Viral Trigger for Type 1 Diabetes: Pros and Cons
Christophe M. Filippi; Matthias G. von Herrath

Introduction
The most popular hypothesis circulating within and beyond the scientific community is that viral infections enhance or elicit autoimmune disorders such as type 1 diabetes. Indeed, viruses can injure â-cells and have been isolated in pancreatic tissues from diabetic patients. However, accumulating evidence suggests that the opposite scenario, which is prevention or amelioration of type 1 diabetes, might be at least as common an outcome of viral infection. Here, we discuss epidemiological and experimental evidence for the main mechanisms accounting for the role of viruses in type 1 diabetes to better understand the complex relationship between viral infections and autoimmune diabetes.

The Influence of the Environment
Type 1 diabetes is a genetic autoimmune disorder caused by autoreactive CD4+ and CD8+ T-cells that recognize pancreatic antigens such as insulin or GAD and subsequently destroy insulin-producing â-cells. The subject of very active research is the question of how endogenous â-cell antigens become immunogenic. Infiltration of the islets of Langerhans, where â-cells reside, by activated autoreactive T-cells is considered to be the major driving force in type 1 diabetes progression. The islet infiltrate in humans consists primarily of CD8+ T-cells and B-cells, followed by macrophages and dendritic cells of different subtypes. Interestingly, significantly fewer T-cells are found in human islets compared with islets from nonobese diabetic (NOD) mice. The reduced numbers of T-cells, and in this way a limited autoreactive component in human islets, leads one to consider whether other contributing factors may be involved in disease development. Otherwise, sufficient insulitic infiltrate to destroy islet â-cells might not be easily maintained in humans. Further supporting a role for nongenetic factors in the control of type 1 diabetes is the observation that disease concordance among monozygotic twins is below 50%.

Migrant studies also suggest the involvement of an environmental factor in type 1 diabetes, since disease incidence in migrating populations appears to conform to the incidence of the region to which there is migration. There is an ever-increasing body of literature suggesting that the significant environmental component to type 1 diabetes development and progression is a viral infection. However, this has not been clearly demonstrated. In fact, viral infections appear to have both detrimental and protective effects on type 1 diabetes development, which might be contingent upon the nature of the virus, but also the immune status of the host and thus the timing of infection.

DOWNLOAD PDF COMPLETE HERE

Read More..

Metabolic Changes Following a 1-year Diet and Exercise Intervention in Patients with Type 2 Diabetes
Jeanine B. Albu; Leonie K. Heilbronn; David E. Kelley; Steven R. Smith; Koichiro Azuma; Evan S. Berk; F. Xavier Pi-Sunyer; Eric Ravussin; the Look AHEAD Adipose Research Group

Abstract
ObjectiveTo characterize the relationships among long-term improvements in peripheral insulin sensitivity (glucose disposal rate [GDR]), fasting glucose, and free fatty acids (FFAs) and concomitant changes in weight and adipose tissue mass and distribution induced by lifestyle intervention in obese individuals with type 2 diabetes.

Research Design and MethodsWe measured GDR, fasting glucose, and FFAs during a euglycemic clamp and adipose tissue mass and distribution, organ fat, and adipocyte size by dual-energy X-ray absorptiometry, CT scan, and adipose tissue biopsy in 26 men and 32 women in the Look-AHEAD trial before and after 1 year of diet and exercise aimed at weight loss.

ResultsWeight and fasting glucose decreased significantly (P < 0.0001) and significantly more in men than in women (12 vs. 8% and 16 vs. 7%, respectively; P < 0.05), while FFAs during hyperinsulinemia decreased and GDR increased significantly (P < 0.00001) and similarly in both sexes (53 vs. 41% and 63 vs. 43%; P = NS). Men achieved a more favorable fat distribution by losing more from upper compared with lower and from deeper compared with superficial adipose tissue depots (P < 0.01). Decreases in weight and adipose tissue mass predicted improvements in GDR but not in fasting glucose or fasting FFAs; however, decreases in FFAs during hyperinsulinemia significantly determined GDR improvements. Hepatic fat was the only regional fat measure whose change contributed independently to changes in metabolic variables. ConclusionsPatients with type 2 diabetes undergoing a 1-year lifestyle intervention had significant improvements in GDR, fasting glucose, FFAs and adipose tissue distribution. However, changes in overall weight (adipose tissue mass) and hepatic fat were the most important determinants of metabolic improvements.

