Lipohypertrophy and Insulin: An Update From the Diabetes Technology Society.

Lipohypertrophy is a common skin complication associated with insulin-treated diabetes. The impact of lipohypertrophy as a contributing factor to suboptimal glycemic control, glucose variability, and hypoglycemia is often under-recognized by health care professionals. In a recent Webinar on April 26, 2023, Diabetes Technology Society asked international experts to provide updates on the latest knowledge related to lipohypertrophy for practicing clinicians and educators, researchers, and industries involved in insulin delivery. A recording of the Webinar is freely available on the Diabetes Technology Society Web site (https://www.diabetestechnology.org/).

Insulin-induced lipodystrophy and predisposing factors in children and adolescents with type 1 diabetes mellitus (T1DM) in a tertiary care Egyptian center.

BACKGROUND: Lipodystrophy (LH) is one of the most common complications of subcutaneous insulin injection. Many factors are incriminated in the evolution of LH in children with diabetes type 1 (T1DM). LH may affect insulin absorption in the skin areas involved, resulting in a negative impact on blood glucose levels and glycemic variability. PATIENTS AND METHODS: We calculated and evaluated the prevalence of LH in relation to possible clinical factors associated with the development of LH in a cohort of children (n =115) with T1DM using insulin pens or syringes and we studied possible predisposing factors including their age, duration of T1DM, injection technique, insulin dose/kg, degree of pain perception, and HbA1c level. RESULTS: In our cross-sectional study, 84% of patients were using pens for insulin injection and 52.2 % of them were rotating the site of injection on daily basis. 27 % did not experience pain during an injection while 6 % had the worst hurt. 49.5 % had clinically detectable LH. Those with LH had higher HbA1c levels and more unexplained hypoglycemic events compared to those without LH (P: 0.058). The hypertrophied site was related to the preferred site of injection which was the arms in 71.9 % of the cases. Children who had LH were older with a longer duration of T1DM, rotating sites of injection less frequently, and were more frequently reusing needles compared to children without LH (P: < 0.05). CONCLUSION: Improper insulin injection technique, older age, and longer duration of T1DM were associated with LH. Proper education of patients and their parents must include correct injection techniques, rotating injection sites, and minimal reuse of needles.

Lipohypertrophy and Insulin: An Old Dog That Needs New Tricks.

OBJECTIVE: To review the current status of practical knowledge related to insulin-associated lipohypertrophy (LH) - an accumulation of fatty subcutaneous nodules commonly caused by repeated injections and/or infusions of insulin into the same site. METHODS: Review of published literature with additional contributions from leading multidisciplinary experts with the emphasis on clinical aspects including pathophysiology, clinical and economic consequences, diagnosis, prevention and treatment. RESULTS: LH is the most common dermatologic complication of insulin therapy. Risk factors for the development of lipohypertrophy include repeated delivery of large amounts of insulin into the same location over time, repeated injection trauma to the skin and subcutaneous tissue, and multiple injections using the same needle. Subcutaneous insulin injection in skin areas with lipohypertrophy is associated with reduced pain; however, this problem can interfere with insulin absorption, thereby increasing the likelihood of glucose variability, hypo- and hyperglycemia when a site is changed. Modern visualization technology of the subcutaneous space with ultrasound can demonstrate lipohypertrophy early in the course of its development. CONCLUSIONS: The physiological and psychological consequences of developing insulin lipohypertrophy can be prevented and treated with education focusing on insulin injection techniques.

A retrospective study on side effects of first-line antiretroviral drugs on HIV patients based on 1A, 2A, and 5A regimen records at Zomba Central Hospital, Malawi.

