCK), peptide YY (PYY), anandamide (AEA), 2-arachidonoyl-glycerol (2-AG), palmitoylethanolamide (PEA) and oleoylethanolamide (OEA) in eight satiated adult PWS patients after consumption of chocolate and, on a separate day, of a non-palatable isocaloric food with the same macronutrient composition. Evaluation of hunger and satiety was also performed by visual analogic scale. The anticipatory phase and the consumption of food for pleasure were associated with decreased circulating levels of PYY. An increase in PEA levels was also observed. By contrast, circulating levels of ghrelin, CCK, AEA, 2-AG and OEA did not differ before and after the exposure/ingestion of either chocolate or non-palatable foods. Hunger and satiety were similar in the hedonic and non-palatable sessions. In conclusion, when motivation to eat is promoted by highly palatable foods, a depressed post-prandial PYY secretion is observed in PWS. Although preliminary, these findings seem to hypothesize a possible role of PYY agonists in the management of PWS patients. Abbreviations: AEA, Anandamide; 2-AG, 2-arachidonoyl-glycerol; CB1, cannabinoid receptor type 1; OEA, oleoylethanolamide; PEA, palmitoylethanolamide; PWS: Prader-Willi syndrome; VAS, visual analog scales.

Total IgG and IgG subclass specific antibody responses to insulin in diabetic patients.

Abnormal antibody responses to insulin in diabetic patients have been associated with syndromes of insulin hypersensitivity and abnormal insulin pharmacokinetics. In this study, we evaluated total and IgG subclass antibody responses to insulin in 70 diabetic subjects on insulin distributed into five clinical groups, and in two control groups using ELISAs with CDC/WHO recommended monoclonal antibodies. As expected, levels of total IgG insulin antibody were greater in diabetic patients treated with insulin than in the control group of diabetic patients on oral agents or nondiabetic controls. Insulin antibody responses of the IgG2 subclass were negligible to absent in all groups. Adult diabetic patients on insulin without complications and those with insulin associated anaphylaxis had mean values of IgG1, IgG3, and IgG4 insulin antibodies no different from those of controls. Patients with local hypersensitivity had elevated IgG1 responses. Type I diabetic patients had elevated IgG3 responses. A group of Type II diabetic patients selected for high levels of total IgG insulin antibodies had elevated levels of IgG1, IgG3, and IgG4 antibody responses. Thus, the IgG subclass response to insulin primarily involves IgG subclasses 1, 3, and 4 and varies with the type of diabetes and complications of insulin therapy.

Comparison of the safety and effectiveness of human and bovine long-acting insulins.

Since ultralente insulin pharmacokinetics suggest faster absorption by human insulin when compared with bovine insulin using the subcutaneous route, the safety and efficacy of human ultralente in the outpatient setting was evaluated. Twenty type I patients participated in a randomized study using a crossover design of four six-week phases: (a) one daily injection of human ultralente; (b) two daily injections of human ultralente; (c) one daily injection of bovine ultralente and (d) two daily injections of bovine ultralente. Pre-meal human regular insulin was used with ultralente insulins and comprised 39 +/- 2% of the total daily insulin dose. Total and ultralente daily insulin doses were lower with human ultralente insulin (51.3 +/- 3.0 total and 30.9 +/- 3.4 ultra lente u/day) when compared to bovine ultralente insulin (57.8 +/- 4.4 and 36.1 +/- 4.4 u/day, p less than 0.01), yet the metabolic control achieved was virtually identical during both phases: (hemoglobin Alc 8.6 +/- 0.2% human vs. 8.4 +/- 0.4 bovine, p = NS). The frequency of mild hypoglycemia was 3.0 +/- 0.5 events per week vs 2.0 +/- 0.3 (p = NS). No severe hypoglycemia occurred. There were no differences between blood glucose daily profiles, insulin doses, hemoglobin Alc (8.6 +/- 0.4% BID vs. 8.4 +/- 0.3% QD injections) and occurrence of hypoglycemia between the single and two-dose long-acting regimens. These data indicate that long-acting semi-synthetic human insulin (a) can be effectively used as a once daily injection, (b) may be more biologically active than bovine, and (c) can be associated with safe and effective diabetes control.

Efficacy of a premixed semisynthetic human insulin regimen.

