case study on diabetes mellitus type 1

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Case Report

Newly diagnosed type 1 diabetes complicated by ketoacidosis and peripheral thrombosis leading to transfemoral amputation, line bisgaard jørgensen.

1 Department of Medical Endocrinology, Odense University Hospital (OUH), Odense C, Denmark

2 Department of Orthopaedic Surgery, Odense University Hospital (OUH),, Odense C, Denmark

Knud Yderstræde

Peripheral vascular thromboembolism is a rarely described complication of diabetic ketoacidosis. We report a 41-year-old otherwise healthy man admitted with ketoacidosis and ischaemia of the left foot. The patient was unsuccessfully treated with thromboendarterectomy, and the extremity was ultimately amputated. The patient had no family history of cardiovascular disease, and all blood sample analyses for hypercoagulability were negative. We recommend an increased focus on peripheral thromboembolism, when treating patients with severe ketoacidosis.

Diabetes mellitus is associated with an increased incidence of thromboembolic complications. In type 2 diabetes mellitus there is clear evidence of thrombophilia partly explained by an increased level of plasminogen activator inhibitor . 1 It is not certain whether there is an increased risk of peripheral vascular thrombosis/embolism in patients with diabetic ketoacidosis. We present a case of diabetic ketoacidosis in a newly diagnosed individual with type 1 diabetes complicated by peripheral vascular insufficiency.

Case presentation

A 41-year-old man was admitted to hospital in a serious medical condition. Besides a history of herniated lumbar disc the patient was healthy. The patient had no history of hypertension, but blood pressure was 156/111 mmHg on admission. During the stay in hospital blood pressure stabilised at around 135/80 mmHg. There was no family history of cardiovascular disease. A few days before admission the patient had episodes of nausea, vomiting and abdominal pain. Additionally, he had polyuria and polydipsia. A few hours before admission, the patient reported acute pain in his left foot and was found to have a pulseless foot without vital signs. On admission an arterial blood gas showed metabolic acidosis (pH 7.02, base excess 24.6 , blood glucose 26 mmol/L) and blood ketones (acetone, acetoacetic acid and β-hydroxybutyric acid) were 6.6 mmol/L.

Investigations

The patient was diagnosed with type 1 diabetes mellitus supported by a low C peptide level of 43 (370–1470 pmol/L) and an antiglutamic acid decarboxylase (GAD) antibody titre of 4.7 (ref. 0–1.0). The complete blood count showed high white cell count of 20.9×10 9 /L but normal haemoglobin level of 8.4 mmol/L and platelet count of 199×10 9 /L. C reactive protein was below 1.0. Screening for a diversity of systemic inflammatory disorders including vasculitis and systemic lupus erythematosus (eg, antinuclear antibodies, antineutrophil cytoplasmic antibodies, lupus anticoagulant and cardiolipin antibodies) were all negative. Protein S and C levels were normal, antithrombin III level was reduced and the coagulation factors were increased (factor II, VII and X were 1.40 units (0.70–1.30) and factor VIII was 3.89 (0.60–1.30)). APTT (activated partial thromboplastin time) was prolonged to 46 s (27–40). Blood lipids were normal with total cholesterol 2.6 mmol/L, LDL-cholesterol 1.5 mmol/L, HDL-cholesterol 0.8 mmol/L and triglycerides 0.72 mmol/L. The ECG showed sinus rhythm without ischaemia, and an echocardiogram also was found normal. A duplex ultrasonography of the lower limbs showed no blood flow in the arteries of the left crus and foot.

Differential diagnosis

Buerger's disease, which is caused by inflammation of the arterial wall, is a relevant differential diagnosis. It mostly appears in smoking men between 20 and 40 years of age, corresponding to the individual in this case who reported smoking 10 cigarettes daily. However, symptoms are mostly less acute in Buerger's disease and the vascular surgeons found no evidence for this condition.

The patient was treated according to the guidelines for management of diabetic ketoacidosis and subsequently referred to a university hospital. Vascular surgery was performed including thromboendarterectomy in several large arteries in the left leg and medication to provide fibrinolysis was injected in the small arteries in the foot, which were too peripherally located to be accessible to surgery. But sufficient blood flow was not obtained due to peripheral thrombosis, and a below-knee amputation was performed. The amputation related wound did not heal after 1 week of observation, and eventually a transfemoral amputation was performed.

Only a few case reports on diabetic ketoacidosis complicated by thrombosis are present in the literature. The fibrinolytic system is disturbed in conditions of metabolic acidosis. Carl et al 2 described the haemolytic factors during diabetic ketoacidosis. They found decreased activity of proteins S and C, which are some of the most important inhibitors of the coagulation process. They also found increased activity of von Willebrand factor, which facilitates platelet adhesion. 3

Thus, it can be speculated that there is an increased risk of venous and arterial thrombosis and atheromatous plaques are prevailing, related to endothelial factors. In the case report presented here, the coagulation factors were affected in a way which indicated increased activity. Proteins S and C were normal, however, they were analysed 36 h after the initial treatment for ketoacidosis. The level of antithrombin III was reduced, probably related to the use of heparin.

Zipser et al 4 described a similar case report of a newly diagnosed individual with diabetes with ketoacidosis and acute aortoiliac and femoral artery occlusion. The patient was also amputated below the knee, but had a fatal outcome. Lin et al 5 describe a case report of ketoacidosis complicated by acute brachial artery thrombosis in a patient with a diabetes duration of 4 years. The brachial artery was rescued by surgical thrombectomy. Insufficiently regulated diabetes can also cause dyslipidemia with increased risk of atheroma formation and embolism arising from vascular endothelium with disintegrated morphology. Congenital hyperlipidaemia has been described to cause coronary artery disease and acute myocardial infarction in children. 6

In the case report presented here, the patient was newly diagnosed with diabetes with a short duration of symptoms of the disease. The patient had no history of thromboembolism and an echocardiogram could not identify any cardiac source of the embolism. The patient had sinus rhythm but it cannot conclusively exclude the likelihood of a transient arrhythmia precipitated by ketoacidosis, which could have caused the embolism. 7 The patient was not influenced by any intercurrent disease, but he was dehydrated because of vomiting during a couple of days. Dehydration in combination with diabetic ketoacidosis increases venous stasis and thereby the risk of deep venous thrombosis according to Virchow's triad. However, it has not been shown to be an independent variable as a cause of venous thrombosis. 5

The marked peripheral vascular changes resulted in significant oedema of the affected extremity, and even though compartment syndrome was excluded, it was not possible to achieve adequate healing. Abrupt onset of peripheral ischaemic symptoms without any history of claudication mitigated the possibility of Buerger's disease.

We present a case of diabetic ketoacidosis complicated by peripheral thromboembolism, which is a rare complication of diabetic ketoacidosis but can have devastating consequences with limb amputation or even death. We recommend an increased focus on peripheral thromboembolism, including assessment of pulse and general signs of peripheral vascular insufficiency (eg, pallor, pain and coldness), when treating patients with severe ketoacidosis. However, other causes of thromboembolism should be excluded before establishing diabetic ketoacidosis as the cause.

Learning points

• Diabetic ketoacidosis can promote a prothrombotic state.
• Peripheral thrombosis/embolism is a rarely described complication of diabetic ketoacidosis, and can have a devastating consequence with limb amputation or death.
• Other causes of thrombosis including cardiac source, thrombophilia, dyslipidemia should be excluded before determining diabetic ketoacidosis as a causative agent.

