Beta-cell Function In Individuals Research Articles

Prevention and treatment of type 1 diabetes: in search of the ideal combination therapy targeting multiple immunometabolic pathways

Type 1 diabetes (T1D) represents an autoimmune disease caused by the gradual immune-mediated destruction of the insulin-producing beta cells within the pancreatic islets of Langerhans, resulting in the lifelong need for exogenous insulin therapy. According to recent estimates, T1D currently affects about 8.4 million individuals worldwide. Since a definitive biological cure for this disease is not available yet, there is a great need for novel therapeutic strategies aimed at safely and effectively altering the natural history of the disease during its sequential stages. Ideal therapeutic goals in T1D include the prevention of autoimmune beta-cell destruction, the preservation of residual beta-cell mass and endogenous insulin secretion, the replacement and/or regeneration of beta cells, as well as automated insulin delivery through advanced closed-loop artificial pancreas systems. With this regard, an important research area focused on the identification of a definitive biological cure for T1D is represented by the investigation of immunotherapeutic and beta-cell-protective agents used as disease-modifying therapies to forestall or eliminate insulin dependence. In this commentary, we discuss the reasons why the use of combination therapies targeting the multiple immunometabolic dysfunctions associated with T1D (other than beta-cell autoimmunity) is likely to be more effective in preserving beta cell function in individuals at different stages of T1D, as compared to the use of single therapeutic agents.

A Cross-sectional Study to Assess Beta-Cell Function in Individuals with Recently Diagnosed Young-Onset Type 2 Diabetes Mellitus and Its' Complications.

The primary objective was to assess beta-cell function of recently-diagnosed young-onset type 2 diabetes mellitus (T2DM) individuals using basal and stimulated C-peptide levels. The secondary objective was to examine the association between C-peptide with metabolic factors and diabetes complications. A cross-sectional study was conducted for young-onset T2DM individuals aged 18-35 years with a disease duration of not more than 5 years. Plasma C-peptide was measured before and after intravenous glucagon injection. Demographic data, medical history and complications were obtained from medical records and clinical assessment. Continuous data were expressed as median and interquartile range (IQR). Categorical variables were described as frequency or percentage. Multivariable linear regression analysis was used to determine factors associated with C-peptide levels. 113 participants with young-onset T2DM with a median (IQR) age of 29.0 (9.5) years and 24 (36) months were included in this study. The median (IQR) basal and stimulated C-peptide was 619 (655) pmol/L and 1231 (1024) pmol/L. Adequate beta-cell function was present in 78-86% of the participants based on the basal and stimulated C-peptide levels. We found hypertension, obesity and diabetic kidney disease (DKD) to be independently associated with higher C-peptide levels. In contrast, females, smokers, those on insulin therapy and with longer duration of disease had lower C-peptide levels. Most recently diagnosed young-onset T2DM have adequate beta-cell function. Elevated C-peptide levels associated with obesity, hypertension and diabetic kidney disease suggest insulin resistance as the key driving factor for complications.

278-LB: The Effect of Combining Very-Low-Calorie Diet with Semaglutide on Beta-Cell Function in Individuals with Type 2 Diabetes

Type 2 diabetes (T2D) is characterised by the loss of the first phase response of insulin-producing pancreatic beta cells. Recently, Very-low calorie diets (VLCD - defined as less than 800 kilocalories per day) have been shown to restore this first phase response to induce remission of T2D, while Glucagon-like peptide-1 agonists also improve the first phase response by enhancing postprandial insulin secretion. Here, we present interim results of an investigation exploring the effect of combining these two interventions on beta cell function, in individuals with T2D. Eighteen individuals with T2D and body mass index >27kg.m-2 were randomly allocated into 3 groups: i) Semaglutide (S), ii) VLCD (V), and iii) Semaglutide-plus-VLCD (SV). Semaglutide was administered once weekly gradually up titrated to a maximum dose of 1mg and VLCD regime was provided by LighterLife® total meal replacement. Beta cell function was assessed using intravenous glucose tolerance tests (IVGTT) performed at baseline and 12 weeks. First-phase insulin response was calculated as the incremental area under the suprabasal plasma insulin concentration curve during 0-10 minutes of the IVGTT (µU.min.ml-1). Data were analysed using GraphPad Prism 9.5.0 (La Jolla, USA). All groups were equally matched at baseline. Mean weight loss was 6.4, 14.1 and 14.9 kg in S, V and SV, respectively. A significant improvement in first phase response was observed in all groups (S: +398.5; V: +88.4; SV: +547.8 µU.min.ml-1, all p<0.05 vs. baseline). At 12 weeks, first phase response in SV was significantly higher than in V (583.9 vs. 169.2 µU.min.ml-1 respectively, p<0.05). These data suggest that combination of VLCD and Semaglutide results in a significantly greater improvement in first phase response than VLCD alone. This approach could result in a more robust remission of T2D in the longer-term, and may have important implications for the future design of interventions for the clinical management of T2D. Disclosure O. Anyiam: None. B. E. Phillips: None. D. J. Wilkinson: None. K. Smith: None. P. J. Atherton: None. I. R. Idris: None. Funding Medical Research Council Confidence in Concept Scheme

