Newer insulin analogues and inhaled insulin

Diabetes is a metabolic disease with high prevalence worldwide. Exogenous insulin is used in the management of this condition. The development of human insulin has provided tighter control of glycaemia in diabetic patients. Insulin analogues like insulin lispro and aspart were developed to closely match its profile with physiological secretion. The newer additions to this armamentarium are insulin glulisine, insulin detemir and albulin. Insulin glulisine is a short acting analogue with a rapid onset of action. The antiapoptotic property, mediated through insulin substrate receptor-2 has a favourable protective action on beta cells. Insulin detemir is a long acting analogue, soluble at neutral pH, which reversibly binds to albumin in plasma, prolonging its action. Its lower affinity for insulin receptors necessitates higher doses compared to human insulin. The reduction in body weight is an additional advantage of detemir. A major concern about all newer insulin analogues is their altered mitogenic properties and resultant risk of carcinogenicity on long term use. Albulin is a latest addition of insulin analogue which is under various in vitro and in vivo studies. Inhaled insulin in powder form (Exubera) is recently approved by FDA and appears promising.     

Hypoglycaemia and insulin resistance in uraemia associated with insulin fragments

The pathogenetic role of insulin fragments in spontaneous hypoglycaemia and insulin resistance in chronic renal failure is discussed. Four different evidences are presented. In our studies, a dialysable 'toxin' with insulin-like actions was found in uraemia. Indeed small polypeptide fragments of hormones with potent activities have been recently identified in uraemic plasma. The varying bioactivities of different insulin fragments can explain the coexistence of insulin resistance and hypoglycaemia in these patients. As shown by our studies, removal of these fragments by haemodialysis results in normalisation of metabolic disturbances. However actual proof is difficult with the present technological problems.     

Delayed-type allergy against various insulin preparations including human semisynthetic insulin

The authors present a patient with delayed-type allergy against insulin preparations of different species including highly purified monocomponent insulin and human semisynthetic insulin. Positive results for cutaneous delayed-type hypersensitivity and for lymphocyte blastogenesis suggested a type IV immunopathogenic reaction. Intradermal tests performed with various components of insulin preparations revealed delayed-type allergy to insulins of different species (bovine, porcine and human) but not to any of the other components.     

Production of insulin antibodies by mice rejecting insulin transfected cells

Antibodies to insulin appear prior to the development of Type I diabetes and their concentration may correlate with the rate of autoimmune beta cell destruction. In order to study potential mechanisms involved in the production of antibodies to insulin, we transplanted different strains of mice with histoincompatible non-islet cells (AtT20-Ins and NIH-3T3-Ins) synthesizing homologous insulin, in contrast to immunization with non-transfected cells and insulin in Freund's adjuvant. The pituitary cell line (AtT20) and the fibroblast cell line (NIH-3T3) were transfected with the rat insulin-II gene (which encodes an insulin molecule identical to that of mouse insulin-II). No antibodies to insulin were found after subcutaneous injection of AtT20-control cells (without the integrated rat insulin gene) or after injection of rat insulin complete Freund's adjuvant. After subcutaneous injections of living AtT20-Ins or NIH-3T3-Ins cells producing insulin (40 to 60 ng insulin/10(6) cells per injection) in two strains (BALB/cJ, C3H/HeJ) but not in a third (SJL/J), antibodies to insulin rapidly appeared. In addition, when AtT20-Ins cells were transplanted into Wistar-Furth rats, insulin antibodies appeared in three out of four animals. The level of antibodies induced was similar to the concentrations of insulin antibodies of prediabetic NOD mice. This finding suggests that during the immune destruction of a cell synthesizing insulin, humoral 'tolerance' to insulin can be rapidly abrogated. Genetic control of this response is suggested by the difference between response of BALB/cJ and C3H/He vs SJL/J.     

Human insulin allergy

A 70-year-old female presented with a generalized allergic reaction to heterologous insulin. Subsequent epicutaneous testing to human insulin (Humulin) evoked a large wheal and flare reaction and generalized pruritus. The institution of human insulin therapy in patients allergic to heterologous insulin may cause further allergic reactions.     

Therapy with insulin

Hyperglycemia contributes to morbidity and mortality in diabetic patients. Reaching treatment targets with regard to control of glycemia is thus a central goal in the treatment of diabetic patients. The present article represents the recommendations of the Austrian Diabetes Association for the practical use of insulin according to current scientific evidence.     