Introduction
Most obese patients with type 2 diabetes have an unfavorable adipose tissue distribution compared with that of similarly obese men and women without type 2 diabetes.[12] We have shown that they manifest proportionally less metabolically protective adipose tissue (gluteo-femoral) and more metabolically adverse fat depots such as abdominal adipose tissue or hepatic fat.[2]

Such patterns correlate with increased fasting glucose and decreased insulin sensitivity[35] in cross-sectional studies. From the perspective of intervention, in type 2 diabetes, both caloric restriction and relatively modest weight reduction result in fasting glucose[610] as well as hepatic[7,9,1113] and peripheral insulin sensitivity[810,1213] improvements. However, not all studies reporting significant weight loss or favorable fat distribution changes have observed a concomitant improvement in peripheral insulin sensitivity.[11,14] Furthermore, there is a surprising paucity of data regarding the relationship between sustained lifestyle interventioninduced changes in fat mass and regional adipose tissue distribution and parallel metabolic improvements.

In several weight loss studies conducted for up to 6 months, in type 2 diabetes favorable changes in fat distribution and organ fat did not correlate with improved peripheral insulin sensitivity independent of the changes in body weight.[1114] Even fewer studies reported on longer-term (of up to 1 year) effects of weight loss on fat distribution and metabolic variables in type 2 diabetes.[10,1516] In one study, while parallel 1-year improvements were observed both in the fat distribution (measured by the waist-to-hip ratio) and in fasting glucose and fasting insulin,[15] the metabolic improvements did not relate to the waist-to-hip ratio change but rather to the overall amount of weight loss.[15]

One interpretation is that loss of adipose tissue, regardless of depot, is the predominant factor related to the metabolic improvement in obese patients with type 2 diabetes, challenging the tenet, built mostly from cross-sectional studies, that adipose tissue distribution is a crucial and interactive determinant of the improvement. Yet, it is not clear from these studies whether the variability of the weight loss, the sometime limited number of subjects, or incomplete adipose tissue distribution measurements permitted robust evaluation of the role of specific fat depots in the improvements in metabolic control. In addition, changes in other adipose tissue characteristics, such as fat cell sizes or circulating free fatty acids (FFAs), have not been accounted for in previous studies. Larger subcutaneous abdominal fat cells predict insulin resistance and the development of type 2 diabetes,[1719] while increased circulating FFAs play an important role in the etiology of insulin resistance and hyperglycemia in type 2 diabetes.[12,2021] Whether regional fat loss contributes to improvements in FFAs during weight loss in type 2 diabetes has not previously been reported.

The current study was therefore undertaken to examine the importance of changes in adipose tissue distribution and other closely related characteristics as determinants of the improvements in metabolic fitness in response to weight loss in type 2 diabetes. We tested the hypothesis that simple measures of weight loss rather than various relative changes and permutations of adipose tissue distribution are the predominant determinant of metabolic improvement induced by a 1-year lifestyle intervention in obese patients with type 2 diabetes. Multiple aspects of adipose tissue mass and its distribution were assessed, including upper and lower adipose tissue mass (using dual-energy X-ray absorptiometry [DEXA]), adipose tissue subdivisions in the abdomen and lower extremity (using computed tomography [CT] imaging), and estimations of fat content in liver and muscle (using CT imaging). This was performed along with an adipose tissue biopsy in order to measure mean fat cell size within the abdominal subcutaneous depot both at baseline and following the 1 year of lifestyle intervention.

DOWNLOAD PDF COMPLETE HERE

Read More..

Mid- and Late-life Diabetes in Relation to the Risk of Dementia: A Population-based Twin Study
Weili Xu; Chengxuan Qiu; Margaret Gatz; Nancy L. Pedersen; Boo Johansson; Laura Fratiglioni

Abstract
Objective: We aimed to verify the association between diabetes and the risk of dementia, Alzheimer's disease, and vascular dementia in twins and to explore whether genetic and early-life environmental factors could contribute to this association.

Research Design and Methods: This study included 13,693 twin individuals aged 65 years. Dementia was diagnosed according to DSM-IV (Diagnostic Manual of Mental Disorders, 4th ed.) criteria. Information on diabetes was collected from the inpatient registry and self- or informant-reported history of diabetes. Data were analyzed following two strategies: 1) unmatched case-control analysis for all participants using generalized estimating equation (GEE) models and 2) cotwin matched case-control analysis for dementia-discordant twin pairs using conditional logistic regression.

Results: Of all participants, 467 were diagnosed with dementia, including 292 with Alzheimer's disease and 105 with vascular dementia, and an additional 170 were diagnosed with questionable dementia. Diabetes was present in 1,396 subjects. In GEE models, diabetes was associated with adjusted odds ratios (ORs) (95% CI) of 1.89 (1.51-2.38) for dementia, 1.69 (1.16-2.36) for Alzheimer's disease, and 2.17 (1.36-3.47) for vascular dementia. Compared with late-life diabetes (onset age 65 years), the risk effect of mid-life diabetes (onset age < 65 years) on dementia was stronger. Conditional logistic analysis of 210 dementia-discordant twin pairs led to ORs of 2.41 (1.05-5.51) and 0.68 (0.30-1.53) for dementia related to mid- and late-life diabetes, respectively. Conclusions: Diabetes increases the risk of Alzheimer disease and vascular dementia. The risk is stronger when diabetes occurs at mid-life than in late life. Genetic and early-life environmental factors might contribute to the late-life diabetesdementia association but could not account for the mid-life diabetes-dementia association.

