Association of Metformin Use with Outcomes in Advanced Endometrial Cancer Treated with Chemotherapy

There is increasing evidence that metformin, a commonly used treatment for diabetes, might have the potential to be repurposed as an economical and safe cancer therapeutic. The aim of this study was to determine whether stage III-IV or recurrent endometrial cancer patients who are using metformin during treatment with chemotherapy have improved survival. To test this we analyzed a retrospective cohort of subjects at two independent institutions who received chemotherapy for stage III-IV or recurrent endometrial cancer from 1992 to 2011. Diagnosis of diabetes, metformin use, demographics, endometrial cancer clinico-pathologic parameters, and survival duration were abstracted. The primary outcome was overall survival. The final cohort included 349 patients, 31 (8.9%) had diabetes and used metformin, 28 (8.0%) had diabetes but did not use metformin, and 291 (83.4%) did not have diabetes. The results demonstrate that the median overall survival was 45.6 months for patients with diabetes who used metformin compared to 12.5 months for patients with diabetes who did not use metformin and 28.5 months for patients without diabetes (log-rank test comparing the three groups P = 0.006). In a model adjusted for confounders, the difference in survival between the three groups remained statistically significant (P = 0.023). The improvement in survival among metformin users was not explained by better baseline health status or more aggressive use of chemotherapy. Overall, the findings in this retrospective cohort of endometrial cancer patients with stage III-IV or recurrent disease treated with chemotherapy indicate that patients with diabetes who were concurrently treated with metformin survived longer than patients with diabetes who did not use metformin.     

Anti-Insulin Immune Responses Are Detectable in Dogs with Spontaneous Diabetes

Diabetes mellitus occurs spontaneously in dogs. Although canine diabetes shares many features with human type-1 diabetes, there are differences that have cast doubt on the immunologic origin of the canine disease. In this study, we examined whether peripheral immune responses directed against islet antigens were present in dogs with diabetes. Routine diagnostics were used to confirm diabetic status, and serum samples from dogs with (N = 15) and without (N = 15) diabetes were analyzed for the presence of antibodies against islet antigens (insulin, glutamic acid decarboxylase, insulinoma-associated protein tyrosine phosphatase, and islet beta-cell zinc cation efflux transporter) using standard radioassays. Interferon-γ production from peripheral blood T cells stimulated by porcine insulin and by human insulin was tested using Elispot assays. Anti-insulin antibodies were detectable in a subset of diabetic dogs receiving insulin therapy. Pre-activated T cells and incipient insulin-reactive T cells in response to porcine or human insulin were identified in non-diabetic dogs and in dogs with diabetes. The data show that humoral and cellular anti-insulin immune responses are detectable in dogs with diabetes. This in turn provides support for the potential to ethically use dogs with diabetes to study the therapeutic potential of antigen-specific tolerance.     

Placental triglyceride accumulation in maternal type 1 diabetes is associated with increased lipase gene expression

Maternal diabetes can cause fetal macrosomia and increased risk of obesity, diabetes, and cardiovascular disease in adulthood of the offspring. Although increased transplacental lipid transport could be involved, the impact of maternal type 1 diabetes on molecular mechanisms for lipid transport in placenta is largely unknown. To examine whether maternal type 1 diabetes affects placental lipid metabolism, we measured lipids and mRNA expression of lipase-encoding genes in placentas from women with type 1 diabetes (n = 27) and a control group (n = 21). The placental triglyceride (TG) concentration and mRNA expression of endothelial lipase (EL) and hormone-sensitive lipase (HSL) were increased in placentas from women with diabetes. The differences were more pronounced in women with diabetes and suboptimal metabolic control than in women with diabetes and good metabolic control. Placental mRNA expression of lipoprotein lipase and lysosomal lipase were similar in women with diabetes and the control group. Immunohistochemistry showed EL protein in syncytiotrophoblasts facing the maternal blood and endothelial cells facing the fetal blood in placentas from both normal women and women with diabetes. These results suggest that maternal type 1 diabetes is associated with TG accumulation and increased EL and HSL gene expression in placenta and that optimal metabolic control reduces these effects.     

