Endogenous Beta-cell Function Research Articles

Phase III, randomised, double-blind, placebo-controlled, multicentre trial to evaluate the efficacy and safety of rhGAD65 to preserve endogenous beta cell function in adolescents and adults with recently diagnosed type 1 diabetes, carrying the genetic HLA DR3-DQ2 haplotype: the DIAGNODE-3 study protocol

IntroductionType 1 diabetes (T1D) is an autoimmune disease leading to the destruction of the insulin-producing beta cells resulting in insulin deficiency and hyperglycaemic. Today, no approved therapy exists to halt...

Exploratory study reveals far reaching systemic and cellular effects of verapamil treatment in subjects with type 1 diabetes

Currently, no oral medications are available for type 1 diabetes (T1D). While our recent randomized placebo-controlled T1D trial revealed that oral verapamil had short-term beneficial effects, their duration and underlying mechanisms remained elusive. Now, our global T1D serum proteomics analysis identified chromogranin A (CHGA), a T1D-autoantigen, as the top protein altered by verapamil and as a potential therapeutic marker and revealed that verapamil normalizes serum CHGA levels and reverses T1D-induced elevations in circulating proinflammatory T-follicular-helper cell markers. RNA-sequencing further confirmed that verapamil regulates the thioredoxin system and promotes an anti-oxidative, anti-apoptotic and immunomodulatory gene expression profile in human islets. Moreover, continuous use of oral verapamil delayed T1D progression, promoted endogenous beta-cell function and lowered insulin requirements and serum CHGA levels for at least 2 years and these benefits were lost upon discontinuation. Thus, the current studies provide crucial mechanistic and clinical insight into the beneficial effects of verapamil in T1D.

B Quiet: Autoantigen-Specific Strategies to Silence Raucous B Lymphocytes and Halt Cross-Talk with T Cells in Type 1 Diabetes.

Islet autoantibodies are the primary biomarkers used to predict type 1 diabetes (T1D) disease risk. They signal immune tolerance breach by islet autoantigen-specific B lymphocytes. T-B lymphocyte interactions that lead to expansion of pathogenic T cells underlie T1D development. Promising strategies to broadly prevent this T-B crosstalk include T cell elimination (anti-CD3, teplizumab), B cell elimination (anti-CD20, rituximab), and disruption of T cell costimulation/activation (CTLA-4/Fc fusion, abatacept). However, global disruption or depletion of immune cell subsets is associated with significant risk, particularly in children. Therefore, antigen-specific therapy is an area of active investigation for T1D prevention. We provide an overview of strategies to eliminate antigen-specific B lymphocytes as a means to limit pathogenic T cell expansion to prevent beta cell attack in T1D. Such approaches could be used to prevent T1D in at-risk individuals. Patients with established T1D would also benefit from such targeted therapies if endogenous beta cell function can be recovered or islet transplant becomes clinically feasible for T1D treatment.

Serum fibroblast growth factor 19 and endogenous islet beta cell function in type 2 diabetic patients