AIDS is an incurable disease that is common in Africa. Patients with HIV/AIDS having a CD4 count of less than 240 are put on life prolonging ARV drugs. The ARVs have serious side effects on some patients which may be handled by treating them or switching patient's drug to one with no or less serious side effects. However, before doing this, more understanding of the circumstances that lead to a side effect is vital. We use statistical analyses to link side effects of 1A, 2A, and 5A treatment regimens to the patient's social and demographic characteristics based on hospital data records. A retrospective review of patients' master cards (2011-2014) was done to assess adverse effects associated with different ARV regimens. Out of the 901 patients that showed side effects, 65.37% were females aged 31-40 and 34.63% were males. Comparatively, 1A regimen showed more side effects than 2A and 5A regimens. Age, gender and occupation correlated significantly with regimen symptoms (p< 0.05). Unlike men, women had the following extra side effects; cough, peripheral neuropathy and leg pains as compared to lipodystrophy. Our results show that old people (50years+) are less likely to get skin rash and other symptoms compared to lipodystrophy (RRR=0.973). Further, the probability of either having cough (0.0021, p< 0.05), or skin rash (0.0021, p< 0.05), as a side effect, on average, decreases as age increases with the same sex and weight. The probability of having peripheral neuropathy (0.0042, p< 0.01), however, increases with age. Knowledge of HIV patient's socio-demographics and the patient's regimen side effects can be utilised to appropriately manage severe ARV side effects. A therapy consideration that takes into account chemicals in ARV regimen responsible for specific side effects can be directed to patients with compatible socio-demographic characteristics.

Centrifugal lipodystrophy on a spectrum with lupus erythematosus panniculitis in children and efficacy and safety of hydroxychloroquine: A clinicopathological study.

This study aimed to investigate the relationship between centrifugal lipodystrophy (CLD) and lupus erythematosus panniculitis (LEP), and the efficacy and safety of hydroxychloroquine (HCQ) for treating CLD in children. A total of 29 cases clinically diagnosed as CLD (n = 24) and CLD/LEP overlap (n = 5) were enrolled and all were confirmed by skin biopsies of CLD and LEP. The clinicopathological findings, clinical outcomes, and prognosis with the treatment of HCQ between CLD and LEP were compared. All 29 cases (male: female = 1:1.6; median age at onset: 3 years) had cutaneous lesions of centrifugally expanding lipoatrophy, of which five cases overlapped with LEP lesions presented as erythematous indurated plaque (n = 2), subcutaneous nodules (n = 2) and alopecia along Blaschko's lines (n = 1). Antinuclear antibodies were found in six (25.0%) CLD and two (40.0%) overlapped patients (p = 0.597). Histopathologically, of the 24 cases of CLD, 14 (58.5%) exhibited subcutis loss or mild lobular inflammation. Ten (41.7%) cases displayed lobular panniculitis with moderate to dense lymphohistiocytic infiltrate and plasma cells, similar to the five cases of overlap. Small clusters of CD123 positive plasmacytoid dendritic cells were found in 62.5% (5/8) of CLD and 66.7% (2/3) of overlap cases (p > 0.99). HCQ (5 mg/kg/d) treatment showed improvement in 91.3% (21/23) of CLD and all overlap cases, including four cases unresponsive to previous oral glucocorticosteroid treatment. Our findings suggested that CLD and LEP represent a spectrum within the same disease. HCQ (5 mg/kg/d) was effective and safe for treating CLD (age >1.5 years), and early treatment and a regular long-term follow-up are essential.

Suggestive Evidence for an Antidepressant Effect of Metreleptin Treatment in Patients with Lipodystrophy.