Rotavirus infection accelerates type 1 diabetes in mice with established insulitis

Infection modulates type 1 diabetes, a common autoimmune disease characterized by the destruction of insulin-producing islet beta cells in the pancreas. Childhood rotavirus infections have been associated with exacerbations in islet autoimmunity. Nonobese diabetic (NOD) mice develop lymphocytic islet infiltration (insulitis) and then clinical diabetes, whereas NOD8.3 TCR mice, transgenic for a T-cell receptor (TCR) specific for an important islet autoantigen, show more rapid diabetes onset. Oral infection of infant NOD mice with the monkey rotavirus strain RRV delays diabetes development. Here, the effect of RRV infection on diabetes development once insulitis is established was determined. NOD and NOD8.3 TCR mice were inoculated with RRV aged > or = 12 and 5 weeks, respectively. Diabetes onset was significantly accelerated in both models (P < 0.024), although RRV infection was asymptomatic and confined to the intestine. The degree of diabetes acceleration was related to the serum antibody titer to RRV. RRV-infected NOD mice showed a possible trend toward increased insulitis development. Infected males showed increased CD8(+) T-cell proportions in islets. Levels of beta-cell major histocompatibility complex class I expression and islet tumor necrosis factor alpha mRNA were elevated in at least one model. NOD mouse exposure to mouse rotavirus in a natural experiment also accelerated diabetes. Thus, rotavirus infection after beta-cell autoimmunity is established affects insulitis and exacerbates diabetes. A possible mechanism involves increased exposure of beta cells to immune recognition and activation of autoreactive T cells by proinflammatory cytokines. The timing of infection relative to mouse age and degree of insulitis determines whether diabetes onset is delayed, unaltered, or accelerated.     

Bone mass in young patients with type I diabetes

We measured bone mineral content (BMC) with single photon absorptiometry in two groups of young patients with type I diabetes: the first group (prospective study) consists of 48 patients followed from onset to the third year of diabetes and the second group (cross-sectional study) consists of 66 long-term diabetics. Bone mineral content at onset of disease was lower than normal in only two cases. After 3 years of diabetes no male revealed BMC below the normal range but two females (6.6%) had low BMC values. In our cross-sectional study we found a BMC reduction in 12% of the cases. We did not find a relationship between bone deficit and duration of diabetes, or bone mass values and HbA1.     

Cause of death in 1144 patients with diabetes mellitus: an autopsy study.

The pathological reports for all patients over 13 years of age who had had an autopsy at one of three university-affiliated hospitals between 1967 and 1976 were reviewed to determine the principal cause of death. The clinical records of the patients with diabetes were reviewed to verify the diagnosis and to determine the known duration of diabetes. There were 1144 patients with diabetes mellitus and 5674 without. The sex distribution was similar in the two groups. The patients with diabetes were slightly older, males by 2.2 years and females by 3.2 years. Disease of the circulatory system was the principal cause of death in males (53.7%) and females (58.9%) with diabetes. The rates in the corresponding patients without diabetes were 37.6% and 35.2%. Neoplasms accounted for 18.9% of deaths in males with diabetes, compared with 35.7% in males without diabetes; the corresponding figures in females were 16.0% and 39.4%. Renal disease accounted for 5.9% of deaths in patients with diabetes.     

Number and sex ratio of children and impact of parental diabetes in individuals with Type 1 diabetes

Diabet. Med. 29, 1268-1271 (2012) ABSTRACT: Objective To assess the number and sex ratio of children in individuals with Type?1 diabetes mellitus and the influence of parental diabetes on age at onset of Type?1 diabetes in our cohort. Methods In a cross-sectional study in a German region comprising 350?000 inhabitants, 697 subjects with Type?1 diabetes (364 women, 333 men) underwent a standardized assessment regarding the number and sex of their children and the family history of diabetes. Results Compared with 1.36 children per woman in the German background population, the total fertility rate in the calendar year of 2010 in our female cohort with Type?1 diabetes (age 18-49?years) was 0.88. Men with Type?1 diabetes had a fertility rate of 0.65. More men (51.1%) than women (35.7%; P?相似文献   

High Peritoneal Transport Status Was Not Associated with Mortality in Peritoneal Dialysis Patients with Diabetes

Background

Continuous ambulatory peritoneal dialysis (CAPD) patients with diabetes are at increased risk of mortality and high peritoneal transporters appear to contribute to poor survival. However, little is known about the combined impacts of high peritoneal transporters and diabetes on mortality.

