Impact of Islet Autoimmunity on the Progressive β-Cell Functional Decline in Type 2 Diabetes

OBJECTIVECross-sectional studies have suggested that islet autoimmunity may be more prevalent in type 2 diabetes (T2D) than previously appreciated and may contribute to the progressive decline in β-cell function. In this study, we longitudinally evaluated the effect of islet autoimmune development on the progressive β-cell dysfunction in T2D patients.RESULTSOf the 23 patients, 6 (26%) remained negative for islet autoimmunity (Ab−T−), 14 (61%) developed Ab+ and/or T+, and 3 (13%) were unclassifiable because they developed islet autoimmunity at only one study visit. Islet Ab+ was observed to be less stable than islet-specific T-cell responses. Development of islet autoimmunity was significantly associated with a more rapid decline in fasting (P < 0.0001) and glucagon-stimulated (P < 0.05) C-peptide responses.CONCLUSIONSThese pilot data suggest that the development of islet autoimmunity in T2D is associated with a significantly more rapid β-cell functional decline.     

Pancreatic β-Cell Dysfunction and Risk of New-Onset Diabetes After Kidney Transplantation

OBJECTIVE

Chronic exposure to calcineurin inhibitors and corticosteroids poses renal transplant recipients (RTR) at high risk for development of new-onset diabetes after transplantation (NODAT). Pancreatic β-cell dysfunction may be crucial to the pathophysiology of NODAT and specific markers for β-cell dysfunction may have additive value for predicting NODAT in this population. Therefore, we prospectively investigated whether proinsulin, as a marker of pancreatic β-cell dysfunction, is associated with future development of NODAT and improves prediction of it.

RESEARCH DESIGN AND METHODS

All RTR between 2001 and 2003 with a functioning graft for ≥1 year were considered eligible for inclusion, except for subjects with diabetes at baseline who were excluded. We recorded incidence of NODAT until April 2012.

RESULTS

A total of 487 RTR (age 50 ± 12 years, 55% men) participated at a median time of 6.0 (interquartile range [IQR], 2.6–11.5) years after transplantation. Median fasting proinsulin levels were 16.6 (IQR, 11.0–24.2) pmol/L. During median follow-up for 10.1 (IQR, 9.1–10.4) years, 42 (35%) RTR had development of NODAT in the highest quartile of the distribution of proinsulin versus 34 (9%) in the lowest three quartiles (P < 0.001). In Cox regression analyses, proinsulin (hazard ratio, 2.29; 95% CI, 1.85–2.83; P < 0.001) was strongly associated with NODAT development. This was independent of age, sex, calcineurine inhibitors, prednisolone use, components of the metabolic syndrome, or homeostasis model assessment.

CONCLUSIONS

In conclusion, fasting proinsulin is strongly associated with NODAT development in RTR. Our results highlight the role of β-cell dysfunction in the pathophysiology of NODAT and indicate the potential value of proinsulin for identification of RTR at increased risk for NODAT.New-onset diabetes after transplantation (NODAT) is one of the main metabolic complications of renal transplantation (1). It is estimated to affect ∼20% of renal transplant recipients (RTR) (2). NODAT places RTR at an increased risk for infections, cardiovascular disease, graft failure, and mortality (2–4). Comparable with type 2 diabetes, NODAT may be a result of increased insulin resistance and decreased insulin production by the pancreatic β-cell (5). Early identification of increased risk for NODAT, allowing for early intervention, could be of great importance to renal transplant health care considering the detrimental effects associated with NODAT.The presence of pretransplantation insulin resistance in the final stage of kidney failure is seen as a mechanism in the development of NODAT (6). The chronic exposure to calcineurin inhibitors and corticosteroids aggravates the insulin resistance and poses RTR at high risk for NODAT development (7,8). Another potential mechanism in NODAT is a defect in insulin secretion as a consequence of pancreatic β-cell dysfunction, leading to an inability to compensate for insulin resistance (5,6).As a precursor of insulin, intact proinsulin has been proposed as a specific marker of β-cell dysfunction (5). In the past, nonspecific assays showed high cross-reactivity that could lead to incorrect conclusions on β-cell dysfunction and prediction of diabetes. A new, specific, intact proinsulin ELISA (no cross-reactivity) has been developed that can be easily used in routine laboratories (9).It is unknown whether proinsulin is a good marker of β-cell dysfunction in RTR and whether it is independently associated with future development of NODAT or if it predicts NODAT beyond established clinical risk predictors. Therefore, we prospectively investigated the association between β-cell dysfunction, insulin resistance, and NODAT development in RTR. Furthermore, we investigated whether proinsulin had additive value in the prediction of NODAT.     

Effectiveness of Early Intensive Therapy on β-Cell Preservation in Type 1 Diabetes

OBJECTIVE

To assess effectiveness of inpatient hybrid closed-loop control (HCLC) followed by outpatient sensor-augmented pump (SAP) therapy initiated within 7 days of diagnosis of type 1 diabetes on the preservation of β-cell function at 1 year.

RESEARCH DESIGN AND METHODS

Sixty-eight individuals (mean age 13.3 ± 5.7 years; 35% female, 92% Caucasian) were randomized to HCLC followed by SAP therapy (intensive group; N = 48) or to the usual-care group treated with multiple daily injections or insulin pump therapy (N = 20). Primary outcome was C-peptide concentrations during mixed-meal tolerance tests at 12 months.

