Increased cardiovascular risk in people with LADA in comparison to type 1 diabetes and type 2 diabetes: Findings from the DPV registry in Germany and Austria.

Introduction: We aimed to characterise and compare individuals diagnosed with type 1 diabetes (T1D), latent autoimmune diabetes in adults (LADA) and type 2 diabetes (T2D), in a real-world setting.

Methods: Anthropometric and clinical data from 36 959 people with diabetes diagnosed at age 30-70 years enrolled in the prospective diabetes patients follow-up (DPV) registry from 1995 to 2022 were analysed cross-sectionally at diagnosis and follow-up (≥6 months after diagnosis). LADA was defined as clinical diagnosis of T2D, positivity of ≥1 islet autoantibody and an insulin-free interval of ≥6 months upon diabetes diagnosis.

Congenital Hyperinsulinism in Humans and Insulin Secretory Dysfunction in Mice Caused by Biallelic Variants.

The BiP co-chaperone DNAJC3 protects cells during ER stress. In mice, the deficiency of DNAJC3 leads to beta-cell apoptosis and the gradual onset of hyperglycemia. In humans, biallelic variants cause a multisystem disease, including early-onset diabetes mellitus.

The N-Methyl-D-Aspartate Receptor Antagonist Dextromethorphan Improves Glucose Homeostasis and Preserves Pancreatic Islets in NOD Mice.

For treatment of type 1 diabetes mellitus, a combination of immune-based interventions and medication to promote beta-cell survival and proliferation has been proposed. Dextromethorphan (DXM) is an -methyl-D-aspartate receptor antagonist with a good safety profile, and to date, preclinical and clinical evidence for blood glucose-lowering and islet-cell-protective effects of DXM have only been provided for animals and individuals with type 2 diabetes mellitus. Here, we assessed the potential anti-diabetic effects of DXM in the non-obese diabetic mouse model of type 1 diabetes.

Delayed-Onset Transient Hyperinsulinism in Infants with Very Low and Extremely Low Birth Weights: A Cohort Study.

We describe 16 infants born preterm with birth weights <1500 g and transient hyperinsulinism. The onset of hyperinsulinism was delayed and often coincident with clinical stabilization. We hypothesize that postnatal stress caused by prematurity and associated problems may contribute to development of delayed-onset transient hyperinsulinism.

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.

Interleukin-7 and soluble Interleukin-7 receptor levels in type 1 diabetes - Impact of IL7RA polymorphisms, HLA risk genotypes and clinical features.

High soluble IL-7 receptor (sIL-7R) serum levels and associated single nucleotide polymorphisms in the IL7RA gene were found in autoimmune diseases including type 1 diabetes. Further determinants on sIL-7R and IL-7 availability as well as changes during type 1 diabetes disease course remain elusive. Here we performed multiparameter analysis to identify influential genetic and disease-associated factors on sIL-7R and IL-7 serum levels during type 1 diabetes disease course (239 children) and in healthy controls (101 children).

Next Generation Sequencing Identifies the HLA-DQA1*03:03 Allele in the Type 1 Diabetes Risk-Associated HLA-DQ8 Serotype.

The highest genetic type 1 diabetes risk is conferred by HLA class II haplotypes defined by alleles at the and - loci. The combination of and alleles (summarized as 'HLA-DQ8') is reported to be among the two most prevalent HLA class II haplotypes in Caucasian type 1 diabetes patients. This classification is based on conventional genotyping of exon 2 of the DQ gene locus and excludes exon 3.

Long-term trends of BMI and cardiometabolic risk factors among adults with type 1 diabetes: An observational study from the German/Austrian DPV registry.

Aims: To analyse time-trends in BMI, obesity and cardiometabolic risk in adults with type 1 diabetes (T1DM) from the Diabetes Prospective Follow-up registry DPV.

Methods: Data from 62,519 individuals with T1DM (age ≥ 18 years, BMI ≥ 18.5 kg/m) were analysed.