BackgroundFibroblast growth factor 19 (FGF19) takes part in maintaining the balance of glycolipids and may be involved in regulating the secretory activity of islet beta cells in patients with type 2 diabetes. This study aimed to evaluate the relationship between the levels of serum FGF19 and endogenous islet beta cell function in type 2 diabetic patients.MethodsSamples were obtained from 271 subjects: 85 drug-naïve type 2 diabetes participants exclusively on lifestyle intervention (N-DM group), 122 type 2 diabetes subjects previously used medications (DM group) and 64 normal controls (NC group). Serum FGF19 concentrations were measured by ELISA. The insulin sensitivity (MI), insulin secretion (AUCins/AUCglu) and insulin secretion-sensitivity index-2 (ISSI-2) were also measured in the N-DM and DM.ResultsSerum FGF19 levels decreased, in order, from the NC group [median (interquartile range), 245.03 (126.23–317.43) pg/mL] to the N-DM group [170.05 (89.01–244.70) pg/mL] and, finally, to the DM group [142.25 (55.55–187.58) pg/mL] (p for trend < 0.05). Among subjects in the DM group, there was a positive trend in the serum FGF19 concentration; plasma insulin levels at 60 min, 120 min (INS60, INS120, respectively); and area under the insulin curve (AUCins) at two points (r = 0.214, p = 0.025; r = 0.189, p = 0.048; r = 0.188, p = 0.049). However, the differences were no longer observed among the N-DM subjects. Simultaneously, the ISSI-2 was closely related to the serum FGF19 levels (r = 0.297, p = 0.002) among DM subjects. Furthermore, after adjusting for age, sex, duration, therapy and other clinical factors via multiple logistic regression analysis, ISSI-2 was a key independent factor in the levels of FGF19 (β = 0.281, t = 2.557, p = 0.013).ConclusionsThe serum FGF19 level has a close relation with endogenous beta cell function among DM subjects, as assessed by the ISSI-2. As ISSI-2 is higher in N-DM group, FGF19 may be a main protector in dysfunction of beta cell.

Verapamil and beta cell function in adults with recent-onset type 1 diabetes

Pancreatic beta cell loss is a key factor in the pathogenesis of type 1 diabetes (T1D), but therapies to halt this process are lacking. We previously reported that the approved antihypertensive calcium-channel blocker verapamil, by decreasing the expression of thioredoxin-interacting protein, promotes the survival of insulin-producing beta cells and reverses diabetes in mouse models1. To translate these findings into humans, we conducted a randomized double-blind placebo-controlled phase 2 clinical trial ( NCT02372253 ) to assess the efficacy and safety of oral verapamil added for 12 months to a standard insulin regimen in adult subjects with recent-onset T1D. Verapamil treatment, compared with placebo was well tolerated and associated with an improved mixed-meal-stimulated C-peptide area under the curve, a measure of endogenous beta cell function, at 3 and 12 months (prespecified primary endpoint), as well as with a lower increase in insulin requirements, fewer hypoglycemic events and on-target glycemic control (secondary endpoints). Thus, addition of once-daily oral verapamil may be a safe and effective novel approach to promote endogenous beta cell function and reduce insulin requirements and hypoglycemic episodes in adult individuals with recent-onset T1D.

Diabetic ketoacidosis: a challenging diabetes phenotype.

SummaryWe describe three patients presenting with diabetic ketoacidosis secondary to ketosis prone type 2, rather than type 1 diabetes. All patients were treated according to a standard DKA protocol, but were subsequently able to come off insulin therapy while maintaining good glycaemic control. Ketosis-prone type 2 diabetes (KPD) presenting with DKA has not been described previously in Irish patients. The absence of islet autoimmunity and evidence of endogenous beta cell function after resolution of DKA are well-established markers of KPD, but are not readily available in the acute setting. Although not emphasised in any current guidelines, we have found that a strong family history of type 2 diabetes and the presence of cutaneous markers of insulin resistance are strongly suggestive of KPD. These could be emphasised in future clinical practice guidelines.Learning points:Even in white patients, DKA is not synonymous with type 1 diabetes and autoimmune beta cell failure. KPD needs to be considered in all patients presenting with DKA, even though it will not influence their initial treatment.Aside from markers of endogenous beta cell function and islet autoimmunity, which in any case are unlikely to be immediately available to clinicians, consideration of family history of type 2 diabetes and cutaneous markers of insulin resistance might help to identify those with KPD and are more readily apparent in the acute setting, though not emphasised in guidelines.Consideration of KPD should never alter the management of the acute severe metabolic derangement of DKA, and phasing out of insulin therapy requires frequent attendance and meticulous and cautious surveillance by a team of experienced diabetes care providers.

Gastric Band Surgery Leads to Improved Insulin Secretion in Overweight People with Type 2 Diabetes.