Contributors: LBJ was involved in the concept and design, literature search and drafting the article. KY was involved in the management of the patient, concept and design, drafting and critical review. OS participated in the management of the patient, reviewed and edited the article.

Competing interests: None.

Patient consent: Obtained.

Provenance and peer review: Not commissioned; externally peer reviewed.

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Prompt recognition of new-onset type 1 diabetes is everyone’s responsibility—even on weekends.

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Laura M. Jacobsen; Prompt Recognition of New-Onset Type 1 Diabetes Is Everyone’s Responsibility—Even on Weekends. Diabetes Care 25 March 2024; 47 (4): 646–648. https://doi.org/10.2337/dci23-0096

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While the complex etiopathogenesis and heterogeneity of type 1 diabetes (T1D) creates many challenges regarding disease-modifying interventions, there are ways to meaningfully reduce the morbidity ( 1 , 2 ), and mortality, associated with new-onset T1D when it presents with life-threatening diabetic ketoacidosis (DKA). Early diagnosis and prompt initiation of insulin can prevent DKA, as has been shown in research programs that monitor children at risk for T1D.

In theory, early recognition of T1D to prevent severe metabolic decompensation consists of a simple exchange of knowledge regarding the signs and symptoms with all stakeholders and access to specialized health care. However, we have not been able to reduce the frequency of DKA in the population despite awareness and educational campaigns. Individual efforts have reduced DKA rates within a study setting, such as in Italy through an educational program in clinics, homes, and schools ( 3 ); however, the incidence of DKA at onset continues to rise in Italy and other regions ( 4 – 6 ). The rate of DKA at T1D diagnosis in children and adolescents remains unacceptably high and variable across countries (25–77%) ( 7 – 9 ).

In a study published in this issue of Diabetes Care , Kamrath et al. ( 9 ) analyzed the German Prospective Diabetes Registry (DPV) to assess for differences in when (e.g., the day of the week) individuals were diagnosed with, and started treatment for, new-onset T1D. In addition, over the 10-year period analyzed they assessed the rate of DKA, DKA severity, and effect of the coronavirus disease 2019 (COVID-19) pandemic. These are straightforward but previously unanswered questions that have implications for families, health care systems, and payors.

In this study of the DPV registry, DKA that occurred at diagnosis in children was 1 ) highest (in absolute counts) on Mondays and Tuesdays , but 2 ) highest proportional to the number of new cases of T1D each day on Saturday and Sunday. Similarly, looking at public holidays in Germany and school vacations by region, T1D (and DKA) was less likely to be diagnosed on weekends compared with weekdays.

In 9.1% of cases, insulin was not started on the day of diagnosis. Of note, DKA occurred in 21.2% of cases where treatment initiation was delayed. While the rate of DKA was higher (28%) in children without a treatment delay, if someone were near DKA, often tell-tale signs are evident that should alert a medical provider to the urgent need for treatment, although presentations vary and laboratory studies may not be readily available on weekends. This is especially apparent with the high rate of diabetes diagnosed on public holidays (21.8%), when laboratories may be closed, for example, as opposed to weekends and school vacations (14.4% and 12.4%, respectively). In comparison to 2013–2019, during the COVID-19 pandemic (2020–2022), the proportions of DKA and severe DKA at diagnosis did rise, as seen in other reports. However, there were no significant differences when comparing the type of day (workday versus other) between these time periods.

The analysis by Kamrath et al. ( 9 ) is well designed and includes a large number of children and adolescents. The DPV receives data from the vast majority (93%) of T1D diagnoses throughout the country, increasing its generalizability. While the type of health care system varies between countries, I would still expect these differences between workdays and nonworkdays to be present in many countries. In support of this assumption, in Colorado it was found that while DKA rates in children increased from 2010 to 2017, the increase was driven by insured children ( 5 ), meaning other variables, as Kamrath et al. explore, may play a role. Direct evidence of what information families may have received from acute care clinics, general providers, and on-call answering services is not available.

This study should provide renewed motivation for specialized diabetes-specific trainings for all who care for children. In addition, we can advocate for updates to health care policy to require that all patients have access to pediatric/specialized health care services 24 h a day, 7 days a week, 365 days a year. An influx of monetary support in this area could reduce DKA and intensive care unit hospitalizations for children which may actually save health care dollars. In addition, many children requiring critical care often must be transferred to another hospital that may be far from the family’s home and support system. We can focus on the stakeholders involved in primary prevention of DKA, which include the person with T1D and their family, primary care providers, acute care providers, and on-call services. The latter two especially are used more on weekends and holidays. For children who are likely to have a more rapid metabolic decompensation, parents are a vital stakeholder, as the child may not be able to adequately express their symptoms. Each of these stakeholders interacts with a child developing T1D before a specialist does. Kamrath et al. ( 9 ) bring up valuable points about differences in care that children receive outside standard weekdays. Might we take a multipronged approach to reach these stakeholders, as depicted in Fig. 1 ?

Key stakeholders can help identify T1D before the development of DKA. The specialist, on the right, is on the lookout for cases of T1D and DKA. The specialist, though, is not the first person to interact with a child developing symptoms of diabetes (shown on the left). These people, or stakeholders (in the middle circle), include family members, pediatric or primary care providers, acute care providers, and on-call answering services. Each stakeholder group proposes a potential solution for prompt identification of T1D. Figure created with BioRender.com.

Identifying T1D early, before the development of DKA, is possible, as has been shown in the U.S., Germany, Finland, Sweden, Australia, and New Zealand, where rates of DKA were ≤6% when children at risk for T1D (multiple islet autoantibodies present) were involved in monitoring ( 5 , 10 – 13 ). We, as readers of Diabetes Care , should be taking lessons from these groups as we work toward the goal of zero cases of DKA. We can affect change regarding early recognition of T1D.

See accompanying article, p. 649 .

Funding. L.M.J. is funded by the National Institutes of Health.

Duality of Interest. No potential conflicts of interest relevant to this article were reported.

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A case report: First presentation of diabetes mellitus type 1 with severe hyperosmolar hyperglycemic state in a 35-month-old girl

Affiliations.

• 1 Division of Pediatric Intensive Care Department of Pediatrics Shiraz University of Medical Sciences Shiraz Iran.
• 2 Division of Pediatric Metabolism and Endocrinology Department of Pediatrics Shiraz University of Medical Sciences Shiraz Iran.
• PMID: 34765201
• PMCID: PMC8572339
• DOI: 10.1002/ccr3.4984

Hyperglycemic hyperosmolar syndrome (HHS) is a rare complication of diabetes mellitus among pediatric patients. Since its treatment differs from diabetic ketoacidosis (DKA), hence, pediatricians should be aware of its diagnosis and management.

Keywords: case report; diabetes mellitus; hyperglycemic hyperosmolar syndrome (HHS); pediatric patients; rhabdomyolysis; thrombosis.

© 2021 The Authors. Clinical Case Reports published by John Wiley & Sons Ltd.

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Case report

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• Published: 02 June 2021

A case report of a boy suffering from type 1 diabetes mellitus and familial Mediterranean fever

• Maria Francesca Gicchino   ORCID: orcid.org/0000-0003-0329-6583 1 ,
• Dario Iafusco 1 ,
• Angela Zanfardino 1 ,
• Emanuele Miraglia del Giudice 1 &
• Alma Nunzia Olivieri 1  

Italian Journal of Pediatrics volume  47 , Article number:  127 ( 2021 ) Cite this article

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Type 1 diabetes mellitus could be associated with other autoimmune diseases, such as autoimmune thyroid disease, celiac disease, but the association with Familial Mediterranean Fever is rare, we describe a case of a boy with type 1 Diabetes Mellitus associated with Familial Mediterranean Fever (FMF).