INTRODUCTION: Lipodystrophy (LD) syndromes are rare heterogeneous disorders characterized by reduction or absence of subcutaneous fat, low or nondetectable leptin concentrations in blood and impaired hunger/satiety regulation. Metreleptin treatment reverses metabolic complications and improves eating behavior in LD. Because depression in anorexia nervosa (AN), which is also characterized by hypoleptinemia, improves substantially upon treatment with metreleptin, we hypothesized that metreleptin substitution may be associated with an antidepressant effect in patients with LD, too. METHODS: In this ancillary study, 10 adult patients with LD were treated with metreleptin. To assess depressive symptoms, the self-rating questionnaire Beck's Depression Inventory (BDI) was filled in at preestablished time points prior (T1) and after initiation of metreleptin (T2: 1 week; T3: 4 weeks; T4: 12 weeks) dosing. The differences between time points were tested with nonparametric Friedman's analysis of variance. Sensitivity analyses were performed upon exclusion of the BDI items addressing appetite and weight changes. RESULTS: According to their BDI scores, 4 patients had mild depression and 2 had moderate depression at baseline. Friedman's test revealed significant differences in BDI scores between the four time points. Post hoc analyses revealed that the difference between T1 and T3 was significant upon Bonferroni correction (p = 0.034, effect size r = 0.88). The sensitivity analyses upon exclusion of the appetite and weight change items again revealed a significant Friedman's test and significant Bonferroni corrected differences in the revised BDI scores between T1 versus T2 (p = 0.002, r = 0.99) and T1 versus T3 (p = 0.007, r = 0.79). DISCUSSION/CONCLUSION: Our study for the first time revealed suggestive evidence for an antidepressant effect of metreleptin in patients with LD. Metreleptin caused a rapid drop in depression scores within 1 week of treatment. A reduction of the depression score was also observed in 2 of the 3 LD patients whose BDI scores were in the normal range before start of the treatment. The reduction in total scores of BDI was still apparent after 3 months (T4) of dosing. This observation matches findings obtained in clinical case studies of AN patients, in whom depression scores also dropped during the first week of metreleptin treatment. It needs to be noted that by the nature of this observational study without a placebo group, nonspecific treatment expectation affecting mood cannot fully be ruled out.

Determination of insulin-related lipohypertrophy frequency and risk factors in patients with diabetes.

INTRODUCTION: Insulin, which is used in the treatment of diabetes mellitus (DM), may lead to the development of lipohypertrophy (LH) which can negatively affect the management of diabetes mellitus. Two common methods to detect LH are palpation and superficial subcutaneous ultrasonography (SSU). We investigated the frequency of non-palpable LH using SSU, as well as examining risk factors. METHOD: We included in our study patients who had been receiving insulin injections at least twice a day for over one year without palpable LH. The epidermis and the subcutaneous tissue thickness of each region were examined using SSU. The presence of LH and associated risk factors for LH were evaluated. RESULTS: We included 136 patients in our study. The mean age of all patients was 52.87±14.93 years, 59.6% were female and 73.5% had type 2 DM. The duration of DM and insulin usage were 15.76±9.20 and 11.42±8.26 years, respectively. The mean body mass index (BMI) of all patients was 30.59±7.40kg/m2. Non-palpable LH was detected in 87.5% (n=116) of the patients using SSU. In the multivariate logistic regression analyses, total cholesterol level, short-acting insulin dose and coronary artery disease (CAD) were associated with LH presence. CONCLUSION: Non-palpable LH can be seen at high rates in patients who have multiple insulin injections. Palpation is likely not enough to detect LH and we believe it would be appropriate to evaluate the presence of LH using SSU, especially for those who need high-dose insulin to control hyperglycaemia.

Lipodystrophy related to HIV-The Brazilian Public Health approach.

BACKGROUND: Lipodystrophy associated with the human immunodeficiency virus (HIV) is an unpleasant disorder found in 6%-80% of patients infected with HIV. Brazil has a universal public health system, an effective program for patients diagnosed with HIV, providing lipodystrophy treatment since 2004. The objective of this article is to describe the Brazilian approach to this complication. METHOD: A search in the Brazilian Health Care Legislation and the Brazilian Health System database was conducted to identify all the inclusion criteria and surgical treatment offered to HIV patients with lipodystrophy, identify all the facilities that offer this, and describe their geographic distribution. In addition, the number of procedures performed was obtained. RESULTS: The inclusion criteria were the following:1 diagnosis of HIV/AIDS and lipodystrophy due to the use of antiretroviral drugs for at least 12 months;2 no response or the impossibility of changing ART;3 clinical stability for six months without clinical manifestations suggestive of immunodeficiency in the last 6 months;4 laboratory results showing CD4 cell count >250 cells/mm3 and viral load <10,000 copies/ml in the last 6 months; and5 stable clinical and laboratory parameters. A total of 4,760 procedures were performed, with the most common procedure being facial filler with polymethylmethacrylate. Eleven hospitals were registered to offer this treatment. CONCLUSION: The Brazilian Health Care System approach to lipodystrophy has an organized plan with universal and integral coverage. All the procedures offered were safe and well-tolerated, according to the literature. However, regional distribution is the main issue and needs to be improved.

