Triple hormone receptor agonist retatrutide for metabolic dysfunction-associated steatotic liver disease: a randomized phase 2a trial.

Retatrutide is a novel triple agonist of the glucose-dependent insulinotropic polypeptide, glucagon-like peptide 1 and glucagon receptors. A 48-week phase 2 obesity study demonstrated weight reductions of 22.8% and 24.2% with retatrutide 8 and 12 mg, respectively. The primary objective of this substudy was to assess mean relative change from baseline in liver fat (LF) at 24 weeks in participants from that study with metabolic dysfunction-associated steatotic liver disease and ≥10% of LF. Here, in this randomized, double-blind, placebo-controlled trial, participants (n = 98) were randomly assigned to 48 weeks of once-weekly subcutaneous retatrutide (1, 4, 8 or 12 mg dose) or placebo. The mean relative change from baseline in LF at 24 weeks was -42.9% (1 mg), -57.0% (4 mg), -81.4% (8 mg), -82.4% (12 mg) and +0.3% (placebo) (all P < 0.001 versus placebo). At 24 weeks, normal LF (<5%) was achieved by 27% (1 mg), 52% (4 mg), 79% (8 mg), 86% (12 mg) and 0% (placebo) of participants. LF reductions were significantly related to changes in body weight, abdominal fat and metabolic measures associated with improved insulin sensitivity and lipid metabolism. The ClinicalTrials.gov registration is NCT04881760 .

Stratification of obesity phenotypes to optimize future therapy (SOPHIA).

INTRODUCTION: Obesity is considered a poor lifestyle choice. 'Obesity' is not a sufficient definition for patients, any more than 'cancer' or 'arthritis' would be. A major obstacle is the lack of understanding of pathogenesis. The disease of obesity is considered homogenous, while response to treatment is thought of as heterogeneous. This can change if pathogenesis, risk profiles for complications, and treatment responses are viewed within the context of obesity consisting of several subsets of disease. AREAS COVERED: The European Union-funded Innovative Medicine Initiative project Stratification of Obesity Phenotypes to Optimize Future Obesity Therapy is part of a momentum shift. Operational variables are being used to develop tests and therapies which may allow the prediction of risk of obesities and the prediction of response to obesity treatments. However, changing stakeholder perspectives on obesity may require more than high-quality data and analysis. EXPERT OPINION: For patients to benefit, clinicians need to integrate evidence-based treatments and payers need to reimburse the management of the disease of obesity. This will generate commercial opportunities for industry. We need to involve stakeholders (patients, clinicians, regulators, payer, patient organisations) to create a shared value for mutual gain.

Characterizing Diabetes Empowerment and Motivation for Changing Health Behaviors Among People with Type 2 Diabetes: A Cross-Sectional Survey.

INTRODUCTION: Effectively engaging people with type 2 diabetes (T2D) earlier in their health journeys is critical to prevent downstream complications. Digitally based diabetes programs are a growing component of care delivery that have the potential to engage individuals outside of traditional clinic-based settings and use personalized data to pair people to tailored diabetes self-management interventions. Knowing an individuals' diabetes empowerment and health-related motivation can help drive appropriate recommendations for personalized interventions. We aimed to characterize diabetes empowerment and motivation towards changing health behaviors among participants in Level2, a T2D specialty care organization in the USA that combines wearable technology with personalized clinical support. METHODS: A cross-sectional online survey was conducted among people enrolled in Level2 (February-March 2021). Distributions of respondent-reported diabetes empowerment and health motivation were analyzed using Motivation and Attitudes Toward Changing Health (MATCH) and Diabetes Empowerment Scale Short Form (DES-SF) scales, respectively. Associations between MATCH and DES-SF scores with Level2 engagement measures and glycemic control were analyzed. RESULTS: The final analysis included 1258 respondents with T2D (mean age 55.7 ± 8.4 years). Respondents had high average MATCH (4.19/5) and DES-SF (4.02/5) scores. The average MATCH subscores for willingness (4.43/5) and worthwhileness (4.39/5) were higher than the average ability subscore (3.73/5). Both MATCH and DES-SF scores showed very weak correlations with Level2 engagement measures and glycemic control (ρ = - 0.18-0.19). CONCLUSIONS: Level2 survey respondents had high average motivation and diabetes empowerment scores. Further research is needed to validate sensitivity of these scales to detect changes in motivation and empowerment over time and to determine whether differences in scores can be used to pair people to personalized interventions.