Sixty-one insulin-requiring non-insulin-dependent (type II) diabetic patients who had been transferred from a regimen of mixed intermediate and short-acting insulin to a fixed regimen of premixed insulin (70% neutral protamine Hagedorn and 30% regular, human semisynthetic insulin) given twice daily were studied retrospectively. The average age was 65 years (range, 35 to 84) and the average duration of their diabetes was 13.8 years (range, 1.5 to 33 years). Thirty-one percent were men, 69% women. Hemoglobin A1c (HbA1c) dropped significantly after transfer from a mean of 12.3% to a mean of 9.2% (P less than 0.001). After an average of 14.1 months, 40 patients still had a lower HbA1c (P less than 0.01), showing sustained improvement. The mean HbA1c at the last visit was 10.2% (normal range, 5.5% to 8.5%) with the average reduction in HbA1c being 2.1%. This sustained improvement occurred without a significant gain in weight (P = 0.63) or a significant increase in total insulin doses (median, 2 units), and was independent of the type of insulin used previously. Hypoglycemic episodes actually declined from an average of 1.0 to 0.6 per month. Of those patients who had previously not reported hypoglycemia, only 28% reported hypoglycemic events, and of those reporting previous hypoglycemia, 57% experienced a reduction. This surprising improvement in glycemic control was not due to compliance with insulin injections or remote premixing of insulin but possibly due to the increased accuracy of measuring the premixed insulin dose. The convenience and stability of a premixed insulin regimen results in better glycemic control in the insulin-requiring non-insulin-dependent diabetic population.

Comparison of fixed-ratio versus variable-ratio regular and NPH semisynthetic human insulin in insulin-requiring diabetic patients.

The efficacy and safety of a fixed combination of semisynthetic human insulin (Novolin) providing a 70:30 ratio of NPH to regular insulin versus a varying ratio of semisynthetic human insulin, regular and NPH (control group), were compared in adult insulin-dependent and noninsulin-dependent diabetic patients whose glycemic control had been stable on customized split-mix regimens of animal insulin. Seventy-eight patients were enrolled, of whom 72 were evaluated for efficacy of the respective regimens. Although the baseline fasting serum glucose concentrations were significantly higher in the fixed-ratio group than in the control group, mean serum glucose and glycosylated hemoglobin values throughout the 12 weeks of experimental treatment were not significantly different between groups. The mean serum glucose and glycosylated hemoglobin values in the fixed-ratio group also did not differ significantly from baseline; however, statistically significant increases were observed in the control group at weeks 4 and 8, but not at week 12. Total daily insulin dosages were comparable between the two groups, and body weight did not change significantly in either group. At the end of the study, the investigators judged 90% of the patients in the fixed-ratio group and 88% of the patients in the control group to be either improved or unchanged with respect to glycemic control. The frequency of hypoglycemic episodes and other clinical events did not change significantly from baseline in either group or differ significantly between the two groups at any time. The results of this study suggest that stable diabetic patients receiving animal insulin can safely be transferred to semisynthetic human insulin and that the majority of patients can maintain acceptable glycemic control with a fixed 70:30 ratio of NPH to regular semisynthetic human insulin.

Insulin antibodies in non-insulin-dependent diabetes mellitus: effect of treatment with semisynthetic human insulin.

This multicenter study of patients with non-insulin-dependent diabetes mellitus (NIDDM) was undertaken (1) to determine the incidence of insulin antibody formation in such patients before exposure to exogenous insulin; (2) to assess the long-term immunologic response to semisynthetic human insulin (ssHI) in new insulin users and in patients transferred from animal insulin; and (3) to document the efficacy and safety of ssHI in both new and transfer patients. In addition, a substudy at one participating center was designed to compare the effects of a twice-daily versus a once-daily regimen in initiating ssHI therapy in new patients with uncontrolled NIDDM. Among the 37 new patients, only one had detectable insulin antibody levels before administration of insulin. After ssHI therapy was begun, this patient's antibody levels rapidly fell below the assay's limit of detection. Detectable levels of antibodies to human insulin were found in only 36% of 28 new patients after 12 months of therapy. As expected, the prevalence of insulin antibodies among animal-insulin users was high: 82% of the 17 transfer patients had detectable insulin antibody levels (mean, 2.27 mU/ml) at baseline. After six months of treatment with ssHI, antibody levels decreased significantly (mean, 0.75 mU/ml; P less than 0.05). Control of glycemia was assessed by measurement of glycosylated hemoglobin. Values decreased significantly (P less than 0.01) in the new patients after the introduction of ssHI and remained stable in the transfer group after initiation of ssHI therapy. Hypoglycemic episodes were infrequent in both groups. In initiating ssHI therapy in new patients hospitalized with uncontrolled NIDDM, a twice-daily regimen resulted in a more rapid normalization of glycemia and earlier discharge than did the standard once-daily regimen. In conclusion, the results of this study provide further evidence that NIDDM and insulin-dependent diabetes mellitus (IDDM) are immunologically different disorders, with the immune system probably not involved in the pathogenesis of NIDDM. The data also indicate that ssHI is less immunogenic than animal insulin and that it is effective and safe in the management of NIDDM both in first-time insulin users and in patients transferred from animal-species insulin. Thus ssHI would appear to be useful in treating NIDDM, especially in patients who require intermittent insulin therapy.