Endocrine immune-related adverse events: Adrenal, parathyroid, diabetes insipidus, and lipoatrophy.

Immune checkpoint inhibitors are being prescribed increasingly widely for a range of malignancies. They are effective at treating certain cancers, but also have significant side effects. Evidence suggests that efficacy is greatest in patients who experience one or more immune-related adverse events (irAEs). Common irAEs include skin and hepatic reactions, and a range of immune-related endocrinopathies. These include hypophysitis, thyroid disease, and autoimmune diabetes mellitus, and rarer endocrinopathies such as primary adrenal insufficiency, diabetes insipidus, parathyroid disease, autoimmune polyglandular syndrome, lipodystrophy, and ACTH-dependent Cushing's syndrome. Herein, we review the current literature related to these rarer immunotherapy-induced endocrinopathies.

Localized lipoatrophy and inadvertent subcutaneous administration of a COVID-19 vaccine.

A 60-year-old woman presented with a depressed lesion at the site of her first COVID-19 (Astra Zeneca) vaccine injection. The lesion was diagnosed as a case of injection related localized lipoatrophy as markers of autoimmune disease were negative and biopsy differentiated it from localized involutional lipoatrophy. This case of localized lipoatrophy was likely due to inadvertent subcutaneous injection of the COVID-19 vaccine with a 16 mm long needle.

Genetic and cytometric analyses of subcutaneous adipose tissue in patients with hemophilia and HIV-associated lipodystrophy.

BACKGROUND: The authors recently performed plastic surgeries for a small number of patients with hemophilia, HIV infection, and morphologic evidence of lipodystrophy. Because the pathophysiological mechanism of HIV-associated lipodystrophy remains to be elucidated, we analyzed subcutaneous adipose tissues from the patients. METHODS: All six patients had previously been treated with older nucleoside analogue reverse-transcriptase inhibitors (NRTIs; stavudine, didanosine or zidovudine). Abdominal and inguinal subcutaneous fat samples were obtained from the HIV+ patients with hemophilia and HIV- healthy volunteers (n = 6 per group), and analyzed via DNA microarray, real-time PCR, flow cytometry and immunohistochemistry. RESULTS: The time from initial NRTI treatment to collecting samples were 21.7 years in average. Cytometric analysis revealed infiltration of inflammatory M1 macrophages into HIV-infected adipose tissue and depletion of adipose-derived stem cells, possibly due to exhaustion following sustained adipocyte death. Genetic analysis revealed that adipose tissue from HIV+ group had increased immune activation, mitochondrial toxicity, chronic inflammation, progressive fibrosis and adipocyte dysfunction (e.g. insulin resistance, inhibited adipocyte differentiation and accelerated apoptosis). Of note, both triglyceride synthesis and lipolysis were inhibited in adipose tissue from patients with HIV. CONCLUSIONS: Our findings provide important insights into the pathogenesis of HIV-associated lipodystrophy, suggesting that fat redistribution may critically depend on adipocytes' sensitivity to drug-induced mitochondrial toxicity, which may lead either to atrophy or metabolic complications.

Lipoatrophy, a rare complication of diabetes: a single-center experience.