PSAT118 Elevated Serum IgA at Onset of Type 1 Diabetes in Children

Abstract IgA is the most produced antibody in the body. There are two major forms of IgA, monomeric serum IgA and dimeric mucosal (secretory) IgA. During infection or inflammation, IgA binding to its antigen induces crosslinking of FcaRI, which activates immune effector cells to carry out their functions and can thus induce pro-inflammatory responses, which is hypothesized to occur when IgA titers are high. (1,2) Elevated serum IgA has been associated with autoimmune diseases (3) including type 1 diabetes (T1D) but its role in disease pathogenesis is not well known. To address this gap in knowledge, we aimed to test the hypothesis that at diagnosis of T1D, children and adolescents with elevated serum IgA have different demographic, clinical and laboratory characteristics than those with normal serum IgA. We analyzed 612 children 9.7 [4.2] (mean [SD]) years old (59% Non-Hispanic White, 20% Hispanic, 16% Black, 5% Other) with new onset T1D diagnosed between 1/2008-2/2012 at a large, academic pediatric hospital. Serum IgA values above age-adjusted normal ranges were defined as elevated serum IgA. Patients with low IgA were excluded because of known association between IgA deficiency and autoimmune disease. Demographic and clinical variables were compared between youth with and without elevated serum IgA. Univariable and multivariable regression models were used to compare baseline characteristics that were associated with elevated serum IgA. A significance level of 0.05 was used. We found that elevated serum IgA was present in 21% (128/612) of the children at T1D onset. By multivariate analysis, compared to children with normal IgA, those with elevated IgA were more likely to be of Hispanic ethnicity (Odds Ratio (OR)=3.27, 95% Confidence Interval (CI)=2.00, 5.35) and had a higher hemoglobin A1c (A1c) (OR=1.13, 95% CI=1.01, 1.26). They also had higher odds of having insulin autoantibody (IAA) positivity at diagnosis (OR=1.65, 95% CI=1.10, 2.45) and lower odds of GAD autoantibody (GADA) positivity (OR= 0.57, 95% CI=0.36, 0.93) (all, p<0.05), while there were no significant associations with age, glucose level or presence of DKA. In sum, at diagnosis of T1D, 21% of youth have elevated serum IgA and this was associated with Hispanic ethnicity, higher A1C and positivity for IAA. Our findings suggest that elevated serum IgA may help identify youth with T1D, islet autoimmunity and insulin deficiency. Further studies are warranted to investigate potential pathogenic correlates and persistence over time. This knowledge may lead to new targeted strategies to preserve or improve beta-cell function in individuals with clinical or pre-clinical T1D. References (1) Hansen IS et al. Cell Mol Life Sci. 2019 Mar;76(6): 1041-1055. PMID: 30498997 (2) Leong KW et al. DNA Cell Biol. 2014 Dec;33(12): 823-9. PMID: 25188736 (3) Kerr MA. Biochem J. 1990 Oct 15;271(2): 285-96. PMID: 2241915 Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.

