Andreas Pfützner

Background: The conventional definition of diabetes mellitus is based on the presence of hyperglycemia. However, growing evidence indicates that key pathophysiological processes—particularly β-cell dysfunction—occur well before any measurable increase in blood glucose. These early changes remain undetected by standard diagnostics but are clinically significant. Objective: This work introduces the proposed concept of normoglycemic diabetes, defined as a pathophysiological state in which conventional glucose criteria remain normal while measurable evidence of early β-cell dysfunction is already present. Particular emphasis is placed on intact proinsulin as a marker of impaired proinsulin processing and β-cell secretory stress. Methods: A staged model of declining functional β-cell mass is presented, ranging from compensated β-cell stress during normoglycemia to overt secretory failure and dysglycemia, incorporating genetic, epigenetic, and environmental influences. Diagnostic strategies, including extended OGTT assessment and intact proinsulin quantification, and their potential preventive implications are discussed. Results: Early impairment of functional β-cell mass can be detectable while fasting glucose, HbA1c, and conventional glucose tolerance criteria remain normal. Intact proinsulin and proinsulin-related ratios may provide information on impaired hormone processing and secretory stress before overt hyperglycemia develops. The proposed concept therefore identifies a biological state that may become a target for earlier, marker-guided prevention. Conclusions: Normoglycemic diabetes is proposed as an early pathophysiological disease concept complementary to established glucose-defined categories. It is distinct from diabetes prevention itself: the former describes measurable β-cell pathology during normoglycemia, whereas prevention describes interventions intended to delay or avoid progression to dysglycemia and overt type 2 diabetes. Prospective studies are required before this concept can be considered an established diagnostic entity.

Background: Patch insulin pumps are often treated as a single class, although fully disposable and semi-reusable designs differ in cost and waste. We evaluated real-world clinical, pharmacoeconomic, and environmental outcomes of a semi-reusable tubeless insulin pump (Microtech Equil™, referred as SR-TIP). Methods: Prospective, multicentre, open-label real-world study in adults with type 1 or type 2 diabetes transitioning from continuous subcutaneous insulin infusion (CSII) or multiple daily injections (MDI). Follow-up was 3 months. Primary endpoints were HbA1c non-inferiority and change in hypoglycaemic event frequency. Secondary endpoints included safety, device deficiencies, patient-reported outcomes (Diabetes Treatment Satisfaction Questionnaire, Device Assessment Questionnaire), monthly disposable treatment costs, and waste based on disposable component counts and material composition. Results: Ninety-seven participants completed follow-up (CSII n = 79; MDI n = 18). HbA1c changes met non-inferiority criteria in both groups. Hypoglycaemic events decreased by 45% in CSII users and 86% in MDI users. Device-related adverse events were infrequent and mainly mild. Among participants previously using fully disposable tubeless pumps, mean monthly disposable treatment costs decreased by €108.6 (p < 0.001). The semi-reusable architecture eliminated routine disposal of batteries/electronic components and reduced overall waste. Conclusions: In routine care, a semi-reusable tubeless pump maintained glycaemic control while reducing hypoglycaemia and disposable costs versus fully disposable patch pumps, with measurable reductions in electronic waste. These data support value-based, sustainable diabetes technology adoption.

Conventional diabetes therapy primarily targets HbA1c using a standardized, stepwise approach, often neglecting individual clinical and diagnostic phenotypes. In this second part of our discussion, we present an alternative strategy. After phenotyping the patient, we initiate a targeted pharmacological combination therapy tailored to the individual’s underlying pathophysiology, alongside lifestyle modifications. Sulfonylureas are completely avoided in this approach. Instead, medications are selected based on their alignment with the patient’s phenotype and absence of contraindications. Early insulin therapy, for example, is particularly effective in patients with β-cell-dysfunction-driven diabetes, whereas GLP-1-supported weight reduction and glitazone therapy are more suitable for insulin-resistance-driven diabetes. For monitoring and determining when temporary therapy intensification may be necessary, we rely on a combination of functional biomarkers (intact proinsulin, adiponectin, hsCRP, and leptin) and conventional clinical parameters (HbA1c, BMI, lipids, blood pressure). Using this personalized strategy, we have consistently achieved long-term glycemic control—often maintaining normal HbA1c levels for up to 15 years in our patients so far.