Case presentation

A 13 year old boy already suffering from Diabetes Mellitus type 1 since the age of 4 years, came to our attention because of periodic fever associated with abdominal pain, chest pain and arthralgia. The fever appeared every 15–30 days with peaks that reached 40 °C and lasted 24–48 h. Laboratory investigation, were normal between febrile episodes, but during the attacks revealed an increase in inflammatory markers. Suspecting Familial Mediterranean Fever molecular analysis of MEFV gene, was performed. The genetic analysis showed homozygous E148Q mutation. So Familial Mediterranean Fever was diagnosed and colchicine treatment was started with good response.

Familial Mediterranean Fever could be associated with other autoimmune diseases such as Ankylosing Spondylitis, Rheumatoid Arthritis, Polyarteritis Nodosa, Behcet disease, Systemic Lupus, Henoch-Schönlein Purpura, and Hashimoto’s Thyroiditis. Association of type 1 Diabetes Mellitus and Familial Mediterranean Fever has been newly reported in the medical literature, this is the third association of these two diseases described in the medical literature so far.

Familial Mediterranean fever (FMF) is a monogenic autoinflammatory disease with autosomal recessive inheritance [ 1 ]. The main clinical findings of FMF are recurrent and self-limited fever attacks lasting between 12 to 72 h. Severe abdominal, articular and/or chest pain, due to inflammation of the peritoneum, synovia or pleura usually accompany fever [ 2 ]. The most important factor determining the prognosis of FMF is the development of amyloidosis, which could lead to renal failure [ 3 ]. FMF is the most common hereditary recurrent fever syndrome [ 1 ]. Approximately 150,000 people worldwide are estimated to have this condition. FMF has been report all around the world, but its prevalence is very high among certain ethnic groups such as Jewish, Turkish, Armenian and Arabs, reaching figures as high as 1/500 individuals [ 4 ].FMF result from a mutation of the Mediterranean fever (MEFV) gene, located on chromosome 16 [ 5 ] and is inherited in an autosomal recessive manner. Nearly 30% of documented FMF patients carry only one mutation, and up to 20% of patients do not have detectable mutations [ 6 , 7 ]. More than 50 FMF-associated mutations in MEFV have been reported [ 8 ]. The most frequent are: M694V, V726A, M694I, and M680I located at exon 10 and E148Q located at exon 2 [ 1 ]. The MEFV gene encodes the protein pyrin, that has an important role in the inflammatory response by regulating caspase-1 activation and processing mature IL-1β [ 9 ]. The diagnosis of FMF relies mainly on clinical findings, and molecular analysis of the MEFV gene provides genetic confirmation [ 10 ]. There are different sets criteria for FMF diagnosis. The first set criteria was created for adults by a group of experts [ 11 ]. In 2009 Yalcikaya et al. validated a set criteria for paediatric patients [ 12 ]. Recently, the Eurofever group proposed a new set criteria for autoinflammatory recurrent fevers (these sets criteria are compared in Table  1 ) [ 13 ] . Colchicine is the standard treatment for FMF. However, it could be ineffective or associated with side effects in 5 to 10% of patients [ 13 ]. Interleukin-1(IL-1) inhibition could be useful in colchicine resistant FMF patients [ 14 , 15 , 16 ] . Canakinumab is the only biologic agent approved by the U.S. FDA for the treatment of FMF [ 17 ].

FMF could be associated with other autoimmune diseases such as ankylosing spondylitis, rheumatoid arthritis, polyarteritis nodosa, Behcet,, and Systemic Lupus, and Hashimoto’s thyroiditis [ 18 , 19 ]. Association of type 1 diabetes mellitus (T1D) and FMF has been newly reported in the medical literature [ 20 , 21 ]. We report a case of a boy suffering from T1D, who developed FMF. This is the third association of these two diseases described in the medical literature.

The patient was in follow up in the Paediatric Diabetological Center of our Department because he developed T1D at the age of 4. At the age of 13 he was referred to the Paediatric Rheumatological Centre of our Department because of episodes of recurrent fever since the age of 6. Fever attacks, with temperature ranging between 39 to 40 °C, lasted 24 to 72 h and occurred every 21–30 days. These episodes where associated with arthralgia, abdomen, and chest pain.

Over the years because of fever and abdominal pain, the patient usually referred to Emergency, where he underwent to abdomen ultrasounds in order to exclude acute appendicitis. Blood tests performed during fever attacks showed increase in inflammatory parameters, erythrocyte sedimentation rate (ERS) and C-reactive protein (CRP).

Fever attacks were treated with antipyretic drugs and in some occasion with antibiotic. Between attacks patient was well and blood tests were normal. The patient came to our attention during a febrile attack. Physical examination revealed: fever (body temperature up to 40 °C), abdominal and chest pain, arthritis of the right ankle. Blood tests revealed an increase in white cells (17.000/mm 3 , normal value < 10.000/mm 3 ), ERS (60 mm/ h), CRP (3.7 mg/dl) serum amyloid A (SAA,200 mg/dL). Blood tests were unremarkable for: viral serology, liver and kidney function, serum immunoglobulins,coeliac screening, thyroid hormone, antinuclear antibodies, extractable nuclear antigens, anti neutrophil Cytoplasmic antibodies, rheumatoid factor, anti-double stranded DNA, serum antistreptolysin O titre and complement levels. Throat swab was negative and so were the urinalysis, and the abdomen ultrasound. Chest ultrasound showed pleural effusion. Given his personal history, clinical and laboratory findings FMF was suspected, so colchicine therapy (1 mg/day) was prescribed and genetic investigation was performed. The molecular analysis of MEFV gene, showed homozygous E148Q mutation. Colchicine determined the immediate disappearance of the symptoms and normalization of inflammatory parameters. Colchicine was well tolerated.

After 1 year a renal biopsy was performed because of onset of persistent microalbuminuria. On biopsy Congo red staining was negative, so amyloidosis was excluded, but a slight and irregular thickening of the lamina densa of some glomerular capillaries was detected, so diabetic nephropathy was diagnosed and Ramipril treatment (2, 5 mg/day) was prescribed. Regarding FMF, after 18 months without symptoms, the patient presented again fever and abdominal pain, associated with an increase in inflammatory parameters, so colchicine was increased to 1.5 mg/day. On his recent follow up visit, at 17 years of age, the patient was in good general conditions. Daily insulin requirement was 0,8 U/kg/day. Patient did not refer fever or abdominal pain, and urynalysis did not reveal microalbuminuria. As he did not refer any side effects, both colchicine (1,5 mg/day) and ramipril (2,5 mg/day) were confirmed.

Discussion and conclusion

FMF is an autoinflammatory disease with autosomal recessive inheritance. Our patient presented homozygous E148Q mutation. E148Q is the most frequent variant among carriers, its pathogenic role is uncertain [ 22 ]. In a recent analysis Topaloglu et al. demonstrated that patients homozygous for E148Q displayed typical FMF phenotype and half of these patients had moderate/severe disease before colchicine treatment [ 22 ].

Aydin et al. demonstrated that E148Q mutation is associated with a milder disease course, despite patients may have similar clinical findings and well response to colchicine therapy, when compared to patients with other mutations [ 23 ] . In our case, the patient presented recurrent fever episodes associated to abdominal, chest pain, and arthralgia and presented a good response to colchicine treatment.