We aimed to determine the effects of laparoscopic adjustable gastric band (LAGB) on beta-cell function in overweight people with type 2 diabetes and to assess the relationship between baseline beta-cell function and glycemic outcomes. We studied 44 overweight but not obese people with type 2 diabetes who participated in a randomized trial whose primary outcome was the rate of diabetes remission after 2 years of multidisciplinary diabetes care (MDC group) or multidisciplinary care combined with LAGB. Dynamic beta-cell function was assessed by intravenous glucose challenge, and basal beta-cell function (HOMA-B) and insulin sensitivity (HOMA-S) were determined using the homeostatic model. Twelve LAGB participants and two MDC participants were in diabetes remission at 2 years. HOMA-S and the C-peptide response to intravenous glucose increased significantly in LAGB but not in MDC participants. The insulin response to glucose did not change in LAGB participants, whereas their fasting C-peptide/insulin ratio increased. Baseline measures of beta-cell function correlated with diabetes remission but not with reduction in HbA1c following LAGB. In overweight people with diabetes, LAGB improves endogenous beta-cell function after 2 years. Baseline beta-cell function correlated with diabetes remission, but not with HbA1c change following LAGB.

Erratum to: Diagnostic criteria for slowly progressive insulin-dependent (type 1) diabetes mellitus (SPIDDM) (2012): report by the Committee on Slowly Progressive Insulin-Dependent (Type 1) Diabetes Mellitus of the Japan Diabetes Society

Diagnostic criteria for slowly progressive insulin-dependent (Type 1) diabetes mellitus (SPIDDM) have been proposed by the Committee on Slowly Progressive Insulin-dependent (type 1) Diabetes Mellitus of the Japan Diabetes Society. Two criteria must be met for definitive diagnosis: the presence of glutamic acid decarboxylase antibodies (GADAb) and/or islet cell antibodies (ICA) at some time during the clinical course of the diabetes, and the absence of ketosis or ketoacidosis at the onset (or diagnosis) of diabetes mellitus and no need for insulin treatment to correct hyperglycemia immediately after diagnosis. It is still unclear whether insulinoma-associated antigen-2 autoantibodies (IA-2Ab), insulin autoantibodies (IAA), or zinc transporter 8 autoantibodies (ZnT8Ab) are essential markers for diagnosis for SPIDDM. Hence, the presence of IA-2Ab, IAA, and ZnT8Ab were excluded from these diagnostic criteria for SPIDDM. Furthermore, ketosis or ketoacidosis can be observed in cases in which SPIDDM is complicated by soft-drink ketosis. Supplementary information for diagnosis include: most SPIDDM patients will need insulin treatment more than 3 months after onset (or diagnosis) of diabetes mellitus and frequently progress to an insulin-dependent state; sometimes, for clinical reasons, early insulin treatment is started when GADAb or ICA are positive both for child and adult-onset cases; GADAb and/or ICA often become negative during the course of the disease; and a small proportion of patients might maintain endogenous beta-cell function more than 10 years after the onset (or diagnosis) of diabetes mellitus, irrespective of the titer of GADAb and ICA.

Review: The importance of residual endogenous beta-cell preservation in type 1 diabetes

Achieving tight glycaemic control in type 1 diabetes remains very challenging for patients. However, some individuals retain a degree of endogenous beta-cell function for 5 or more years after diagnosis, and prospective studies confirm that this is associated not only with lower glycated haemoglobin A1c levels, and less hypoglycaemia, but also a reduced incidence of long-term complications. An independent effect of insulin C-peptide may contribute to this beneficial effect. Retention of even small amounts of endogenous beta-cell function for as long as possible should therefore be a key therapeutic goal in type 1 diabetes. Tight glycaemic control from diagnosis has already been shown to help in this regard, and we argue that the introduction of novel immunotherapies which achieve this important goal should be strongly encouraged, even if they fall short of an insulin-free 'cure'.

C‐peptide in the natural history of type 1 diabetes

Type 1 diabetes is diagnosed when the patient's endogenous insulin secretion decreases to a level which results in hyperglycemia. After diagnosis, insulin secretion continues to decline. As a reference for clinical trials trying to preserve endogenous beta-cell function in patients with recently diagnosed type 1 diabetes, in this short review I attempt to summarize the natural history of endogenous beta-cell function after the diagnosis of type 1 diabetes.