Methods

This was a prospective observational cohort study. 776 incident CAPD patients were enrolled. Unadjusted and adjusted Cox proportional regression models were used to evaluate the association and interaction of peritoneal transport and diabetic status with mortality

Results

In the entire cohort, high peritoneal transport status was associated with an increased risk of all-cause mortality in unadjusted model [hazard ratio (HR) 2.35, 95% confidence interval (CI) 1.30 to 4.25, P = 0.01], but this association was not significant in multivariable model. There was an interaction between peritoneal membrane transport status and diabetes (P = 0.028). Subgroup analyses showed that compared to low and low average transporters, high transporters was associated with a higher risk of all-cause mortality (adjusted HR 1.78, 95% CI 1.07 to 4.70, P = 0.04) in CAPD patients without diabetes, but not in those with diabetes (adjusted HR 0.79, 95%CI 0.33 to 1.89, P = 0.59). Results were similar when transport status was assessed as a continuous variable.

Conclusions

The association between high peritoneal transport and all-cause mortality was likely to vary with diabetes status. High peritoneal transport was associated with an elevated risk of death among CAPD patients without diabetes, but not in those with diabetes.     

Anaemia, Haemoglobin Level and Cause-Specific Mortality in People with and without Diabetes

Background

Both anaemia and cardiovascular disease (CVD) are common in people with diabetes. While individually both characteristics are known to raise mortality risk, their combined influence has yet to be quantified. In this pooling project, we examined the combined impact of baseline haemoglobin levels and existing CVD on all-cause and CVD mortality in people with diabetes. We draw comparison of these effects with those apparent in diabetes-free individuals.

Methods/Principal Findings

A combined analyses of 7 UK population-based cohorts resulted in 26,480 study members. There were 946 participants with physician-diagnosed diabetes, 2227 with anaemia [haemoglobin<13 g/dl (men) or <12 (women)], 2592 with existing CVD (stroke, ischaemic heart disease), and 21,396 with none of the conditions. Across diabetes and anaemia subgroups, and using diabetes-free, non-anaemic participants as the referent group, the adjusted hazard ratios (HR) were 1.46 (95% CI: 1.30–1.63) for anaemia, 1.67 (1.45–1.92) for diabetes, and 2.10 (1.55–2.85) for diabetes and anaemia combined. Across combined diabetes, anaemia and CVD subgroups, and compared with non-anaemic, diabetes-free and CVD-free participants, HR (95% CI) for all-cause mortality were 1.49 (1.32–1.69) anaemia, 1.60 (1.46–1.76) for existing CVD, and 1.66 (1.39–1.97) for diabetes alone. Equivalents were 2.13 (1.48–3.07) for anaemia and diabetes, 2.68 (2.14–3.36) for diabetes and existing CVD, and 3.25 (1.88–5.62) for the three combined. Patterns were similar for CVD mortality.

Conclusions/Significance

Individually, anaemia and CVD confer similar mortality risks in people with diabetes, and are excessively fatal in combination. Screening for anaemia would identify vulnerable diabetic patients whose outcomes can potentially be improved.     

Depression in Persons with Diabetes by Age and Antidiabetic Treatment: A Cross-Sectional Analysis with Data from the Hordaland Health Study

BackgroundPersons with diabetes have increased risk of depression, however, studies addressing whether the risk varies by age and type of antidiabetic treatment have yielded conflicting results. The aim of this study was to investigate if the association between diabetes and depression varied by type of antidiabetic treatment in a large community based sample of middle-aged (40–47 years) and older adults (70–72 years).MethodsData from 21845 participants in the Hordaland Health Study (HUSK) were analyzed in a cross-sectional design. Diabetes was assessed by self-report and classified as un-medicated, treated by oral antidiabetic agents or by insulin. Depression was defined as a score ≥8 on the depression subscale of the Hospital Anxiety and Depression Scale and/or self-reported use of antidepressant agents. Associations between diabetes and depression were estimated using logistic regression.ResultsPersons in their forties with diabetes had a doubled prevalence of depression (OR: 1.96 (95% C.I.: 1.35, 2.83)) compared to persons without diabetes, while a lower and non-significant association was found among persons in their seventies. Persons in their forties with orally treated diabetes had about three times higher prevalence of depression (OR: 2.92 (95% C.I.: 1.48, 5.77)) after adjustment for gender, BMI, physical activity, alcohol consumption and education, compared to non-diabetic persons in the same age-group. No association between depression and insulin or un-medicated diabetes was found.ConclusionsClinicians should be aware that persons in their forties with orally treated diabetes are at a marked increased risk of depression.     