It has been reported that E148Q mutation could induce a nonamyloidosis renal involvement. In particular Eroglu et al. described a case of mesangial proliferative glomerulonephritis in a woman affected by FMF with an heterozygous E148Q mutation [ 24 ]. Ardalan et al. reported a case of an acute glomerulonephritis with proteinuria in a patient affected from FMF with an heterozygous E148Q mutation [ 25 ]. Our patient presented persistent microalbuminuria 1 year later FMF diagnosis, so a renal biopsy was performed that revealed slight and irregular thickening of the lamina densa of some glomerular capillaries. This histopathological finding was compatible with diabetic nephropathy, so treatment with Ramipril was started [ 26 ].

Pyrin, the protein product of MEFV, is a 781-aminoacid protein expressed in serosal and synovial fibroblasts, granulocytes, and cytokine-activated monocytes.

The role of pyrin in IL-1 activation is controversial [ 8 ], Campbell et al. supposed that pyrin suppresses the activation of pro-caspase-1, by competing for ASC (apoptosis-associated speck-like protein containing a caspase recruitment domain), and therefore pyrin interferes with NALP3 inflammasome activation [ 8 ]. Chae et al demonstrated that Pyrin containing FMF-associated mutations has less of an inhibitory effect on the inflammasome, leading to upregulated synthesis of IL-1β [ 9 ].

T1D is a T-cell–mediated autoimmune disease characterized by the destruction of pancreatic beta cells in genetically predisposed individuals [ 27 ].

As in other autoimmune conditions, both innate and adaptive immunity play a role in disease pathogenesis [ 28 , 29 ].

Kumar et al. demonstrated that T-helper type 17 (Th17) cells, have a pivotal role in T1D pathogenesis [ 30 ]. Proinflammatory cytokine, in particular interleukin 1 (IL-1) and 6 (IL-6), are involved in differentiation of T-cells in Th17 [ 30 ]. It has been demonstrated that TNFα, IL-1 and IL-6 are increased in diabetic subjects compared to control subjects at onset of clinical disease. These cytokine inducing differentiation of T-cells in Th17 are involved in T1D pathogenesis [ 31 , 32 ].

Recent studies have demonstrated NLRP3 inflammosome and IL-1 iper-production could play an important role in the development of T1D in mice [ 33 ]. The coexistence of FMF and type T1D is a rare finding. In 2006 Atabek et al. described a case of a 9 years old girl affected from T1D who developed FMF 11 months later diabetes onset [ 20 ]. In 2009 Baş et al. reported a second patient with type T1D associated with FMF who also had autoimmune thyroid disease (ATD), celiac disease (CD) [ 21 ].

According to the recent progress in the understanding of T1D pathogenesis, in particular regarding the increase in serum levels of IL1 and IL6 at the onset of diabetes, we can suppose that the higher production of IL1 in FMF could be involved in development of T1D. Further studies or case series are needed to demonstrate this possible association.

Here we report the third association of FMF and T1D. FMF should be kept in mind in the differential diagnosis of disorders associated with T1D in the presence of recurrent and limited attacks of fever, associated with abdominal or chest pain or arthritis. The emerging role of the inflammatory cytokine (TNFα, IL-1 and IL-6)in the development of T1D adds a further dimension to our understanding of the multifactorial nature of the immunopathology that leads to the development of T1D but also opens a new area of research for potential therapy.

Availability of data and materials

Not applicable.

Abbreviations

Familial Mediterranean Fever

Interleukine 1

Interleukine 6

Type 1 diabetes mellitus

Erythrocyte sedimentation rate

C-reactive protein

Serum amyloid A

Apoptosis-associated speck-like protein containing a caspase recruitment domain

Tumor necrosis factor alfa

T-helper type 17

Autoimmune thyroid disease

Celiac disease

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Maria Francesca Gicchino, Dario Iafusco, Angela Zanfardino, Emanuele Miraglia del Giudice & Alma Nunzia Olivieri

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MFG: involvement in medical diagnosis and follow up of the patient; first writers of the manuscript (they contributed equally to this work). AZ, DI, ANO: involvement in diagnosis and management of the patient. ANO, EM: supervision of the medical procedures and of the process of the manuscript. All authors read and approved the final manuscript.

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Gicchino, M.F., Iafusco, D., Zanfardino, A. et al. A case report of a boy suffering from type 1 diabetes mellitus and familial Mediterranean fever. Ital J Pediatr 47 , 127 (2021). https://doi.org/10.1186/s13052-021-01077-6

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Italian Journal of Pediatrics

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Evaluation of cardiac autonomic dysfunctions in children with type 1 diabetes mellitus

• Davut Gözüküçük   ORCID: orcid.org/0000-0001-5918-3161 1 ,
• Berkut A. İleri   ORCID: orcid.org/0000-0002-3918-4455 2 ,
• Serra Karaca Başkan   ORCID: orcid.org/0000-0001-5421-0191 3 ,
• Ece Öztarhan   ORCID: orcid.org/0000-0001-9359-9005 4 ,
• Dilek Güller   ORCID: orcid.org/0000-0002-8306-5445 5 ,
• Hasan Önal   ORCID: orcid.org/0000-0001-9676-7086 6 &
• Kazım Öztarhan   ORCID: orcid.org/0000-0001-9919-1414 3  

BMC Pediatrics volume  24 , Article number:  229 ( 2024 ) Cite this article

Metrics details

Cardiovascular autonomic neuropathy (CAN) is a serious complication of diabetes, impacting the autonomic nerves that regulate the heart and blood vessels. Timely recognition and treatment of CAN are crucial in averting the onset of cardiovascular complications. Both clinically apparent autonomic neuropathy and subclinical autonomic neuropathy, particularly CAN pose a significant risk of morbidity and mortality in children with type 1 diabetes mellitus (T1DM). Notably, CAN can progress silently before manifesting clinically. In our study, we assessed patients with poor metabolic control, without symptoms, following the ISPAD 2022 guideline. The objective is is to determine which parameters we can use to diagnose CAN in the subclinical period.

Our study is a cross-sectional case–control study that includes 30 children diagnosed with T1DM exhibiting poor metabolic control (average HbA1c > 8.5% for at least 1 year) according to the ISPAD 2022 Consensus Guide. These patients, who are under the care of the pediatric diabetes clinic, underwent evaluation through four noninvasive autonomic tests: echocardiography, 24-h Holter ECG for heart rate variability (HRV), cardiopulmonary exercise test, and tilt table test.

The average age of the patients was 13.73 ± 1.96 years, the average diabetes duration was 8 ± 3.66 years, and the 1-year average HbA1c value was 11.34 ± 21%. In our asymptomatic and poorly metabolically controlled patient group, we found a decrease in HRV values, the presence of postural hypotension with the tilt table test, and a decrease in ventricular diastolic functions that are consistent with the presence of CAN. Despite CAN, the systolic functions of the ventricles were preserved, and the dimensions of the cardiac chambers and cardiopulmonary exercise test were normal.

Conclusions

CAN is a common complication of T1DM, often associated with the patient’s age and poor glycemic control. HRV, active orthostatic tests, and the evaluation of diastolic dysfunctions play significant roles in the comprehensive assessment of CAN. These diagnostic measures are valuable tools in identifying autonomic dysfunction at an early stage, allowing for timely intervention and management to mitigate the impact of cardiovascular complications associated with T1DM.