RESULTS

Intensive-group participants initiated HCLC a median of 6 days after diagnosis for a median duration of 71.3 h, during which median participant mean glucose concentration was 140 mg/dL (interquartile range 134–153 mg/dL). During outpatient SAP, continuous glucose monitor (CGM) use decreased over time, and at 12 months, only 33% of intensive participants averaged sensor use ≥6 days/week. In the usual-care group, insulin pump and CGM use were initiated prior to 12 months by 15 and 5 participants, respectively. Mean HbA_1c levels were similar in both groups throughout the study. At 12 months, the geometric mean (95% CI) of C-peptide area under the curve was 0.43 (0.34–0.52) pmol/mL in the intensive group and 0.52 (0.32–0.75) pmol/mL in the usual-care group (P = 0.49). Thirty-seven (79%) intensive and 16 (80%) usual-care participants had a peak C-peptide concentration ≥0.2 pmol/mL (P = 0.30).

CONCLUSIONS

In new-onset type 1 diabetes, HCLC followed by SAP therapy did not provide benefit in preserving β-cell function compared with current standards of care.Retention of islet cell function in patients with type 1 diabetes has been associated with lower HbA_1c levels and reductions in short- and long-term complications (1,2). Several therapeutic approaches have been tried to preserve residual β-cell function in such patients. One approach, based on animal and human studies, is to optimize glycemic control as soon as possible after diagnosis. In vitro, resting β-cells are less immunogenic and more resistant to autoimmune damage than active β-cells (3). Tight metabolic control at the onset of type 1 diabetes can protect against insulitis in the BB rat (4–6) and insulin therapy in the NOD mouse has immunologic and metabolic effects (7). In humans, β-cell rest induced by closed-loop therapy shortly after the diagnosis of type 1 diabetes was reported to preserve β-cell function as assessed by C-peptide levels 1 year after diagnosis (8). The Diabetes Control and Complications Trial found that assignment to the well-controlled, intensively managed group slowed the rate of decline of stimulated C-peptide levels compared with that in the poorly controlled, conventionally treated group even when intensive metabolic control was initiated between 1 and 5 years after diagnosis (2).With current technology, it may be possible to optimize glycemic control quickly after diagnosis with in-patient closed-loop control followed by home use of sensor-augmented pump (SAP) therapy. To test the hypothesis that use of advanced diabetes technologies within 7 days of onset of type 1 diabetes can preserve endogenous insulin production to a greater extent than current standard care of new-onset type 1 diabetes, we conducted a randomized trial comparing hybrid closed-loop control (HCLC) followed by home use of SAP therapy versus conventional management; the primary outcome was stimulated C-peptide levels 1 year after diagnosis.     

β- and α-Cell Dysfunctions in Africans With Ketosis-Prone Atypical Diabetes During Near-Normoglycemic Remission

OBJECTIVE

Ketosis-prone atypical diabetes (KPD) is a subtype of diabetes in which the pathophysiology is yet to be unraveled. The aim of this study was to characterize β- and α-cell functions in Africans with KPD during remission.

RESEARCH DESIGN AND METHODS

We characterized β- and α-cell functions in Africans with KPD during remission. The cohort comprised 15 sub-Saharan Africans who had been insulin-free for a median of 6 months. Patients in remission were in good glycemic control (near-normoglycemic) and compared with 15 nondiabetic control subjects matched for age, sex, ethnicity, and BMI. Plasma insulin, C-peptide, and glucagon concentrations were measured in response to oral and intravenous glucose and to combined intravenous arginine and glucose. Early insulin secretion was measured during a 75-g oral glucose tolerance test. Insulin secretion rate and glucagon were assessed in response to intravenous glucose ramping.

RESULTS

Early insulin secretion and maximal insulin secretion rate were lower in patients compared with control participants. In response to combined arginine and glucose stimulation, maximal insulin response was reduced. Glucagon suppression was also decreased in response to oral and intravenous glucose but not in response to arginine and insulin.

CONCLUSIONS

Patients with KPD in protracted near-normoglycemic remission have impaired insulin response to oral and intravenous glucose and to arginine, as well as impaired glucagon suppression. Our results suggest that β- and α-cell dysfunctions both contribute to the pathophysiology of KPD.Ketosis-prone atypical diabetes (KPD) is a frequent specific subtype of diabetes in African Americans and sub-Saharan Africans (1–3). Patients with KPD present at onset with acute hyperglycemia and ketosis or ketoacidosis owing to an insulin secretory deficiency, but autoimmune markers against islet β-cells are absent (4–6). A prolonged insulin-free near-normoglycemic remission phase frequently follows the acute phase after insulin treatment and is associated with a significant recovery of the insulin secretory function (4,7,8). These observations have suggested that the blunting in insulin secretion at disease onset may be due to a functional disorder of β-cells rather than to cell destruction. We previously hypothesized that KPD is a subtype of type 2 diabetes with acute onset at diagnosis as the result of an environmental triggering factor, such as a viral infection, that severely impairs glucose-stimulated insulin secretion and favors ketogenesis (9). KPD patients display insulin resistance at the level of muscles, liver, and adipose tissue during remission (10). However, maximal insulin secretory capacity and surrogates of α-cell mass have not been evaluated, and whether α-cell dysfunction also contributes to the pathophysiology of KPD, as described in type 2 diabetes (11–14) is not known.In the current study, we therefore measured early insulin secretion in response to oral glucose, dose-response insulin secretion to intravenous glucose, and maximum secretory response to arginine combined with glucose (glucose potentiation of arginine-induced insulin secretion) in Africans with KPD during near-normoglycemic remission compared with control subjects of the same ethnic background. Function of α-cells was assessed by measuring glucagon in response to glucose, insulin, and arginine.     