Clinical characteristics, treatment patterns, and persistence in individuals with type 2 diabetes initiating a glucagon-like peptide-1 receptor agonist: A retrospective analysis of the Diabetes Prospective Follow-Up Registry.

AIMS: To describe clinical characteristics, treatment patterns and glucagon-like peptide-1 receptor agonist (GLP-1 RA) persistence in individuals with type 2 diabetes (T2D) initiating their first GLP-1 RA. MATERIALS AND METHODS: A real-world analysis of adults with T2D initiating GLP-1 RA therapy between 2007 and June 2020 from the multicentre Diabetes Prospective Follow-Up (DPV) Registry, stratified by antidiabetes therapy at the time of GLP-1 RA initiation: oral antidiabetic drugs (OAD), insulin ± OAD or lifestyle modification (LM). GLP-1 RA treatment persistence in individuals with ≥12 months follow-up was determined by Kaplan-Meier analysis. RESULTS: Overall, 15 111 individuals with T2D initiating GLP-1 RA therapy (55% men) were identified; median [interquartile range (IQR)] age [58.7 (50.6-66.7) years], diabetes duration [8.5 (3.6-14.7) years], glycated haemoglobin [HbA1c; 8.2 (7.1-9.8)%]. Median (95% confidence interval) GLP-1 RA persistence in eligible individuals (n = 5189) was 11 (10-12) months; OAD 12 (11-14) months (n = 2453); insulin ± OAD 11 (9-12) months (n = 2204); and LM 7 (5-9) months (n = 532). Median treatment persistence tended to increase from 2007-2012 to 2017-2020. Median (IQR) HbA1c decreased from baseline [8.2 (7.1-9.8)%] to discontinuation [7.5 (6.6-8.7)%], with a greater decrease observed in individuals with persistence >12 months versus ≤12 months. Individuals who discontinued GLP-1 RA therapy predominantly switched to insulin (if not already using) or dipeptidyl peptidase-4 inhibitors. CONCLUSION: Real-world registry data revealed improved outcomes with longer median GLP-1 RA persistence; ~50% of patients overall achieved HbA1c <7% at 12 months. Persistence was highest with baseline OAD and/or insulin, and tended to increase over the period 2007-2020.

Clinical characteristics and cardiovascular risk profile in children and adolescents with latent autoimmune diabetes: Results from the German/Austrian prospective diabetes follow-up registry.

AIMS: To characterize children and adolescents with latent autoimmune diabetes of the young (LADY), and to assess the utility of classifying individuals as LADYs regarding their cardiovascular (CV) risk factors. METHODS: Data from 25,520 individuals (age at diagnosis <18 years) of the Prospective Diabetes Follow-up Registry Diabetes-Patienten Verlaufsdokumentation (DPV) were analyzed. LADY was defined as positivity of ≥one islet autoantibody (iAb+) and an insulin-free interval of ≥6 months upon diabetes diagnosis. LADYs were compared to iAb+ individuals immediately requiring insulin ("immunologically confirmed" type 1 diabetes, T1DM), iAb-/Ins- individuals ("classical" T2DM) and to those clinically defined as T2DM (iAbs not measured). RESULTS: Clinical characteristics of LADYs (n = 299) fell in between those with T1DM (n = 24,932) and T2DM (iAb-/Ins-, n = 152) or suspected T2DM (iAB not measured, n = 137). Stratifying LADYs according to their clinical diagnosis however revealed two distinct populations, highly resembling either T1DM or T2DM. Particularly, CV risk profile, precisely prevalence rates of arterial hypertension and dyslipidemia, was significantly higher in LADYs clinically classified as T2DM compared to LADYs classified as T1DM, and did not differ from those with "classical" T2DM. CONCLUSIONS: In terms of CV risk, classifying children and adolescents with diabetes as LADYs provides no additional benefit. Instead, clinical diagnosis seems to better assign individuals to appropriate risk groups for increased CV risk profiles.