INNODIA Master Protocol for the evaluation of investigational medicinal products in children, adolescents and adults with newly diagnosed type 1 diabetes

BackgroundThe INNODIA consortium has established a pan-European infrastructure using validated centres to prospectively evaluate clinical data from individuals with newly diagnosed type 1 diabetes combined with centralised collection of clinical samples to determine rates of decline in beta-cell function and identify novel biomarkers, which could be used for future stratification of phase 2 clinical trials.MethodsIn this context, we have developed a Master Protocol, based on the “backbone” of the INNODIA natural history study, which we believe could improve the delivery of phase 2 studies exploring the use of single or combinations of Investigational Medicinal Products (IMPs), designed to prevent or reverse declines in beta-cell function in individuals with newly diagnosed type 1 diabetes. Although many IMPs have demonstrated potential efficacy in phase 2 studies, few subsequent phase 3 studies have confirmed these benefits. Currently, phase 2 drug development for this indication is limited by poor evaluation of drug dosage and lack of mechanistic data to understand variable responses to the IMPs. Identification of biomarkers which might permit more robust stratification of participants at baseline has been slow.DiscussionThe Master Protocol provides (1) standardised assessment of efficacy and safety, (2) comparable collection of mechanistic data, (3) the opportunity to include adaptive designs and the use of shared control groups in the evaluation of combination therapies, and (4) benefits of greater understanding of endpoint variation to ensure more robust sample size calculations and future baseline stratification using existing and novel biomarkers.

The Role of Vegan Diets in Lipotoxicity-Induced Beta-Cell Dysfunction in Type-2-Diabetes

Type-2-diabetes is considered the new plague of the current century and both, its incidence and prevalence are rapidly increasing. Chronic insulin resistance and a progressive decline in beta-cell function are discussed as the root causes of type-2-diabetes. Both were associated with obesity and pathologically elevated concentrations of circulating free fatty acids in the blood.
 The harmful effects of chronically elevated free fatty acid levels on glucose homeostasis and non-adipose tissues are referred to as lipotoxicity. Pancreatic beta-cells appear to be particularly vulnerable and both, dietary fat quantity and quality may impact beta-cell function.
 Diets high in saturated fats are especially harmful to beta-cells while (poly-)unsaturated fatty acids were associated with beta-cell protective effects. This review examined how a dietary modification towards a low-fat vegan diet, which is particularly low in saturated and trans-fats, could help to prevent or reduce lipotoxicity-induced beta cell dysfunction.
 Several potential mechanisms of action were identified including: (1) reduced total fat intake (fat quantity), (2) a more favorable polyunsaturated fatty acid to saturated fatty acid ratio (fat quality), (3) improved body weight and a reduction in adipose tissue mass, and finally (4) improved glycemic control. The latter appears of paramount importance in light of the accumulating evidence that lipotoxic events are tightly coupled to excess glucose levels.
 All four mechanisms are likely to contribute complementarily to improved beta-cell function in individuals with type-2-diabetes and may reduce the likelihood of lipotoxic events to occur. Physicians must consider these findings when counseling patients on lifestyle and nutrition.

Triglyceride is independently correlated with insulin resistance and islet beta cell function: a study in population with different glucose and lipid metabolism states

