minocycline and Diabetes-Mellitus--Type-1

Studies indicate that a dual pathway between diabetes mellitus and periodontal disease exists. Elimination of periodontal infection by using systemic antibiotics in conjunction with scaling and root planing (SRP) improved metabolic control in diabetic patients, as defined by reduction in glycated haemoglobin or reduction in insulin requirements (Grossi and Genco, 1998). The aim of this randomised pilot clinical trial was to determine if type 1 diabetes patients with periodontitis will experience a reduction in HbA1c levels when treated with locally delivered minocycline microspheres (Arestin) as an adjunct to scaling and root planing. Twenty adult patients with poorly controlled diabetes (HbA1c 7.5%) and adult periodontitis, as determined by the presence of four teeth with 5 mm periodontal pockets, two of which had 6-9 mm pockets and bleeding on probing, were included in the study. All patients received full mouth SRP at baseline. Arestin was administered to all pockets > or => or = 5 mm at baseline and again at 12 weeks in the test group. Probing depth (PD), clinical attachment level (CAL), plaque index (PI), gingival index (GI), and HbA1c were evaluated at baseline and at weeks 6, 12, 18 and 24. The results demonstrated that local administration of Arestin as an adjunct to scaling and root planing is significantly more effective in reducing probing depths and providing a gain in clinical attachment levels than scaling and root planing alone in type 1 diabetic patients. Hb1Ac was reduced in all patients; however the difference between the test and control groups was not significant.

Topics: Adult; Anti-Bacterial Agents; Blood Glucose; Diabetes Mellitus, Type 1; Female; Humans; Male; Middle Aged; Minocycline; Periodontal Diseases; Pilot Projects; Single-Blind Method

A common and devastating complication of diabetes mellitus is painful diabetic neuropathy (PDN) that can be accompanied by emotional disorders such as depression. A few studies have suggested that minocycline that inhibits microglia may attenuate pain hypersensitivity in PDN. Moreover, a recent study reported that minocycline has an acute antidepressive-like effect in diabetic animals. Here we studied whether (i) prolonged minocycline treatment suppresses pain behaviour in PDN, (ii) the minocycline effect varies with submodality of pain, and (iii) the suppression of pain behaviour by prolonged minocycline treatment is associated with antidepressive-like effect. The experiments were performed in streptozotocin-induced rat model of type-1 diabetes. Pain behaviour was evoked by innocuous (monofilaments) and noxious (paw pressure) mechanical stimulation, innocuous cold (acetone drops) and noxious heat (radiant heat). Depression-like behaviour was assessed using forced swimming test. Minocycline treatment (daily 80mg/kg per os) of three-week duration started four weeks after induction of diabetes. Diabetes induced mechanical allodynia and hyperalgesia, cold allodynia, heat hypoalgesia, and depression-like behaviour. Minocycline treatment significantly attenuated mechanical allodynia and depression-like behaviour, while it failed to produce significant changes in mechanical hyperalgesia, cold allodynia or heat hypoalgesia. The results indicate that prolonged per oral treatment with minocycline has a sustained mechanical antiallodynic and antidepressive-like effect in PDN. These results support the proposal that minocycline might provide a treatment option for attenuating sensory and comorbid emotional symptoms in chronic PDN.

Topics: Analgesics; Animals; Antidepressive Agents; Cold Temperature; Depressive Disorder; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Diabetic Neuropathies; Hyperalgesia; Hypoglycemic Agents; Male; Minocycline; Random Allocation; Rats, Wistar; Touch

Topics: Acne Vulgaris; Adolescent; Allergens; Anti-Bacterial Agents; Autoantibodies; Cross Reactions; Diabetes Mellitus, Type 1; Drug Hypersensitivity Syndrome; Female; Humans; Immunomodulation; Immunosuppressive Agents; Liver Transplantation; Minocycline