Digital Diabetes Management: A Literature Review of Smart Insulin Pens.

Digital health management is increasingly pivotal in the care of patients with diabetes. The aim of this review was to evaluate the clinical benefits of using smart insulin pens with connectivity for diabetes management. The search was performed using PubMed and PubMed Central on May 15, 2019, to identify publications investigating the use of insulin pens. Studies evaluating insulin pens with connectivity via Bluetooth/Near Field Communication, with an associated electronic device enabling connectivity, or with a memory function were included in the review. Nine studies were identified in the search. Overall, these studies lacked data on smart insulin pens with a connectivity function, with eight of the available studies investigating only pens with a memory function. The studies focused primarily on assessing patient preference, usability, and technical accuracy. The number of studies assessing clinical outcomes was small (n = 3). However, the majority of studies (n = 8) reported that patients preferred smart insulin pens because they increased confidence with regard to diabetes self-management. These results suggest a lack of published data regarding smart insulin pens with connectivity for the management of diabetes. However, the available published data on usability and patient preference suggest that the use of smart insulin pens holds promise for improving and simplifying diabetes self-management.

Ketone bodies: from enemy to friend and guardian angel.

During starvation, fasting, or a diet containing little digestible carbohydrates, the circulating insulin levels are decreased. This promotes lipolysis, and the breakdown of fat becomes the major source of energy. The hepatic energy metabolism is regulated so that under these circumstances, ketone bodies are generated from ß-oxidation of fatty acids and secreted as ancillary fuel, in addition to gluconeogenesis. Increased plasma levels of ketone bodies thus indicate a dietary shortage of carbohydrates. Ketone bodies not only serve as fuel but also promote resistance to oxidative and inflammatory stress, and there is a decrease in anabolic insulin-dependent energy expenditure. It has been suggested that the beneficial non-metabolic actions of ketone bodies on organ functions are mediated by them acting as a ligand to specific cellular targets. We propose here a major role of a different pathway initiated by the induction of oxidative stress in the mitochondria during increased ketolysis. Oxidative stress induced by ketone body metabolism is beneficial in the long term because it initiates an adaptive (hormetic) response characterized by the activation of the master regulators of cell-protective mechanism, nuclear factor erythroid 2-related factor 2 (Nrf2), sirtuins, and AMP-activated kinase. This results in resolving oxidative stress, by the upregulation of anti-oxidative and anti-inflammatory activities, improved mitochondrial function and growth, DNA repair, and autophagy. In the heart, the adaptive response to enhanced ketolysis improves resistance to damage after ischemic insults or to cardiotoxic actions of doxorubicin. Sodium-dependent glucose co-transporter 2 (SGLT2) inhibitors may also exert their cardioprotective action via increasing ketone body levels and ketolysis. We conclude that the increased synthesis and use of ketone bodies as ancillary fuel during periods of deficient food supply and low insulin levels causes oxidative stress in the mitochondria and that the latter initiates a protective (hormetic) response which allows cells to cope with increased oxidative stress and lower energy availability. KEYWORDS: Ketogenic diet, Ketone bodies, Beta hydroxybutyrate, Insulin, Obesity, Type 2 diabetes, Inflammation, Oxidative stress, Cardiovascular disease, SGLT2, Hormesis.

Satisfaction, Preference and Injection Habits of Switching to 200 Units/ml Insulin Lispro Pen from 100 Units/ml: A Patient Survey in Germany.