Preservation of ��-Cell Function in Autoantibody-Positive Youth With Diabetes

OBJECTIVE

To determine the extent of β-cell function in youth with diabetes and GAD65 and/or IA2 autoantibodies.

RESEARCH DESIGN AND METHODS

Fasting C-peptide levels from 2,789 GAD65- and/or IA2 autoantibody-positive youth aged 1–23 years from the SEARCH for Diabetes in Youth study were used. Preserved β-cell function was defined on the basis of cut points derived from the Diabetes Control and Complications Trial (DCCT) (fasting C-peptide ≥0.23 ng/ml) and from the U.S. adolescent population of the National Health and Nutrition Examination Survey (NHANES) 5th percentile for fasting C-peptide (≥1.0 ng/ml). We compared the clinical characteristics between those with and without preserved β-cell function.

RESULTS

Within the first year of diagnosis, 82.9% of youth had a fasting C-peptide ≥0.23 ng/ml and 31.2% had values ≥1.0 ng/ml. Among those with ≥5 years of diabetes duration, 10.7% had preserved β-cell function based on the DCCT cutoff and 1.0% were above the 5th percentile of the NHANES population.

CONCLUSIONS

Within the 1st year of diagnosis, four of five youth with autoantibody-positive diabetes have clinically significant amounts of residual β-cell function and about one-third have fasting C-peptide levels above the 5th percentile of a healthy adolescent population. Even 5 years after diagnosis, 1 of 10 has fasting C-peptide above a clinically significant threshold. These findings have implications for clinical classification of youth with diabetes as well as clinical trials aimed to preserve β-cell function after diabetes onset.Immune-mediated β-cell destruction, marked by the presence of diabetes autoantibodies, occurs before and continues after the clinical diagnosis of type 1 diabetes. This model has served as the foundation of pathophysiological studies of the disease process and clinical studies designed to identify future risk for diabetes and to modify clinical course. The resultant perception is that most individuals with type 1 diabetes will have complete destruction of β-cells within a few years after diagnosis without a targeted intervention to sustain β-cell function.Despite frequent use of this model in research and patient care, it represents only part of the picture. Data from placebo-controlled populations in clinical intervention trials suggest that some individuals with type 1 diabetes will have persistent β-cell function years after diagnosis (1,2). The screening phase of the Diabetes Control and Complications Trial (DCCT) demonstrated that 48% of adults had significant C-peptide levels within 5 years of diagnosis, and 8% had significant C-peptide 5–15 years after diagnosis (3). Another study reported similar findings in 15% of individuals with measurable C-peptide levels 8–15 years after diagnosis (4). Multiple studies have reported that the loss of β-cell function after diagnosis is related to age of onset as well as to factors linked to autoimmunity such as autoantibodies (5–11). Nonetheless, there is a common belief that persistence of β-cell function is rare in young children with type 1 diabetes.The SEARCH for Diabetes in Youth (SEARCH) study, designed to determine the prevalence, incidence, and characteristics of diabetes in U.S. youth, provides an opportunity to examine the frequency of residual β-cell function in a population-based sample of GAD65⁺ or IA2⁺ youth with diabetes.     

Preexisting Insulin Autoantibodies Predict Efficacy of Otelixizumab in Preserving Residual β-Cell Function in Recent-Onset Type 1 Diabetes

OBJECTIVE

Immune intervention trials in recent-onset type 1 diabetes would benefit from biomarkers associated with good therapeutic response. In the previously reported randomized placebo-controlled anti-CD3 study (otelixizumab; GlaxoSmithKline), we tested the hypothesis that specific diabetes autoantibodies might serve this purpose.

RESEARCH DESIGN AND METHODS

In the included patients (n = 40 otelixizumab, n = 40 placebo), β-cell function was assessed as area under the curve (AUC) C-peptide release during a hyperglycemic glucose clamp at baseline (median duration of insulin treatment: 6 days) and every 6 months until 18 months after randomization. (Auto)antibodies against insulin (I[A]A), GAD (GADA), IA-2 (IA-2A), and ZnT8 (ZnT8A) were determined on stored sera by liquid-phase radiobinding assay.

RESULTS

At baseline, only better preserved AUC C-peptide release and higher levels of IAA were associated with better preservation of β-cell function and lower insulin needs under anti-CD3 treatment. In multivariate analysis, IAA (P = 0.022) or the interaction of IAA and C-peptide (P = 0.013) independently predicted outcome together with treatment. During follow-up, good responders to anti-CD3 treatment (i.e., IAA⁺ participants with relatively preserved β-cell function [≥25% of healthy control subjects]) experienced a less pronounced insulin-induced rise in I(A)A and lower insulin needs. GADA, IA-2A, and ZnT8A levels were not influenced by anti-CD3 treatment, and their changes showed no relation to functional outcome.