Neuroinflammation and neurodegeneration have been observed in the brain in type 1 diabetes (T1D). However, little is known about the mediators of these effects. In T1D mice with 12- and 35-wk duration of diabetes we examined two mechanisms of neurodegeneration, loss of the neuroprotective factors insulin-like growth factor I (IGF-I) and IGF-binding protein-3 (IGFBP-3) and changes in indoleamine 2,3-dioxygenase (IDO) expression in the brain, and compared the response to age-matched controls. Furthermore, levels of matrix metalloproteinase-2 (MMP-2), nucleoside triphosphate diphosphohydrolase-1 (CD39), and ionized calcium-binding adaptor molecule 1 (Iba-1) were utilized to assess inflammatory changes in astrocytes, microglia, and blood vessels. In the diabetic hypothalamus (HYPO), we observed 20% reduction in neuronal soma diameter (P<0.05) and reduced neuronal expression of IGFBP-3 (-32%, P<0.05) and IGF-I (-15%, P<0.05) compared with controls at 35 wk. In diabetic HYPO, MMP-2 expression was increased in astrocytes (46%, P<0.01), and IDO⁺ cell density rose by (62%, P<0.05). CD39 expression dropped by 30% (P<0.05) in microglia and blood vessels. With 10 wk of systemic treatment using minocycline, an anti-inflammatory agent that crosses the blood-brain barrier, MMP-2, IDO, and CD39 levels normalized (P<0.05). Our results suggest that increased IDO and early loss of CD39⁺ protective cells lead to activation of inflammation in sympathetic centers of the CNS. As a downstream effect, the loss of the neuronal survival factors IGFBP-3 and IGF-I and the neurotoxic products of the kynurenine pathway contribute to the loss of neuronal density observed in the HYPO in T1D.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Astrocytes; Diabetes Mellitus, Type 1; Diabetic Neuropathies; Disease Progression; Down-Regulation; Encephalitis; Hypothalamus; Indoleamine-Pyrrole 2,3,-Dioxygenase; Inflammation Mediators; Insulin-Like Growth Factor Binding Protein 3; Insulin-Like Growth Factor I; Macrophages; Male; Mice, Inbred C57BL; Microglia; Minocycline; Nerve Tissue Proteins; Neurons; Sympathetic Nervous System; Up-Regulation

Poststroke hyperglycemia is associated with resistance to tissue plasminogen activator (tPA) reperfusion, higher risk of intracerebral hemorrhage, and worse neurological outcomes. In this study, we asked whether minocycline combined with intravenous tPA may ameliorate inflammation and brain injury after focal embolic stroke in type 1 diabetic rats.. Type 1 diabetic rats were subjected to a focal embolic stroke. Three treatment groups were used: (1) saline at 1.5 hours after stroke; (2) tPA alone at 1.5 hours after stroke; (3) combined minocycline (intravenously) at 1 hour plus tPA at 1.5 hours, and second treatment of minocycline (intraperitoneally) at 12 hours after stroke. Acute brain tissue damages were assessed at 24 hours after stroke. Inflammatory biomarkers interleukin-1β and matrix metalloproteinases 2 and 9 were examined in plasma. Neutrophil infiltration, microglia activation, matrix metalloproteinase activation, and degradation of the tight junction protein claudin-5 were examined in the brain.. Compared with saline or tPA alone treatments, minocycline plus tPA combination therapy significantly reduced brain infarction, intracerebral hemorrhage, and hemispheric swelling at 24 hours after stroke. The combination also significantly suppressed the elevated plasma levels of matrix metalloproteinase-9 and interleukin-1β up to 24 hours after stroke. At 16 hours after stroke, neutrophil infiltration, microglia activation, matrix metalloproteinase-9, and tight junction protein claudin-5 degradation in the peri-infarct brain tissues were also significantly attenuated by the combination therapy.. Combination therapy with minocycline plus tPA may be beneficial in ameliorating inflammation and reducing infarction, brain swelling, and hemorrhage after ischemic stroke with diabetes mellitus/hyperglycemia.

Topics: Animals; Anti-Bacterial Agents; Cerebral Hemorrhage; Claudin-5; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Disease Models, Animal; Drug Therapy, Combination; Fibrinolytic Agents; Interleukin-1beta; Male; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Minocycline; Rats; Rats, Wistar; Risk Factors; Streptozocin; Stroke; Tissue Plasminogen Activator

By using pseudorabies virus expressing green fluorescence protein, we found that efferent bone marrow-neural connections trace to sympathetic centers of the central nervous system in normal mice. However, this was markedly reduced in type 1 diabetes, suggesting a significant loss of bone marrow innervation. This loss of innervation was associated with a change in hematopoiesis toward generation of more monocytes and an altered diurnal release of monocytes in rodents and patients with type 1 diabetes. In the hypothalamus and granular insular cortex of mice with type 1 diabetes, bone marrow-derived microglia/macrophages were activated and found at a greater density than in controls. Infiltration of CD45(+)/CCR2(+)/GR-1(+)/Iba-1(+) bone marrow-derived monocytes into the hypothalamus could be mitigated by treatment with minocycline, an anti-inflammatory agent capable of crossing the blood-brain barrier. Our studies suggest that targeting central inflammation may facilitate management of microvascular complications.