INTRODUCTION: The study was designed to assess patient satisfaction, preferences and injection habits for patients using insulin lispro 200 units/ml pen (IL200) compared to their previously used disposable 100 units/ml mealtime insulin pen ("MTI-100 pen") in Germany. METHODS: A site-based, cross-sectional study involving a self-reported survey and medical record extraction in patients with diabetes currently using IL200 for between 3 and 12 months and had previously used any disposable MTI-100 pen. RESULTS: Of 114 patients included, 83.3% were satisfied with IL200 and 3.5% were dissatisfied; 70.2% preferred IL200 over their previous MTI-100 pen and 4.4% preferred their previous MTI-100 pen. The main reasons for IL200 preference were the amount of insulin the pen carries, longer use before discarding, number of non-empty pens discarded, injection volume and frequency replacing pens. Patients discarded (median) 4 IL200 pens per month with 5.3% discarding more than 10 units in their last pen. When insufficient insulin remained to complete a dose, 74.6% injected the remainder and completed with a new pen, 19.3% discarded the pen with remaining insulin, 7.0% saved it for future use and 1.8% left the dose incomplete. CONCLUSIONS: Satisfaction and preference for IL200 was high in this sample of patients using IL200 for 3-12 months. Reasons were consistent with IL200 features, explaining the better patient experience and potential resource saving transitioning from a disposable MTI-100 pen.

Leukocyte Counts and T-Cell Frequencies Differ Between Novel Subgroups of Diabetes and Are Associated With Metabolic Parameters and Biomarkers of Inflammation.

Frequencies of circulating immune cells are altered in those with type 1 and type 2 diabetes compared with healthy individuals and are associated with insulin sensitivity, glycemic control, and lipid levels. This study aimed to determine whether specific immune cell types are associated with novel diabetes subgroups. We analyzed automated white blood cell counts (n = 669) and flow cytometric data (n = 201) of participants in the German Diabetes Study with recent-onset (<1 year) diabetes, who were allocated to five subgroups based on data-driven analysis of clinical variables. Leukocyte numbers were highest in severe insulin-resistant diabetes (SIRD) and mild obesity-related diabetes (MOD) and lowest in severe autoimmune diabetes (SAID). CD4+ T-cell frequencies were higher in SIRD versus SAID, MOD, and mild age-related diabetes (MARD), and frequencies of CCR4+ regulatory T cells were higher in SIRD versus SAID and MOD and in MARD versus SAID. Pairwise differences between subgroups were partially explained by differences in clustering variables. Frequencies of CD4+ T cells were positively associated with age, BMI, HOMA2 estimate of ß-cell function (HOMA2-B), and HOMA2 estimate of insulin resistance (HOMA2-IR), and frequencies of CCR4+ regulatory T cells with age, HOMA2-B, and HOMA2-IR. In conclusion, different leukocyte profiles exist between novel diabetes subgroups and suggest distinct inflammatory processes in these diabetes subgroups.

Long-Term Efficacy and Safety of Ultra Rapid Lispro (URLi) in Adults with Type 1 Diabetes: The PRONTO-T1D Extension.

INTRODUCTION: The PRONTO-T1D study, which evaluated the efficacy and safety of ultra rapid lispro (URLi) versus lispro in adults with type 1 diabetes (T1D), met the primary endpoint of noninferiority of HbA1c change from baseline compared to lispro at 26 weeks. We present results of an additional 26-week treatment phase evaluating long-term efficacy and safety of URLi. METHODS: In this phase 3, treat-to-target study, subjects were randomized to double-blind mealtime URLi, lispro, or open-label postmeal URLi with insulin degludec or glargine for 26 weeks. Subjects in the double-blind URLi (n = 451) and lispro (n = 442) groups continued for another 26 weeks to assess long-term efficacy and safety. RESULTS: HbA1c increased marginally during the long-term maintenance period (week 26-52) in both groups to 7.47% (URLi) and 7.54% (lispro). At week 52, there were no statistically significant treatment differences in change from baseline HbA1c with a least-squares mean treatment difference (95% confidence interval) of - 0.06% (- 0.16, 0.03). Proportions of patients with HbA1c < 7% at week 52 were similar (URLi, 26.8%; lispro, 24.5%). Self-monitored blood glucose (SMBG) showed that 1-h (9.23 versus 10.14 mmol/L) and 2-h (8.40 versus 9.53 mmol/L) postmeal daily mean glucose was statistically significantly (p < 0.001) lower with URLi than lispro. The rate and incidence of severe, documented, and postprandial hypoglycemia (< 54 mg/dl [3.0 mmol/L]) were similar between treatments, but URLi demonstrated a 31% lower rate in the period more than 4 h after meals, (p = 0.023). Injection site reactions were reported by 3.3% of patients on URLi and 0.9% on lispro. The incidence of treatment-emergent adverse events was similar between treatments. CONCLUSION: Overall glycemic control and improved postprandial glucose via SMBG were maintained after 52 weeks with URLi versus lispro, suggesting that the efficacy of URLi is preserved during long-term treatment in patients with T1D. No long-term safety issues were identified with URLi. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03214367.

