Effect of Policaptil Gel Retard on Liver Fat Content and Fibrosis in Adults with Metabolic Syndrome and Type 2 Diabetes: A Non-invasive Approach to MAFLD.

INTRODUCTION: Non-alcoholic fatty liver disease (NAFLD) is part of a disease spectrum ranging from steatosis to steatohepatitis (NASH), fibrosis, and cirrhosis, and when associated with metabolic syndrome (MS), and overt diabetes is defined as metabolic NAFLD (MAFLD). Some easily available, inexpensive biomarkers have been validated based on common anthropometric and laboratory parameters, including the Fatty Liver Index (FLI), the Fibrosis (FIB)-4 Score (FIB-4), and the NAFLD Fibrosis Score (NFS). In people with overweight/obesity, MS, and diabetes, the pathogenesis of fatty liver involves parameters known to be positively affected by Policaptil Gel Retard (PGR), a phytocomplex already successfully used in adolescents and adults with MS and type 2 diabetes mellitus (T2DM). This study's primary outcome was to assess PGR's ability to improve indirect validated signs of liver steatosis and fibrosis, i.e., FLI, FIB-4, and NFS Scores; as the secondary outcome, we aimed to confirm PGR's positive effects on anthropometric parameters and lipid levels and to assess any eventually occurring cytolysis liver marker changes in patients with MS/T2DM and MAFLD/NASH. METHODS: In this spontaneous, longitudinal, single-blind, randomized clinical study, 245 outpatients with MS/T2DM were enrolled and randomized to PGR or placebo for 24 weeks. All underwent a low-calorie diet (20-25% less than the calories required to maintain current weight) and were encouraged to intensify physical activity. Fat distribution, liver fat content/fibrosis, and biochemical parameters were evaluated at baseline and after 24 weeks. RESULTS: Our data show for the first time in adults with MAFLD that, when added to lifestyle changes including a hypocaloric diet and intensified physical activity, PGR improves lipid and glucose metabolism-related parameters, including insulin-resistance, and significantly reduces not only visceral fat but also liver fat content and related liver fibrosis severity. The prevalence of subjects with severe steatosis (FLI > 60) significantly decreased from 95.08 to 47.53% (p < 0.001) only in the treatment group, which also displayed a significantly decreased prevalence of medium-severe cases (F3-F4) from 83.62% to 52.35% (p < 0.001) and a markedly increased prevalence of low degree cases (F0-F1) from 9.01 to 42.15% (p < 0.001). CONCLUSIONS: The effect of PGR is related to a reduction in the post-meal blood glucose and insulin peaks. As glucose absorption (GA) directly regulates pancreatic insulin release, the attenuated insulin response is likely due to delayed GA with decreased body weight, visceral fat, and cardiovascular risk. Also, an effect on the intestinal microbiota, already documented in the animal model, cannot be excluded, especially considering the reported PGR-related shift from the Firmicutes, notoriously responsible for increased lipid gut absorption, to the Bacteroides phylum.

Why Do So Many People with Type 2 Diabetes Who Take Insulin Have Lipohypertrophy? Fate or Educational Deficiencies?