The diagnosis of type 2 diabetes using classical clinical and laboratory biomarkers (HbA1c, glucose, lipids, BMI, and blood pressure) is a classification by symptoms and does not provide insight into the underlying pathophysiological disorders (insulin resistance, β-cell dysfunction, visceral adipose tissue hormonal secretion, and chronic systemic inflammation). A better understanding of these disorders may help in the selection of appropriate and potentially more successful personalized therapeutic interventions. Based on extensive clinical trial experience, a method for individual phenotyping and consecutive personalized diabetes therapy has been developed in our practice, which we have been using for more than 15 years and would like to share for discussion and debate. In this Part 1, the pathophysiological background and diagnostic approach to phenotyping is described. A consecutive Part 2 will present the translation of the phenotyping result into a personalized diabetes therapy, and another consecutive Part 3 will provide more comprehensive real-world patient observations when practicing this concept. This article is intended as a discussion/concept paper and does not present unpublished patient-level outcome data or formal effectiveness analyses. Prospective validation studies are needed to evaluate the clinical utility of this phenotype-based framework.

Atherosclerosis remains the leading cause of death worldwide and imposes a major healthcare burden. Physiologically, elimination of cholesterol from the arterial wall depends on reverse cholesterol transport (RCT). RCT requires access to HDL and apolipoprotein A-I (ApoA-I) to lesional macrophages/foam cells. The endothelial glycocalyx is a dynamic and injury-sensitive layer of proteoglycans and glycosaminoglycans (including hyaluronan). It contributes to vascular barrier properties, leukocyte adhesion, mechanotransduction, and macromolecular transport. In atherosclerosis, glycocalyx structure and function are altered; this may facilitate entry/retention of atherogenic lipoproteins and may also alter transport conditions relevant to cholesterol efflux pathways. This article presents a mechanistic hypothesis: short, transient, systemic hyaluronidase exposure could temporarily remodel glycocalyx/extracellular matrix components and thereby facilitate conditions permissive for regulated transport processes relevant to RCT. However, the proposed link between glycocalyx remodeling and improved lesional cholesterol efflux remains theoretical. Direct in vivo evidence that the endothelial glycocalyx is a dominant barrier limiting HDL- or ApoA-I-mediated cholesterol efflux from plaque macrophages is currently limited. Moreover, glycocalyx degradation is widely associated with endothelial dysfunction, increased permeability, inflammation, and thrombosis, all of which could aggravate rather than ameliorate atherosclerosis. Human pharmacokinetic data indicate a very short plasma half-life of circulating hyaluronidase activity, suggesting that any systemic enzymatic effect is brief. Nevertheless, the biological consequences of repeated degradation–regeneration cycles, especially in high-risk states such as diabetes, inflammation, oxidative stress, or chronic kidney disease, remain incompletely understood. Evidence supporting clinical benefit in atherosclerosis is currently limited to heterogeneous animal experiments, historical uncontrolled reports, and a small number of anecdotal case observations, whereas randomized trials have only been performed in other settings such as acute myocardial infarction and do not establish efficacy for plaque regression. We therefore provide a balanced evaluation of knowns, uncertainties, alternative interpretations, potential risks, dosing unknowns, and a translational research agenda including mechanistic preclinical studies, biomarker development, imaging, and carefully designed early-phase clinical investigation.