Lipid metabolism in children and adolescents with insulin dependent diabetes. II. Evaluation of changes in lipoprotein A-I in children and adolescents with insulin dependent diabetes]

The levels of lipoprotein A-I (LP A-I) containing apolipoprotein A-I (apo A-I) and devoid of apolipoprotein A-II (apo A-II) have been determined in a group of 86 children and adolescents with insulin-dependent diabetes of age between 1.3 and 22 years. The duration of diabetes in the studied group ranged between 0.25 and 15 years. The patients studied were further divided into subgroups taking into account the duration of diabetes as well as the occurrence of complications of diabetes, obesity and predisposition to early development of atherosclerosis in family history. The analysis of the results took into account the relations between the levels of LP A-I and other parameters of lipid metabolism like cholesterol, triglycerides, HDL-cholesterol, apo A-I and apo A-II concentrations as well as the effectiveness of metabolic control of diabetes. LP A-I concentration was the lowest in group of children with diabetes lasting up to one year. This parameter was correlated positively with the levels of HDL-cholesterol and apo A-I, and negatively with HbA1c. It was not related to the coexisting complications, obesity or predisposition to atherosclerosis in family history. The above results indicate that the state of metabolic control of diabetes significantly influences the level of LP A-I. Considering the importance of LP A-I in preventing atherosclerosis it should be stressed that a decrease in its level during the period of prolonged hypoglycemia constitutes still another risk factor for development of atherosclerosis in diabetic children and adolescents.     

Predictors of type 2 diabetes in a nationally representative sample of adults with psychosis

Antipsychotic drugs such as clozapine and olanzapine are associated with an increased risk for type 2 diabetes, but relatively little is known about the relationship between risk factors for type 2 diabetes established in the general population and type 2 diabetes in people with psychosis. We estimated the prevalence of established risk factors and their association with type 2 diabetes in a nationally representative sample of people with an ICD‐10 psychosis (N=1642) who gave a fasting blood sample (N=1155). Logistic regression was used to summarize associations adjusted for age and sex. In this sample, whose mean duration of psychosis was 14.7 years, 12.1% (13.1% of women and 11.5% of men) had type 2 diabetes at age 18–64 years based on current fasting blood glucose levels or treatment with a hypoglycaemic drug. Risk was greatly increased in young adults compared with the general population and peaked in middle age. Risk factors in the general population were common in people with psychosis and strongly associated with type 2 diabetes in those people. Treatment with clozapine was associated with an increased risk and treatment with olanzapine with a decreased risk for type 2 diabetes. The development of diabetes or pre‐diabetes may therefore influence the likelihood of treatment with olanzapine over time. The strongest predictors of type 2 diabetes in a multivariate model were a body mass index of at least 40 and treated hypercholesterolemia, followed by a body mass index between 35 and 39.9, a family history of diabetes and treated hypertension. There was minimal to no confounding of the association between type 2 diabetes and current clozapine or olanzapine treatment, but neither association remained significant after adjustment for other predictors. Longitudinal relationships among predictors are likely to be complex, and previous antipsychotic drug treatment may at least partly explain risks associated with severe obesity, dyslipidemia and hypertension. A focus on weight loss is warranted in people with psychosis, but prevention strategies for type 2 diabetes should be broadened to include those with emerging dyslipidemia, hypertension and a family history of diabetes.     

Selected indicators of calcium-phosphate metabolism in patients with diabetes mellitus

The changes in blood serum concentrations of calcium, magnesium, inorganic phosphate, total activity of alkaline phosphatase and the activity of its bone fraction, as well as urinary excretion of calcium, phosphate, hydroxyproline and oxalate have been measured in 31 patients with insulin-dependent (type I) diabetes, in 31 patients with non-insulin-dependent (type II) diabetes and in 29 healthy subjects in the condition of low-calcium diet. The elevated urinary excretion of calcium, phosphate, hydroxyproline and oxalate, lowered blood serum level of magnesium, and increased total and bone fraction activities of alkaline phosphatase were found in diabetic patients. The urinary excretion of calcium and hydroxyproline, and the activity of bone fraction alkaline phosphatase were significantly higher in patients with type II diabetes than in those with type I diabetes. It was concluded that there is a significant relation between the state of metabolic normalization of diabetes and the degree of biochemical aberrations concerning calcium-phosphate metabolism.     