BACKGROUND: Lipoatrophy (LA), a rare skin complication in patients with type 1 diabetes (T1D), has decreased dramatically over the past decades due to the use of human purified insulin preparations. METHODS: We collected data from the records of T1D patients with LA. Types of insulin and insulin regimen, presence of eosinophilia, anti-insulin (IAA), anti-GAD, anti-IA2 autoantibodies, other autoimmune disorders, site of atrophy and its relationship to catheter, HbA1c at LA onset and after resolution, and different treatment modalities (i.e., change of insulin type or site, sodium cromoglycate (SCG) cream, cortisone cream or percutaneous injections, and laser treatment) were recorded. RESULTS: Thirteen out of 1200 T1D subjects (1%) presented with LA. The majority were on insulin pump using rapid-acting analogs. Twelve out of 13 patients had changed the type of insulin, and most of them had switched injection sites. Ten out of 13 patients used SCG cream and 7/10 showed complete/partial improvement. One patient used dexamethasone injection with improvement. Five patients showed self-improvement. In 3/7 patients who were receiving SCG, treatment was combined with change of insulin type (glulisine); however, in 1/3, the result should be attributed to concomitant laser treatment. In 4/7 patients, there was a clear, beneficial effect of SCG. In 1/4 with partial resolution of LA, laser treatment was used after SCG, which further improved the result. CONCLUSIONS: LA is a rare skin complication seen even today with the use of insulin analogs. SCG alone or combined with change of insulin type seems to be the most effective treatment. Laser treatment is a promising new therapy.

Endogenous Leptin Concentrations Poorly Predict Metreleptin Response in Patients With Partial Lipodystrophy.

CONTEXT: Leptin replacement with metreleptin improves glycemia and hypertriglyceridemia in severely hypoleptinemic patients with generalized lipodystrophy (GLD), but its effects are variable in partially leptin-deficient patients with partial lipodystrophy (PLD). OBJECTIVE: Compare 3 leptin assays (Study I); identify diagnostic performance of leptin assays to detect responders to metreleptin for each assay (Study II). DESIGN: Study I: cross-sectional analysis of average bias between leptin assays. Study II: retrospective analysis of diagnostic accuracy of potential leptin cut points to detect clinical responders to metreleptin. SETTING: National Institutes of Health; University of Michigan. PARTICIPANTS AND INTERVENTIONS: Study I: Metreleptin-naïve patients with lipodystrophy (GLD, n = 33, PLD, n = 67) and healthy volunteers (n = 239). Study II: GLD (n = 66) and PLD (n = 84) patients treated with metreleptin for 12 months. OUTCOME MEASURES: Leptin concentrations by Millipore radioimmunoassay (RIA), Millipore enzyme-linked immunosorbent assay (MELISA), and R&D Systems enzyme-linked immunosorbent assay (RDELISA). Response to metreleptin therapy was defined as either reduction ≥1.0% in A1c or ≥30% in serum triglycerides. RESULTS: RDELISA measured 3.0 ± 9.5 ng/mL higher than RIA; MELISA measured 11.0 ± 17.8 and 14.0 ±19.2 less than RIA and RDELISA, respectively. Leptin by RIA, MELISA, and RDELISA modestly predicted metreleptin response in GLD + PLD [receiver operating characteristic (ROC) area under the curve (AUC) 0.74, 0.69, and 0.71, respectively; P < 0.01 for all] with lower predictive power in PLD (ROC AUC 0.63, 0.61 and 0.65, respectively; P > 0.05 for all). The only reproducible cut point identified on sensitivity analyses was RIA leptin 7.2 ng/mL (sensitivity 56%; specificity 78%). CONCLUSIONS: Three common leptin assays are not interchangeable, and a reliable cut point to select responders to metreleptin was not identified.

Non-glycemic Adverse Effects of Insulin.

