Endocrines, Volume 5, Issue 2 (June 2024) – 7 articles

Basal insulin analogs, typically administered once or twice daily, have been one of the two pillars of the multiple daily injection (MDI) insulin therapy of patients with type 1 diabetes (T1D) for the last twenty years. Recently, once-weekly basal insulin analogs have been developed and are in late-phase clinical trials. One of these analogs is insulin icodec (icodec), appropriately developed to bind reversibly to albumin and to be gradually released into the patient’s circulation. Icodec has been tried mostly in clinical trials of adult patients with type 2 diabetes. A recent phase 3a clinical trial comprising adult patients with T1D was designed to evaluate icodec’s efficacy and safety compared with a daily basal insulin analog (degludec) after a 26-week main phase plus a safety extension of another 26 weeks. Icodec showed non-inferiority to once-daily degludec in glycated hemoglobin (HbA1c) reduction at week 26, and no significant differences in time in range (TIR) (70–180 mg/dL) and in time above range (TAR) (>180 mg/dL). On the other hand, it was associated with increased rates of clinically significant hypoglycemia (blood glucose < 54 mg/dL) and severe hypoglycemia (external assistance need for recovery), remaining either below or close to the internationally recommended targets for hypoglycemia. Another once-weekly insulin analog, basal insulin Fc (BIF), has been investigated in a phase 2 clinical trial comprising adult patients with T1D, with equally promising results. These preliminary data suggest that once-weekly insulin analogs could be of use for some patients with T1D, for example, patients not taking insulin regularly or those who are on MDI and wish for fewer injections. In addition, due to its prolonged mode of action, it could decrease the risk of diabetic ketoacidosis and the need for hospitalization. Additionally, patients with T1D that struggle with wearing diabetes mellitus devices/closed-loop insulin pumps either due to the cost or due to skin issues may also benefit from long-acting insulin. There is increasing evidence of the benefits of adjunctive therapies to insulin in T1D patients, but these therapies are not FDA-approved due to a possible higher risk of diabetic ketoacidosis. These long-acting insulin analogues could be used with adjunctive therapies in selected patients. This review aims to present available data on the mode of action, clinical trial results, and possible benefits of once-weekly insulin analogs for patients with T1D. In addition, it intends to suggest a future research framework for important clinical questions, such as once-weekly insulin analog use and exercise, sick days, or surgery, that will enhance our knowledge regarding this indisputable innovation in insulin management. Full article

Adult-onset diabetes increases one’s risk of neurodegenerative disease including Alzheimer’s disease (AD); however, the risk associated with youth-onset diabetes (Y-DM) remains underexplored. We quantified plasma biomarkers of neurodegeneration and AD in participants with Y-DM from the SEARCH cohort at adolescence and young adulthood (Type 1, n = 25; Type 2, n = 25; 59% female; adolescence, age = 15 y/o [2.6]; adulthood, age = 27.4 y/o [2.2]), comparing them with controls (adolescence, n = 25, age = 14.8 y/o [2.7]; adulthood, n = 21, age = 24.9 y/o [2.8]). Plasma biomarkers, including glial fibrillary acidic protein (GFAP), neurofilament light chain protein (NfL), phosphorylated tau-181 (pTau181), and amyloid beta (Aβ40, Aβ42), were measured via Simoa. A subset of participants (n = 7; age = 27.5 y/o [5.7]) and six controls (age = 25.1 y/o [4.5]) underwent PET scans to quantify brain amyloid and tau densities in AD sensitive brain regions. Y-DM adolescents exhibited lower plasma levels of Aβ40, Aβ42, and GFAP, and higher pTau181 compared to controls (p < 0.05), a pattern persisting into adulthood (p < 0.001). All biomarkers showed significant increases from adolescence to adulthood in Y-DM (p < 0.01), though no significant differences in brain amyloid or tau were noted between Y-DM and controls in adulthood. Preliminary evidence suggests that preclinical AD neuropathology is present in young people with Y-DM, indicating a potential increased risk of neurodegenerative diseases. Full article

(1) Background: Subclinical hypothyroidism (SHT) is a condition that has been a subject of controversy in the literature due to its association with psychological and psychiatric symptoms as well as autonomic imbalances. To gain a better understanding of the effects of SHT on patients, a research study has been undertaken to investigate the presence of psychological symptoms and autonomic imbalances in a group of individuals diagnosed with SHT. (2) Methods: In this case–control study, 50 patients diagnosed with SHT who accessed the Department of Endocrinology of the University of Pisa were consecutively recruited. Psychological symptoms were measured through the Crown–Crisp Experiential Index (CCEI), whereas autonomic imbalance was described using the Psychophysiological Stress Profile (PSP), with simultaneous recording of the following psychophysiological parameters: Surface Electromyogram (sEMG), Skin Conductance Level (SCL), heart rate (HR), and peripheral temperature (PT). The patients’ values were compared to those of 50 healthy control subjects. (3) Results: The comparison between groups highlighted significant differences in the CCEI and PSP. In particular, patients reported higher rates of psychological symptoms (anxiety, depression, somatic complaints, and hysteria behavior). Significantly higher levels of autonomic arousal were also recorded. More specifically, the sEMG, SCL, HR, and PT values were different between the two groups. (4) Conclusions: The study has confirmed the presence of autonomic hyperarousal in patients diagnosed with subclinical hypothyroidism. This is likely due to the body’s attempt to compensate for a general lack of energy by accelerating the autonomic activity. The findings also underline the significance of a comprehensive assessment approach that takes into account various dimensions such as psychological and psychophysical well-being. Such an approach helps in evaluating the impact of subclinical diseases on overall health and well-being. Full article