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Type 1 Diabetes Mellitus (T1DM) is a prevalent chronic disorder affecting children and adolescents. Clinical symptoms typically peak between 5 and 7 years old and during early puberty. These peaks are attributed to increased infection rates during school ages, elevated sex steroids, growth hormone levels, and heightened psychological stress in adolescents [ 1 , 2 ].

Complications of T1DM can be broadly categorized as microvascular (e.g., peripheral neuropathies, autonomic neuropathies, retinopathy, nephropathy) and macrovascular (e.g., coronary heart disease, cerebrovascular disease, peripheral vascular disease) [ 3 ].

Autonomic neuropathies in adult patients have been identified as significant contributors to diabetes-related mortality, leading to dysregulations in cardiovascular, gastrointestinal, and genitourinary functions, pupillary responses, sweat gland activity, and regulatory responses against hypoglycemia. Cardiovascular autonomic neuropathy, an important yet lesser-known complication of diabetes mellitus, is associated with nearly doubling mortality rates [ 4 ]. Studies have established a correlation between autonomic function disorders and factors such as age, prolonged diabetes duration, and poorly maintained metabolic control, with increased prevalence in patients exhibiting poor glycemic control [ 5 ].

Recognizing disruption in baroreceptor susceptibility is crucial for identifying autonomic function disorders in T1DM patients [ 6 ]. A decrease in baroreceptor susceptibility heightens sympathetic nervous system excitability, potentially leading to tachycardia by affecting the sinoatrial node [ 7 , 8 ]. The presence of cardiac autonomic neuropathy (CAN) is linked with arterial stiffness in both adult and young diabetes patients. Factors contributing to decreased baroreceptor susceptibility include endothelial dysfunction [ 9 , 10 ], oxidative stress [ 11 , 12 ], the Rho/Rho Kinase pathway [ 13 ], arginase mechanism, and adhesion molecules involved in initiating sympatho-sympathetic feedback reflexes [ 14 , 15 ].

Controversy exists regarding the early detection of subclinical signs of autonomic dysfunction in children with diabetes [ 16 , 17 , 18 ]. However, not only clinically apparent autonomic neuropathy but also subclinical autonomic neuropathy, particularly cardiac autonomic neuropathy (CAN), pose a significant risk of morbidity and mortality in children with T1DM. Some suggest that CAN may progress silently over time before becoming clinically manifest [ 1 , 19 ]. It has been estimated that diabetic patients with CAN have a 3.4 times higher risk of mortality than those without CAN.Recognition and treatment of autonomic cardiac functions not only decrease cardiovascular damage but may also decrease the disease’s mortality and morbidity rates with proper breathing and exercise education [ 13 , 20 ].

Our study aimed to recognize CAN early in the subclinical period in patients with poor metabolic control. As per the ISPAD 2022 consensus guideline, the categorization of metabolic control is defined as follows: good metabolic control (%HbA1c < 7.5%), moderate metabolic control (%HbA1c 7.5–8.5%), and poor metabolic control (HbA1c% > 8.5%) [ 21 ]. who are without clinical symptoms of CAN. We examined the parameters necessary for the early diagnosis of cardiovascular dysfunctions that may develop due to cardiac autonomic dysfunctions in pediatric patients with T1DM.

Our study is a cross-sectional case–control investigation involving 30 children diagnosed with Type 1 Diabetes Mellitus (T1DM) exhibiting poor metabolic control (HbA1c% > 8.5%), as per the ISPAD 2022 Consensus Guide, at the pediatric endocrinology clinic of the University of Health Sciences. Comprehensive medical, endocrinological, cardiological, and neurological histories were obtained, examined, and meticulously recorded for all participants.

Relevant diabetes-related factors, including the duration of diabetes, insulin dosage, glycemic control, and instances of hypoglycemic events, were extracted from medical records. Adhering to the ISPAD 2022 guideline [ 21 ], well-controlled T1DM was defined by an HbA1c < 7%, whereas poor metabolic control was indicated by HbA1c > 8.5%. To ensure a representative measure of poor glycemic control, HbA1c values over a 1-year period were averaged.

In our study, the inclusion criteria for the study group are as follows: a minimum 1-year average HbA1c level > 8.5, patients aged between 5–18, and the ability to comply with and complete all the tests. For the control group, we selected healthy children with similar demographic characteristics to the study group, devoid of any additional diseases, and capable of adapting to and completing all the tests.

Excluded from the study were children with associated issues known to influence the outcomes of cardiac autonomic function, such as medical diseases (e.g., heart failure), medications impacting heart rate or rhythm (e.g., beta-blockers, digitalis, theophylline, thyroid hormones, tricyclic antidepressants, anti-arrhythmic drugs, atropine, and its derivatives), symptoms suggesting cardiac arrhythmia documented by electrocardiography (ECG) recording, history of febrile illness in the past week, conditions with symptoms mimicking autonomic neuropathy but not true autonomic neuropathy (e.g., syncope), presence of ketoacidosis or hypoglycemia during the study period, clinically manifest autonomic neuropathy, and children with test results that have suboptimal precision.

All children in both control and study groups underwent evaluation by the same cardiologist physician, who had no prior information about the patients. Traditional echocardiographic measurements were conducted using a 3.5–5 MHz transducer device (General ElectricTM Vivid-5S model), incorporating M mode, CW Doppler, PW Doppler, and Doppler Tissue Imaging mods. Video-recorded samples were analyzed, and to mitigate the impact of heart rate on diastolic functions, 7 cycle samples were collected, and the arithmetic mean was calculated. Systolic and diastolic functions of the ventricles were assessed through cardiac measurements using M mode, PW Doppler, and Doppler Tissue Imaging. Myocardial Performance Index (MPI) was calculated for both ventricles separately, obtained by dividing the sum of isovolumetric contraction time (IVCT) and isovolumetric relaxation time (IVRT) by ventricular contraction time ejection time (VCT) [ 22 ]. Conventional echocardiographic methods included measuring E wave, A wave, E/A wave ratio, and deceleration time with mitral valve PW Doppler. Tissue Doppler was employed to measure ejection time, relaxation time, contraction time from the septum, and myocardial systolic and diastolic waves from the apical four chambers and the lateral wall.

Left Ventricular Mass Index (LVMI), expressed in grams per square meter (g/m 2 ), was used to normalize left ventricular mass to body surface area. LVMI values greater than 115 g/m 2 in men and greater than 95 g/m 2 in women were indicative of Left Ventricular Hypertrophy (LVH). Relative Wall Thickness (RWT) was calculated by dividing the sum of septal and posterior wall thicknesses by the left ventricular internal diameter at end-diastole (LVIDd). The formula for calculating RWT is: RWT = (Septal wall thickness + Posterior wall thickness) / LVIDd. Relative Wall Thickness (RWT) assesses left ventricular remodeling, with a normal RWT typically considered to be less than 0,42 [ 23 , 24 , 25 ].

MPI, unaffected by heart rate, ventricular structure, and afterload, is a Doppler index evaluating systolic and diastolic functions together. This index, previously demonstrated to increase in diabetic patients and be effective in revealing diastolic dysfunction, was calculated by dividing the sum of isovolumetric relaxation time (ICZ) and isovolumetric relaxation time (IVRT) by ejection time (ET), as suggested by Tei et al. [ 26 ].