Increased spontaneous CCL2 (MCP-1) and CCL5 (RANTES) secretion in vitro in LADA compared to type 1 diabetes and type 2 diabetes: Action LADA 14.

AIMS: Immune-mediated type 1 diabetes (T1D) in adulthood and latent autoimmune diabetes in adults (LADA) share similar pathological mechanisms but differ clinically in disease progression. The aim of this study was to acquire insights into spontaneous and stimulated chemokine secretion of immune cells in different diabetes types. MATERIALS AND METHODS: We investigated in vitro spontaneous, mitogen (PI) and antigen (HSP60, p277, pGAD, pIA2) stimulated chemokine secretion of leucocytes from patients with T1D (n = 32), LADA (n = 22), type 2 diabetes (T2D; n = 49), and glucose-tolerant individuals (n = 13). Chemokine concentration in supernatants was measured for CCL2 (MCP-1), CXCL10 (IP10) and CCL5 (RANTES) using a multiplex bead array assay. RESULTS: Spontaneous secretion of CCL2 and CCL5 were higher in LADA compared to T1D and T2D (all p < 0.05) while CXCL10 was similar in the groups. Mitogen-stimulated secretion of CCL2 in LADA was lower compared to T1D and T2D (all p < 0.05) while CXCL10 and CCL5 were similar in all groups. Upon stimulation with pIA2 the secretion of CCL2 in LADA was lower compared to T2D (p < 0.05). Spontaneous CXCL10 secretion in LADA was positively associated with body mass index (r2  = 0.35; p = 0.0035) and C-peptide (r2  = 0.30; p = 0.009). CONCLUSIONS: Chemokine secretion is altered between different diabetes types. Increased spontaneous secretion of CCL2 and CCL5 and decreased secretion of CCL2, upon stimulation with PI and pIA2, in LADA compared to T1D and T2D could reflect altered immune responsiveness in LADA patients in association with their slower clinical progression compared to insulin dependence.

Patient characteristics of insulin lispro 200 units/mL users in real world setting in Germany.

OBJECTIVE: Insulin lispro 200 U/mL (IL200) is a treatment choice for people with diabetes who have daily mealtime insulin (MTI) requirements of >20 U/day. We report clinical characteristics of real world IL200 users in Germany to understand clinical settings and the type of patients who would benefit from IL200 treatment. METHODS: This retrospective database analysis used the patient-level data from "IMS Disease Analyzer" in Germany from February 2015 to June 2016. Clinical and demographic information were collected and analyzed for IL200 users alongside that of those who were using more than 20 U a day of 100 U/mL analog MTI. RESULTS: Of the 17,261 patients using insulin, 811 were identified in IL200 group. The IL200 group had 60% men, mean ± SD age of 63.6 ± 11.9 years, and BMI of 36.2 ± 6.7 kg/m2. Of these, 63.5% (n = 515) were seen by diabetologists, while 36.5% (n = 296) were seen by general practitioners (GPs). In the IL200 group, 77.7% used basal insulin concomitantly, >90% had ≥1 comorbidity, and 52% had ≥4 comorbidities; the most common being hypertension (75.2%), neuropathy (66.0%), and nephropathy (59.6%). Diabetologist-treated IL200 users were more likely to have multiple comorbidities as compared with those treated by GPs (15.0% vs. 12.9% for >5 comorbidities). CONCLUSIONS: IL200 is prescribed to people with diabetes who need more than 20 U/day of mealtime insulin and tend to be more obese, older, and with multiple comorbidities. Future research should explore how concentrated MTI can impact adherence and long-term glycemia.

