Prophylactic insulin treatment in relatives at high risk for type 1 diabetes

Ziegler, Anette‐G.; Bachmann, W. E.; Rabl, Wolfgang

doi:10.1002/dmr.5610090409

Cited by 29 publications

(12 citation statements)

References 14 publications

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“…It has been shown that prophylactic insulin treatment of subjects at high risk of developing IDDM significantly delayed the onset of diabetes [7,8]. The same improvement was observed in different animal models of type 1 diabetes, either induced by neonatal streptozotocin [9], or the spontaneous models, the BB rat [10][11][12] and the NOD mouse [13].…”

Section: Introductionmentioning

confidence: 72%

Effect of Prophylactic Insulin Treatment on the Number of ER-MP23+Macrophages in the Pancreas of NOD Mice. Is the Prevention of Diabetes Based on β-cell Rest?

Jansen

Rosmalen

Homo‐Delarche

et al. 1996

Journal of Autoimmunity

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Prophylactic insulin treatment has been shown to have beneficial effects in type 1 diabetes, both in humans and in various animal models of the disease. In experimental models, the protective effect of prophylactic insulin treatment was observed in two parameters: (1) progression of insulitis and (2) diabetes incidence. The mechanism of protection still remains to be investigated. We therefore analysed by immunohistochemistry the effect of prophylactic insulin treatment vs placebo treatment (from 4 to 13 weeks of age) on ER-MP23 + macrophage infiltration in and around pancreatic islets in the non-obese diabetic (NOD) mouse, a spontaneous model for type 1 diabetes. BALB/c mice were used as diabetes-free controls. Using conventional haematoxylin-eosin staining, we detected a protective effect of prophylactic insulin treatment in NOD females on the lymphocytic insulitis, significant at 13 weeks, but not at 9 weeks of age. However, when assessed by immunostaining for early infiltration of ER-MP23 + macrophages around islets, the reduction in severity of insulitis could already be detected as early as 9 weeks of age. With regard to the early accumulation of ER-MP23 + cells, we observed that their numbers per mm 2 surface area of the exocrine pancreas and per m at the circumference of the islet were higher in placebo-treated NODs (197±13.8 and 14±0.9, respectively) as compared to age-matched BALB/c mice (123.1±7.1 and 3.5±0.9, respectively). Prophylactic insulin treatment of NODs lowered the attraction of ER-MP23 + macrophages to the exocrine pancreas and to the circumference of the islets (156.3±8.5 and 7.9±1, respectively). Interestingly also, the islet size was found to be larger in placebo-treated NODs (51% was larger than 10 m 2 ) than in age-matched BALB/c mice (9% larger than 10 m 2 ). Prophylactic insulin treatment of NODs reduced their islet size to sizes found in the control BALB/c strain. In conclusion, the decrease in islet size by early insulin administration, and the lower attraction of ER-MP23 + macrophages to the islets are morphological indications that prevention of diabetes development by prophylactic insulin treatment results from a downregulation of islet metabolism and growth, with a concomitant decline in the release of islet factors attracting macrophages.

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Section: Introductionmentioning

confidence: 72%

Effect of Prophylactic Insulin Treatment on the Number of ER-MP23+Macrophages in the Pancreas of NOD Mice. Is the Prevention of Diabetes Based on β-cell Rest?

Jansen

Rosmalen

Homo‐Delarche

et al. 1996

Journal of Autoimmunity

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“…7). Pilot studies suggest that low-dose insulin therapy may also delay the onset of diabetes in individuals with insulin and other autoantibodies (31)(32)(33), although a recent clinical trial failed to delay the onset of diabetes in patients with a high risk for type 1 diabetes (34). The most likely mechanism for the prevention of diabetes in mice and people by low-dose insulin therapy is the induction of tolerance to insulin.…”