Systemic Transforming Growth Factor-??1 Gene Therapy Induces Foxp3+ Regulatory Cells, Restores Self-Tolerance, and Facilitates Regeneration Of Beta Cell Function in Overtly Diabetic Nonobese Diabetic Mice

Type 1 diabetes results from auto-aggressive T-cell-mediated destruction of beta cells of the pancreas. Recent data suggest that restoration of self-tolerance may facilitate islet-cell regeneration/recovery. In view of the immunoregulatory activity of transforming growth factor (TGF)-beta1, we investigated whether systemic TGF-beta1 gene therapy blocks islet destructive autoimmunity and facilitates regeneration of beta-cell function in overtly diabetic nonobese diabetic (NOD) mice. We used site-directed mutagenesis to create cysteine to serine mutation at sites 224 and 226 and constructed a replication deficient adenovirus (Ad) vector encoding active form of human TGF-beta1 (Ad-hTGF-beta1). Overtly diabetic NOD mice received intravenous injection of Ad-hTGF-beta1. Seven to 14 days after the injection, the mice received transplants with 500 syngeneic islets under the kidney capsule. Islet-graft survival and regeneration of endogenous beta-cell function were examined. Syngeneic islet grafts failed by day 17 in all untreated mice, whereas Ad-hTGF-beta1 therapy prolonged survival of islet grafts. Islet grafts from treated mice showed well-preserved islets with a peri-islet infiltrate primarily of CD4+ T cells and expression of CD25 and Foxp3. Systemic TGF-beta1 gene therapy was associated with islet regeneration in the native pancreas. Native pancreas of treated mice revealed islets staining strongly for insulin. Similar to what was found in the syngeneic islet graft, there were well-demarcated peri-islet infiltrates that were positive for CD4, TGF-beta1, and Foxp3. Our data demonstrate that systemic TGF-beta1 gene therapy blocks islet destructive autoimmunity, facilitates islet regeneration, and cures diabetes in diabetic NOD mice.

The identification of a R201H mutation in KCNJ11, which encodes Kir6.2, and successful transfer to sustained-release sulphonylurea therapy in a subject with neonatal diabetes: evidence for heterogeneity of beta cell function among carriers of the R201H mutation

To the Editor Diabetes caused by severe mutations in beta cell genes is usually diagnosed as neonatal diabetes [1] or MODY [2]. Activating mutations in KCJN11, the gene encoding the ATP-sensitive potassium channel subunit Kir6.2, have been described in very-early-onset diabetes ( A) was found in a single patient. This child was born at 40 weeks’ gestation and weighed 2,450 g. He was diagnosed with diabetes during the third week of life based on a plasma glucose of 35–50 mmol/l, without ketoacidosis, which was measured when he presented with pneumonia and bilateral acute otitis media. The patient was treatedwith insulin, with a dose of 0.7–1.0 U/kg used initially and subsequently decreased. At 9 years, 11 months he weighed 27.5 kg and his daily insulin requirement was 7 U (0.25 U/kg) as a single morning injection of intermediate-acting insulin. Despite little modification to his diet he rarely experienced hyperglycaemia above 11 mmol/l, and had an HbA1c level of 6.6%. These observations suggested endogenous beta cell function, which was confirmed by a fasting plasma C-peptide of 443 pmol/l (glucose 6.7 mmol/l) and an increase in plasma insulin concentration of 70 pmol/l during an IVGTT (Fig. 1). As patients with Kir6.2 diabetes may respond to sulphonylureas, we assessed whether this patient could successfully transfer to sulphonylurea tablets [3, 4]. Glipizide gastrointestinal therapeutic system (GITS), a controlledrelease sulphonylurea, was introduced [5]. A dose of 5 mg was administered for 2 days, then 10 mg; insulin was simultaneously slowly withdrawn over a period of 5 days. As the patient experienced a few mild hypoglycaemic episodes during the first 2 days after the discontinuation of insulin the glipizide GITS dose was decreased to 5 mg. While on this dose, a day profile of his capillary glucose concentrations revealed that they were between 4 and 6 mmol/l; a result confirmed by a 72-h record obtained using a continuous glucose monitoring system (Medtronic, Northridge, CA, USA). The IVGTT was repeated 3 weeks after a stable glipizide dose was achieved. At this time the patient’s fasting glucose level was 5.4mmol/l, and his C-peptide level was 347 pmol/l. T. Klupa and E. L. Edghill contributed equally to this work