Genetic Discrimination Between LADA and Childhood-Onset Type 1 Diabetes Within the MHC.

OBJECTIVE: The MHC region harbors the strongest loci for latent autoimmune diabetes in adults (LADA); however, the strength of association is likely attenuated compared with that for childhood-onset type 1 diabetes. In this study, we recapitulate independent effects in the MHC class I region in a population with type 1 diabetes and then determine whether such conditioning in LADA yields potential genetic discriminators between the two subtypes within this region. RESEARCH DESIGN AND METHODS: Chromosome 6 was imputed using SNP2HLA, with conditional analysis performed in type 1 diabetes case subjects (n = 1,985) and control subjects (n = 2,219). The same approach was applied to a LADA cohort (n = 1,428) using population-based control subjects (n = 2,850) and in a separate replication cohort (656 type 1 diabetes case, 823 LADA case, and 3,218 control subjects). RESULTS: The strongest associations in the MHC class II region (rs3957146, ß [SE] = 1.44 [0.05]), as well as the independent effect of MHC class I genes, on type 1 diabetes risk, particularly HLA-B*39 (ß [SE] = 1.36 [0.17]), were confirmed. The conditional analysis in LADA versus control subjects showed significant association in the MHC class II region (rs3957146, ß [SE] = 1.14 [0.06]); however, we did not observe significant independent effects of MHC class I alleles in LADA. CONCLUSIONS: In LADA, the independent effects of MHC class I observed in type 1 diabetes were not observed after conditioning on the leading MHC class II associations, suggesting that the MHC class I association may be a genetic discriminator between LADA and childhood-onset type 1 diabetes.

Concentrated insulins in current clinical practice.

New concentrated insulins (exceeding 100 units/mL) and dedicated devices have recently become available, offering new treatment options for people with diabetes, for basal and prandial insulin supplementation. The concentrated insulin formulations range from 2-fold concentration (insulin lispro 200 units/mL) with rapid-acting prandial action to 5-fold concentration (human regular insulin, 500 units/mL) with basal and short-acting prandial actions. Long-acting basal insulins include degludec 200 units/mL and glargine 300 units/mL. Concentrated insulins have been developed with the goal of easing insulin therapy by reducing the volume and number of injections and in some cases making use of altered pharmacokinetic and pharmacodynamic properties. This review summarizes the unique characteristics of each concentrated insulin to help healthcare providers and people with diabetes understand how to best use them.

First Genome-Wide Association Study of Latent Autoimmune Diabetes in Adults Reveals Novel Insights Linking Immune and Metabolic Diabetes.

OBJECTIVE: Latent autoimmune diabetes in adults (LADA) shares clinical features with both type 1 and type 2 diabetes; however, there is ongoing debate regarding the precise definition of LADA. Understanding its genetic basis is one potential strategy to gain insight into appropriate classification of this diabetes subtype. RESEARCH DESIGN AND METHODS: We performed the first genome-wide association study of LADA in case subjects of European ancestry versus population control subjects (n = 2,634 vs. 5,947) and compared against both case subjects with type 1 diabetes (n = 2,454 vs. 968) and type 2 diabetes (n = 2,779 vs. 10,396). RESULTS: The leading genetic signals were principally shared with type 1 diabetes, although we observed positive genetic correlations genome-wide with both type 1 and type 2 diabetes. Additionally, we observed a novel independent signal at the known type 1 diabetes locus harboring PFKFB3, encoding a regulator of glycolysis and insulin signaling in type 2 diabetes and inflammation and autophagy in autoimmune disease, as well as an attenuation of key type 1-associated HLA haplotype frequencies in LADA, suggesting that these are factors that distinguish childhood-onset type 1 diabetes from adult autoimmune diabetes. CONCLUSIONS: Our results support the need for further investigations of the genetic factors that distinguish forms of autoimmune diabetes as well as more precise classification strategies.

