Scientific letter
Ultra-rapid insulin in mitochondrial diabetes: Two clinical cases
Insulina ultrarrápida en diabetes mitocondrial: dos casos clínicos
Francisco Simões de Carvalho
, Francisca de Brito Marques, Ana Elisa Lopes, Joana Lima Ferreira, Pedro Carneiro de Melo
Corresponding author
Department of Endocrinology, Hospital Pedro Hispano, Matosinhos Local Health Unit, Matosinhos, Portugal
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[ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Scientific letter</span>" "titulo" => "Ultra-rapid insulin in mitochondrial diabetes: Two clinical cases" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "364" "paginaFinal" => "366" ] ] "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "Francisco Simões de Carvalho, Francisca de Brito Marques, Ana Elisa Lopes, Joana Lima Ferreira, Pedro Carneiro de Melo" "autores" => array:5 [ 0 => array:4 [ "nombre" => "Francisco" "apellidos" => "Simões de Carvalho" "email" => array:1 [ 0 => "franciscosimoesdecarvalho@live.com.pt" ] "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">*</span>" "identificador" => "cor0005" ] ] ] 1 => array:2 [ "nombre" => "Francisca" "apellidos" => "de Brito Marques" ] 2 => array:2 [ "nombre" => "Ana Elisa" "apellidos" => "Lopes" ] 3 => array:2 [ "nombre" => "Joana" "apellidos" => "Lima Ferreira" ] 4 => array:2 [ "nombre" => "Pedro" "apellidos" => "Carneiro de Melo" ] ] "afiliaciones" => array:1 [ 0 => array:2 [ "entidad" => "Department of Endocrinology, Hospital Pedro Hispano, Matosinhos Local Health Unit, Matosinhos, Portugal" "identificador" => "aff0005" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Insulina ultrarrápida en diabetes mitocondrial: dos casos clínicos" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 2938 "Ancho" => 3258 "Tamanyo" => 655008 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Adapted from FreeStyle Libre – Libreview reports for Patient 1 and Patient 2.</p>" ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">Mitochondrial diseases are a group of genetic disorders characterised by defects in oxidative phosphorylation and caused by mutations in genes in the nuclear DNA or mitochondrial DNA. Mitochondrial DNA mutations occur in 1 per 5000 adults and are transmitted through maternal inheritance.<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">1</span></a> Diabetes is the most common endocrinopathy among mitochondrial disorders. Defects in the tricarboxylic acid cycle and electron transport chain lead to reduced oxidative phosphorylation, resulting in inefficient and suboptimal glucose-stimulated insulin secretion.<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">1</span></a> Mitochondrial encephalomyopathy, lactic acidosis, stroke-like episodes (MELAS), and maternally inherited diabetes and deafness (MIDD) are the most common mitochondrial diabetes disorders,<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">2</span></a> Although the m.3243A>G mtDNA pathogenic variant is more frequently linked to diabetes, other mutations can occur. Mitochondrial diabetes typically affects adults over 35 years, and most patients require insulin treatment a few years after its onset.<a class="elsevierStyleCrossRefs" href="#bib0065"><span class="elsevierStyleSup">3,4</span></a> The severity of diabetes has been strongly associated with increasing age, consistent with the clinical picture of a progressive disease.<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">5</span></a> Hearing loss in MIDD frequently precedes the diagnosis of diabetes and tends to develop in early adulthood.<a class="elsevierStyleCrossRefs" href="#bib0080"><span class="elsevierStyleSup">6,7</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">To our knowledge, no studies exist on ultra-rapid insulin therapy in mitochondrial diabetes. Two cases of mitochondrial diabetes under basal-bolus insulin therapy with fast-acting insulin aspart will be discussed.</p><p id="par0015" class="elsevierStylePara elsevierViewall">Patient 1 is a 50-year-old male with a chronic kidney disease known since childhood, and currently undergoing peritoneal dialysis and waiting for a kidney transplant. Notwithstanding occupational noise exposure, bilateral sensorineural hearing loss was identified in childhood. Diabetes was diagnosed during a routine evaluation when he was 30 years old (normal weight, c-peptide level 2.2<span class="elsevierStyleHsp" style=""></span>ng/mL, and negative beta-cell antibodies), and insulin was started at diagnosis. To determine diabetes aetiology, he was submitted to genetic testing that revealed MT-TL1 mutation, m.3243A>G, 20% heteroplasmy in peripheral