Introduction
Population-based longitudinal studies have shown that the risk of dementia in general is increased in people with diabetes. Even pre-diabetes has been associated with an increased risk of dementia and Alzheimer disease. Although diabetes may be linked to dementia through several biologically plausible pathways, our understanding of the mechanisms for such an association is still limited. Both dementia and diabetes are complex age- and lifestyle-related disorders. In addition to strong influence of environmental elements, genetic components also play a part in both Alzheimer's disease and diabetes.

Epidemiological and clinical studies have reported that environmental factors acting in early life, such as birth weight and childhood socioeconomic situation, are also involved in the development of diabetes as well as dementia. Evidence from genetic and epidemiological studies has indicated that genetic and environmental factors may interact to affect the association between diabetes and dementia during the life course. The recent upsurge of interest in applying a life-course approach to chronic disease epidemiology and the hypothesis of "developmental origins of adult disease" prompt renewed attention to twin studies.

Twins provide naturally matched pairs, in which confounding effects of a large number of potentially causal factors (e.g., genetics and childhood environment) may be removed when comparisons are made between twins. Because twins are generally reared together, they share their early-life environment. Twin studies involving a life-course approach may help to identify genetic influences and timing of environmental influences on the relationship between age-related disorders. In the current study, we sought to 1) verify the association between diabetes and risk of dementia and its main subtypes in twins, 2) examine whether the effect of diabetes on dementia risk varies according to age of diabetes onset, and 3) explore whether genetic and early-life familial environmental factors could explain this association using data from the population-based Swedish twin cohort.

DOWNLOAD PDF COMPLETE HERE

Read More..

Hyperglycemia and Adverse Pregnancy Outcome (HAPO) Study : Associations with Neonatal Anthropometrics
The HAPO Study Cooperative Research Group

Abstract
ObjectiveTo examine associations of neonatal adiposity with maternal glucose levels and cord serum C-peptide in a multicenter multinational study, the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) Study, thereby assessing the Pederson hypothesis linking maternal glycemia and fetal hyperinsulinemia to neonatal adiposity.

Research Design and MethodsEligible pregnant women underwent a standard 75-g oral glucose tolerance test between 24 and 32 weeks gestation (as close to 28 weeks as possible). Neonatal anthropometrics and cord serum C-peptide were measured. Associations of maternal glucose and cord serum C-peptide with neonatal adiposity (sum of skin folds >90^th percentile or percent body fat > 90^th percentile) were assessed using multiple logistic regression analyses, with adjustment for potential confounders, including maternal age, parity, BMI, mean arterial pressure, height, gestational age at delivery, and the baby's sex.

ResultsAmong 23,316 HAPO Study participants with glucose levels blinded to caregivers, cord serum C-peptide results were available for 19,885 babies and skin fold measurements for 19,389. For measures of neonatal adiposity, there were strong statistically significant gradients across increasing levels of maternal glucose and cord serum C-peptide, which persisted after adjustment for potential confounders. In fully adjusted continuous variable models, odds ratios ranged from 1.35 to 1.44 for the two measures of adiposity for fasting, 1-h, and 2-h plasma glucose higher by 1 SD.

ConclusionsThese findings confirm the link between maternal glucose and neonatal adiposity and suggest that the relationship is mediated by fetal insulin production and that the Pedersen hypothesis describes a basic biological relationship influencing fetal growth.

Introduction
The objective of the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) Study was to clarify the risk of adverse outcome associated with degrees of glucose intolerance during pregnancy that are less severe than overt diabetes. Glucose tolerance was measured by a 75-g 2-h oral glucose tolerance test (OGTT) in a large, heterogeneous, multinational, ethnically diverse cohort of women at 2432 (mean 28) weeks gestation with medical caregivers blinded to status of glucose tolerance (except when predefined thresholds were met).[1] Associations between maternal glycemia and increased size at birth, delivery by cesarean section, development of neonatal hypoglycemia, and the presence of fetal hyperinsulinemia were the predefined primary outcomes of the study. Results of the study showing continuous relationships of maternal glucose levels below those diagnostic of diabetes with each of the primary outcomes have been reported.[2] Associations of maternal glucose and birth weight >90th percentile and fetal hyperinsulinemia [cord C-peptide concentration greater than the HAPO Study 90th percentile (1.7 ìg/l)] were strong. Weaker associations were found with cesarean delivery and clinical neonatal hypoglycemia.[2]