NPH human insulin: does it work in a once-a-day regimen?

A clinical transfer trial was conducted to ascertain whether semisynthetic human NPH insulin has a full 24-hour duration of therapeutic effect comparable to that of NPH insulin from animal sources. Diabetic patients requiring insulin and stabilized on a once-a-day (QD) regimen of animal NPH insulin were enrolled and entered a two-week run-in period during which the constancy of their insulin requirements and the stability of their glycemic control were assessed. At the end of the run-in phase, baseline measurements were made of fasting blood glucose (FBG), hemoglobin A1 C, C-peptide, and insulin antibodies. Patients then were transferred to a QD regimen of semisynthetic human NPH insulin (Novolin N) in the same dose as the animal insulin. Glycemic control was reassessed after 1, 4, and 8 weeks of therapy, and a global assessment of overall glycemic control was made at the conclusion of the study. Efficacy variables were analyzed for 39 patients. Most had non-insulin-dependent diabetes mellitus (NIDDM) and most were transferred from mixed beef/pork insulin. Six (15%) patients required significant adjustments in insulin dose or regimen; the remaining 85% completed the eight weeks of treatment with minimal changes in insulin dose. Mean values for FBG and hemoglobin A1 C did not change significantly between baseline and the end of the study. The only statistically significant change was an increase in mean body weight (P less than or equal to 0.01). Results of the investigators' global assessments showed that 74% of the patients had unchanged or improved control of glycemia after transferring to semisynthetic human NPH insulin. The average frequency of hypoglycemic events was not significantly changed.(ABSTRACT TRUNCATED AT 250 WORDS)

Cellular immune alterations associated with human insulin therapy.

To evaluate the immunogenicity of human insulin preparations, the treatment of 10 insulin-dependent diabetic patients was changed from purified porcine insulins to lente and regular semisynthetic human insulin (SSHI, N = 5) or NPH and regular biosynthetic human insulin (BHI, N = 5). Circulating levels of T lymphocyte subsets, in vitro responses of enriched mononuclear cells to mitogens and circulating insulin antibody measurements were performed before and during the 24 weeks of treatment. Insulin antibody levels did not change significantly in either human insulin treatment group. Circulating levels of Leu 1 and Leu 3 positive cells, identifying total and helper/inducer T lymphocyte populations respectively, and the Leu 3:Leu 2 (helper/inducer: suppressor/cytotoxic) T cell ration were all reduced (p less than 0.025) at eight weeks in the BHI treatment group. Cells identified with murine monoclonal antibody, Leu 7 defining a natural killer cell phenotype, were increased in the SSHI group at four weeks of study (p less than 0.05). There was a decreased pokeweed mitogen-induced proliferation of mononuclear cells in SSHI treated patients (p less than 0.01) at 12 weeks and both insulin treatment groups had increased responses to phytohemagglutinin (p less than 0.05) but not concanavalin A at 24 weeks. These data indicate that changes in the cellular immune system without associated changes in circulating anti-insulin antibody levels can be observed in patients whose treatment was changed from purified porcine to human insulin preparations. Thus, cellular immune responses may be more sensitive than humoral immune responses as indicators of immunological alterations to insulin preparations.

Rapid decrease of insulin-specific IgG antibody levels in insulin-dependent patients transferred to semi-synthetic human insulin.

A multicenter, open trial was designed to examine the efficacy and safety of semi-synthetic human insulin (SSHI; Novolin R and Novolin L, SQUIBB-NOVO) in patients with insulin-dependent diabetes mellitus who were transferred from other commercially-available insulins. Whether such a change in therapy would reduce circulating IgG antibodies to antibovine insulin was also evaluated. A total of 68 males and females, 8-62 yr of age, were maintained on their original insulin therapy for 4 weeks, when both glycosylated hemoglobin and fasting blood glucose were assessed. IgG antibody titers to antibovine insulin were also measured. All patients were then transferred to SSHI for a period of 20 weeks. The same variables were evaluated at Weeks 2, 4, 8, and 20. Mean fasting blood glucose levels rose monotonically from 189-226.3 mg/dl over the course of the 20-week clinical trial. There was a slight but insignificant increase in glycosylated hemoglobin by the end of the test period. The average value for antibovine insulin IgG antibodies decreased from 2.54 mu/ml at baseline to 1.32 mu/ml by the completion of the trial. Significant decreases were first observed 4 weeks after the patients were placed on SSHI therapy. After transfer to SSHI, 43.3% of the patients achieved some improvement in glycemic control and only 16.4% were worse than at baseline. A decrease in weekly hypoglycemic reactions occurred during the course of the SSHI therapy. It appears that SSHI provides safe and effective treatment for insulin-dependent diabetic patients and that its use results in a rapid and significant decrease in insulin antibody formation.