Section: Discussionmentioning

confidence: 99%

Extrapancreatic insulin-producing cells in multiple organs in diabetes

Kojima

Fujimiya

Matsumura

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

192

183

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Insulin-producing cells normally occur only in the pancreas and thymus. Surprisingly, we found widespread insulin mRNA and protein expression in different diabetic mouse and rat models, including streptozotocin-treated mice and rats, ob͞ob mice, and mice fed high-fat diets. We detected in diabetic mice proinsulinand insulin-positive cells in the liver, adipose tissue, spleen, bone marrow, and thymus; many cells also produced glucagon, somatostatin, and pancreatic polypeptide. By in situ nucleic acid hybridization, diabetic, but not nondiabetic, mouse liver exhibited insulin transcript-positive cells, indicating that insulin was synthesized by these cells. In transgenic mice that express GFP driven by the mouse insulin promoter, streptozotocin-induced diabetes led to the appearance of GFP-positive cells in liver, adipose tissue, and bone marrow; the fluorescent signals showed complete concordance with the presence of immunoreactive proinsulin. Hyperglycemia produced by glucose injections in nondiabetic mice led to the appearance of proinsulin-and insulin-positive cells within 3 days. Bone marrow transplantation experiments showed that most of the extrapancreatic proinsulin-producing cells originated from the bone marrow. Immunoreactive proinsulin-and insulin-positive cells were also detected in the liver, adipose tissue, and bone marrow of diabetic rats, indicating that extrapancreatic, extrathymic insulin production occurs in more than one species. These observations have implications for the regulation of insulin gene expression, modulation of selftolerance by insulin gene expression, and strategies for the generation of insulin-producing cells for the treatment of diabetes.pancreatic islets ͉ hyperglycemia ͉ ob͞ob ͉ obesity ͉ bone marrow transplantation I nsulin is normally produced in highly specialized cells of the endocrine pancreas. The tissue-specific expression of insulin is tightly regulated at the transcriptional level, and the major regulatory elements are located in the 5Ј flanking region of the insulin gene (1). Insulin expression is specific to ␤ cells in the pancreatic islets, although proinsulin has also been detected in the fetal and postnatal thymus and spleen͞lymphoid tissues (2, 3), a pattern of promiscuous expression of normally tissuerestricted ''peripheral'' proteins in these tissues (4, 5). Immunoreactivity to insulin plays a key role in autoimmune diabetes in NOD mice (6, 7) and in type 1 diabetes in humans (7); expression of minute amounts of insulin in the thymus is believed to be important in the induction of tolerance to insulin and other ''self-antigens '' (8-11). In this study, we found insulin gene transcription and protein expression in multiple tissues outside the pancreas and thymus in mice and rats with diabetes. The widespread occurrence of extrapancreatic, extrathymic insulin gene products in diabetic animals is surprising; it suggests that we should revise our thinking on the regulation of insulin gene expression, the mechanism of immune tolerance to insulin, the pathophysi...

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“…It is possible to screen newborn children to identify those at increased risk for developing type 1 diabetes (267)(268)(269). This strategy cannot be recommended until a proven intervention is available to delay or prevent the disease (270 ).…”

Section: Recommendation: Routine Measurement Of Genetic Markers Is Nomentioning

confidence: 99%

Guidelines and Recommendations for Laboratory Analysis in the Diagnosis and Management of Diabetes Mellitus

et al. 2011

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BACKGROUND Multiple laboratory tests are used to diagnose and manage patients with diabetes mellitus. The quality of the scientific evidence supporting the use of these tests varies substantially. APPROACH An expert committee compiled evidence-based recommendations for the use of laboratory testing for patients with diabetes. A new system was developed to grade the overall quality of the evidence and the strength of the recommendations. Draft guidelines were posted on the Internet and presented at the 2007 Arnold O. Beckman Conference. The document was modified in response to oral and written comments, and a revised draft was posted in 2010 and again modified in response to written comments. The National Academy of Clinical Biochemistry and the Evidence Based Laboratory Medicine Committee of the AACC jointly reviewed the guidelines, which were accepted after revisions by the Professional Practice Committee and subsequently approved by the Executive Committee of the American Diabetes Association. CONTENT In addition to long-standing criteria based on measurement of plasma glucose, diabetes can be diagnosed by demonstrating increased blood hemoglobin A1c (Hb A1c) concentrations. Monitoring of glycemic control is performed by self-monitoring of plasma or blood glucose with meters and by laboratory analysis of Hb A1c. The potential roles of noninvasive glucose monitoring, genetic testing, and measurement of autoantibodies, urine albumin, insulin, proinsulin, C-peptide, and other analytes are addressed. SUMMARY The guidelines provide specific recommendations that are based on published data or derived from expert consensus. Several analytes have minimal clinical value at present, and their measurement is not recommended.

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Prophylactic insulin treatment in relatives at high risk for type 1 diabetes

Cited by 29 publications

References 14 publications

Effect of Prophylactic Insulin Treatment on the Number of ER-MP23+Macrophages in the Pancreas of NOD Mice. Is the Prevention of Diabetes Based on β-cell Rest?

Effect of Prophylactic Insulin Treatment on the Number of ER-MP23+Macrophages in the Pancreas of NOD Mice. Is the Prevention of Diabetes Based on β-cell Rest?

Extrapancreatic insulin-producing cells in multiple organs in diabetes

Guidelines and Recommendations for Laboratory Analysis in the Diagnosis and Management of Diabetes Mellitus

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