24-h rhythm Holter ECG recordings were obtained from all patients using a DMS-300 Holter recording device (DMS, Nevada, USA). Recordings were analyzed by the same cardiologist physician utilizing the DMS Cardioscan model 10 analyzer system (DMS, Nevada, USA). Various heart rate parameters, including 24-h mean heart rate, ectopic beats, presence of block, Standard Deviations of all NN intervals (SDNN), mean of the standard deviations of all NN intervals for all 5-min segments of the entire recording (SDNNI), the standard deviation of the averages of NN intervals in all 5-min segments of the entire recording (SDANNI), the square root of the mean of the sum of the squares of differences between adjacent NN intervals (rMSSD), the number of pairs of adjacent NN intervals differing by more than 50 ms divided by the total number of all NN intervals (pNN50), total power (TPow), very low-frequency range power (VLF power), high-frequency range power (HF power), and low-frequency range power (LF power), were recorded. This analysis aimed to determine the relationship between heart rate changes (using time parameters) and poor glycemic index and durations of diabetes [ 27 ].

All patients underwent evaluation through a cardiopulmonary exercise test (CPET) using a treadmill device model Mortara. The cardiopulmonary exercise tests were conducted following the Bruce protocols. Twelve-lead electrocardiographs were recorded both at the initiation and during the procedures. Blood pressure levels were monitored during exercise at 3-min intervals and at the 0th, 5th, 10th, and 30th minutes of the resting period. The duration of exercise, maximum systolic blood pressure (SBP), diastolic blood pressure (DBP) during exercise, and maximum apex beat were recorded. Test termination criteria were established, including ST depressions equal to or more than 2 mm compared to the starting electrocardiography, ST segment elevations equal to or more than 2 mm compared to the starting electrocardiography, systolic blood pressure lowering by more than 10%, onset of bradycardia, systolic blood pressure elevation to more than 210 mmHg in males and 180 mmHg in females, onset of class 3–4 angina, onset of severe arrhythmias, reaching the targeted heart rate, and feeling overwhelmed to the extent of being unable to continue testing. This part of our study aims to determine the relationship between effort capacity, effort duration, poor glycemic index, and the duration of diabetes.

All patients were evaluated by a tilt table test. Patients fasted for 4 to 6 h before the test. The procedure was conducted with a tilt-adjustable table. Patients lay down on the table when it was in a horizontal state, and they remained in this position for 5 min before starting the test. Vascular access was established, and patients were monitored to track heart rate and blood pressure values. After the test started, patients waited for 20 to 45 min on a 60 to 70-degree angled table; this phase of the test is referred to as the passive phase. If no syncope developed, patients proceeded to the second phase. In the second phase, 300 μg sublingual nitroglycerine was applied, and patients waited at the table, under the same conditions as the passive phase, for 15 to 20 min. The entire process lasted about 45 to 85 min (5 min for lying down, 20 to 45 min for the passive phase, and 15 to 20 min for the second phase). Test termination criteria were established as the onset of syncope (accompanied by arrhythmias and/or hypotension) or the patient not wanting to continue testing. Rates of developing orthostatic hypotension, syncope, and presyncope in patients were recorded. The definition of postural hypotension was determined as SBP decreasing by equal to or more than 20 mmHg or DBP decreasing equal to or more than 10 mmHg during the test compared to the start of the test. This part of our study aims to determine the relationship between sympathetic vasoreflexes, poor glycemic index, and the duration of diabetes.

The recorded data were analyzed using the program “IBM Corp. Released 2016. IBM SPSS Statistics for Macintosh, Version 24.0. Armonk, NY: IBM Corp.” The normal distribution of the data was tested through both visual (Q-Q, Box Plot, Stem, and Leaf, and histogram graphs) and analytical (Shapiro–Wilk and Kolmogorov–Smirnov tests) methods. Descriptive statistics were presented using Mean ± standard deviation (SD) for data showing normal distribution graphs (parametric), and median (lowest-highest value) for data not showing normal distribution graphs (non-parametric). Non-parametric data between groups were evaluated using Mann Whitney U and Kruskal Wallis tests, while parametric data between groups were assessed using the student’s T test. Categorical data were compared using Chi-square and Fisher Exact tests. Spearman and Pearson correlation analysis tests were employed to evaluate the relationship between metric data. The confidence interval was set at 95%, and cases where the p-value was below 0.05 were considered statistically significant.

Patients diagnosed with T1DM in the pediatric cardiology outpatient clinic and individuals in the healthy control group underwent comprehensive assessments based on height, weight, and BMI. No statistically significant differences were identified between the patient and control groups concerning age, weight, height, and body surface area, as indicated in Table  1 .

Thirty patients (female/male: 18/12) were followed up with a diagnosis of type 1 diabetes mellitus, with an average age of 13.73 ± 1.96 (10–17) for the patient group. For the control group, data from a total of 60 healthy individuals with an average age of 11.46 ± 3.04 (8–12) (girls/boys: 16/14) were evaluated. The average duration of diabetes in the patient group was 8 ± 3.66 (1 to 16) years. The 1-year average of HbA1C values for our patients was 11.34% ± 2.14% (8.5% to 16.4%).

In our investigation, echocardiographic M-mode examinations disclosed an increase in left ventricular end-systolic diameter (LVDs), left ventricular diastolic diameter (LVDd), left ventricular mass (LVM), and left ventricular mass index (LVMI). Nevertheless, this increase did not achieve statistical significance. Notably, BMI was significantly higher in the patient group, and echocardiographic findings aligned with the elevation in BMI. In Group A, there were noteworthy increments in pulmonary artery late diastolic flow velocity (PA) and pulmonary artery late diastolic flow time (PAT), indicative of right ventricular diastolic dysfunction. This increase was statistically significant when compared to the control group, as depicted in Table  2 .

When assessing right ventricular systolic and diastolic functions using tissue Doppler, a reduction in E RV , E/A RV , VCT RV , and TD RV , indicative of diastolic dysfunction, was observed. Additionally, an elevation in A RV was noted, and these changes were statistically significant. However, no statistically significant differences were found in the evaluation of E/E’ RV , VC RV , IVCT RV , IVRT RV , ET RV , AT RV , VC RV , IVCT RV , IVRT RV , DECT RV , and PHT RV . The study revealed a statistically significant difference in the average right ventricular myocardial performance index (MPI-RV) values between the patient group (0.27, range: 0.21–0.65) and the healthy group (0.23, range: 0.16–0.28) ( p  < 0.001). Details are provided in Table  3 .

When assessing left ventricular systolic and diastolic functions using Tissue Doppler, no statistically significant difference was observed in E LV , E/A LV , E/E’ LV , VCT LV , TD LV , A LV , VC LV , ET LV , AT LV , IVCT LV , and IVRT LV . However, there was an increase in IVCT LV values and a decrease in VCT LV , IVRT LV , TD LV , DECT LV , and PHT LV , and these changes were found to be statistically significant. The study revealed a statistically significant difference in the average left ventricular myocardial performance index (MPI-LV) values between the patient group (0.26, range: 0.18–0.55) and the healthy group (0.2, range: 0.16–0.3) ( p  < 0.001). Please refer to Table  3 for comprehensive details.

In the study, 24-h Holter electrocardiography measurements exhibited statistically significant differences between groups in variables such as 24-h mean heart rate (MHR), standard deviations of all NN intervals (SDNN), mean of the standard deviations of all NN intervals for all 5-min segments of the entire recording (SDNNI), the standard deviation of the averages of NN intervals in all 5-min segments of the entire recording (SDANNI), rMSSD, pNN50, total power (TPow), very low-frequency range power (VLF power), high-frequency range power (HF power), and low-frequency range power (LF power). Refer to Table  4 for comprehensive data.Upon evaluating data from cardiopulmonary exercise test (CPET) measurements, it was determined that the maximum systolic blood pressure was significantly higher during exercise, and this increase achieved statistical significance compared to the control group. However, no significant differences were found between the groups concerning maximum exercise capacity, maximum heart rate, and maximum systolic blood pressure values, as detailed in Table  5 .