CONCLUSIONS

There is important specificity of IAA among other diabetes autoantibodies to predict good therapeutic response of recent-onset type 1 diabetic patients to anti-CD3 treatment. If confirmed, future immune intervention trials in type 1 diabetes should consider both relatively preserved functional β-cell mass and presence of IAA as inclusion criteria.     

Residual β-Cell Function 3–6 Years After Onset of Type 1 Diabetes Reduces Risk of Severe Hypoglycemia in Children and Adolescents

OBJECTIVE

To determine the prevalence of residual β-cell function (RBF) in children after 3–6 years of type 1 diabetes, and to examine the association between RBF and incidence of severe hypoglycemia, glycemic control, and insulin requirements.

RESEARCH DESIGN AND METHODS

A total of 342 children (173 boys) 4.8–18.9 years of age with type 1 diabetes for 3–6 years were included. RBF was assessed by testing meal-stimulated C-peptide concentrations. Information regarding severe hypoglycemia within the past year, current HbA_1c, and daily insulin requirements was retrieved from the medical records and through patient interviews.

RESULTS

Ninety-two children (27%) had RBF >0.04 nmol/L. Patients with RBF <0.04 nmol/L were significantly more likely to have severe hypoglycemia than patients with RBF >0.04 nmol/L (odds ratio, 2.59; 95% CI, 1.10–7.08; P < 0.03). HbA_1c was significantly higher in patients with RBF <0.04 nmol/L compared with patients with RBF >0.04 nmol/L (mean, 8.49 ± 0.08% [69.3 ± 0.9 mmol/mol] vs. 7.92 ± 0.13% [63.1 ± 1.4 mmol/mol]; P < 0.01), and insulin requirements were significantly lower in patients with RBF >0.2 nmol/L (mean ± SE: 1.07 ± 0.02 vs. 0.93 ± 0.07 units/kg/day; P < 0.04).

CONCLUSIONS

We demonstrated considerable phenotypic diversity in RBF among children after 3–6 years of type 1 diabetes. Children with RBF are at lower risk for severe hypoglycemia, have better diabetes regulation, and have lower insulin requirements compared with children without RBF. There appears to be a lower limit for stimulated RBF of ∼0.04 nmol/L that confers a beneficial effect on hypoglycemia and metabolic control.Type 1 diabetes is the result of a selective immune-mediated destruction of the insulin-producing β-cells in the islets of Langerhans in the pancreas (1). Partial remission of type 1 diabetes often is seen in children and adolescents soon after initiating insulin treatment, and it is characterized by continuous and effective endogenous insulin secretion. After this period of remission of variable duration, the autoimmune cellular-mediated destruction of the β-cells continues and the endogenous insulin production declines gradually (2–4).The Diabetes Control and Complication Trial (DCCT) showed that a significant proportion of adults had sustained β-cell function several years after the onset of type 1 diabetes (5), and some type 1 diabetic patients even have detectable C-peptide after 50 years of diabetes (6). In adults, residual β-cell function (RBF) may have positive effects on diabetes regulation and complications. RBF may reduce the risk of hypoglycemia, improve metabolic control estimated by HbA_1c, lower exogenous insulin requirements, and lower the risk of long-term complications (5,7–13). Based on data from the DCCT adult population, it was reported that the incidence of severe hypoglycemia varied with differences in RBF (7). In the group with the highest RBF, the lowest incidence of hypoglycemia occurred (7). Yet, even those with “minimal” RBF, defined as stimulated C-peptide level of 0.04–0.2 nmol/L, showed lower incidence of severe hypoglycemia compared with the group with undetectable RBF (7).In children, the majority of studies of RBF have focused on the first year after clinical diagnosis (14–18). Data for RBF in children during later stages of type 1 diabetes and its effect on metabolic control and complications are scarce. In a population of 151 children with type 1 diabetes for 3 years, 23% had a stimulated C-peptide level of >0.06 nmol/L (19). Furthermore, in a case-control study, it was demonstrated that RBF was significantly higher in children without severe hypoglycemia compared with children with severe hypoglycemia (20).The increasing incidence of diabetes in children with reduced contribution of high-risk HLA haplotypes (21,22) may have changed the type 1 diabetes phenotype toward an increased number of children with detectable C-peptide years after diagnosis, which may have favorable effects on the incidence of severe hypoglycemia and glycemic control. Therefore, the aims of this study were to investigate the phenotypical characteristics regarding RBF among Danish children with type 1 diabetes for a duration of 3–6 years; to examine possible benefits of RBF on the incidence of severe hypoglycemia, glycemic control, and insulin requirements; and, finally, to evaluate the data to determine whether there is a lower limit of RBF at which RBF exerts beneficial effect on the incidence of severe hypoglycemia and metabolic control.     