Characterization of circulating leukocytes and correlation of leukocyte subsets with metabolic parameters 1 and 5 years after diabetes diagnosis.

AIMS: Infiltration of pancreatic islets with different leukocyte subtypes likely contributes to deterioration of glycemia in diabetes mellitus. Different subsets of leukocytes have been previously associated with type 1 or type 2 diabetes. This study aimed at examining these subsets at different stages of diabetes progression and possible relationships with metabolic parameters. METHODS: A total of 206 patients, 76 with type 1 and 130 with type 2 diabetes, were studied within the first year of diabetes diagnosis. In addition, 31 patients with type 1 and 73 with type 2 diabetes were examined at 5 years after diagnosis. Whole body insulin sensitivity was assessed by hyperinsulinemic-euglycemic clamps; insulin secretion by glucagon stimulation tests and white blood cells were analyzed by flow cytometry. RESULTS: The percentage of peripheral CD8+ cells was 15% lower in patients with type 1 diabetes at 5 years than in patients at diabetes onset and correlated positively with fasting glycemia, total cholesterol and high-sensitive C-reactive protein (hsCRP) (all r > 0.37, p < 0.05), but not with insulin secretion. Patients with type 2 diabetes had 7% higher percentages of CD4+ cells after 5 years than those at diagnosis. CD4+ cells correlated with hsCRP (r = 0.36, p < 0.05), whereas CD8+ cytotoxic T-cells did not correlate with any metabolic parameter. CONCLUSION: CD8+ T-cells associate with worse glycemia, lipidemia and inflammation after 5 years of type 1 diabetes, whereas CD4+ T-cells associate with increased inflammation after 5 years upon onset of type 2 diabetes.

Dulaglutide treatment results in effective glycaemic control in latent autoimmune diabetes in adults (LADA): A post-hoc analysis of the AWARD-2, -4 and -5 Trials.

AIMS: Patients with a type-2-diabetes (T2D) phenotype positive for glutamic acid decarboxylase antibodies (GADA) represent the majority of cases of latent autoimmune diabetes of the adult (LADA). The GLP-1 receptor agonist dulaglutide, recently introduced for treatment of T2D, has yet to be evaluated in LADA patients. Our primary objective was to evaluate the effect of dulaglutide on glycaemic control (HbA1c) in GADA-positive LADA vs GADA-negative T2D patients. METHODS: A post-hoc analysis was performed using data from 3 randomized phase 3 trials (AWARD-2,-4,-5; patients with GADA assessment) which were part of the dulaglutide clinical development programme in T2D. LADA patients were identified by GADA ≥5 IU/mL (ELISA). Changes in HbA1c during 12 months of treatment with dulaglutide or comparator were analysed using mixed-effect model repeated measures. RESULTS: Of 2466 adults tested for GADA (dulaglutide, 1710; glargine, 298; sitagliptin, 294; placebo, 164), 2278 (92.4%) were GADA-negative and 188 (7.6%) were GADA-positive, including 58 GADA-high patients (> 200 IU/mL) and 130 GADA-low patients (≤200 and ≥5 IU/mL). Overall, baseline parameters were comparable between the groups. Dulaglutide resulted in comparable HbA1c reductions in GADA-negative (LS mean change [95%CI], -1.09% [-1.15, -1.03]) and GADA-positive patients (-0.94% [-1.15, -0.72]) at 12 months. HbA1c reductions were numerically, but not statistically, significantly larger in GADA-low patients (-1.02% [-1.26, -0.78]) vs GADA-high patients (-0.72% [-1.21,-0.24]) at 12 months. Similar outcomes were observed at 3 and 6 months. CONCLUSIONS: These data are the first to indicate that dulaglutide was effective in reducing HbA1c in LADA patients.

Metabolic Characteristics of Recently Diagnosed Adult-Onset Autoimmune Diabetes Mellitus.