INTRODUCTION: Cutaneous lipohypertrophy (LH) is a thickened, "rubbery" lesion in the subcutaneous tissue following multiple injections performed at the same site, i.e., an incorrect injection technique. It is widespread, averaging 47% of insulin patients worldwide, and has severe direct and indirect consequences. Direct consequences consist mainly of poor metabolic control and frequent hypoglycemic events (HYPOs), and indirect ones of markedly increased healthcare costs related to hospital access due to acute events and long-term disease complications. This observation also holds for Italy, despite the National Health System organization expecting every patient with diabetes to undergo a series of visits by different care team members, each performing a specific treatment/education task. Indeed, the recent literature points to poor awareness of LH relevance and metabolic consequences among doctors from general and diabetic hospital wards, with educational deficiencies on correct injection practice in nurses too. The aim was to establish if, to what extent, and by whom they had received training on correct insulin injection techniques, and how many initially received notions had persisted over time. METHODS: We investigated the possible causes of such a failure from the point of view of 1160 insulin-requiring subjects with type 2 diabetes (T2DM), reporting for the first time to specialized diabetic structures through a validated questionnaire and, in the same patients, we searched for LH by inspection/palpation according to international guidelines, further confirmed by ultrasound scans. We then analyzed differences in education and injecting behavior between subjects classified as LH+ or LH- depending on the presence or absence of LH lesions. RESULTS: We documented significant educational gaps, with 50% of patients failing to refer to healthcare professionals and relying on their peers with diabetes, thought to be more experienced in 15% of the cases. Seventy-five percent of LH- patients received education from healthcare providers, while 90% of LH+ learned from another patient or could not remember how they knew, and 68% of LH+ versus 52% of LH- (p < 0.01) patients had failed to receive training on injection techniques by healthcare providers. All of this enabled the most disabling features of diabetes from the very beginning of the disease history. CONCLUSIONS: This study documents, from the patients' point of view, that educational gaps are significant and that, even in initially trained subjects, education on correct injection techniques has a fleeting effect if not regularly recalled. Therefore, to rehabilitate LH+ patients as soon as possible and prevent LH- patients from inadvertently slipping into the other group, there is an urgent need to educate doctors and nurses repeatedly on the importance of correctly injecting insulin to improve patients' knowledge and skills.

The Economic Burden of Insulin Injection-Induced Lipohypertophy. Role of Education: The ISTERP-3 Study.

INTRODUCTION: The history of insulin-induced skin lipohypertrophy (LH) runs parallel to that of insulin's 100 years, and an average of 47% of insulin-treated patients still suffer from it today. The metabolic and economic effects of LH are significant, with hypoglycemia being the most striking. The objective of the study was to perform a 52-week follow-up of 713 insulin-treated patients with type 2 diabetes (T2DM) and LH to detect any differences in the occurrence of hypoglycemic events (HYPOs) and related healthcare costs as well as in LH rates and injection habits between an intensive education intervention group (IG) and control group (CG) provided with a single educational session at the starting point. METHODS: All participants were trained in accurately self-monitoring blood glucose and recording all HYPOs for 6 months, which allowed baseline recordings before they were randomized into the IG, comprising 395 insulin-treated subjects undergoing repeated, structured multimodal education on correct injection techniques as a longstanding behavioral rehabilitation strategy, and the CG, comprising 318 subjects receiving the same structured, multimodal educational session, but only initially. RESULTS: Changes in LH rate and size and in performance were large in the IG and only slight and transient in the CG. A striking difference in the rate of decrease of HYPOs was also apparent between groups. Indeed, estimated costs of health interventions for severe and symptomatic HYPOs, which were on the order of €70,000 and €9300, respectively, in the two groups at baseline decreased by 5.9 times and 13.7 times, respectively, at the end of follow-up in the IG and by only approximately half in the CG. Full details of the changes occurring as a result of intensive education are provided in the text. CONCLUSIONS: The effect of only initial education in the CG was not significant, thus providing evidence of the virtual worthlessness of a single training session on injection techniques, typical of worldwide daily clinical practice, and easily explaining the extremely high prevalence of LH in insulin-treated patients. Conversely, highly positive effects on LH prevalence and size as well as costs expected from decreased HYPO rate were obtained in the IG. To our knowledge, ours is the first 18-month randomized trial in the field. If our experimental model were to be used as an effective, longstanding behavioral rehabilitation strategy and therefore adapted to real-world settings universally, LH prevalence and costs related to their clinical consequences would be drastically reduced. However, only with a strong, relentless commitment of universities, scientific societies, and patient associations can we achieve this ambitious goal, which would provide great institutional savings and improved quality of life for people with diabetes.

Insulin-induced skin lipohypertrophies: A neglected cause of hypoglycemia in dialysed individuals with diabetes.

BACKGROUND: Diabetes mellitus (DM) is the leading cause of end-stage renal disease and 50% of dialysis patients are insulin-treated. AIM: to search for unexplained hypoglycemia (HYPO). METHODS: identify a possible cause of HYPO due to altered insulin absorption. RESULTS: insulin injected into subcutaneous lipo-hypertrophy (LH) nodules leads to unpredictable HYPOS. CONCLUSION: looking for LH systematically and training patients to the best injection technique are new challenges for nephrologists to reduce HYPO and emergency hospitalization rates, thus sparing healthcare resources and improving the quality of life of insulin-treated dialysis patients.