In our study, data collected from tilt table tests revealed statistically significant differences ( p  = 0.024) in the rates of developing orthostatic hypotension, syncope, and presyncope between groups, as presented in Table  6 .

Diabetic autonomic neuropathy (DAN) is a significant complication of T1DM. Until the last two decades, DAN was often overlooked, and its prevalence was underestimated. It was commonly perceived as a rare and/or late complication of diabetes [ 1 ]. DAN is characterized by dysfunction or damage to the parasympathetic and/or sympathetic branches of the autonomic nervous system (ANS) in individuals with diabetes, following the exclusion of other potential causes of autonomic neuropathy [ 28 ]. Clinical manifestations of DAN vary depending on the affected organ and can include symptoms related to the cardiovascular, gastrointestinal, genitourinary, respiratory, neurovascular, neuroendocrine, and pupillomotor systems. Studies have reported a wide range of prevalence estimates for DAN in individuals with T1DM, ranging from 1 to 90%. While clinically manifest DAN is rare, subclinical DAN has been observed to develop within 2 years in patients with T1DM [ 29 ].

Certain researchers have proposed that CAN might advance silently before becoming clinically evident. Nevertheless, both clinically manifest autonomic neuropathy and subclinical forms, particularly CAN, pose a significant risk of morbidity and mortality in children with T1DM [ 1 ].

Symptoms indicative of cardiac autonomic neuropathy (CAN) encompass palpitations at rest, exercise intolerance, and signs suggestive of orthostatic hypotension (e.g., poor posture, fainting, dizziness, visual impairment, and syncope) [ 30 ].

Indeed, studies have demonstrated a relationship between poor metabolic control, older age, and longer duration of diabetes with autonomic dysfunction. There is evidence to suggest that increased autonomic dysfunction is often observed in patients with poor glycemic control.

In individuals with CAN, there is often a decrease in cardiac vagal regulation, which refers to the influence of the vagus nerve on the heart, and an increase in sympathetic cardiovascular markers. With a decrease in baroreflex sensitivity, the sympathetic system is stimulated, and tachycardia develops with its effect on the sinoatrial node. The duration of T1DM and impaired glycemic control (HbA1c > 8.5) over time have been associated with arterial stiffness and postural hypotension. In one study, we observed that compared to children without CAN, children with CAN had a longer duration of diabetes (more than 5 years), a significant number of diabetic complications, and worse glycemic control compared to those without CAN, but no differences were observed in age, gender, BMI, or blood pressure [ 30 ].

In our study, we enrolled asymptomatic patients with a mean age of 13.73 ± 1.96 years and a mean duration of diabetes of 8 ± 3.66 years. The one-year average HbA1c value was 11.34 ± 2.14%, ranging from 8.5 to 16.4%, indicating poor metabolic control according to the ISPAD 2022 consensus guidelines [ 21 ]. The patients enrolled in our study did not exhibit comorbidities and complications commonly associated with T1DM, such as hypertension, dyslipidemia, retinopathy, nephropathy, and neuropathy. In our study, we included patients who shared similar age, height, weight, and BMI. The specific focus of the study was on individuals at a high risk of developing CAN with poor metabolic control.

Our objective was to identify diagnostic tests capable of detecting CAN in asymptomatic patients within this cohort. All patients in the study underwent a comprehensive set of diagnostic assessments, including echocardiography, a 24-h rhythm Holter examination to assess HRV, a CPET, and a tilt table test.

In healthy individuals, the constant variation in intervals between heartbeats is a normal physiological occurrence. These periodic fluctuations in heart rate result from respiratory, thermoregulation, and baroreflex mechanisms. Vagal indices of heart rate variability tend to increase at night, while sympathetic indices show an increase during the day. Heart rate monitoring is a non-invasive technique used to illustrate autonomic neural dysfunction of the heart. A reduction in heart rate variability serves as a crucial indicator of the risk of sudden death and overall mortality. Parasympathetic and sympathetic autonomic dysfunctions have been reported at significantly higher frequencies in children with moderate and poor glycemic control. Increased adrenergic activity or decreased protective parasympathetic activity have been proved to cause diastolic dysfunction and fatal dysrhythmias, eventually increasing the mortality of T1DM as a complication. The findings from various studies indicate that the duration of diabetes exceeding 5 years, the presence of diabetes complications, and poor glycemic control are significantly associated with CAN in children with T1DM. However, no significant associations were observed with age, gender, or BMI [ 31 , 32 ].

During the 24-h Holter examination of patients in our study group, it was observed that the average heart rate exceeded the average heart rate calculated based on age (Table  4 ). Subclinical CAN is prevalent in children and adolescents with T1DM. Parasympathetic and sympathetic autonomic dysfunctions have been reported at significantly higher frequencies in children with moderate and poor glycemic control [ 30 ]. Notably, there is a marked impact on parasympathetic nervous system dysfunction in comparison to sympathetic dysfunction.Chessa et al. [ 17 ] conducted a 24-h analysis of heart rate variability (HRV) in 50 asymptomatic patients with T1DM. Their findings revealed significant alterations in the square root of the mean square differences of successive RR intervals (r-MSSD), the percentage of differences between adjacent normal RR intervals > 50 ms (pNN50), and the abnormal high-frequency (HF) band of spectral analysis of HRV. Young et al. [ 33 ] observed a significant correlation between poor glycemic control and the duration of diabetes with nerve dysfunction. The authors also noted significant abnormalities in HRV among individuals with poor metabolic control.

In our study, HRV was assessed through 24-h rhythm Holter monitoring in our patient group. The findings revealed that the average heart rate in the patient group was significantly higher than that in the control group. Additionally, there was a decrease in SDNN, SDANNI, SDNNI, RMSSD, pNN50, Total Power, LF, HF, and VLF values. In our study, we observed a decrease in total power, a reduction in heart rate variability, a decline in both low-frequency (LF) and high-frequency (HF) components, and no change in the LF/HF ratio. These findings are indicative of tachycardia associated with heightened sympathetic activity. These parameters are of particular significance for the early detection of diabetic autonomic neuropathy. Once diabetic autonomic neuropathy findings manifest, the 5-year mortality rate reaches 50%. Hence, it becomes crucial to detect it during the subclinical period. Observing changes in heart rate provides us with an opportunity for early detection and intervention.

Tachycardia resulting from sympathetic activation is typically accompanied by a notable decrease in total power. The reduction in time domain parameters of heart rate variability (HRV) not only holds negative prognostic significance but also facilitates the identification of autonomic neuropathy before the manifestation of clinical signs. Under controlled conditions, a decrease in the absolute power of low-frequency (LF) and high-frequency (HF) components has been observed in diabetic patients without apparent autonomic neuropathy. In diabetic neuropathy, LF and HF decrease, but the LF/HF ratio remains unchanged. The inability to increase LF during standing suggests decreased baroreceptor sensitivity or impaired sympathetic response [ 6 ].