The pathophysiological basis for intensive insulin replacement.

Both type I and type II diabetes are characterised by a progressive decrease in beta-cell function and mass. In type I diabetes, autoimmune destruction results in rapid loss of beta-cell function, and insulin therapy is essential to maintain normoglycaemia. In type II diabetes, a diminished or absent first-phase insulin release is the earliest metabolic defect, which is accompanied by lack of prandial suppression of hepatic glucose production, increased postprandial glucose excursions and late insulin hypersecretion. Furthermore, chronic exposure to elevated glucose, even to intermittent postprandial spikes, results in further deterioration of the beta-cell function ('glucotoxicity'). By the time type II diabetes is diagnosed, beta-cell function and mass have declined by about 50%. With the progression of the disease and glucotoxicity there is continuous decrease in beta-cell mass due to increased apoptosis that results in absolute insulin deficiency. By then, patients require insulin administration to maintain glucose control. An increasing body of evidence demonstrates the importance of preserving endogenous beta-cell function both in type I and type II diabetes. Early and intensive glycaemic control, using regimens which re-create a physiological insulin profile, controlling postprandial as well as fasting glucose levels, offers the most promise for preserving beta-cell function, decreasing disease progression, and reducing the chronic complications of diabetes.

Recovery of the endogenous beta cell function in the NOD model of autoimmune diabetes.

In light of accumulating evidence that the endocrine pancreas has regenerative properties and that hematopoietic chimerism can abrogate destruction of beta cells in autoimmune diabetes, we addressed the question of whether recovery of physiologically adequate endogenous insulin regulation could be achieved in the nonobese diabetic (NOD) mice rendered allogeneic chimerae. Allogeneic bone marrow (BM) was transplanted into NOD mice at the preclinical and overtly clinical stages of the disease using lethal and nonlethal doses of radiation for recipient conditioning. Islets of Langerhans, syngeneic to the BM donors, were transplanted under kidney capsules of the overtly diabetic animals to sustain euglycemia for the time span required for recovery of the endogenous pancreas. Nephrectomies of the graft-bearing organs were performed 14 weeks later to confirm the restoration of endogenous insulin regulation. Reparative processes in the pancreata were assessed histologically and immunohistochemically. The level of chimerism in NOD recipients was evaluated by flow cytometric analysis. We have shown that as low as 1% of initial allogeneic chimerism can reverse the diabetogenic processes in islets of Langerhans in prediabetic NOD mice, and that restoration of endogenous beta cell function to physiologically sufficient levels is achievable even if the allogeneic BM transplantation is performed after the clinical onset of diabetes. If the same pattern of islet regeneration were shown in humans, induction of an autoimmunity-free status by establishment of a low level of chimerism, or other alternative means, might become a new therapy for type 1 diabetes.

Insulin autoantibodies are of less value compared with islet antibodies in the clinical diagnosis of autoimmune type 1 diabetes in children older than 3 yr of age.