Effect of Exenatide,Sitagliptin, or Glimepiride on β-Cell Secretory Capacity in Early Type 2 Diabetes

OBJECTIVE

Agents that augment GLP-1 effects enhance glucose-dependent β-cell insulin production and secretion and thus are hoped to prevent progressive impairment in insulin secretion characteristic of type 2 diabetes (T2D). The purpose of this study was to evaluate GLP-1 effects on β-cell secretory capacity, an in vivo measure of functional β-cell mass, early in the course of T2D.

RESEARCH DESIGN AND METHODS

We conducted a randomized controlled trial in 40 subjects with early T2D who received the GLP-1 analog exenatide (n = 14), the dipeptidyl peptidase IV inhibitor sitagliptin (n = 12), or the sulfonylurea glimepiride (n = 14) as an active comparator insulin secretagogue for 6 months. Acute insulin responses to arginine (AIR_arg) were measured at baseline and after 6 months of treatment with 5 days of drug washout under fasting, 230 mg/dL (glucose potentiation of arginine-induced insulin release [AIR_pot]), and 340 mg/dL (maximum arginine-induced insulin release [AIR_max]) hyperglycemic clamp conditions, in which AIR_max provides the β-cell secretory capacity.

RESULTS

The change in AIR_pot was significantly greater with glimepiride versus exenatide treatment (P < 0.05), and a similar trend was notable for the change in AIR_max (P = 0.1). Within each group, the primary outcome measure, AIR_max, was unchanged after 6 months of treatment with exenatide or sitagliptin compared with baseline but was increased with glimepiride (P < 0.05). α-Cell glucagon secretion (AGR_min) was also increased with glimepiride treatment (P < 0.05), and the change in AGR_min trended higher with glimepiride than with exenatide (P = 0.06).

CONCLUSIONS

After 6 months of treatment, exenatide or sitagliptin had no significant effect on functional β-cell mass as measured by β-cell secretory capacity, whereas glimepiride appeared to enhance β- and α-cell secretion.     

Effects of Exenatide Alone and in Combination With Daclizumab on ��-Cell Function in Long-Standing Type 1 Diabetes

OBJECTIVE

In patients with long-standing type 1 diabetes, we investigated whether improved β-cell function can be achieved by combining intensive insulin therapy with agents that may 1) promote β-cell growth and/or limit β-cell apoptosis and 2) weaken the anti–β-cell autoimmunity.

RESEARCH DESIGN AND METHODS

For this study, 20 individuals (mean age 39.5 ± 11.1 years) with long-standing type 1 diabetes (21.3 ± 10.7 years) were enrolled in this prospective open-label crossover trial. After achieving optimal blood glucose control, 16 subjects were randomized to exenatide with or without daclizumab. Endogenous insulin production was determined by repeatedly measuring serum C-peptide.

RESULTS

In 85% of individuals with long-standing type 1 diabetes who were screened for participation in this trial, C-peptide levels ≥0.05 ng/ml (0.02 nmol/l) were found. Residual β-cells responded to physiological (mixed-meal) and pharmacological (arginine) stimuli. During exenatide treatment, patients lost 4.1 ± 2.9 kg body wt and insulin requirements declined significantly (total daily dose on exenatide 0.48 ± 0.11 vs. 0.55 ± 0.13 units · kg⁻¹ · day⁻¹ without exenatide; P = 0.0062). No signs of further activation of the underlying autoimmune disease were observed. Exenatide delayed gastric emptying, suppressed endogenous incretin levels, but did not increase C-peptide secretion.

CONCLUSIONS

In long-standing type 1 diabetes, which remains an active autoimmune disease even decades after its onset, surviving β-cells secrete insulin in a physiologically regulated manner. However, the combination of intensified insulin therapy, exenatide, and daclizumab did not induce improved function of these remaining β-cells.In the past 2 decades, several lines of research dominated the field of type 1 diabetes: trials to alter the immunological response against β-cells and attempts to develop and replace β-cells. The latter, represented by islet transplantation in the clinical arena, has led to the realization that lasting insulin independence could not be achieved (1), but progress was made by gaining insight into β-cell development (2–4) and immunomodulation. Experimental therapies such as administration of the monoclonal antibody anti-CD3 and the β-cell antigen GAD65 slowed β-cell destruction when administered soon after disease onset (5,6). Currently, however, no therapy is available that results in a complete halt or reversal of β-cell failure.We initiated this trial in patients with well-controlled long-standing type 1 diabetes who had evidence of endogenous insulin production documented by measurable C-peptide concentrations ≥0.3 ng/ml (0.1 nmol/l). The study participants received exenatide, a glucagon-like peptide (GLP)-1 agonist, to stimulate β-cell recovery and possibly regeneration (7,8); 50% of patients also received daclizumab to diminish the underlying autoimmunity and to curb a potential autoimmune reactivation. β-Cell function was repeatedly assessed by measuring basal and stimulated C-peptide concentrations (9). We speculated that the difference between greater β-cell mass and improved function could be determined by observing the duration of any treatment effect; i.e., if the intervention resulted in increased β-cell mass, improved pancreatic insulin production would be expected to persist beyond the exenatide treatment. Daclizumab was chosen as a mild immunosuppressive agent because of its safety profile and its demonstrated efficacy in other T-cell–mediated autoimmune conditions such as uveitis and multiple sclerosis (10,11).     

