Original Data

Inflammation in Diabetic Encephalopathy is Prevented by C-Peptide

Anders A.F. Sima^1,2, Weixian Zhang¹, Christian W. Kreipke³, José A. Rafols³, William H. Hoffman⁴

Abstract

Encephalopathy is an increasingly recognized complication of type 1 diabetes. The underlying mechanisms are not well understood, although insulin deficiency has been implicated. The spontaneously diabetic BB/Wor-rat develops neuro-behavioral deficits and neuronal cell death in hippocampus and frontal cortex, which can be prevented by insulinomimetic C-peptide. Here we examined whether contributing factors such as activation of innate immune mediators are responsive to C-peptide replacement. Seven-month diabetic BB/Wor-rats and those treated with full C-peptide replacement were compared to age-matched control rats. Hippocampi of diabetic rats showed upregulation of RAGE and NF-κB, the former being localized to proliferating astrocytes. These changes were associated with increased expression of TNF-α, IL-1β, IL-2 and IL-6 in hippocampi of diabetic rats. Full C-peptide replacement, which did not induce hyperglycemia, resulted in significant prevention of upregulation of RAGE expression, activation of NF-κB and activation of pro-inflammatory factors. In conclusion, impaired insulin activity is associated with upregulation of RAGE and pro-inflammatory factors, and these are likely to contribute to previously described oxidative and apoptotic neuronal cell death. Replacement of insulinomimetic C-peptide significantly prevents this cascade of events.

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GAD65-Specific Cytotoxic T Lymphocytes Mediate Beta-Cell Death and Loss of Function

Sarah Rasche, Rhea Y. Busick, Anthony Quinn

Abstract

Autoimmunity to islet cell antigens like glutamic acid decarboxylase 65kD (GAD65) is associated with the destruction of insulin-producing β-cells and progression to type 1 diabetes (T1D) in NOD mice and humans. T cell responses to GAD65 are detectable in the spleen of prediabetic NOD mice and in the peripheral blood of humans prior to the onset of overt hyperglycemia. Previous findings from our lab revealed that GAD65_546-554-specific cytotoxic T lymphocytes (CTL) are present in naïve NOD mice and are able to induce islet inflammation upon adoptive transfer into NOD.scid recipients. Additionally, we found that professional antigen-presenting cells (APC) generate the p546-554 epitope from a soluble GAD65 fragment, p530-554, and from GAD65 released by injured β-cells in vivo. Here, we report that the GAD65 fragment p546-554 is a dominant CTL-inducing epitope which is naturally processed and presented by a GAD65-expressing β-cell line. Further, co-culture of GAD65_546-554-specific CTL with the β-cells leads to a reduction in insulin production and the induction of perforin-mediated cell death. Collectively, these findings support a role for the cross-presentation of GAD65 antigen in the priming and enhancement of dominant GAD65-specific CTL responses, which can directly target β-cells that display GAD65 epitopes.

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Factors Associated with the Prevalence of Diabetes Mellitus Among Elderly Men and Women Living in Mediterranean Islands: The MEDIS Study

Stefanos Tyrovolas¹, Akis Zeimbekis², Vassiliki Bountziouka¹, Katia Voutsa¹, George Pounis¹, Stalo Papoutsou¹, George Metallinos¹, Evangelia Ladoukaki³, Evangelos Polychronopoulos¹, Christos Lionis³, Demosthenes B. Panagiotakos¹

Abstract

BACKGROUND: The aim of the present work was to evaluate the relationships between socio-demographic, clinical, lifestyle and psychological characteristics and the presence of diabetes mellitus, among elderly individuals without known cardiovascular disease. METHODS: During 2005-2007, 1190 elderly (aged 65 to 100 years) men and women (from Cyprus, Mitilini, Samothraki, Cephalonia, Crete, Lemnos, Corfu and Zakynthos) were enrolled. Socio-demographic, clinical and lifestyle factors were assessed using standard procedures. Diabetes mellitus was defined as fasting blood glucose >125 mg/dl or use of special medication. RESULTS: 21% of males and 23% of females had diabetes. Only 70% of diabetic participants were on a special diet and 76% were receiving pharmaceutical treatment. Diabetic individuals had higher prevalence of hypertension (80% vs. 64%, p < 0.001) and hypercholesterolemia (63% vs. 51%, p < 0.001) and reported lower physical activity status (p < 0.001), compared with non-diabetic participants. After adjusting for various confounders, hypertension and hypercholesterolemia were associated with a 144% (95% CI, 1.37-4.35) and 83% (95% CI, 1.13-2.94) higher likelihood of having diabetes, while moderate and vigorous exercise correlated with a 82% (95% CI, 0.09-0.81) and 67% (95% CI, 0.11-0.97) lower likelihood of diabetes. CONCLUSIONS: A considerable proportion of our elderly sample had diabetes and other metabolic disorders, almost 25% of which were untreated. Promotion of physical activities, even in the elderly, may contribute to reducing their burden of diabetes and provide them with a better quality of living.

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Effect of Zinc Supplementation on Serum Homocysteine in Type 2 Diabetic Patients with Microalbuminuria

Esfandiar Heidarian, Massoud Amini, Mahmoud Parham, Ashraf Aminorroaya

Abstract

OBJECTIVES: Elevated homocysteine levels are considered to be an independent risk factor for cardiovascular complications in diabetic patients. The aim of this study was to find out if zinc supplementation improves homocysteine levels, which may exert vascular-protective effects in type 2 diabetes subjects with microalbuminuria. METHODS: In a randomized, double-blind, controlled, crossover study, 50 type 2 diabetic patients with microalbuminuria were subdivided into two groups and supplemented with 30 mg/d of zinc (group 1) or placebo (group 2) for three months with a four-week wash out period. Serum creatinine, vitamin B₁₂, folate, fasting plasma glucose, HbA1c, lipid profiles, zinc, homocysteine levels and random urine albumin were measured before and after the first and second phase of the study in all participants. RESULTS: Mean serum zinc was significantly increased after zinc supplementation (from 76 ± 16 μg/dl to 93 ± 20 µg/dl; p < 0.05), while there was no change in the placebo group (75 ± 16 µg/dl to 75 ± 15 µg/dl). With zinc supplementation, homocysteine levels reduced significantly (from 13.71 ± 3.84 μmol/l to 11.79 ± 3.06 μmol/l; p < 0.05), which did not occur on placebo (from 12.59 ± 2.13 μmol/l to 13.36 ± 2.03 μmol/l). Simple regression was used to show a positive correlation between urine albumin excretion and serum homocysteine (r = 0.37, p = 0.023). Vitamin B₁₂ and folate levels increased significantly in patients who received zinc in comparison to those who received placebo. A negative correlation was observed between homocysteine and vitamin B₁₂ concentration (r = -0.36, p = 0.025). CONCLUSION: Zinc supplementation reduced serum homocysteine and increased vitamin B₁₂ and folate concentrations in type 2 diabetic patients with microalbuminuria.

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