blood leucocyte DNA. He was on basal insulin alone for 17 years after his diabetes diagnosis. During this period, sitagliptin 25<span class="elsevierStyleHsp" style=""></span>mg od was started. However, HbA1c levels started to rise to 7.5–8.0%, and the flash glucose monitoring device Freestyle Libre was employed, showing significant post-prandial hyperglycemia with insulin glargine U-100 9<span class="elsevierStyleHsp" style=""></span>IU/day. He was then started on fast-acting insulin aspart before the three main meals, according to pre-prandial glucose levels. His basal insulin is now glargine U-100 3<span class="elsevierStyleHsp" style=""></span>IU in the morning, and his daily insulin dose (TDI) is 10–15<span class="elsevierStyleHsp" style=""></span>IU/d (0.15–0.23<span class="elsevierStyleHsp" style=""></span>IU/kg/d). Glucose control has significantly improved, as shown by monitoring reports, and basal insulin needs are now less than 30% of TDI (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>). Apart from chronic kidney disease, no other target-organ diabetes complications were present years before the diabetes diagnosis. A family history of diabetes was present in Patient 1's mother and two siblings.</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0020" class="elsevierStylePara elsevierViewall">Patient 2 is a 56-year-old male with bilateral sensorineural hearing loss. A family history of hearing loss was present in the patient's mother and maternal aunt. Diabetes was diagnosed when he was 40 years old during routine evaluation (normal weight, c-peptide level 3.1<span class="elsevierStyleHsp" style=""></span>ng/mL, and negative beta-cell antibodies), and insulin was started at diagnosis. Genetic testing revealed a variant in the MT-CO3 gene, m.9325T>C, p.(Met40Thr) in homoplasmy. Different basal-bolus regimens had been employed with inconsistent results. Due to HbA1c levels persistently over 8%, flash glucose monitoring Freestyle Libre was used. Due to significant post-prandial hyperglycemia, insulin glulisine was switched to fast-acting insulin aspart. Bolus insulin was adjusted, and basal insulin dosing was reduced to less than 30% of TDI (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>). Despite not achieving optimal glycemic control, ambulatory glucose profile reports have improved. Annual retinopathy screening was normal, and no other diabetes-related complications were known.</p><p id="par0025" class="elsevierStylePara elsevierViewall">Management of mitochondrial diabetes is challenging, as there are no guidelines or clinically riented recommendations.</p><p id="par0030" class="elsevierStylePara elsevierViewall">Due to the risk of lactic acidosis, metformin is usually contraindicated. It has also been proposed that metformin could trigger neurological manifestations in this condition.<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">8</span></a> Sulfonylureas were traditionally viewed as first-line therapy in patients with MIDD. However, the risk of hypoglycemia with this therapy remains. DPP4-inhibitors are considered safe and well-tolerated in patients with MIDD.<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">7</span></a> Patient 1 is being treated with sitagliptin.</p><p id="par0035" class="elsevierStylePara elsevierViewall">Novel therapies, such as SGLT2 inhibitors or GLP-1 receptor agonists, have demonstrated clinical benefit in some case reports.<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">9</span></a></p><p id="par0040" class="elsevierStylePara elsevierViewall">In order to achieve reasonable glycemic control, both of our patients require basal-bolus insulin regimens. Compared with first-generation rapid-acting insulin analogues, ultra-rapid insulins have demonstrated benefits in post-prandial glycemic control in type 1 and type 2 diabetes.<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">10</span></a> Since glucose-stimulated insulin secretion is impaired in mitochondrial diabetes, we have decided to use fast-acting insulin aspart to target post-prandial hyperglycemia more efficiently. Our results are satisfactory, as demonstrated by glucose monitoring reports.</p><p id="par0045" class="elsevierStylePara elsevierViewall">Haemoglobin A1c has not been validated for diagnosis or follow-up of mitochondrial diabetes. Since these patients have significant post-prandial hyperglycemia, other methods of glycemic evaluation might be more suitable. We have opted for a flash glucose monitoring device for our patients, and the ambulatory glucose report has significantly impacted insulin therapy adjustment, with continuous reductions in basal insulin and bolus insulin.