Insulin is primarily considered for its glycemic effects in patients with diabetes. There are, however, non-glycemic adverse effects of insulin that may significantly impact patient health and interfere with glycemic control. Insulinogenic edema primarily occurs with rapid improvement in glycemic control either in patients with newly discovered diabetes or in patients with poorly-controlled diabetes. Insulin-induced sympathetic activation, vasodilation, changes in vascular permeability, and most importantly, sodium retention play significant etiologic roles in the development of edema. Clinically, it is usually self-limited, but significant complications can develop. Allergic reactions to all insulin preparations and various compounds used in insulin formulations with a wide range of severity have been reported. Frequently, changing the type of insulin or delivery method is sufficient, but more advanced treatments such as insulin desensitization and anti-IgE antibody treatment may be needed. Lipohypertrophy and lipoatrophy frequently develop with the overuse of injection sites. Lipohypertrophy can affect tissue insulin absorption and glycemic control.

Values of ultrasound for diagnosis and management of insulin-induced lipohypertrophy: A prospective cohort study in China.

ABSTRACT: The aim of this study was to explore the values of ultrasound for diagnosis and management of insulin-induced lipohypertrophy and further analyzing the impact of body mass index and subcutaneous fat thickness on ultrasound manifestations of lipohypertrophy.In this 3-month, prospective cohort study, a total of 162 patients with diabetes who used insulin therapy more than 1 year with unknown lipohypertrophy status were enrolled into this study. Demographic information, assessment of glycemic control and insulin injection technique were evaluated. Physical and ultrasound examination were separately performed to detect lipohypertrophy by a team of diabetes educator nurses or ultrasonographer in a blinded fashion. Patients with lipohypertrophy received insulin injection technique education based on ultrasound examination and Chinese guideline.Ultrasound examination detected 41.1% more patients (74.1% vs 52.5%; P < .001) with lipohypertrophy and 61.2% more lesions (216 vs 134; P < .001) than physical examination. Glycosylated hemoglobin A1c and fasting blood glucose were significantly decreased in patients with lipohypertrophy or subclinical lipohypertrophy (lipohypertrophy without visual and palpation changes) after receiving insulin injection technique education based on ultrasound examination and Chinese guideline than baseline at 3 months (P < .001). The proportion of lesions with ultrasound manifestation 2 (distortion of surrounding connective tissue) in obese and STF (>15 mm) groups were no more than 50% and showed a decreased trend with increased subcutaneous fat thickness and body mass index (P < .001).Lipohypertrophy has characteristic ultrasound manifestations which can detect more accurate results than palpation alone and provide detailed information to promote effective education on lipohypertrophy management, thereby improving glycemic control.

Acquired localised lipoatrophy secondary to transgluteal drainage.

Acquired localised lipoatrophy is a focal loss of subcutaneous fat, which is commonly secondary to trauma, injections of medications such as antibiotics or corticosteroids, pressure, previous surgery or panniculitis. We present a case of a patient who experienced focal fat loss in the left gluteal region from a previous left transgluteal drainage of a suspected abscess. There was no medical history of corticosteroid, antibiotic injection or use of highly active antiretroviral therapy. Lipoatrophy occurring as a consequence of a deep pelvic abscess drainage has not been reported in the literature; however, based on the lack of other aetiologies, the diagnosis of acquired localised lipoatrophy secondary to a transgluteal drainage was made in this patient. The aim of this report was to present this rare cause of lipoatrophy that has not previously been described and to acknowledge lipoatrophy as a potential side effect of a deep abscess drainage.

Hundred-year experience with insulin and lipohypertrophy: An unresolved issue.

In the article recently published in Diab Res Clin Pract (1), we described one of the most exciting paths in the history of medicine from the perspective of diabetologists and people with type 1 diabetes. Such a history lasted 100 years, from the discovery of insulin to the most technologically advanced technologies aimed at making treatment as close to physiology and user-friendly as possible. Indeed, we are luckier than others because, by living in Italy and the USA, respectively, we have access to miniaturized and computerized insulin delivery systems, but this is not the case worldwide. Due to that, while receiving many favorable comments from colleagues and friends, we were encouraged to further expand on the issue and go deeper into insulin injection technique.