In 1952, Pedersen[3] postulated that maternal hyperglycemia was transmitted to the fetus, which, in turn, produced and released large amounts of insulin, with the resultant fetal hyperinsulinemia being the cause of various aspects of diabetic fetopathy, including deposition of large amounts of body fat, which gave the infant its characteristic appearance. Pedersen documented increased body weight in infants of diabetic mothers compared with control subjects. Fetal hyperinsulinemia, in the absence of maternal diabetes, has been demonstrated to cause "diabetes-like" fetopathy in rhesus monkey offspring.[4] At least some of the increased fetal weight has been shown to be attributable to increased fat accretion.[5]

In 1977, Whitelaw[6] reported an association between diabetic control and skin fold thickness in infants of diabetic mothers. Sparks reported that body fat more specifically represents effects of the in utero environment, whereas lean body mass represents more of the genetic component of growth.[7] For example, male neonates have greater birth weight than females primarily because of increases in lean body mass.[8] Therefore, we elected to estimate body composition, in particular fat mass and percent body fat, as specific outcomes in the HAPO Study cohort.

These reports and many others validate the basic tenets of the Pedersen hypothesis. However, efforts to define the strength of associations with hyperglycemia are confounded by treatment. Furthermore, the direct link between maternal glycemia, fetal insulin response, and neonatal body composition has not yet been demonstrated in the subdiabetic glucose range. Goals of this report are 1) to examine associations of maternal glycemia with newborn anthropometrics (skin folds, percent body fat); and 2) to present data linking fetal hyperinsulinemia (assessed by cord serum C-peptide) to the development of larger and more obese babies.

DOWNLOAD PDF COMPLETE HERE

Read More..

Can We Learn from Viruses How to Prevent Type 1 Diabetes? : The Role
of Viral Infections in the Pathogenesis of Type 1 Diabetes and the
Development of Novel Combination Therapies
Matthias von Herrath

Abstract
We will take a journey from basic pathogenetic mechanisms elicited by viral infections that play a role in the development of type 1 diabetes to clinical interventions, where we will discuss novel combination therapies. The role of viral infections in the development of type 1 diabetes is a rather interesting topic because in experimental models viruses appear capable of both accelerating as well as decelerating the immunological processes leading to type 1 diabetes. Consequently, I will discuss some of the underlying mechanisms for each situation and consider methods to investigate the proposed dichotomy for the involvement of viruses in human type 1 diabetes.

Prevention of type 1 diabetes by infection supports the so-called "hygiene hypothesis." Interestingly, viruses invoke mechanisms that need to be exploited by novel combinatorial immune-based interventions, the first one being the elimination of autoaggressive T-cells attacking the â-cells, ultimately leading to their immediate but temporally limited amelioration. The other is the invigoration of regulatory T-cells (Tregs), which can mediate long-term tolerance to â-cell proteins in the pancreatic islets and draining lymph nodes. In combination, these two immune elements have the potential to permanently stop type 1 diabetes. It is my belief that only combination therapies will enable the permanent prevention and curing of type 1 diabetes.

Introduction
It is a great honor for me to receive this year's American Diabetes Association Outstanding Scientific Achievement Award, and I would like to express my sincere gratitude to my peers. What do we know about type 1 diabetes? Well, we can be pretty certain that it is an autoimmune disease. Data from partial pancreas transplants between monozygotic twins showed that the nondiabetic pancreas was rapidly destroyed following transplantation[1] and was accompanied by infiltration of the islets, called insulitis, which is indicative of a strong autoreactive response, in the affected diabetic twin who received the transplant. In addition, autoantibodies to â-cell antigens precede the clinical onset of hyperglycemia and can predict the risk of developing diabetes.[2,3] It is, however, still unclear what causes this autoreactivity to begin with. In addition to a strong genetic component, environmental factors, such as viral infections, lifestyle, and nutrition, have been implicated.

One noteworthy and striking observation in human type 1 diabetes is that the degree of islet inflammation is rather mild, that is, only a small percentage of islets are affected, especially in comparison with animal models. Pipeleers and colleagues[4] found that only 34% of all islets in pre-diabetic patients are affected by insulitis, a percentage that increased to somewhat higher levels at the time of diabetes diagnosis. Although the pathogenetic implication of this low degree of inflammation is unclear, it might be important in understanding how viral infections, as an additional factor, might contribute to the disease process.

Thus, there are many open questions, some of which we will need to answer in order to cure this terrible disease. Usually, and this is also the case for our group, animal models are utilized to better understand these and other immunological processes in type 1 diabetes pathogenesis as well as to define novel interventions. However, translation of at least some of the findings to human type 1 diabetes has been frustrating and ineffective. In this presentation, I will touch on several of the aforementioned issues and delineate present and future strategies that could help improve our mechanistic understanding and translational successes.

DOWNLOAD PDF COMPLETE HERE

Read More..