The multifaceted nature of diabetes mellitus induced by checkpoint inhibitors.

Immune checkpoint inhibitors (CPI) are increasingly being used in oncology, and many autoimmune side effects have been described. Diabetes mellitus (DM) has been reported in approximately 1% of subjects treated with programmed cell death-1 and programmed death ligand 1 (PD-1/PD-L1) inhibitors, alone or in association with CTLA-4 inhibitors. In the present mini-review, we aimed to describe different clinical pictures and pathophysiology associated with these forms of diabetes. Data on CPI-related DM was gathered from the largest case series in the literature and from our centre dedicated to immunotherapy complications (ImmuCare-Hospices Civils de Lyon). Most cases are acute autoimmune insulin-dependent diabetes which are similar to fulminant diabetes (extremely acute onset with concomitant near-normal HbA1c levels). Other cases, however, have a phenotype close to type 2 diabetes or appear as a decompensation of previously known type 2 diabetes. The occurrence of diabetes can also be a complication of autoimmune pancreatitis induced by CPI use. Finally, two cases of diabetes in a context of autoimmune lipoatrophy have recently been described. Regarding the wide variety of CPI-induced diabetes, the discovery of a glucose disorder under CPI should motivate specialised care for aetiological diagnosis and appropriate treatment.

Lipoatrophy with insulin analogues in type I diabetes.

Lipoatrophy is a rare complication of treatment with insulin analogues. It has been reported with insulin Lispro (Eli Lilly, Indianapolis, Indiana, USA) and insulin Glargine (Sanofi-Aventis, Paris, France). To our knowledge, this is one of the first reports of lipoatrophy with Aspart, biphasic Aspart and Detemir insulin analogues (Novo Nordisk, Bagsvaerd, Denmark). We report the cases of four children with type I diabetes who were commenced on NovoMix 30 or NovoRapid/Levemir insulin injections. They developed lipoatrophy at the injection sites after 2-3 years of treatment. In two of our patients, lipoatrophy resolved when the injection sites were changed, suggesting that local factors could be the cause of lipoatrophy. However, lipoatrophy developed at the new sites in the other two patients, requiring a change of insulin preparation. Regular examination of the injection sites facilitated early detection of lipoatrophy in our patients. Lipoatrophy completely resolved over 1-2 years in all patients with no recurrence after 3-4 years of follow-up.

Lipoatrophy associated with the use of insulin analogues: a new case associated with the use of insulin glargine and review of the literature.

IMPORTANCE OF THE FIELD: Any insulin formulation can in principle cause lipoatrophy; even cases associated with recombinant human insulin have been reported. An increasing number of case reports have been published indicating that lipoatrophy also develops after treatment with various insulin analogues. AREAS COVERED IN THIS REVIEW: In this review, we summarise the literature on lipoatrophy associated with the use of insulin analogues published to date. A new case of lipoatrophy associated with the use of glargine is presented. WHAT THE READER WILL GAIN: Readers will gain insight into: i) pathogenesis of lipoatrophy associated with the use of insulin analogues and ii) clinical features of lipoatrophy. TAKE HOME MESSAGE: Twelve cases with lipoatrophy under treatment with insulin analogues have been reported so far. The exclusive occurrence in lean type 1 diabetic patients, its overlap with further autoimmune diseases and the overrepresentation of female individuals point to an immune pathogenesis. The respective exposition to the analogues lispro, aspart, glargine and detemir prior to lipoatrophy development varied considerably between 4 weeks and 2 years. No spontaneous substantial recovery of lipoatrophic areas has been reported. Frequent use of the same pen needle and lack of rotating of insulin injection sites seem to favour the development of lipoatrophy.

Diagnosis, prediction, and natural course of HIV-1 protease-inhibitor-associated lipodystrophy, hyperlipidaemia, and diabetes mellitus: a cohort study.

BACKGROUND: The prevalence and severity of lipodystrophy syndrome with long-term therapy for HIV-1 infection that includes a protease inhibitor is unknown. We studied the natural course of the syndrome to develop diagnostic criteria and identifying markers that predict its severity. METHODS: We assessed 113 patients who were receiving HIV-1 protease inhibitors (mean 21 months) and 45 HIV-1-infected patients (28 with follow-up) never treated with a protease inhibitor. Lipodystrophy was assessed by questionnaire (including patients' rating of severity), physical examination, and dual-energy x-ray absorptiometry. Body composition and fasting lipid and glycaemic variables were compared with data obtained 8 months previously. Oral glucose tolerance was investigated. FINDINGS: There was 98% concordance between patients' reports of the presence or absence of lipodystrophy (reported by 83% of protease-inhibitor recipients and 4% of treatment-naïve patients; p=0.0001) and physical examination. Patients' ratings of lipodystrophy were significantly associated with declining total body fat (p=0.02). Lower body fat was independently associated with longer duration of protease-inhibitor therapy and lower bodyweight before therapy, and more severe lipodystrophy was associated with higher previous (p < 0.03) and current (p < or = 0.01) triglyceride and C-peptide concentrations, and less peripheral and greater central fat (p=0.005 and 0.09, respectively). Body fat declined a mean 1.2 kg over 8 months in protease-inhibitor recipients (p=0.05). The prevalence of hyperlipidaemia remained stable over time (74% of treated patients vs 28% of naïve patients; p=0.0001). Impaired glucose tolerance occurred in 16% of protease-inhibitor recipients and diabetes mellitus in 7%; in all but three patients these abnormalities were detected on 2 h post-glucose load values. INTERPRETATION: Diagnosis and rating severity of lipodystrophy is aided by the combination of physical examination, patient's rating, and measurement of body fat, fasting triglycerides, and C-peptide. Weight before therapy, fasting triglyceride, and C-peptide concentrations early in therapy, and therapy duration seem to predict lipodystrophy severity. Lipodystrophy was common and progressive after almost 2 years of protease inhibitor therapy, but was not usually severe. Hyperlipidaemia and impaired glucose tolerance were also common.

Human insulin-induced lipoatrophy. Successful treatment using a jet-injection device.

OBJECTIVE: To evaluate the efficacy of the administration of insulin by a jet-injector device in stopping and reversing severe human insulin-induced lipoatrophy. CASE: We report a case of a woman with severe human insulin-induced lipoatrophy who has been treated exclusively with recombinant DNA human insulin since the onset of IDDM. RESULTS: The loss of subcutaneous tissue in the injection areas was demonstrated and measured by high-frequency ultrasound. Dermatologic exam demonstrated a severe reduction of fat tissue. After 8 months of administration of human insulin by a jet injector, there were no more new lesions of lipoatrophy and those affected areas were substantially ameliorated. CONCLUSIONS: Jet-injection devices might constitute a helpful method to treat those patients affected by severe human insulin-induced lipoatrophy.

Insulin-resistant diabetes during growth hormone therapy in a child with SHORT syndrome.

We report the case of a 13-year-old boy with SHORT syndrome, including lipoatrophy and insulin resistance, who developed diabetes mellitus while receiving growth hormone therapy. The diabetes persisted after cessation of exogenous growth hormone but oral hypoglycaemic therapy was successful and could be discontinued eight months later.

A case of lipoatrophy with human insulin-therapy.

A case of progressive insulin-induced lipoatrophy is reported in an insulin-dependent diabetic patient having been treated exclusively with human insulin. The lipoatrophy was stopped after insulin therapy was changed from subcutaneous injections to continuous subcutaneous infusion with human insulin.