Peripherally active dextromethorphan derivatives lower blood glucose levels by targeting pancreatic islets.

Dextromethorphan (DXM) acts as cough suppressant via its central action. Cell-protective effects of this drug have been reported in peripheral tissues, making DXM potentially useful for treatment of several common human diseases, such as type 2 diabetes mellitus (T2DM). Pancreatic islets are among the peripheral tissues that positively respond to DXM, and anti-diabetic effects of DXM were observed in two placebo-controlled, randomized clinical trials in humans with T2DM.

Novel Approaches to Restore Pancreatic Beta-Cell Mass and Function.

Beta-cell dysfunction and beta-cell death are critical events in the development of type 2 diabetes mellitus (T2DM). Therefore, the goals of modern T2DM management have shifted from merely restoring normoglycemia to maintaining or regenerating beta-cell mass and function. In this review we summarize current and novel approaches to achieve these goals, ranging from lifestyle interventions to N-methyl-D-aspartate receptor (NMDAR) antagonism, and discuss the mechanisms underlying their effects on beta-cell physiology and glycemic control.

Comparative meta-analysis of Kabuki syndrome with and without hyperinsulinaemic hypoglycaemia.

Background And Objective: Kabuki syndrome (KS), caused by pathogenic variants in KMT2D or KDM6A, is associated with hyperinsulinaemic hypoglycaemia (HH) in 0.3%-4% of patients. We characterized the clinical, biochemical and molecular data of children with KS and HH compared to children with KS without HH in a multicentre meta-analysis.

Diabetes management in Wolcott-Rallison syndrome: analysis from the German/Austrian DPV database.

Background: Wolcott-Rallison syndrome (WRS) is characterized by permanent early-onset diabetes, skeletal dysplasia and several additional features, e.g. recurrent liver failure.

Comparing clinical characteristics of pediatric patients with pancreatic diabetes to patients with type 1 diabetes: A matched case-control study.

Background: Only few studies have been conducted on pancreatic diabetes and data from large epidemiological studies are missing. Our main objective was to study the most important differences and similarities between pediatric individuals with pancreatic diabetes and type 1 diabetes (T1D).

Methods: Patients <20 years of age were identified from the diabetes patient follow-up registry (DPV).

Persistent hyperinsulinaemic hypoglycaemia in children with Rubinstein-Taybi syndrome.

Objective: Genetic aetiology remains unknown in up to 50% of patients with persistent hyperinsulinaemic hypoglycaemia (HH). Several syndromes are associated with HH. We report Rubinstein-Taybi syndrome (RSTS) as one of the possible causes of persistent HH.

Characterization of diabetes following pancreatic surgery in patients with congenital hyperinsulinism.

Background: Congenital hyperinsulinism (CHI) is the most common cause of persistent hypoglycaemia in infancy that leads to unfavourable neurological outcome if not treated adequately. In patients with severe diffuse CHI it remains under discussion whether pancreatic surgery should be performed or intensive medical treatment with the acceptance of recurrent episodes of mild hypoglycaemia is justified. Near-total pancreatectomy is associated with high rates of insulin-dependent diabetes mellitus and exocrine pancreatic insufficiency.

NMDAR antagonists for the treatment of diabetes mellitus-Current status and future directions.

Diabetes mellitus is characterized by chronically elevated blood glucose levels accelerated by a progressive decline of insulin-producing β-cells in the pancreatic islets. Although medications are available to transiently adjust blood glucose to normal levels, the effects of current drugs are limited when it comes to preservation of a critical mass of functional β-cells to sustainably maintain normoglycemia. In this review, we recapitulate recent evidence on the role of pancreatic N-methyl-D-aspartate receptors (NMDARs) in β-cell physiology, and summarize effects of morphinan-based NMDAR antagonists that are beneficial for insulin secretion, glucose tolerance and islet cell survival.