Exaggerated epinephrine responses to hypoglycemia in normal and insulin-dependent diabetic children.

To determine whether children with insulin-dependent diabetes mellitus (IDDM) might have exaggerated hormonal responses to hypoglycemia, the euglycemic-hypoglycemic glucose clamp procedure was used to provide a uniform hypoglycemic stimulus (plasma glucose kept at 90 mg/dL for 2 hours, then reduced to 50 to 55 mg/dL for 1 hour) in children and adults with and without IDDM. The chidren with IDDM showed an exaggerated rise in plasma epinephrine levels (625 +/- 112 pg/mL) compared with adults with IDDM (259 +/- 57 pg/mL, P less than 0.02); the same was true for children and adults without IDDM (811 +/- 100 vs 458 +/- 85 pg/mL, P less than 0.05). Among the children, the increase in epinephrine during hypoglycemia was similar in prepubertal and pubertal patients. Children with IDDM showed a greater rise in plasma norepinephrine than did adults with IDDM (P less than 0.001), and both diabetic groups failed to mount a glucagon response. Growth hormone and cortisol responses were unaffected by either childhood or diabetes. Enhanced secretion of epinephrine, induced by mild reductions in plasma glucose, may contribute to the management difficulties characteristically observed in the young patient with diabetes.

Evaluation of patients with local reactions to insulin with skin tests and in vitro techniques.

To better understand the part played by IgE and IgG antibody in the production of dermal reactions to insulin and the usefulness of skin tests in the evaluation of these reactions, we studied 21 diabetic patients referred for evaluation of large local insulin reactions, 46 diabetic patients without local insulin reactions, and 22 healthy nondiabetic controls. Study subjects were skin tested with 15 different insulins, and the results were evaluated over 48 h. All control subjects and 41 of 46 diabetic patients without local reactions were skin-test negative to insulin. The 11% of diabetic patients who reacted had positive wheal-and-flare reactions at 20 min to animal-species insulin but negative skin tests to human insulin. Study revealed two subgroups of patients with histories of local reactions. Ten (48%) of these patients had negative skin tests to insulin. Five of this subgroup remained skin-test negative to quantities of less than or equal to 8 U insulin/skin test. Eleven (52%) of the patients formed a subgroup with positive insulin skin tests; most of these patients were skin-test positive to human insulin and to beef, pork, or both insulins as well. Although the group mean insulin-specific IgE values of this latter subgroup were significantly higher than those of any other study group, overlap of these individual IgE values did not allow separation of specific individuals with positive skin tests from those of patients on insulin without dermal reactions.(ABSTRACT TRUNCATED AT 250 WORDS)

Impaired insulin action in puberty. A contributing factor to poor glycemic control in adolescents with diabetes.

Patients with insulin-dependent diabetes mellitus often have poor metabolic control during puberty. To determine whether puberty is associated with decreased insulin-stimulated glucose metabolism, we compared the results of euglycemic insulin-clamp studies in adults and prepubertal and pubertal children with and without insulin-dependent diabetes. In nondiabetic pubertal children, insulin-stimulated glucose metabolism (201 +/- 12 mg per square meter of body surface area per minute) was sharply reduced, as compared with that of prepubertal children and adults (316 +/- 34 and 290 +/- 21 mg per square meter, respectively; P less than 0.01), despite comparable hyperinsulinemia (insulin levels of 80 to 90 microU per milliliter). Similarly, the response to insulin was 25 to 30 percent lower in the diabetic pubertal children than in the diabetic prepubertal children (P less than 0.05) and adults (P = 0.07). At each stage of development, the stimulating effect of insulin on glucose metabolism was decreased by 33 to 42 percent in the children with diabetes (P less than 0.01). In all the groups of children studied, the response to insulin was inversely correlated with mean 24-hour levels of growth hormone (r = -0.52, P = 0.01). Among the diabetic children, the glycosylated hemoglobin levels were substantially higher in the pubertal children than in the prepubertal children (P less than 0.02), although the daily insulin doses tended to be higher. These data suggest that insulin resistance occurs during puberty in both normal children and children with diabetes. The combined adverse effects of puberty and diabetes on insulin action may help explain why control of glycemia is so difficult to achieve in adolescent patients.