BackgroundPrevious studies on the effects of lipotoxicity and oxidative stress on islet beta cell function mainly focused on patients with diabetes, whereas studies on normal glucose tolerance (NGT) are few. The aim of this study was to explore the relationships among triglyceride (TG), high-density lipoprotein cholesterol (HDL-c), low-density lipoprotein cholesterol (LDL-c), oxidative stress indicators, insulin resistance, and beta cell function in populations with different glucose and lipid metabolism states.MethodsA total of 517 individuals were recruited from a rural community in Beijing, China. Glucose metabolism status was defined according to the results of a 75-g oral glucose tolerance test (OGTT). Dyslipidemia was defined as abnormal TG, HDL-c, or LDL-c levels. The population was divided into four groups: individuals with normal glucose and lipid levels (group A, n = 62); those with dyslipidemia alone (group B, n = 82); those with dysglycemia alone (group C, n = 121); and those with dysglycemia and dyslipidemia (group D, n = 247). Oxidative stress indicators, including superoxide dismutase (SOD), glutathione reductase (GR) and 8-hydroxydeoxyguanosine (8-OHdG), were measured. Homeostasis model assessment of insulin resistance (HOMA-IR) and glucose disposition index (DI30, DI120) were calculated to assess insulin resistance and islet beta cell function, respectively. Stratified multiple linear regression analysis was used to explore relationships between TG, HDL-c, LDL-c, oxidative stress indicators, and insulin resistance (natural log transformation of HOMA-IR, LnHOMA-IR) and beta cell function (natural log transformation of DI30, Ln DI30).ResultsCompared with the control group, populations with dyslipidemia and/or dysglycemia showed significantly increased insulin resistance. Dyslipidemia aggravated insulin resistance and beta cell dysfunction in individuals with dysglycemia. Stratified regression analysis showed that TG positively correlated with LnHOMA-IR in individuals with normal glucose levels (beta = 0.321, 0.327, P = 0.011, 0.003 in groups A and B, respectively) and negatively correlated with LnDI30 in participants with dyslipidemia (beta = − 0.225, − 0.122, P = 0.035, 0.048 in groups B and D, respectively). Reduced serum SOD levels in individuals with dysglycemia plus dyslipidemia were observed, and a negative association between TG and SOD levels was found (r = − 0.461, P < 0.001).ConclusionTG correlated with both insulin resistance and beta cell function in individuals with dyslipidemia alone. SOD negatively correlated with TG, indicating a close relationship between oxidative stress and glucose-lipid metabolism. Due to the adverse effect of hypertriglyceridemia on insulin sensitivity and islet beta cell function, more attention should be paid to the detection and management of hypertriglyceridemia.

The Role of Vegan Diets in Lipotoxicity-induced Beta-cell Dysfunction in Type-2-Diabetes: A Narrative Review.

Type-2-diabetes is considered the new plague of the current century and its incidence and prevalence are rapidly increasing. Chronic insulin resistance and a progressive decline in beta-cell function are discussed as the root causes of type-2-diabetes. Both are associated with obesity and prolonged exposure to pathologically elevated concentrations of circulating free fatty acid (FFA) levels in the blood. Fatty acid derivatives may interfere with beta-cell function and ultimately lead to their death through lipoapoptosis. The harmful effects of chronically elevated FFA levels on glucose homeostasis and non-adipose tissues are generally referred to as lipotoxicity. Pancreatic beta-cells appear to be particularly vulnerable, and both dietary fat quantity and quality may impact their function. Diets high in saturated fat are especially harmful to beta-cells while (poly-)unsaturated fatty acids (PUFA) are associated with beta-cell protective effects. Therefore, this narrative review suggests that a dietary modification toward a low-fat vegan diet might help to prevent or reduce lipotoxicity-induced beta-cell dysfunction. By cutting the oversupply of saturated fat and reducing total calorie intake, and by improving both body weight and glycemic control, low-fat vegan diets may reduce the likelihood of lipotoxic events to occur. In light of the accumulating evidence that lipotoxic events are tightly coupled to excess glucose levels, improved glycemic parameters appear to be of utmost importance. These mechanisms are likely to contribute complementarily to improved beta-cell function in individuals with type-2-diabetes who choose a low-fat vegan diet. Physicians must consider these findings when counseling patients on lifestyle modifications and healthy nutrition.

Therapeutic approaches for latent autoimmune diabetes in adults: One size does not fit all.

Recent advances in the understanding of latent autoimmune diabetes in adults (LADA) pathophysiology make it increasingly evident that people with LADA comprise a heterogenous group of patients. This makes the establishment of a standard treatment algorithm challenging. On top of its glucose-lowering action, insulin may exert anti-inflammatory effects, rendering it an attractive therapeutic choice for a type of diabetes in which autoinflammation and beta cell insufficiency play major pathogenetic roles. However, there is growing evidence that other antidiabetic drugs, such as metformin, dipeptidyl peptidase-4 inhibitors, glucagon-like peptide-1 receptor agonists, and thiazolidinediones, might have a role in optimizing glycemic control and preserving beta cell function in individuals with LADA, either alone or in combination with insulin. Although most of these drugs have been routinely used in the daily clinical setting for years, large prospective randomized trials are needed to assess whether they are capable of delaying progression to insulin dependence as well as their effects on diabetic complications. The aim of the present review is to discuss the current state and future perspectives of LADA therapy, emphasizing the need for individualized and patient-centered therapeutic approaches.