Utility of Homeostasis Model Assessment of ��-Cell Function in Predicting Diabetes in 12,924 Healthy Koreans

OBJECTIVE

It is unclear how well homeostasis model assessment of β-cell function (HOMA-β) predicts diabetes development beyond its components, especially glucose.

RESEARCH DESIGN AND METHODS

We identified 12,924 nondiabetic Koreans who had fasting plasma glucose and insulin concentrations measured in 2003 and again in 2008. To minimize the impact of differences in baseline glucose concentration, individuals were divided into three glucose categories: normal fasting glucose (NFG, glucose <5.6 mmol/l), impaired fasting glucose (IFG-100) (5.6–6.0 mmol/l), and IFG-110 (6.1–6.9 mmol/l).

RESULTS

Diabetes developed in 29% of individuals in the IFG-110 group, compared with 5% in IFG-100 and 0.3% in NFG groups. Within each glucose category, those who progressed to diabetes had higher baseline glucose concentrations (P ≤ 0.04). Baseline HOMA-β, however, was not lower but higher in individuals who developed diabetes in the NFG group (P = 0.009) and similar in the IFG-100 and IFG-110 groups.

CONCLUSIONS

These data question the utility of using HOMA-β to predict the development of diabetes.The homeostasis model assessment of β-cell function (HOMA-β) is an index of insulin secretory function derived from fasting plasma glucose and insulin concentrations (1). It has been used to predict diabetes development in nondiabetic individuals in four studies (2–5), and the conclusion in each instance was that a decrease in insulin secretory function, as estimated by HOMA-β, predicted the development of diabetes and/or impaired glucose tolerance. However, because it was also shown in these studies that baseline glucose concentration was higher in individuals who developed diabetes, it could be argued that the lower values for HOMA-β may only be reflecting the difference in glucose concentration. The current analysis was initiated to see if HOMA-β provided a more sensitive assessment of the likelihood of developing type 2 diabetes than did knowledge of individual fasting plasma glucose and insulin concentrations.     

Pancreatic Islet Autoantibodies as Predictors of Type 1 Diabetes in the Diabetes Prevention Trial�CType 1

OBJECTIVE

There is limited information from large-scale prospective studies regarding the prediction of type 1 diabetes by specific types of pancreatic islet autoantibodies, either alone or in combination. Thus, we studied the extent to which specific autoantibodies are predictive of type 1 diabetes.

RESEARCH DESIGN AND METHODS

Two cohorts were derived from the first screening for islet cell autoantibodies (ICAs) in the Diabetes Prevention Trial–Type 1 (DPT-1). Autoantibodies to GAD 65 (GAD65), insulinoma-associated antigen-2 (ICA512), and insulin (micro-IAA [mIAA]) were also measured. Participants were followed for the occurrence of type 1 diabetes. One cohort (Questionnaire) included those who did not enter the DPT-1 trials, but responded to questionnaires (n = 28,507, 2.4% ICA⁺). The other cohort (Trials) included DPT-1 participants (n = 528, 83.3% ICA⁺).

RESULTS

In both cohorts autoantibody number was highly predictive of type 1 diabetes (P < 0.001). The Questionnaire cohort was used to assess prediction according to the type of autoantibody. As single autoantibodies, ICA (3.9%), GAD65 (4.4%), and ICA512 (4.6%) were similarly predictive of type 1 diabetes in proportional hazards models (P < 0.001 for all). However, no subjects with mIAA as single autoantibodies developed type 1 diabetes. As second autoantibodies, all except mIAA added significantly (P < 0.001) to the prediction of type 1 diabetes. Within the positive range, GAD65 and ICA autoantibody titers were predictive of type 1 diabetes.

CONCLUSIONS

The data indicate that the number of autoantibodies is predictive of type 1 diabetes. However, mIAA is less predictive of type 1 diabetes than other autoantibodies. Autoantibody number, type of autoantibody, and autoantibody titer must be carefully considered in planning prevention trials for type 1 diabetes.Autoantibodies to islet cell antigens are known predictors of type 1 diabetes and are commonly present at its diagnosis (1–12). Islet cell autoantibodies (ICAs), the first identified (1,2), actually represent autoimmunity to several different antigens. More recently, autoantibodies specific to single tissue antigens, termed biochemical autoantibodies, have been identified (4,7,8,11–13). These include antibodies to GAD 65 (GAD65), the antibody to an insulinoma-associated antigen-2 (ICA512), and antibodies to insulin (IAA).Type 1 diabetes prevention trials have used autoantibodies to screen for individuals at increased risk who might be candidates for participation (14–16). The Diabetes Prevention Trial–Type 1 (DPT-1) assessed parenteral and oral insulin as potential prevention modalities. First- and second-degree relatives of type 1 diabetic patients were screened for the presence of ICA, which was required for eligibility. Although not relevant to the trials, biochemical autoantibodies were subsequently measured from screening samples to learn more about their prediction of type 1 diabetes. The prevalence of autoantibodies according to various subgroups has been reported for DPT-1 (17).We used two DPT-1 cohorts to examine the prediction of type 1 diabetes by ICA and biochemical autoantibodies, as few large-scale studies have examined the prediction of type 1 diabetes by a variety of single autoantibodies in large numbers of individuals of whom many ultimately developed type 1 diabetes. One cohort includes DPT-1 participants who participated in the trials (the Trials cohort), and the other cohort includes participants who did not participate in either trial but responded to questionnaires (the Questionnaire cohort) used to ascertain information regarding the diagnosis of type 1 diabetes. The differing perspectives of these two cohorts and the large number of individuals studied, almost 30,000, provide a unique opportunity for studying the prediction of type 1 diabetes by autoantibodies.     

