Diet can influence the ability of nicotinamide to prevent diabetes in the non‐obese diabetic mouse: a preliminary study

Background

The non‐obese diabetic (NOD) mouse is a widely used model of Type 1 diabetes mellitus (Type 1 DM), which displays many of the characteristics of the disease found in humans. Nicotinamide (NA) is currently being tested in large‐scale, multi‐centre human trials for the prevention of Type 1 DM in subjects considered ‘at risk’ of developing the disease. Human trial populations will certainly differ in their dietary patterns and alterations were made to the diet given to NOD mice to determine if this could alter the effect of NA administration on Type 1 DM incidence.

Methods

The effect of NA in the diet was examined, both with and without carbohydrate in the form of a sucrose supplement, on diabetes incidence and insulitis levels in the NOD mouse. The effects of NA and sucrose were each tested alone as well as in combination.

Results

Diabetes was unaltered using a low dose NA‐supplemented diet (625 mg/kg diet). Diabetes incidence was also unaltered using unmodified diet together with drinking water supplemented with either 5% or 10% w/v sucrose or plain water for controls. However, with mice given NA‐supplemented diet (625 mg/kg diet) together with sucrose‐supplemented or plain water as previously, diabetes was reduced in the NA+10% sucrose group (p<0.001). Finally, a higher dose of NA was given in supplemented diet (1000 mg/kg). Again, neither sucrose nor NA alone altered the incidence of diabetes, but NA treatment combined with a 10% w/v sucrose‐supplemented drinking water reduced diabetes incidence (p<0.001). No mice showed alterations in insulitis, blood‐glucose or insulin levels with respect to controls.

Conclusion

Altering dietary patterns using sucrose can affect the ability of NA to prevent diabetes in the NOD mouse. This finding may be relevant for human studies with NA aimed at preventing Type 1 DM and suggests that diet may need to be monitored or even controlled in these studies. Copyright © 1999 John Wiley & Sons, Ltd.

     

Clinical-MRI correlations in a European trial of interferon beta-1b in secondary progressive MS.

BACKGROUND: The recently completed placebo-controlled multicenter randomized trial of interferon beta-1b (Betaferon) in 718 patients with secondary progressive MS shows significant delay of disease progression and reduction of relapse rate. This study provides an opportunity to assess the level of relationship between clinical and MRI outcomes in this cohort of patients with secondary progressive MS. METHODS: Brain T2-weighted lesion volume was measured annually in all available patients, with visual analysis to identify any new or enlarging (active) T2 lesions at each annual time point. A subgroup of 125 patients had monthly gadolinium-enhanced, T1-weighted imaging at months 0 to 6 and 18 to 24. Relapses were documented and expanded disability status scale (EDSS) was measured every 3 months. RESULTS: For the annual MRI outcomes, a significant but modest correlation was identified between the change in T2 lesion volume from baseline to the final scan and the corresponding change from baseline in EDSS (r = 0.17, p < 0.0001). There were significant correlations between the cumulative number of active T2 lesions and 1) change in EDSS (r = 0.18, p < 0.0001) and 2) relapse rate (r = 0.24, p < 0.0001). In the subgroup of 125 patients undergoing monthly imaging, MRI lesion activity was correlated with relapse rate over months 0 to 24 (r = 0.24, p = 0.006) but not with change in EDSS. CONCLUSIONS: These results confirm that the clinical-MRI relationships previously identified in relapsing-remitting MS still are apparent in the secondary progressive phase of the disease and support the use of MRI as a relevant outcome measure. In view of the relatively modest nature of the correlations, it seems unwise to rely on such MRI measures alone as primary efficacy variables in secondary progressive MS trials.     

A 6-year clinical and MRI follow-up study of patients with relapsing–remitting multiple sclerosis treated with Interferon-beta