Bruising: A Neglected, Though Patient-Relevant Complication of Insulin Injections Coming to Light from a Real-Life Nationwide Survey.

INTRODUCTION: Despite the availability of sophisticated devices and suitable recommendations on how to best perform insulin injections, lipohypertrophy (LH) and bruising (BR) frequently occur as a consequence of improper injection technique. AIM: The purpose of this nationwide survey was to check literature-reported LH risk factors or consequences for any association with BR METHOD: This was a cross-sectional, observational, multicenter study based on the identification of skin lesions at all patient-reported insulin injection sites in 790 subjects with diabetes. General and injection habit-related elements were investigated as possible BR risk factors. RESULTS: While confirming the close relationship existing between LH and a full series of factors including missed injection site rotation, needle reuse, long-standing insulin treatment, frequent hypoglycemic events (hypos), and great glycemic variability (GV), the observed data could find no such association with BR, which anyhow came with high HbA1c levels, missed injection site rotation, and long-standing insulin treatment. CONCLUSION: BR most likely depends on the patient's habit of pressing the injection pen hard onto the skin. Despite being worrisome and affecting quality of life, BR seems to represent a preliminary stage of LH but does not affect the rate of hypos and GV. TRIAL REGISTRATION: 207/19.09.2017.

Role of Structured Education in Reducing Lypodistrophy and its Metabolic Complications in Insulin-Treated People with Type 2 Diabetes: A Randomized Multicenter Case-Control Study.

INTRODUCTION: It is essential to use the correct injection technique (IT) to avoid skin complications such as lipohypertrophy (LH), local inflammation, bruising, and consequent repeated unexplained hypoglycemia episodes (hypos) as well as high HbA1c (glycated hemoglobin) levels, glycemic variability (GV), and insulin doses. Structured education plays a prominent role in injection technique improvement. The aim was to assess the ability of structured education to reduce (i) GV and hypos, (ii) HbA1c levels, (iii) insulin daily doses, and (iv) overall healthcare-related costs in outpatients with T2DM who were erroneously injecting insulin into LH. METHODS: 318 patients aged 19-75 years who had been diagnosed with T2DM for at least 5 years, were being treated with insulin, were routinely followed by a private network of healthcare centers, and who had easily seen and palpable LH nodules were included in the study. At the beginning of the 6-month run-in period (T-6), all patients were trained to perform structured self-monitoring of blood glucose and to monitor symptomatic and severe hypos (SyHs and SeHs, respectively). After that (at T0), the patients were randomly and equally divided into an intervention group who received appropriate IT education (IG) and a control group (CG), and were followed up for six months (until T+6). Healthcare cost calculations (including resource utilization, loss of productivity, and more) were carried out based on the average NHS reimbursement price list. RESULTS: Baseline characteristics were the same for both groups. During follow-up, the intra-LH injection rate for the CG progressively decreased to 59.9% (p < 0.001), a much smaller decrease than seen for the IG (1.9%, p < 0.001). Only the IG presented significant decreases in HbA1c (8.2 ± 1.2% vs. 6.2 ± 0.9%; p < 0.01), GV (247 ± 61 mg/dl vs. 142 ± 31 mg/dl; p < 0.01), insulin requirement (- 20.7%, p < 0.001), and SeH and SyH prevalence (which dropped dramatically from 16.4 to 0.6% and from 83.7 to 7.6%, respectively; p < 0.001). In the IG group only, costs-including those due to the reduced insulin requirement-decreased significantly, especially those relating to SeHs and SyHs, which dropped to €25.8 and €602.5, respectively (p < 0.001). CONCLUSION: Within a 6-month observation period, intensive structured education yielded consistently improved metabolic results and led to sharp decreases in the hypo rate and the insulin requirement. These improvements resulted in a parallel drop in overall healthcare costs, representing a tremendous economic advantage for the NHS. These positive results should encourage institutions to resolve the apparently intractable problem of LH by financially incentivizing healthcare teams to provide patients with intensive structured education on proper injection technique. TRIAL REGISTRATION: Trial registration no. 118/15.04.2018, approved by the Scientific and Ethics Committee of Campania University "Luigi Vanvitelli," Naples, Italy, and by the institutional review board (IRB Min. no. 9926 dated 05.05.2018).

