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Treatment-induced neuropathy in diabetes (TIND) is defined by the occurrence of an acute neuropathy within 8 weeks of an abrupt decrease in glycated hemoglobin-A1c (HbA1c). The underlying pathogenic mechanisms are still incompletely understood with only one mouse model being explored to date. The aim of this study was to further explore the hypothesis that an abrupt insulin-induced fall in HbA1c may be the prime causal factor of developing TIND. BB/OKL (bio breeding/ OKL , Ottawa Karlsburg Leipzig) diabetic rats were randomized in three groups, receiving insulin treatment by implanted subcutaneous osmotic insulin pumps for 3 months, as follows: Group one received 2 units per day; group two 1 unit per day: and group three 1 unit per day in the first month, followed by 2 units per day in the last two months. We serially examined blood glucose and HbA1c levels, motor- and sensory/mixed afferent conduction velocities (mNCV and csNCV) and peripheral nerve morphology, including intraepidermal nerve fiber density and numbers of Iba-1 (ionized calcium binding adaptor molecule 1) positive macrophages in the sciatic nerve. Only in BB/OKL rats of group three, with a rapid decrease in HbA1c of more than 2%, did we find a significant decrease in mNCV in sciatic nerves (81% of initial values) after three months of treatment as compared to those group three rats with a less marked decrease in HbA1c <2% (mNCV 106% of initial values, p ≤ 0.01). A similar trend was observed for sensory/mixed afferent nerve conduction velocities: csNCV were reduced in BB/OKL rats with a rapid decrease in HbA1c >2% (csNCV 90% of initial values), compared to those rats with a mild decrease <2% (csNCV 112% of initial values, p ≤ 0.01). Moreover, BB/OKL rats of group three with a decrease in HbA1c >2% showed significantly greater infiltration of macrophages by about 50% ( p ≤ 0.01) and a decreased amount of calcitonin gene related peptide ( CGRP ) positive nerve fibers as compared to the animals with a milder decrease in HbA1c. We conclude that a mild acute neuropathy with inflammatory components was induced in BB/OKL rats as a consequence of an abrupt decrease in HbA1c caused by high-dose insulin treatment. This experimentally induced neuropathy shares some features with TIND in humans and may be further explored in studies into the pathogenesis and treatment of TIND., Competing Interests: The authors declare no conflict of interest.

Background: Iron is an essential but potentially toxic metal in mammals. Here we investigated a pathogenic role of exogenous iron in peripheral diabetic neuropathy (PDN) in an animal model for type 1 diabetes., Methods: Diabetes was induced by a single injection of streptozotocin (STZ) in 4-month-old Sprague-Dawley rats. STZ-diabetic rats and non-diabetic rats were fed with high, standard, or low iron diet. After three months of feeding, animals were tested., Results: STZ-rats on standard iron diet showed overt diabetes, slowed motor nerve conduction, marked degeneration of distal intraepidermal nerve fibers, mild intraneural infiltration with macrophages and T-cells in the sciatic nerve, and increased iron levels in serum and dorsal root ganglion (DRG) neurons. While motor fibers were afflicted in all STZ-groups, only a low iron-diet led also to reduced sensory conduction velocities in the sciatic nerve. In addition, only STZ-rats on a low iron diet showed damaged mitochondria in numerous DRG neurons, a more profound intraepidermal nerve fiber degeneration indicating small fiber neuropathy, and even more inflammatory cells in sciatic nerves than seen in any other experimental group., Conclusions: These results indicate that dietary iron-deficiency rather than iron overload, and mild inflammation may both promote neuropathy in STZ-induced experimental PDN., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Objective: We previously analyzed data from a hemophilus vaccine trial and identified clusters of extra cases of type 1 diabetes mellitus (T1DM) caused by the vaccine that occurred between 36 and 48 months after immunization. Published reports indicate clustering of cases of T1DM occurring approximately 2-4 years after mumps infection. Others have reported a 2-4 year delay between the onset of autoantibodies and the development of T1DM. We attempted to determine whether similar clustering of cases of T1DM occurred after immunization with vaccines other than hemophilus., Methods: We searched MEDLINE and reviewed references from published papers to find databases on the incidence of T1DM and then searched MEDLINE to determine whether changes in immunization occurred in these regions during the times the incidence of DM was being recorded., Results: Distinct rises in the incidence of T1DM occurred 2-4 years following the introduction of the MMR and pertussis vaccines. A drop in the incidence of T1DM was detected between 3-4 years following discontinuation of pertussis and BCG vaccines., Conclusion: The identification of clusters of cases of T1DM occurring in consistent temporal time periods allowed a link between the hemophilus vaccine and T1DM to be established. The current findings indicate the there are also clusters of cases of T1DM occurring 2-4 years post-immunization with the pertussis, MMR, and BCG vaccine. The data are consistent with the occurrence of clusters following mumps infection and the progression to T1DM in patients with antipancreatic autoantibodies.

Immunization with a number of different vaccines, including live and killed vaccines, has been linked to the development of insulin-dependent (type 1) diabetes in humans and animals. Multiple different mechanisms have been proposed to explain the association between vaccines and diabetes. The current paper reviews multiple different mechanisms by which vaccines are known to manipulate the immune system and can induce an autoimmune disease such as type 1 diabetes. Genetic variability may determine which of these pathways, or possible other pathways, predominate in an individual following immunization., (Copyright 2001 Harcourt Publishers Ltd.)

A low cumulative incidence of IDDM was reported in Dutch males born in 1962 (Diabetologia 1992: 35: 139-142) compared to males born in previous or later years. The cause for the decreased risk has not been previously explained. We propose that children born in 1962 during an European smallpox epidemic may have received the smallpox vaccine in the first month of life and this may have attributed to the decreased risk of IDDM in these children. We have shown that immunization with several different vaccines starting in the first month of life prevents diabetes in NOD mice and BB rats (Autoimmunity 1996: 24: 137-145) while immunization at birth with the BCG vaccine is associated with an decreased risk of IDDM in humans (Infectious Diseases in Clinical Practice 1997: 6: 449-454). An even bigger decline in diabetes is seen in rodents and associated in humans when one compares immunization starting in the first month of life to immunization starting after 2 months, since the later has been associated with an increased risk of IDDM. Immunization studies in the past have typically followed patients for only several weeks to determine any unplanned affects on autoimmune disease. Due to the potential benefit of reducing the incidence of diabetes by 50% through age 18 we believe clinical trials are warranted to study the effect of timing of immunization on IDDM.

Background: Insulin-dependant diabetes mellitus (IDDM) is an autoimmune disease that can be altered by immune modulation. NOD mice and BB rats have been used as models of spontaneous IDDM. The development of diabetes in these animals has been altered by several different immune modulators using relatively high doses for the size of the animal. The effect of pharmaceutical doses of vaccines on the development of diabetes in these rodents has not been adequately studied., Methods: I studied the effect of administering killed human vaccines using low concentrations and as few as 3 doses., Results: Administration of human vaccines to diabetic prone newborn animals starting before 2 weeks of age prevented the development of diabetes while administration of the pertussis vaccine starting at 8 weeks of life was associated with an increased incidence of diabetes., Conclusions: Animal studies have demonstrated the timing and content of human vaccines can affect the development of diabetes. Clinical trials of new human vaccines are not designed and generally not powered to detect an effect of immunization on the development of IDDM. These animal toxicology studies indicate that the effect of vaccines on human insulin dependent diabetes needs to be examined.