Topics: Animals; Bone Marrow; Central Nervous System; Cytokines; Diabetes Mellitus, Type 1; Enzyme-Linked Immunosorbent Assay; Green Fluorescent Proteins; Hematopoiesis; Herpesvirus 1, Suid; Humans; Inflammation; Intercellular Signaling Peptides and Proteins; Male; Mice; Mice, Inbred C57BL; Microglia; Minocycline; Models, Biological; Monocytes; Neurons; Neurotransmitter Agents; Proto-Oncogene Proteins c-fos; Rats; Rats, Wistar; Sympathetic Nervous System

Drug hypersensitivity syndrome (DHS) is a severe, multisystem adverse drug reaction that may occur following the use of numerous medications, including anticonvulsants, sulfonamides, and minocycline hydrochloride. Long-term autoimmune sequelae of DHS have been reported, including hypothyroidism.. A 15-year-old female adolescent developed DHS 4 weeks after starting minocycline therapy for acne vulgaris. Seven weeks later she developed autoimmune hyperthyroidism (Graves disease), and 7 months after discontinuing minocycline therapy she developed autoimmune type 1 diabetes mellitus. In addition, she developed elevated titers of several markers of systemic autoimmune disease, including antinuclear, anti-Sjögren syndrome A, and anti-Smith antibodies.. Minocycline-associated DHS may be associated with multiple autoimmune sequelae, including thyroid disease, type 1 diabetes mellitus, and elevated markers of systemic autoimmunity. Long-term follow-up is needed in patients with DHS to determine the natural history of DHS-associated sequelae.

Topics: Acne Vulgaris; Adolescent; Anti-Bacterial Agents; Autoimmune Diseases; Diabetes Mellitus, Type 1; Drug Hypersensitivity; Female; Graves Disease; Humans; Minocycline

Vitamin D research is discussed in light of the hypothesis that the lower average levels of vitamin D frequently observed in autoimmune disease are not a sign of deficiency. Instead, it is proposed that the lower levels result from chronic infection with intracellular bacteria that dysregulate vitamin D metabolism by causing vitamin D receptor (VDR) dysfunction within phagocytes. The VDR dysfunction causes a decline in innate immune function that causes susceptibility to additional infections that contribute to disease progression. Evidence has been accumulating that indicates that a number of autoimmune diseases can be reversed by gradually restoring VDR function with the VDR agonist olmesartan and subinhibitory dosages of certain bacteriostatic antibiotics. Diseases showing favorable responses to treatment so far include systemic lupus erythematosis, rheumatoid arthritis, scleroderma, sarcoidosis, Sjogren's syndrome, autoimmune thyroid disease, psoriasis, ankylosing spondylitis, Reiter's syndrome, type I and II diabetes mellitus, and uveitis. Disease reversal using this approach requires limitation of vitamin D in order to avoid contributing to dysfunction of nuclear receptors and subsequent negative consequences for immune and endocrine function. Immunopathological reactions accompanying bacterial cell death require a gradual elimination of pathogens over several years. Practical and theoretical implications are discussed, along with the compatibility of this model with current research.

Topics: Animals; Anti-Bacterial Agents; Arthritis, Reactive; Arthritis, Rheumatoid; Autoimmune Diseases; Bacterial Infections; Calcifediol; Calcitriol; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Humans; Imidazoles; Minocycline; Psoriasis; Receptors, Calcitriol; Sarcoidosis; Scleroderma, Systemic; Sjogren's Syndrome; Spondylitis, Ankylosing; Tetrazoles; Thyroid Diseases; Uveitis

Topics: Anti-Bacterial Agents; Diabetes Mellitus, Type 1; Humans; Hyperpigmentation; Leg Ulcer; Male; Middle Aged; Minocycline; Prognosis; Staphylococcal Infections

Topics: Anti-Bacterial Agents; Blood Glucose; Cefoxitin; Ciprofloxacin; Diabetes Mellitus, Type 1; Drug Therapy, Combination; Glycated Hemoglobin; Humans; Injections, Subcutaneous; Insulin; Minocycline; Mycobacterium Infections; Recurrence

Topics: Adult; Animals; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Gingiva; Gingival Crevicular Fluid; Humans; Male; Microbial Collagenase; Minocycline; Rats; Rats, Inbred Strains; Tetracyclines