Trends in the Incidence of Lower Extremity Amputations in People with and without Diabetes over a Five-Year Period in the Republic of Ireland

Aims

To describe trends in the incidence of non-traumatic amputations among people with and without diabetes and estimate the relative risk of an individual with diabetes undergoing a lower extremity amputation compared to an individual without diabetes in the Republic of Ireland.

Methods

All adults who underwent a nontraumatic amputation during 2005 to 2009 were identified using HIPE (Hospital In-patient Enquiry) data. Participants were classified as having diabetes or not having diabetes. Incidence rates were calculated using the number of discharges for diabetes and non-diabetes related lower extremity amputations as the numerator and estimates of the resident population with and without diabetes as the denominator. Age-adjusted incidence rates were used for trend analysis.

Results

Total diabetes-related amputation rates increased non-significantly during the study period; 144.2 in 2005 to 175.7 in 2009 per 100,000 people with diabetes (p = 0.11). Total non-diabetes related amputation rates dropped non-significantly from 12.0 in 2005 to 9.2 in 2009 per 100,000 people without diabetes (p = 0.16). An individual with diabetes was 22.3 (95% CI 19.1–26.1) times more likely to undergo a nontraumatic amputation than an individual without diabetes in 2005 and this did not change significantly by 2009.

Discussion

This study provides the first national estimate of lower extremity amputation rates in the Republic of Ireland. Diabetes-related amputation rates have remained steady despite an increase in people with diabetes. These estimates provide a base-line and will allow follow-up over time.     

Risk of hypothermia in elderly patients with diabetes.

The incidence of admissions of patients with hypothermia was determined to examine whether hypothermia was more common in elderly patients with diabetes than in the general population after diabetic metabolic emergency cases had been excluded. A prospective survey of three accident and emergency departments identified 134 cases of hypothermia admitted from a catchment population of almost 157,000 aged 65 or over during the winters of 1981-2 to 1983-4. The predicted number of patients with diabetes in the population was nearly 5600 (3.5%). Twenty three admissions for hypothermia (17%) occurred in 20 patients with previously diagnosed diabetes. Women made up 87% of the diabetic admissions; the ratio of diabetic to non-diabetic admission rates in women was 7.9 (95% confidence interval 5.3 to 12.0). After excluding diabetic metabolic emergency admissions the ratio was 6.4. The ratio in men was 2.4, but the small number of admissions produced wide confidence intervals. Ten of the admissions with diabetes (43%) had pathological disorders that are associated with an increased risk of hypothermia. The frequency of these conditions is higher in patients with diabetes than in the general population and partly explains the increased risk of hypothermia in these patients.     

The connexin 37 (1019C>T) gene polymorphism is associated with subclinical atherosclerosis in women with type 1 and 2 diabetes and in women with central obesity

The gene for connexin 37 (Cx37) is considered to be one of the candidate genes for cardiovascular disease. We evaluated the association between Cx37 (1019C>T) gene polymorphism (Pro319Ser) and ankle brachial blood pressure index (ABI) in women with type 1 (n=178) and type 2 (n=111) diabetes, and in women from general population (n=862). All women were genotyped for Cx37 polymorphism. In addition to traditional cardiovascular risk factors, ABI was analyzed. In women with type 1 diabetes, ABI significantly decreased from TT to CC carriers (p for trend = 0.008). A similar trend was seen in women with type 2 diabetes (p = 0.050) and in women with waist circumference above 75th percentile (94 cm; n=208) of the general population (p = 0.049). The gene for Cx37 was associated with subclinical atherosclerosis in women with type 1 and 2 diabetes and in women with advanced central obesity. The presence of C allele indicated increased risk.     