Background: BeaT-2/Sugarburner is a nutritional supplement based on a co-existing microbial consortium of bacterial strains. The purpose of this study was to investigate potential beneficial effects of the supplement versus placebo on glycemic control and on biomarkers of inflammation, insulin resistance and ß-cell dysfunction. Methods: A total of 40 Patients with type 2 diabetes (31 male, 9 female, age:65.5 ± 8.0 years, BMI: 33.6 ± 5.5 kg/m ^² , HbA1c: 7.2 ± 0.9%) were included into the study. They were randomized to receive 2 capsules of either BeaT-2 or placebo once daily for 6 weeks. Observation parameters were time in normoglycemia as assessed by continuous glucose monitoring, and biomarkers of glycemic control, ß-cell function, insulin resistance and chronic systemic inflammation. Results: Time in range was stable with BeaT-2 between weeks 0 and 2 versus weeks 4 and 6, while it slightly impaired with placebo (−4%, n.s.). At endpoint, there were significant improvements versus baseline with BeaT-2, but not with placebo for biomarkers of glycemic control (BeaT-2 vs Placebo, HbA1c: −0.3% vs 0.1%, fasting glucose: −14% vs +8%, both P < .05), insulin resistance (insulin: −17% vs +14%, HOMA-IR: −26% vs +21%, both P < .05), ß-cell dysfunction (intact proinsulin: −40% vs −2%, P < .05) and chronic systemic inflammation (adiponectin: +8% vs −8%; P < .05, hsCRP: −31% vs +27%, n.s.). In addition, observed changes in the lipid profiles and other parameters of metabolic syndrome were more favorable with BeaT-2 than with placebo. There were no differences between the groups with respect to number and type of adverse events. Conclusion: The results observed with BeaT-2 were comprehensively indicative for improvements in the cardiometabolic situation. BeaT-2 may be a valuable supplement to any existing treatment combination in patients with type 2 diabetes.

Introduction: The active matrix metalloproteinase‐8 (aMMP‐8) is a functional biomarker of active periodontal tissue destruction. It bridges the gap between clinical findings and underlying biological processes, providing information on active collagen degradation that conventional clinical examinations do not capture. Methods: In a prospective within‐subject clinical study, we assessed point‐of‐care (PoC) mouthrinse aMMP‐8 concentrations, periodontal probing depth (PPD), and clinical attachment level (CAL) in 27 adults with stage III/IV (grade C) periodontitis before and 1 month after anti‐infective treatment. aMMP‐8 PoC results were validated by laboratory western blotting using an independent polyclonal MMP‐8 antibody. Results: At baseline, 85.2% of samples showed elevated aMMP‐8 PoC concentrations, declining to 18.5% post‐treatment. Baseline aMMP‐8 was significantly associated with disease severity, correlating with both PPD ( r _s = 0.39, p = 0.045) and CAL ( r _s = 0.39, p = 0.042). Following treatment, aMMP‐8 concentrations decreased significantly ( V = 378, p < 0.001), with mean reductions of 78.5 ± 72.6 ng/mL ( d = –1.08). Biochemical reductions paralleled clinical improvements, with 100% directional concordance between changes in aMMP‐8 and changes in PPD and CAL (95% CI 0.87–1.00). Reductions in aMMP‐8 were correlated with improvements in PPD ( r _s = 0.47, p = 0.014) but not CAL ( r _s = 0.12, p = 0.544). Linear regression analysis indicated that each 10 ng/mL reduction in aMMP‐8 corresponded to an estimated 0.034 mm gain in PPD. Conclusion: These findings demonstrate that aMMP‐8 PoC monitoring aligns with both baseline disease severity and short‐term periodontal healing. aMMP‐8 provides an objective biochemical dimension to periodontal assessment, capturing active collagen degradation and serving as a sensitive and clinically meaningful indicator of treatment response.

Diagnosis of type 2 diabetes using the classical clinical and laboratory biomarkers (HbA1c, glucose, lipids, BMI, and blood pressure) is a classification by symptoms and does not provide insight into the underlying pathophysiological disorders (insulin resistance, ß-cell dysfunction, visceral adipose tissue hormonal secretion, and chronic systemic inflammation). A better understanding of these disorders may help for the selection of appropriate and potentially more successful personalized therapeutic interventions. Based on an extensive clinical trial experience, a method for individual phenotyping and consecutive personalized diabetes therapy has been developed in our practice, which we have been using for more than 15 years and which we would like to share for discussion and debate. In this part 1, the pathophysiological background and the diagnostic approach to phenotyping will be described. A consecutive part 2 will present the translation of the phenotyping result into a personalized diabetes therapy and will provide real-world patient examples when practicing this concept.