</p><p id="par0050" class="elsevierStylePara elsevierViewall">The association of diabetes and sensorineural deafness must prompt an investigation of mitochondrial diabetes, especially if there is a maternal history of diabetes and/or deafness. This diagnosis will allow family screening, education, surveillance for future complications, and personalised care.</p><p id="par0055" class="elsevierStylePara elsevierViewall">In a continuously evolving era in diabetes management, new strategies can also play a role in uncommon types of diabetes. As such, we propose that ultra-rapid insulin shall be considered in managing patients with mitochondrial diabetes when other strategies fail to achieve optimal glycemic control. Also, glucose monitoring devices can be employed to evaluate post-prandial glucose excursions and assist clinicians in decision-making.</p><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0005">Authors’ contributions</span><p id="par0060" class="elsevierStylePara elsevierViewall">FSC drafted the manuscript. All authors were involved in the critical revision of the manuscript and have approved the final version of the manuscript.</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Ethical standards</span><p id="par0065" class="elsevierStylePara elsevierViewall">Written informed consent for publication was obtained.</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Funding</span><p id="par0070" class="elsevierStylePara elsevierViewall">This research received no funding.</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Conflicts of interest</span><p id="par0075" class="elsevierStylePara elsevierViewall">The authors declare no conflicts of interest.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:6 [ 0 => array:2 [ "identificador" => "sec0005" "titulo" => "Authors’ contributions" ] 1 => array:2 [ "identificador" => "sec0010" "titulo" => "Ethical standards" ] 2 => array:2 [ "identificador" => "sec0015" "titulo" => "Funding" ] 3 => array:2 [ "identificador" => "sec0020" "titulo" => "Conflicts of interest" ] 4 => array:2 [ "identificador" => "xack669168" "titulo" => "Acknowledgements" ] 5 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "multimedia" => array:1 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 2938 "Ancho" => 3258 "Tamanyo" => 655008 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Adapted from FreeStyle Libre – Libreview reports for Patient 1 and Patient 2.</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0015" "bibliografiaReferencia" => array:10 [ 0 => array:3 [ "identificador" => "bib0055" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Endocrine manifestations and new developments in mitochondrial disease" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "Y.S. 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Tarnopolsky" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "J Diabetes Complicat" "fecha" => "2021" "volumen" => "35" "paginaInicial" => "1075" "paginaFinal" => "1084" ] ] ] ] ] ] 9 => array:3 [ "identificador" => "bib0100" "etiqueta" => "10" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Ultra-rapid-acting insulins for adults with diabetes: a systematic review and meta-analysis" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "I. Avgerinos" 1 => "G. Papanastasiou" 2 => "T. Karagiannis" 3 => "T. Michailidis" 4 => "A. Liakos" 5 => "M. Mainou" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1111/dom.14461" "Revista" => array:6 [ "tituloSerie" => "Diabetes Obes Metab" "fecha" => "2021" "volumen" => "23" "paginaInicial" => "2395" "paginaFinal" => "2401" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/34105242" "web" => "Medline" ] ] ] ] ] ] ] ] ] ] ] ] "agradecimientos" => array:1 [ 0 => array:4 [ "identificador" => "xack669168" "titulo" => "Acknowledgements" "texto" => "<p id="par0080" class="elsevierStylePara elsevierViewall">The authors would like to thank all the physicians who followed our patient.</p>" "vista" => "all" ] ] ] "idiomaDefecto" => "en" "url" => "/25300180/0000007000000005/v1_202305311257/S2530018023000835/v1_202305311257/en/main.assets" "Apartado" => array:4 [ "identificador" => "64494" "tipo" => "SECCION" "en" => array:2 [ "titulo" => "Scientific letters" "idiomaDefecto" => true ] "idiomaDefecto" => "en" ] "PDF" => "https://static.elsevier.es/multimedia/25300180/0000007000000005/v1_202305311257/S2530018023000835/v1_202305311257/en/main.pdf?idApp=UINPBA00004N&text.app=https://www.elsevier.es/" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2530018023000835?idApp=UINPBA00004N" ]
| Year/Month | Html | Total | |
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