Treatment with long-acting lanreotide autogel in early infancy in patients with severe neonatal hyperinsulinism.

Background: Treatment of severe diffuse congenital hyperinsulinism (CHI) without sufficient response to diazoxide is complicated by the lack of approved drugs. Therefore, patients are often hospitalized long-term or have to undergo pancreatic surgery if episodes of severe hypoglycaemia cannot be prevented. A long-acting somatostatin analogue, octreotide, has been reported to be an effective treatment option that prevents severe hypoglycaemia in children with CHI, and its off-label use is common in CHI.

Hypoinsulinaemic, hypoketotic hypoglycaemia due to mosaic genetic activation of PI3-kinase.

Objective: Genetic activation of the insulin signal-transducing kinase causes syndromic hypoketotic hypoglycaemia without elevated insulin. Mosaic activating mutations in class 1A phospatidylinositol-3-kinase (PI3K), upstream from AKT2 in insulin signalling, are known to cause segmental overgrowth, but the metabolic consequences have not been systematically reported. We assess the metabolic phenotype of 22 patients with mosaic activating mutations affecting PI3K, thereby providing new insight into the metabolic function of this complex node in insulin signal transduction.

Need for Better Diabetes Treatment: The Therapeutic Potential of NMDA Receptor Antagonists.

Diabetes mellitus is the most common metabolic disorder in children and adolescents. Optimal control of blood glucose concentration is essential to prevent acute and diabetic long-term complications. The options to treat diabetes have clearly improved over the last decades, however, to date neither type 1 diabetes nor type 2 diabetes mellitus can be cured.

Long-term medical treatment in congenital hyperinsulinism: a descriptive analysis in a large cohort of patients from different clinical centers.

Background: Up to now, only limited data on long-term medical treatment in congenital hyperinsulinism (CHI) is available. Moreover, most of the drugs used in CHI are therefore not approved. We aimed to assemble more objective information on medical treatment in CHI with regard to type and duration, dosage as well as side effects.

Remission of congenital hyperinsulinism following conservative treatment: an exploratory study in patients with KATP channel mutations.

Background: During conservative treatment, congenital hyperinsulinism (CHI) can resolve spontaneously. This study describes the hormonal and metabolic profiles in three patients with ABCC8/KCNJ11 mutations in clinical remission.

Methods: An age-adapted fasting and oral glucose tolerance test (OGTT) were performed.

DJ-1 Protects Pancreatic Beta Cells from Cytokine- and Streptozotocin-Mediated Cell Death.

A hallmark feature of type 1 and type 2 diabetes mellitus is the progressive dysfunction and loss of insulin-producing pancreatic beta cells, and inflammatory cytokines are known to trigger beta cell death. Here we asked whether the anti-oxidant protein DJ-1 encoded by the Parkinson's disease gene PARK7 protects islet cells from cytokine- and streptozotocin-mediated cell death. Wild type and DJ-1 knockout mice (KO) were treated with multiple low doses of streptozotocin (MLDS) to induce inflammatory beta cell stress and cell death.

Effects of dextromethorphan as add-on to sitagliptin on blood glucose and serum insulin concentrations in individuals with type 2 diabetes mellitus: a randomized, placebo-controlled, double-blinded, multiple crossover, single-dose clinical trial.

In this clinical trial, we investigated the blood glucose (BG)-lowering effects of 30, 60 and 90 mg dextromethorphan (DXM) as well as 100 mg sitagliptin alone versus combinations of DXM and sitagliptin during an oral glucose tolerance test (OGTT) in 20 men with T2DM. The combination of 60 mg DXM plus 100 mg sitagliptin was observed to have the strongest effect in the OGTT. It lowered maximum BG concentrations and increased the baseline-adjusted area under the curve for serum insulin concentrations in the first 30 min of the OGTT (mean ± standard deviation 240 ± 47 mg/dl and 8.