Expression and significance of β-catenin and peroxisome proliferator-activated receptor-γ in hepatocellular carcinoma

Objective To investigate the expression and significance of β-catenin and peroxisome prolifera-tot-activated receptor-γ,(PPARγ) in bepatocellular carcinoma. Methods Tissue microarrays were established to detect β-catenin and PPARγ expression in 49 cases of hepatocellular carcinoma,49 cases of adjacent nontumoral liv-er tissue and 6 cases of normal liver tissue. The relationships between PPARγ and β-catenin as well as between PPARγ and clinicopathological parameters were observed. Results The aberrant expression rate of β-catenin was 69.39%,48.98 % and 0 respectively (P=0.001). The positive expression rate of PPARγ was 51.02%,30.61% and 0 respectively (P=0.016). Clinicopathological analysis revealed that the increase of PPARγ expression was not associated with age,tumor size,serum alpha fetoprotein (AFP) levels,tumor embolus of portal vein or inferior vena cava,and HBsAg infection(χ2=0.214,3.201,0.046,3.201,P>0.05 for each),but correlated with differentiation grades(χ2=4.693,P<0.05). Aberrant expression of β-catenin was associated with PPARγ expression(χ2= 5.130,P<0.05). Conclusion Aberrant expression of β-catenin may involve in the liver carcinogenesis. The high expression of PPARγ in hepatocellular carcinoma is significantly correlated with the clinicopathological characteris-tics. Detection of PPARγ is valuable for diagnosing hepatocellular carcinoma,and evaluating malignancy extent and prognosis.     

Expression and significance of β-catenin and peroxisome proliferator-activated receptor-γ in hepatocellular carcinoma

Objective To investigate the expression and significance of β-catenin and peroxisome prolifera-tot-activated receptor-γ,(PPARγ) in bepatocellular carcinoma. Methods Tissue microarrays were established to detect β-catenin and PPARγ expression in 49 cases of hepatocellular carcinoma,49 cases of adjacent nontumoral liv-er tissue and 6 cases of normal liver tissue. The relationships between PPARγ and β-catenin as well as between PPARγ and clinicopathological parameters were observed. Results The aberrant expression rate of β-catenin was 69.39%,48.98 % and 0 respectively (P=0.001). The positive expression rate of PPARγ was 51.02%,30.61% and 0 respectively (P=0.016). Clinicopathological analysis revealed that the increase of PPARγ expression was not associated with age,tumor size,serum alpha fetoprotein (AFP) levels,tumor embolus of portal vein or inferior vena cava,and HBsAg infection(χ2=0.214,3.201,0.046,3.201,P>0.05 for each),but correlated with differentiation grades(χ2=4.693,P<0.05). Aberrant expression of β-catenin was associated with PPARγ expression(χ2= 5.130,P<0.05). Conclusion Aberrant expression of β-catenin may involve in the liver carcinogenesis. The high expression of PPARγ in hepatocellular carcinoma is significantly correlated with the clinicopathological characteris-tics. Detection of PPARγ is valuable for diagnosing hepatocellular carcinoma,and evaluating malignancy extent and prognosis.     

Restoring Insulin Secretion (RISE): Design of Studies of β-Cell Preservation in Prediabetes and Early Type 2 Diabetes Across the Life Span

OBJECTIVE

The Restoring Insulin Secretion (RISE) Consortium is testing interventions designed to preserve or improve β-cell function in prediabetes or early type 2 diabetes.

RESEARCH DESIGN AND METHODS

β-Cell function is measured using hyperglycemic clamps and oral glucose tolerance tests (OGTTs). The adult medication protocol randomizes participants to 12 months of placebo, metformin alone, liraglutide plus metformin, or insulin (3 months) followed by metformin (9 months). The pediatric medication protocol randomizes participants to metformin or insulin followed by metformin. The adult surgical protocol randomizes participants to gastric banding or metformin (24 months). Adult medication protocol inclusion criteria include fasting plasma glucose 95–125 mg/dL (5.3–6.9 mmol/L), OGTT 2-h glucose ≥140 mg/dL (≥7.8 mmol/L), HbA_1c 5.8–7.0% (40–53 mmol/mol), and BMI 25–40 kg/m². Adult surgical protocol criteria are similar, except for fasting plasma glucose ≥90 mg/dL (≥5.0 mmol/L), BMI 30–40 kg/m², HbA_1c <7.0% (<53 mmol/mol), and diabetes duration <12 months. Pediatric inclusion criteria include fasting plasma glucose ≥90 mg/dL (≥5.0 mmol/L), 2-h glucose ≥140 mg/dL (≥7.8 mmol/L), HbA_1c ≤8.0% (≤64 mmol/mol), BMI >85th percentile and ≤50 kg/m², 10–19 years of age, and diabetes <6 months.