Characterization of diabetes following pancreatic surgery in patients with congenital hyperinsulinism

Background

Congenital hyperinsulinism (CHI) is the most common cause of persistent hypoglycaemia in infancy that leads to unfavourable neurological outcome if not treated adequately. In patients with severe diffuse CHI it remains under discussion whether pancreatic surgery should be performed or intensive medical treatment with the acceptance of recurrent episodes of mild hypoglycaemia is justified. Near-total pancreatectomy is associated with high rates of insulin-dependent diabetes mellitus and exocrine pancreatic insufficiency. Little is known about the management and long-term glycaemic control of CHI patients with diabetes after pancreatic surgery. We searched the German/Austrian DPV database and compared the course of 42 CHI patients with diabetes to that of patients with type 1 diabetes mellitus (T1DM). Study groups were compared at diabetes onset and after a follow-up period of 6.1 [3.3–9.7] (median [interquartile range]) years.

Results

The majority of CHI patients with diabetes were treated with insulin (85.2% [70.9–99.5] at diabetes onset, and 90.5% [81.2–99.7] at follow-up). However, compared to patients with T1DM, significantly more patients in the CHI group with diabetes were treated with conventional insulin therapy (47.8% vs. 24.4%, p?=?0.03 at diabetes onset, and 21.1% vs. 6.4% at follow-up, p?=?0.003), and only a small number of CHI patients were treated with insulin pumps. Daily insulin dose was significantly lower in CHI patients with diabetes than in patients with T1DM, both at diabetes onset (0.3 [0.2–0.5] vs. 0.6?IE/kg/d [0.4–0.8], p?=?0.003) and follow-up (0.8 [0.4–1.0] vs. 0.9 [0.7–1.0] IE/kg/d, p?=?0.02), while daily carbohydrate intake was comparable in both groups. Within the first treatment year, HbA1c levels were significantly lower in CHI patients with diabetes (6.2% [5.5–7.9] vs. 7.2% [6.5–8.2], p?=?0.003), but increased to a level comparable to that of T1DM patients at follow-up. Interestingly, in CHI patients, the risk of severe hypoglycaemia tends to be higher only at diabetes onset (14.8% vs. 5.8%, p?=?0.1).

Conclusions

In surgically treated CHI patients insulin treatment needs to be intensified in order to achieve good glycaemic control. Our data furthermore emphasize the need for improved medical treatment options for patients with diazoxide- and/or octreotide-unresponsive CHI.

     

The immune responses to diabetes in BB rats supplemented with vitamin A

A substantial amount of evidence suggests that in type I diabetes, vitamin A and zinc status could be of concern because of their impaired metabolic availability. Because both vitamin A and zinc play important roles in the regulation of immune function, the present study was undertaken to examine the immune responses to vitamin A and zinc supplements in diabetic-prone Bio-Breed rats (BBdp), and if the supplements increase the incidence of diabetes. Weanling BBdp rats were fed a NIH-07 diet supplemented with vitamin A either alone or in combination with zinc up to 120 days of age. A greater percentage of rats developing diabetes was found in rats that had supplements of vitamin A and zinc (67%) than those on the basal diet (55%) or with vitamin A supplementation alone (50%). The B cells and macrophages were all markedly increased, whereas CD(4)(+) and CD(8)(+) T cells were decreased at the onset of diabetes. However, this immune status was not changed by vitamin A and zinc supplements. The plasma vitamin A levels were significantly decreased in the presence of diabetes and the vitamin A status did not improve when the rats were given vitamin A and zinc supplements. The Natural Killer cell cytotoxicity on a per-cell basis was significantly decreased in the presence of diabetes, irrespective of supplements with vitamin A and zinc. Overall, results indicated that vitamin A and immune status are both affected by type I diabetes; these effects, however, are not responsive to supplemental intakes of vitamin A either alone or in combination with zinc.     

Combination therapy with an antioxidant and a corticosteroid prevents autoimmune diabetes in NOD mice.

Oxygen free radicals have been implicated as mediators of pancreatic islet beta cell damage in autoimmune, insulin-dependent diabetes mellitus (IDDM). In this study, we show that the antioxidant, probucol, produced only a small decrease in diabetes incidence in nonobese diabetic (NOD) mice, an animal model for human IDDM. However, combination of probucol with the antiinflammatory corticosteroid, deflazacort, produced an early synergistic effect, delaying diabetes onset by 3 weeks, and a later additive effect, decreasing diabetes incidence from 68% (17 of 25 mice) to 23% (6 of 26 mice, p < 0.005). Protection against diabetes by the combination of probucol and deflazacort was associated with a significant decrease in pancreatic islet infiltration by macrophages/lymphocytes (insulitis) and prevention of islet beta cell loss.