Insulin autoantibodies (IAA), antibodies against endogenous insulin, may be detected in type 1 diabetic children before the start of insulin treatment. To relate IAA to islet antibodies (i.e., islet cell antibodies [ICA], and antibodies against two ICA-related islet antigens, glutamic acid decarboxylase 65 [GADA] and protein tyrosine phosphatase IA-2 [IA-2 A]) at diagnosis, and to endogenous beta-cell function at follow-up after diagnosis in diabetic children. We investigated 74 children, aged 1-15 yr, at the diagnosis of diabetes and 1-10 yr later. Insulin treatment may induce antibody development against exogenous insulin. Patients with insulin treatment > or = 1 wk (n = 5) were therefore excluded from the final analysis. Radioligand-binding assays based on human recombinant antigen were used to measure IAA, GADA, and IA-2 A. ICA were determined with indirect immunofluorescence. IAA were detected at a significantly lower frequency (43%; p < or = 0.001) than ICA (86%), GADA (72%), and IA-2 A (80%). In agreement, IAA measurements only marginally increased the frequency of positive autoimmune markers at diagnosis of diabetes (from 97 to 99% positive for at least one autoantibody). Preserved beta-cell function (detectable fasting p-C-peptide levels) was found in only nine patients, who were older (13 +/- 3 vs. 7 +/- 6 yr, p = 0.002) and had fewer of the antibodies (IAA, GADA, IA-2 A, ICA) in high titer (> median) compared with 60 patients with undetectable p-C-peptide levels. Insulin autoantibodies are of less clinical value compared with islet antibodies in the diagnosis of autoimmune type 1 diabetes in children.

Blunted prolactin response to metoclopramide in insulin-dependent diabetic patients with secondary amenorrhoea.

In order to investigate the dopaminergic activity in diabetic women with secondary amenorrhoea we studied the response of prolactin to a dopamine receptor antagonist metoclopramide (MTC - 10 mg i.v.) in three groups of women: 5 insulin-dependent diabetic women with secondary amenorrhoea, 5 insulin-dependent diabetics with normal menstrual cycles and 6 non-diabetic women with regular cycles. Patients with diabetes and secondary amenorrhoea had significantly lower basal LH levels (P less than 0.001) and FSH levels (P less than 0.005) than normally cycling diabetic women. Basal and metoclopramide stimulated prolactin levels were lower in diabetic women with secondary amenorrhoea compared to normally cycling diabetics and control subjects. Evaluation of C-peptide levels in peripheral blood revealed that all amenorrheic diabetics had no endogenous beta cell function while diabetic women with normal cycles (except 1 patient) had preserved residual pancreatic beta cell secretion.

Control of juvenile diabetes mellitus and its relationship to endogenous insulin secretion as measured by C-peptide immunoreactivity

Proinsulin is converted to insulin and C-peptide in the pancreatic beta-cells; the latter two peptides are secreted in equimolar concentrations. Thus measurements of C-peptide immunoreactivity may provide a means of assessing residual pancreatic function in insulin-treated diabetic patients. Thirty-five patients with a mean (+/- SE) age of 13.4 +/- .6 years who had diabetes mellitus for 4.8 +/- .3 years were included in this study. Glucose and CPR were measured in the fasting state and one hour after 1 gm/kg (maximum 50 gm) of oral and glucose. Patients were assigned to one of two groups on the basis of adequate or poor control of diabetes. Twenty-five of the 35 (71%) patients had evidence of endogenous beta-cell function, i.e., CPR greater than 0.5 ng/ml. CPR levels over 0.5 ng/ml were present in a significantly (p less than 0.05) greater number of patients with diabetes of less than 5 years duration (19/21) than in those with diabetes greater than 5 years duration (6/14). Only one patient showed a rise in CPR after the glucose load. All patients with CPR greater than 2.0 ng/ml were in the adequately controlled groups, but there were patients with CPR less than 2.0 ng/ml in both adequately and poorly controlled groups. Because the CPR value includes both C-peptide and antibody-bound proinsulin, separate determination of free C-peptide was done in 30 patients. These results confirmed the conclusions based on CPR estimation. Although growth hormone values were higher in patients in the poorly controlled group, there was no correlation between hGH and CPR. We conclude that residual insulin secretion in diabetic patients may facilitate good control, but that low CPR values and hence absent beta-cell reserve is not always associated with poor control.