RESULTS

Primary outcomes are clamp-derived glucose-stimulated C-peptide secretion and maximal C-peptide response to arginine during hyperglycemia. Measurements are made at baseline, after 12 months on treatment, and 3 months after treatment withdrawal (medication protocols) or 24 months postintervention (surgery protocol). OGTT-derived measures are also obtained at these time points.

CONCLUSIONS

RISE is determining whether medication or surgical intervention strategies can mitigate progressive β-cell dysfunction in adults and youth with prediabetes or early type 2 diabetes.     

Expression and significance of β-catenin and peroxisome proliferator-activated receptor-γ in hepatocellular carcinoma

Objective To investigate the expression and significance of β-catenin and peroxisome prolifera-tot-activated receptor-γ,(PPARγ) in bepatocellular carcinoma. Methods Tissue microarrays were established to detect β-catenin and PPARγ expression in 49 cases of hepatocellular carcinoma,49 cases of adjacent nontumoral liv-er tissue and 6 cases of normal liver tissue. The relationships between PPARγ and β-catenin as well as between PPARγ and clinicopathological parameters were observed. Results The aberrant expression rate of β-catenin was 69.39%,48.98 % and 0 respectively (P=0.001). The positive expression rate of PPARγ was 51.02%,30.61% and 0 respectively (P=0.016). Clinicopathological analysis revealed that the increase of PPARγ expression was not associated with age,tumor size,serum alpha fetoprotein (AFP) levels,tumor embolus of portal vein or inferior vena cava,and HBsAg infection(χ2=0.214,3.201,0.046,3.201,P>0.05 for each),but correlated with differentiation grades(χ2=4.693,P<0.05). Aberrant expression of β-catenin was associated with PPARγ expression(χ2= 5.130,P<0.05). Conclusion Aberrant expression of β-catenin may involve in the liver carcinogenesis. The high expression of PPARγ in hepatocellular carcinoma is significantly correlated with the clinicopathological characteris-tics. Detection of PPARγ is valuable for diagnosing hepatocellular carcinoma,and evaluating malignancy extent and prognosis.     

Expression and significance of β-catenin and peroxisome proliferator-activated receptor-γ in hepatocellular carcinoma

Objective To investigate the expression and significance of β-catenin and peroxisome prolifera-tot-activated receptor-γ,(PPARγ) in bepatocellular carcinoma. Methods Tissue microarrays were established to detect β-catenin and PPARγ expression in 49 cases of hepatocellular carcinoma,49 cases of adjacent nontumoral liv-er tissue and 6 cases of normal liver tissue. The relationships between PPARγ and β-catenin as well as between PPARγ and clinicopathological parameters were observed. Results The aberrant expression rate of β-catenin was 69.39%,48.98 % and 0 respectively (P=0.001). The positive expression rate of PPARγ was 51.02%,30.61% and 0 respectively (P=0.016). Clinicopathological analysis revealed that the increase of PPARγ expression was not associated with age,tumor size,serum alpha fetoprotein (AFP) levels,tumor embolus of portal vein or inferior vena cava,and HBsAg infection(χ2=0.214,3.201,0.046,3.201,P>0.05 for each),but correlated with differentiation grades(χ2=4.693,P<0.05). Aberrant expression of β-catenin was associated with PPARγ expression(χ2= 5.130,P<0.05). Conclusion Aberrant expression of β-catenin may involve in the liver carcinogenesis. The high expression of PPARγ in hepatocellular carcinoma is significantly correlated with the clinicopathological characteris-tics. Detection of PPARγ is valuable for diagnosing hepatocellular carcinoma,and evaluating malignancy extent and prognosis.     

Expression and significance of β-catenin and peroxisome proliferator-activated receptor-γ in hepatocellular carcinoma

Objective To investigate the expression and significance of β-catenin and peroxisome prolifera-tot-activated receptor-γ,(PPARγ) in bepatocellular carcinoma. Methods Tissue microarrays were established to detect β-catenin and PPARγ expression in 49 cases of hepatocellular carcinoma,49 cases of adjacent nontumoral liv-er tissue and 6 cases of normal liver tissue. The relationships between PPARγ and β-catenin as well as between PPARγ and clinicopathological parameters were observed. Results The aberrant expression rate of β-catenin was 69.39%,48.98 % and 0 respectively (P=0.001). The positive expression rate of PPARγ was 51.02%,30.61% and 0 respectively (P=0.016). Clinicopathological analysis revealed that the increase of PPARγ expression was not associated with age,tumor size,serum alpha fetoprotein (AFP) levels,tumor embolus of portal vein or inferior vena cava,and HBsAg infection(χ2=0.214,3.201,0.046,3.201,P>0.05 for each),but correlated with differentiation grades(χ2=4.693,P<0.05). Aberrant expression of β-catenin was associated with PPARγ expression(χ2= 5.130,P<0.05). Conclusion Aberrant expression of β-catenin may involve in the liver carcinogenesis. The high expression of PPARγ in hepatocellular carcinoma is significantly correlated with the clinicopathological characteris-tics. Detection of PPARγ is valuable for diagnosing hepatocellular carcinoma,and evaluating malignancy extent and prognosis.