Context and Objective: Among patients diagnosed with type 2 diabetes, autoimmune diabetes often remains undetected. Metabolic features of these patients are insufficiently characterized at present. Design, Setting, and Patients: This study compared age- and sex-matched adult (aged 41 to 62 years) humans with recent-onset diabetes: patients positive for antibodies against glutamic acid decarboxylase (GAD) and/or cytoplasmic islet-cell antigen with an insulin-free period of >6 months [antibody positive/insulin negative (ab+/ins-); previously termed latent autoimmune diabetes of adults], type 1 diabetes [antibody positive/insulin positive (ab+/ins+)], and type 2 diabetes [antibody negative/insulin negative (ab-/ins-)], as well as glucose-tolerant humans (controls) of the German Diabetes Study (n = 41/group). ß-Cell function was assessed from glucagon tests and intravenous glucose tolerance tests (IVGTTs), and insulin sensitivity was determined from hyperinsulinemic-euglycemic clamps. Results: Of the ab+/ins- patients, 33 (81%) were initially diagnosed as having type 2 diabetes. In ab+/ins-, body mass index (BMI) was higher than in ab+/ins+ (27.8 ± 5.3 kg/m2 vs 25.0 ± 3.5 kg/m2, P < 0.05), lower than in ab-/ins- (31.9 ± 5.8 kg/m2, P < 0.05), and similar to controls (29.4 ± 6.6 kg/m2). In ab+/ins-, GAD antibody titers correlated negatively with BMI (r = -0.40, P < 0.05) and with C-peptide secretion in glucagon stimulation tests (r = -0.33, P < 0.05). ß-Cell function from IVGTT was 228% higher in ab+/ins- than in ab+/ins+ but 35% lower than in ab-/ins- and 61% lower than in controls (all P < 0.05). Insulin sensitivity in ab+/ins- was comparable to ab+/ins+ and controls but 41% higher than in ab-/ins- (P < 0.05) after adjustment for BMI and fasting blood glucose or hemoglobin A1c. Conclusion: Even shortly after diagnosis, ab+/ins- patients feature partly preserved ß-cell function and chronic hyperglycemia, which possibly contributes to the observed impairment of whole-body insulin sensitivity.

Relative contribution of type 1 and type 2 diabetes loci to the genetic etiology of adult-onset, non-insulin-requiring autoimmune diabetes.

BACKGROUND: In adulthood, autoimmune diabetes can present as non-insulin-requiring diabetes, termed as 'latent autoimmune diabetes in adults' (LADA). In this study, we investigated established type 1 diabetes (T1D) and type 2 diabetes (T2D) genetic loci in a large cohort of LADA cases to assess where LADA is situated relative to these two well-characterized, classic forms of diabetes. METHODS: We tested the association of T1D and T2D GWAS-implicated loci in 978 LADA cases and 1057 non-diabetic controls of European ancestry using a linear mixed model. We then compared the associations of T1D and T2D loci between LADA and T1D and T2D cases, respectively. We quantified the difference in genetic risk between each given disease at each locus, and also calculated genetic risk scores to quantify how genetic liability to T1D and T2D distinguished LADA cases from controls. RESULTS: Overall, our results showed that LADA is genetically more similar to T1D, with the exception of an association at the T2D HNF1A locus. Several T1D loci were associated with LADA, including the major histocompatibility complex region, as well as at PTPN22, SH2B3, and INS. Contrary to previous studies, the key T2D risk allele at TCF7L2 (rs7903146-T) had a significantly lower frequency in LADA cases, suggesting that this locus does not play a role in LADA etiology. When constrained on antibody status, the similarity between LADA and T1D became more apparent; however, the HNF1A and TCF7L2 observations persisted. CONCLUSION: LADA is genetically closer to T1D than T2D, although the genetic load of T1D risk alleles is less than childhood-onset T1D, particularly at the major histocompatibility complex region, potentially accounting for the later disease onset. Our results show that the genetic spectrum of T1D extends into adult-onset diabetes, where it can clinically masquerade as T2D. Furthermore, T2D genetic risk plays a small role in LADA, with a degree of evidence for the HNF1A locus, highlighting the potential for genetic risk scores to contribute towards defining diabetes subtypes.