Tetraspanin 7 autoantibodies predict progressive decline of beta cell function in individuals with LADA

Aims/hypothesisThe aim of this work was to investigate whether tetraspanin 7 autoantibodies (TSPAN7A) are valuable in predicting poor beta cell function in individuals with latent autoimmune diabetes in adults (LADA).MethodsThe cross-sectional study involved participants with LADA (n = 173), type 1 diabetes (n = 158), type 2 diabetes (n = 204) and healthy control participants (n = 170). The longitudinal study involved 53 participants with LADA, with a 3-year follow-up. In both cohorts, TSPAN7A in the sera were measured by a luciferase immunoprecipitation system assay, and physical and clinical characteristics were recorded.ResultsThe prevalence of TSPAN7A in LADA, type 1 diabetes, type 2 diabetes and healthy control participants was 21.4% (37/173), 26% (41/158), 0.5% (1/204) and 1.2% (2/170), respectively. Importantly, measurement of TSPAN7A significantly increased the number of individuals with LADA found to be positive for multiple antibodies (32.4% vs 22%; p < 0.001). Further logistic regression analysis demonstrated that positivity for TSPAN7A (OR 2.87, p = 0.034), disease duration (OR 1.83, p = 0.019) and GAD antibody titre (OR 2.67, p = 0.009) were risk factors for beta cell function in LADA, while BMI (OR 0.34, p = 0.001) was a protective factor. In the prospective study in individuals with LADA, the median annual decrease in rates of fasting C-peptide and 2 h postprandial C-peptide in individuals who were positive for TSPAN7A was significantly higher when compared with the decrease in those who were negative for TSPAN7A (34.6% vs 7.9%, p = 0.043 and 33.2% vs 11%, p = 0.041, respectively).Conclusions/interpretationTSPAN7A are valid islet autoantibodies for use in East Asian populations with autoimmune diabetes and can discriminate individuals with LADA who have lower beta cell function after disease progression.

Beta cell function and ongoing autoimmunity in long-standing, childhood onset type 1 diabetes.

Aims/hypothesisThis study aimed to determine the frequency of residual beta cell function in individuals with long-standing type 1 diabetes who were recruited at diagnosis, and relate this to baseline and current islet autoantibody profile.MethodsTwo hour post-meal urine C-peptide:creatinine ratio (UCPCR) and islet autoantibodies were measured in samples collected from 144 participants (median age at diagnosis: 11.7 years; 47% male), a median of 23 years (range 12–29 years) after diagnosis. UCPCR thresholds equivalent to mixed meal-stimulated serum C-peptide >0.001 nmol/l, ≥0.03 nmol/l and ≥0.2 nmol/l were used to define ‘detectable’, ‘minimal’ and ‘residual/preserved’) endogenous insulin secretion, respectively. Autoantibodies against GAD (GADA), islet antigen-2 (IA-2A), zinc transporter 8 (ZnT8A) and insulin (IAA) were measured by radioimmunoassay.ResultsEndogenous C-peptide secretion was detectable in 51 participants (35.4%), including residual secretion in seven individuals (4.9%) and minimal secretion in 14 individuals (9.7%). In the 132 samples collected more than 10 years after diagnosis, 86 participants (65.2%) had at least one islet autoantibody: 42 (31.8%) were positive for GADA, 69 (52.3%) for IA-2A and 14 of 104 tested were positive for ZnT8A (13.5%). The level of UCPCR was related to age at diagnosis (p = 0.002) and was independent of diabetes duration, and baseline or current islet autoantibody status.Conclusions/interpretationThere is evidence of ongoing autoimmunity in the majority of individuals with longstanding diabetes. Endogenous insulin secretion continues for many years after diagnosis in individuals diagnosed with autoimmune-mediated type 1 diabetes above age 5. These findings suggest that some beta cells are protected from continued autoimmune attack in longstanding type 1 diabetes.