The Durability of an Intensive, Structured Education-Based Rehabilitation Protocol for Best Insulin Injection Practice: The ISTERP-2 Study.

INTRODUCTION: Studies on the durability of an intensive, structured education protocol on best insulin injection practice are missing for people with type 2 diabetes mellitus (T2DM). The aim of this study was to assess the durability of an intensive, structured education-based rehabilitation protocol on best insulin injection practice in well-trained subjects from our previous intensive, multimedia intervention study registered as the ISTERP-1 study. A total of 158 subjects with T2DM from the well-trained group of the 6-month-long ISTERP-1 study, all of whom had successfully attained lower glucose levels compared to baseline levels with lower daily insulin doses and with less frequent and severe hypoglycemic episodes, participated in the present investigation involving an additional 6-month follow-up period, called the ISTERP-2 study. METHODS: Participants were randomized into an intervention group and a control group, depending on whether they were provided or not provided with further education refresher courses for 6 months. At the end of the 6 months, the two groups were compared in terms of injection habits, daily insulin dose requirement, number of severe or symptomatic hypoglycemic events, and glycated hemoglobin (HbA1c) levels. RESULTS: Despite being virtually superimposable at baseline, the two groups behaved quite differently during the follow-up. The within-group analysis of observed parameters showed that the subjects in the intervention group maintained and even improved the good behavioral results learned during the ISTERP-1 study by further reducing both the rate of injection technique errors (p < 0.001) and size of lipohypertrophic lesions at injection sites (p < 0.02). Conversely, those in the control group progressively abandoned best practice, except for the use of ice-cold insulin and, consequently, had significantly higher HbA1c levels and daily insulin dose requirements at the end of the follow-up than at baseline (p < 0.05). In addition, as expected from all the above, the rate of hypoglycemic episodes also decreased in the intervention group (p < 0.05), resulting in a significant difference between groups after 6 months (p < 0.02). CONCLUSION: Our data provide evidence that intensive, structured education refresher courses have no outstanding durability, so that repeated refresher courses, at least at 6-month intervals, are needed to have positive effects on people with T2DM, contributing not only to prevention but also to long-term rehabilitation. TRIAL REGISTRATION: Trial Registration no. 118 bis/15.04.2018.

Lipohypertrophy in Elderly Insulin-Treated Patients With Type 2 Diabetes.