Most patients with non-alcoholic steatohepatitis (NASH) have insulin resistance, and there is a near-universal association between NASH and insulin resistance. Insulin resistance induces lipid accumulation in the liver, leading to the development of metabolic syndrome. However, most NASH rodent models fail to develop metabolic syndrome. LEW.1WR1 rats that are 23 weeks old showed increased body mass, epididymal fat, and liver mass, suggesting obesity-driven metabolic dysfunction. We have characterized steatosis, inflammation, Mallory–Denk body formation with hematoxylin and eosin (H&E), and fibrosis with Trichome blue staining. The presence of hepatic fibrosis with other features of NASH described above is one of the major strengths of this model since most of the currently available NASH models do not develop microvesicular steatosis or fibrosis. Together with the other important features of NASH described above, we confirm that male LEW.1WR1 rats develop NASH and insulin resistance with a standard diet. Full article

Introduction: Insulin resistance is a common condition affecting thousands of people worldwide. This paper aims to examine the mechanisms underlying insulin resistance among people suffering from obesity. Methods and Design: This study entailed identifying articles related to insulin resistance and obesity. The publications were obtained using different electronic databases, including PubMed, EBSCO, and LILACS. The search terms included “insulin”, “resistance”, “obesity”, and “mechanisms”. Boolean operators were used to combine terms and phrases. Results: Insulin resistance is a physiological condition characterized by the impaired action of insulin in the body. The association between obesity and insulin resistance is linked to inflammatory, neural, and endocrine pathways that affect the sensitivity of organs to the level of insulin in the body. Discussion: Molecular studies have helped discover some of the fundamental mechanisms leading to the development of insulin resistance. Further investigations are needed to enhance our understanding of the connections among the inflammatory, neural, and cellular processes underlying the association between insulin resistance and obesity. Conclusion: This study revealed that a complex correlation exists between insulin resistance and obesity. This relationship involves a wide range of inflammatory, neural, and endocrine processes. Full article

Mangifera indica (Anacardiaceae family) is renowned for its diverse pharmacological properties, encompassing antidiabetic, antioxidant, and anti-inflammatory effects. The present study delves into the insulin-releasing and glucose-lowering potential of the ethanolic extract of Mangifera indica (EEMI) leaves in streptozotocin-induced type 2 diabetic (STZ-T2D) rats, concurrently investigating its phytoconstituents. EEMI’s effects on insulin secretion were measured using BRIN BD11 β-cells and isolated mouse islets. Its enzymatic inhibitory properties on carbohydrate digestion, and absorption, and free radicals were investigated using in vitro methods. In vivo parameters including the lipid profile and liver glycogen content were assessed in STZ-T2D rats. EEMI exhibited a dose-dependent increase in insulin secretion from clonal pancreatic BRIN BD11 β-cells and isolated mouse islets. EEMI inhibited starch digestion, glucose diffusion over time, and DPPH activity in vitro. In acute in vivo studies, EEMI improved food intake and oral glucose tolerance. Moreover, following 28 days of treatment with EEMI, a remarkable amelioration in body weight, fasting blood glucose, plasma insulin, liver glycogen content, total cholesterol, triglyceride, LDL, VLDL, and HDL levels was observed. Further phytochemical analysis with EEMI identified the presence of alkaloids, tannins, saponins, steroids, and flavonoids. The synergistic effects of EEMI, potentially attributable to naturally occurring phytoconstituents, hold promise for the development of enriched antidiabetic therapies, offering a promising avenue for the management of type 2 diabetes. Full article

Purpose: Lipid lowering treatments (LLTs) can reduce the risk of atherosclerotic cardiovascular disease (ASCVD). Despite the availability of potent LLTs, our clinical observations suggest an inadequate use of such agents. To evaluate this treatment deficit, we designed the present study. Methods: We reviewed the charts of all patients with a history of ASCVD (coronary artery disease—CAD; carotid stenosis—CS; or peripheral artery disease—PAD) diagnosed prior to their first visit to one of our clinics. We recorded their gender, age, ASCVD risk factors (diabetes, hypertension, tobacco use, body mass index), lipid values during that visit and the LLT used. We estimated the rates of the attainment of guideline-specific lipid goals by year, and assessed factors influencing the likelihood of treatment success. Results: Overall, n = 1003 subjects were recruited: CAD n = 703 (70.1%), PAD n = 168 (16.8%), CS n = 325 (32.4%); age 64.7 ± 11.2 years; n = 376 (37.5%) females; n = 642 (64.0%) had diabetes; n = 740 (73.8%) had hypertension; n = 299 (29.8%) were former and n = 367 (36.6%) were current smokers. An appropriate LLT was used in 361 (36.0%) subjects, n = 159 (15.9%) were on no treatment, n = 483 (48.2%) were receiving inadequate therapy, n = 434 (43.3%) were on a high-intensity LLT and n = 361 (36.0%) had achieved the year-specific LDL goals. Success rates ranged from 5.7% to 81.5%, with the lowest being 2020–2023 (5.7–14.5%), p < 0.001. The use of a combination of LLTs and PCSK9 inhibitors led to higher rates of LDL-C goals achievement (p < 0.001). Discussion: Recent secondary ASCVD risk prevention guidelines’ goals are rarely achieved in daily clinical practice, producing a major treatment deficit in this population. Newer systematic interventions are needed to curb this public health issue. Full article