There are few long-term clinical and magnetic resonance imaging (MRI) data on patients treated with interferon-beta (IFN-beta) for relapsing-remitting multiple sclerosis (RRMS). The aim of this study was to provide clinical and MRI data on 68 patients with RRMS treated over a 6-year period and to investigate whether a baseline MRI predicts their long-term clinical and MRI outcome. Six MRI scans were performed monthly before treatment and a further 13 scans were performed during treatment with IFN-beta, the last of which 6 years after commencement of treatment. The relapse rate, disability as measured by the Expanded Disability Status Scale (EDSS), and MRI parameters, including Gd-enhancing lesion load (Gd-LL), T2 hyperintense lesion load (T2-LL) T1 hypointense lesion load (T1-LL) and supratentorial brain volume (SBV) were measured throughout the study. The mean annual relapse rate over the 6 years was 0.52 (SD 0.67), which is significantly lower (68.6%) than the mean annual relapse rate of 1.6 observed during the 2-year period before the commencement of treatment (P < 0.01). The median EDSS score increased from 2 to 2.5, remaining stable in 60% of the patients. From the baseline scan to the final scan, there was a median increase of 7% in the T2-LL and 23.9% in the T1-LL, whilst SBV decreased by 2.7%. The increase in the EDSS over the course of the study was significantly correlated with a reduction in brain volume (r = 0.46, P = 0.001). Greater brain damage at baseline, as measured by both T2-LL and T1-LL, was significantly associated with an increase in disability over the 6 years (r = 0.44, P = 0.0009; r = 0.50, P = 0.0007, respectively). This study shows a sustained effect of IFN-beta on the relapse rate, which is lower than during the 2 years before treatment commencement. More than half the patients showed an improvement or stabilization in the EDSS score. The increment in disability was correlated with the development of brain atrophy but not with increases in lesion burden. Finally, the finding that the extent of lesion burden at the baseline was a strong predictor of increasing disability suggests that IFN-beta treatment might have a moderate effect in modifying the multiple sclerosis (MS) disease course over 6 years unless preventive treatment is started early.     

Relation between functional connectivity and disability in multiple sclerosis: a non-linear model

Objective

To characterize the relation between brain functional connectivity and disability in patients with multiple sclerosis; to investigate the existence of critical values of both disability and functional connectivity corresponding to exhaustion of functional adaptive mechanisms.

Methods

Hundred-and-nineteen patients with no-to-severe disability and 42 healthy subjects were studied via 3T resting state functional MRI. Out of 116 regions extracted from Automated Anatomical Labeling atlas, pairs of regions whose functional connectivity correlated with Expanded Disability Status Score were identified. In patients, mathematical modeling was applied to find the best models describing Expanded-Disability-Status-Score vs structural or functional measures. Functional vs structural models intersecting points were identified.

Results

Disability had direct linear relation with lesion load (r?=?0.40, p?<?5E?6), inverse of thalamic volume (r?=?0.31 p?<?1E?3) and functional connectivity in bi-frontal pairs of regions (r?>?0.40, p?<?0.04), while being non-linearly associated with functional connectivity in cerebello-temporal and cerebello-frontal pairs of regions (F?>?1.73, p?<?0.02). Structural vs functional models intersecting points corresponded to Expanded Disability Status Score of 3.0. 85% of patients scoring more than 3.0 showed functional connectivity in cerebello-temporal and cerebello-frontal pairs of regions below confidence intervals (z?=?[2.28–2.88] 95% CI) measured in healthy subjects.

Conclusions

Functional brain connectivity changes may represent mechanisms of adaptation to structural damage and inflammation and may be not always clinically beneficial. Functional connectivity decreases in comparison with structural measure at Expanded Disability Status Score greater than 3.0, which may be critical and indicate exhaustion of compensatory mechanisms.

     

The Role of Insulin Resistance in the Natural History of Type 1 Diabetes

It is well established that peripheral insulin sensitivity is a critical factor in the aetiology of non-insulin dependent (Type 2) diabetes mellitus (NIDDM). Insulin resistance may also play a role at various stages in the natural history of insulin dependent (Type 1) diabetes (IDDM) and this was the topic of a workshop held in London on Friday 14 July 1995. The mechanisms of insulin resistance in IDDM are ill-defined but probably include ‘glucose toxicity’. In the pre-diabetic period, insulin resistance may affect rates of progression to frank hyperglycaemia. Following the clinical onset of IDDM, insulin resistance could influence the length of the ‘honeymoon period’, diabetic control and patterns of growth during puberty, insulin requirements and blood glucose control at any time, the birth weight of infants born to diabetic mothers, and, through an effect on lipid metabolism and hypertension, ultimately contribute to the excess mortality associated with IDDM. In NIDDM, insulin resistance could influence rates of progression to insulin dependence. Treatment using insulin enhancers in NIDDM patients with autoimmune changes might delay or arrest their usual high-risk of progression to insulin dependence. As it is likely that insulin resistance has a wide-ranging influence on the natural history of diabetes in IDDM patients we suggest that treatment with insulin enhancers may prove beneficial in selected patients. © 1997 by John Wiley & Sons, Ltd.