BACKGROUND: The number of older adults with insulin-treated diabetes mellitus (DM) is steadily increasing worldwide. Errors in the insulin injection technique can lead to skin lipohypertrophy (LH), which is the accumulation of fat cells and fibrin in the subcutaneous tissue. While lipohypertrophic lesions/nodules (LHs) due to incorrect insulin injection techniques are very common, they are often flat and hardly visible and thus require thorough deep palpation examination and ultrasonography (US) for detection. Detection is crucial because such lesions may eventually result in poor diabetes control due to their association with unpredictable insulin release patterns. Skin undergoes fundamental structural changes with aging, possibly increasing the risk for LH. We have therefore investigated the effect of age on the prevalence of LHs and on factors potentially associated with such lesions. METHODS: A total of 1227 insulin-treated outpatients with type 2 DM (T2DM) referred to our diabetes centers were consecutively enrolled in the study. These patients underwent a thorough clinical and US evaluation of the skin at injection sites, as previously described, with up to 95% concordance betweenthe clinical and US screening techniques. Of these 1227 patients, 718 (59%) had LH (LH+) and 509 (41%) were LH-free (LH-). These patients were then assigned to two age class groups (≤ 65 years and > 65 years), and several clinical features, diabetes complication rates, and injection habits were investigated. RESULTS: Comparison of the two age subgroups revealed that 396 (48%) and 322 (79%) patients in the younger and older groups, respectively, had LHs (p < 0.001). Compared to the younger subgroup, the older subgroup displayed a higher LH rate in the abdomen (52.9 vs. 38.3%; p < 0.01) and a lower rate in the arms (25.4 vs. 35.8%; p < 0.05), thighs (26.7 vs. 33.4%; p < 0.05), and buttocks (4.9 vs. 26.2%; p < 0.01). In older subjects, the most relevant parameters were: habit of injecting insulin into LH nodules (56 vs. 47% [younger subjects]; p < 0.01), rate of post-injection leakage of insulin from injection site (drop-leaking rate; 47 vs. 39% [younger subjects]; p < 0.05), and rate of painful injections (5 vs. 16% [younger subjects]; p < 0.001). Multivariate analysis showed a stronger association between LH and poor habits, as well as between several clinical parameters, among which the most relevant were hypoglycemic events and glycemic variability. DISCUSSION: The higher rate of post-injection drop-leaking and pain-free injections might find an explanation in skin changes typically observed in older adults, including lower thickness, vascularity and elasticity, and a more prominent fibrous texture, all of which negatively affect tissue distensibility. Consequently, in addition to the well-known association between aging skin impaired drug absorption rate, aging skin displays a progressively decreasing ability to accommodate large volumes of insulin-containing fluid. CONCLUSIONS: The strong association between LH rate and hypoglycemic events plus glycemic variability suggests the need (1) to take specific actions to prevent and control the high risk of acute cardiovascular events expected to occur in older subjects in the case of hypoglycemic events, and (2) to identify suitable strategies to fulfill the difficult task of performing effective educational programs specifically targeted to the elderly. TRIAL REGISTRATION: Trial registration number 172-11:12.2019, Scientific and Ethical Committee of Campania University "Luigi Vanvitelli", Naples, Italy).

Insulin-Related Lipohypertrophy in Hemodialyzed Diabetic People: a Multicenter Observational Study and a Methodological Approach.

INTRODUCTION: End-stage renal disease (ESRD) is associated with increased cardiovascular mortality (CVM) and diabetes mellitus (DM), which in many cases is treated with insulin. Skin lipohypertrophy (LH) very often occurs in insulin-treated (IT) patients as a consequence of inadequate injection technique and is one of the most prominent contributors to hypoglycemia (HYPO), glycemic variability (GV), and poor metabolic control (PMC). METHOD: The aim of our multicenter observational study was to assess LH prevalence at self-injection sites and any possible factors predicting high LH/HYPO rates and GV in 296 dialyzed ITDM patients characterized by 64 ± 7 years of age, 7 ± 2 years disease duration, 2.6 ± 2.2 years dialysis duration, preferred pen utilization (80%), and basal-bolus regimen (87.4%) with self-injections (62.6%) largely surpassing caregiver-assisted ones (16.9%), and a mix of the two injection methods (20.5%). RESULTS: LH was detected in 57% of patients. Univariate analysis followed by backwards stepwise multivariate logistic regression function showed increased odds for developing LH in patients characterized by needle reuse, smaller injection areas, missed injection site rotation, higher HbA1c levels, and more prominent rates of HYPO and GV. CONCLUSION: This was the first time such observation was made. It is now time for further studies aimed at providing evidence also in ESRD ITDM patients for the cause-effect relationship among wrong injection behavior, LH, and poor metabolic control and for the long-term preventative role of suitable educational countermeasures.

Insulin related lipodystrophic lesions and hypoglycemia: Double standards?

Lipohypertophy (LH) is the most common skin complication of incorrect injection technique which does not only represent an aesthetic defect but also severely disrupts insulin pharmacokinetics/pharmacodynamics. As a consequence of that, hormone release is delayed and unexplained/unpredictable hypoglycemia occurs, both deteriorating metabolic control while negatively affecting adherence to treatment and quality of life. The economic burden due to unwanted intra-LH injections is accounted for by inappropriately high insulin requirements, increased emergency-related hospitalizations, and loss of work days. Greater attention has to be paid by diabetes care teams to education programs with periodic refreshers to achieve better metabolic control and reduce the economic burden of diabetes.