Cardiorespiratory fitness and not body fat is independently associated with beta cell function in individuals with metabolic syndrome: Fitness versus fatness

Cardiorespiratory fitness and not body fat is independently associated with beta cell function in individuals with metabolic syndrome: Fitness versus fatness

Failure of β-cell function for compensate variation in insulin sensitivity in hypomagnesemic subjects

To evaluate if decreased insulin sensitivity is appropriately compensated by beta-cell function in subjects with hypomagnesemia, 165 individuals, 20 to 65 years of age, were randomly enrolled in a cross-sectional study. Subjects were allocated into groups with and without hypomagnesemia, matched by age, gender, waist circumference, and body mass index. Pregnancy, smoking, alcohol consumption, high blood pressure, type 2 diabetes, chronic diarrhea, renal disease, malignancy, and heavy physical activity were exclusion criteria. Hypomagnesemia was defined by a serum magnesium concentration of < 1.8 mg/dL. As a surrogate of the hyperbolic model of beta-cell function, the relation between Belfiore's index {2/[1 + (Fasting insulin pmol/L x Fasting glucose mmol/L)]} and the HOMA-beta index {20 X Fasting insulin microU/mL /(Fasting glucose mmol/L - 3.5)} was used. The mean Area Under Curve (AUC) was calculated for each group. Although the Belfiore index was significantly lower (0.041 +/- 0.021 and 0.053 +/- 0.030, p = 0.005) and fasting plasma glucose higher (113.6 +/- 23.0 and 106.8 +/- 18.4 mg/dL, p = 0.04) in the subjects with hypomagnesemia, the HOMA-beta index (82.5 +/- 48.5 and 91.2 +/- 79.9, p = 0.32) and insulin levels (8.6 +/- 5.4 and 9.6 +/- 4.8 mciroU/mL, p = 0.17) were similar between the groups studied. The AUC which evaluates the adaptation of beta-cell function to variation in insulin sensitivity was significantly higher in the normo-magnesemic than the hypomagnesemic group (proportion 1:2.5). Results of this study show that the decrease in insulin sensitivity is not appropriately compensated by beta-cell function in individuals with hypomagnesemia; our finding suggests that hypomagnesemia could be linked to inadequate beta-cell compensation.

β-Cell Function in Individuals Carrying the Mitochondrial tRNA Leu (UUR) Mutation

To assess the beta-cell function in individuals with mitochondrial DNA A3243G mutation with normal glucose tolerance (NGT) or diabetes mellitus (DM). Furthermore, in diabetic individuals, we evaluated the effect of coenzyme Q10 supplementation on insulin secretory response. Eight mutation-positive individuals with NGT (n = 4) or DM (n = 4) were studied. beta-Cell function was evaluated by C-peptide levels before and after a mixed liquid meal (Sustacal) challenge and by first-phase insulin response. Fasting and Sustacal-stimulated C-peptide levels were significantly lower in diabetic patients than that in controls (area under the curve: 104.1 +/- 75.7 vs 520.8 +/- 173.8, P = 0.001), whereas in individuals with NGT, this response was preserved (area under the curve: 537.8 +/- 74.3 vs 520.8 +/- 179.8, P = 0.87). The duration of diabetes was negatively correlated with fasting C-peptide levels (r = -0.961, P = 0.038). Among the 3 patients with residual insulin secretion, the short-term treatment with coenzyme Q10 (3 months) improved C-peptide levels in 2 of them. The first-phase insulin response was diminished in 2 individuals with NGT, the oldest ones. We showed an impaired insulin secretory capacity in individuals carrying the A3243G mutation, this possibly being the primary defect contributing to the development of DM. In addition, our data suggest that this could be a functional defect.

Is reduced first-phase insulin release the earliest detectable abnormality in individuals destined to develop type 2 diabetes?

Insulin is released from the pancreas in a biphasic manner in response to a square-wave increase in arterial glucose concentration. The first phase consists of a brief spike lasting approximately 10 min followed by the second phase, which reaches a plateau at 2-3 h. It is widely thought that diminution of first-phase insulin release is the earliest detectable defect of beta-cell function in individuals destined to develop type 2 diabetes and that this defect largely represents beta-cell exhaustion after years of compensation for antecedent insulin resistance. In this article, the origins of these concepts are reviewed and recent evidence is presented suggesting that reductions in both phases of insulin release are equally early, that they precede insulin resistance other than that simply due to obesity, and that they therefore may represent the primary genetic risk factor predisposing individuals to type 2 diabetes.