Workshop N: Clinical Immunology, Abstract N1 bis N24

N. 1 Potential relevance of the TNF-α promoter polymorphism (-308 G/A) in atherosclerotic complications of hemodialysis patientsN. 2 Impaired immuneresponsiveness in HUVECs obtained from newborns of preeclamptic women: A possible link to an increasing rate of neonatal sepsis?N. 3 Diverse effects of IL-10 and TGF-β on reversal in monocyte deactivation models: Implications for patients with immunoparalysisN. 4 T cell clonotypes associated with viral clearance or persistence in patients with acute and chronic hepatitis BN. 5 Thiol deficiency and immunoregulatory defects in diabetic patients on dialysis: Restitution of T cell activation by flavonoidsN. 6 Does penicillin support viral infections by reducing cytotoxicity of CTLs?N. 7 Individual responsiveness to cyclosporine A in vivo is not attributable to intrinsic resistance to the drug or the existence of serum inhibitorsN. 8 Differential effects of the immune response modifier R-848 on the sensitization and elicitation phase of cutaneous immune responsesN. 9 Clonal T cell expansions in interferon-α treated patients with chronic hepatitis CN. 10 Procalcitonin serum levels in patients after liver, pancreas, and simultaneous kidney-pancreas transplantationN. 11 Correlation of interleukin-18 plasma levels with the clinical course of polytrauma patientsN. 12 Increased concentrations of antibodies to phosphatidylserine and ribosomal P proteins in Behcet's diseaseN. 13 New methods to assess total classical pathway complement activityN. 14 Sera from healthy individuals do not suppress T cell proliferation induced by the SEG/SEI cluster of Staphylococcus aureus superantigensN. 15 EGR-1 and TAXREB107 are differentially expressed genes within GPI-deficient cells from patients with paroxysmal nocturnal hemoglobinuriaN. 16 Development and characterization of an in vitro granuloma model for Wegener's granulomatosisN. 17 Targeting B cells in systemic lupus erythematosus: Successful treatment with anti-CD20 monoclonal antibody (Rituximab®)N. 18 Effector cells and molecules infiltrating rejected skin graftsN. 19 Effects of different anesthetic management and agents on postoperative PBMC proliferation and cytokine productionN. 20 Reduced antiviral Th1 cell stimulation in patients with chronic HBV infection as a result of reduced IL-12 secretion by dendritic cellsN. 21 Hereditary deficiency of C1 inhibitor and immunological reactivityN. 22 Clonal activation of T cells in patients with Wegener's granulomatosis: Shortening of telomere length and loss of the co-stimulatory receptor CD28N. 23 A new classification of patients with common variable immunodeficiency based on B cell phenotypingN. 24 Human monoclonal antibodies against hepatitis B surface antigen: Correlation between binding affinity, epitope recognized, and neutralizing properties     

Increased insulin sensitivity and insulin binding to monocytes after physical training

We studied the effect of physical training on in vivo tissue sensitivity to insulin and insulin binding to monocytes in six previously untrained healthy adults. Physical training (one hour of cycle-ergometer exercise four times per week for six weeks) failed to alter body weight but resulted in a 20 per cent increase (P less than 0.02) in maximal aerobic power (VO2 max) and a 30 per cent increase (P less than 0.01) in insulin-mediated glucose uptake (determined by the insulin clamp technique). The increase in insulin sensitivity correlated directly with the rise in VO2 max (P less than 0.05). Binding of [125I]insulin to monocytes also rose by 35 per cent after physical training (P less than 0.02), primarily because of an increase in the concentration of insulin receptors. Our data indicate that physical training increases tissue sensitivity to insulin in proportion to the improvement in physical fitness. Physical training may have a role in the management of insulin-resistant states, such as obesity and maturity-onset diabetes, that is independent of its effects on body weight.     

Improvement in severe insulin resistance with frequent injections of lispro insulin

Extreme insulin resistance is common in obese African Americans with type 2 diabetes. This case report describes an obese African-American woman who was treated with subcutaneous injections of lispro insulin every 2 hours with resultant decrease of mean daily blood glucose from 264.7 mg/dL to 111 mg/dL and in insulin requirement from 479 U/24 hours to 60 U/24 hours. This case demonstrates that extreme insulin resistance is reversible in the short term.