Children with T1DM exhibited significantly higher heart rate frequencies in response to the standing position (POTs), active standing (30:15 ratio), and Valsalva maneuver, indicating parasympathetic ANS dysfunction. Additionally, there were abnormalities in blood pressure responses to cold, pointing towards sympathetic ANS dysfunction in these individuals.Postural hypotension (PH) is characterized by a decrease in systolic blood pressure (SBP) ≤ 20 mmHg and/or a decrease in diastolic blood pressure (DBP) ≤ 10 mmHg on the Tilt table test. The tilt table test is one of the assessments that reveal sympathetic autonomic dysfunction in T1DM [ 34 , 35 ]. The occurrence of postural hypotension associated with the duration of diabetes and poor glycemic control varies between 3–35% in adult patients. In contrast to adults, there are limited studies on postural hypotension in children with T1DM. In our study, postural hypotension was identified in 6 patients (20%) during the assessment of tilt table test analyses.

Tachycardia is considered the earliest sign of myocardial performance impairment or autonomic dysfunction. Given that the heart rate in our patient group is higher than in the control group, it is anticipated that there may be alterations in diastolic filling patterns. Ventricular functions were assessed using Doppler Tissue Imaging (DTI), a diagnostic method unaffected by heart rate variations, volume, and age [ 25 ]. It was observed that both systolic and diastolic periods were shortened due to the elevated heart rate. Findings consistent with diastolic dysfunction of the ventricles were identified, including increased A, DECT, PHT, and MPI values, as well as decreased E/A and E values. In our study, diastolic dysfunction with preserved systolic functions (EF) was noted in patients with poor metabolic control. Myocardial Performance Index (MPI) tends to increase in diabetic patients. This elevation in MPI is considered indicative of diastolic dysfunction, suggesting that MPI can be an effective tool in revealing early signs of impaired cardiac function in individuals with diabetes. Monitoring MPI can contribute to the assessment and management of diastolic dysfunction, offering insights into the cardiovascular impact of diabetes [ 36 , 37 , 38 , 39 ]. In addition to right ventricular tissue Doppler examinations, Pulmonary Valve (PW) Doppler examination was conducted. When right ventricular compliance decreases, the right ventricle operates as a passive conduit, leading to an anticipated increase in antegrade flow in the pulmonary artery during atrial systole. In our study, there is an observed increase in antegrade flow velocity (PA) and duration (PAT) in the pulmonary artery, consistent with right ventricular diastolic dysfunction.

In M-mode echocardiography examination, no significant differences were observed in heart dimensions and left ventricular systolic functions (EF, SF) measurements based on age. Given that our patients were asymptomatic, it is an expected finding that there was no change in the size of the heart chambers and that systolic functions were preserved.

In our study, we conducted exercise testing on our patients to assess the cardiopulmonary exercise response of individuals with type 1 diabetes and to evaluate the impact of glycemic control on these responses. In healthy children, it is typical for systolic blood pressure to increase with exercise. However, diastolic blood pressure tends to remain relatively unchanged, primarily due to vasodilation in the working skeletal muscles. This response is a normal physiological adaptation to the increased demand for oxygen and nutrients during physical activity. In the diabetic patient group, there is a lower cardiac output during exercise, and higher diastolic blood pressure is observed compared to the control group. Studies have reported an increase in both systolic and diastolic blood pressure during exercise in individuals with diabetes. Moreover, the rise in diastolic blood pressure has been associated with the duration of diabetes and poor diabetic control. Maximal exercise capacity, often measured in metabolic equivalents (METs), is considered one of the most crucial prognostic parameters obtained in exercise testing. It serves as a strong indicator of maximal oxygen consumption. In terms of the blood pressure response to exercise, it is generally expected that blood pressure will increase with the escalating treadmill workload. However, diastolic blood pressure typically remains relatively stable during exercise [ 40 ].

In our study, no significant differences were observed in T1DM patients who underwent exercise testing compared to the healthy group in terms of exercise duration, maximum exercise capacity (MET), maximum heart rate, or maximum systolic and diastolic pressure. These findings suggest that, based on the parameters assessed, there were no significant disparities in exercise performance and cardiovascular response between the two groups.

We acknowledge certain limitations in our study, firstly, the small sample size. To address this, longitudinal and prospective studies are essential for a more comprehensive understanding. Secondly, due to the cross-sectional design of our study, the temporal relationship between the appearance of signs of CAN and the onset of the disease remains unknown.

Cardiovascular autonomic neuropathy is a common complication of T1DM, often associated with the patient’s age and inadequate glycemic control. Autonomic dysfunction, marked by reduced baroreceptor sensitivity, is linked to various impairments such as decreased ventricular diastolic functions, compromised respiratory functions, and diminished exercise capacity. Early detection of this autonomic disorder is crucial, and methods such as assessing heart rate variability and conducting active orthostatic tests play a significant role in its early diagnosis.

Recognizing and addressing cardiac autonomic dysfunction in its initial stages can be crucial in preventing the development of cardiovascular events and improving overall patient outcomes. Regular monitoring and proactive management of glycemic control are essential components of a comprehensive approach to mitigate the impact of cardiovascular autonomic neuropathy in individuals with type 1 diabetes.

Availability of data and materials

The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

We thank Sağlık Bilimleri University, Kanuni Sultan Süleyman Training and Research Hospital for providing us the environment to apply echocardiographic measurements, respiratory function tests, cardiopulmonary exercise tests, and tilt table tests. We thank Arda Deniz ERYİĞİT for statistical calculations.

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

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Davut Gözüküçük

Department of Medicine, T.C. Demiroğlu Bilim University İstanbul Florence Nightingale Hospital, İzzetpaşa Mah, Abide-I Hürriyet Cd No:166, Şişli, 34381, Istanbul, Turkey

Berkut A. İleri

Department of Medicine, Division of Pediatrics, Subdivision of Pediatric Cardiology, Istanbul University, Istanbul Faculty of Medicine Training and Research Hospital, Turgut Özal Millet St., Istanbul, Fatih, Topkapı, 34093, Turkey

Serra Karaca Başkan & Kazım Öztarhan

Department of Medicine, Yeditepe University, Yeditepe Faculty of Medicine Training and Research Hospital, Koşuyolu, Koşuyolu Cd. No: 168, Kadıköy, 34718, Istanbul, Turkey

Ece Öztarhan

Department of Medicine, Division of Pediatrics, Subdivision of Pediatric Gastroenterology, T.C. Demiroğlu Bilim University, İstanbul Florence Nightingale Hospital, İzzetpaşa Mah, Abide-I Hürriyet Cd No:166, Şişli, 34381, Istanbul, Turkey

Dilek Güller

Department of Medicine, Division of Pediatrics, Subdivision of Pediatric Endocrinology and Metabolism, Sağlık Bilimleri University, Başakşehir Çam ve Sakura City Hosptial, Başakşehir Mahallesi G-434 Caddesi No: 2L, Başakşehir, Istanbul, Turkey

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The authors confirm contribution to the paper as follows: Medical practices: Davut GÖZÜKÜÇÜK, Serra KARACA BAŞKAN, Kazım ÖZTARHAN; study conception and design: Davut GÖZÜKÜÇÜK, Dilek GÜLLER, Hasan ÖNAL, Kazım ÖZTARHAN data collection: Berkut A. İLERİ, Serra KARACA BAŞKAN, Ece ÖZTARHAN; analysis and interpretation of results: Davut GÖZÜKÜÇÜK, Dilek GÜLLER, Hasan ÖNAL, Kazım ÖZTARHAN; literature search: Berkut A. İLERİ, Serra KARACA BAŞKAN, Ece ÖZTARHAN, Dilek GÜLLER Hasan ÖNAL, Kazım ÖZTARHAN; writing of the manuscript: Berkut A. İLERİ, Serra KARACA BAŞKAN, Ece ÖZTARHAN. All authors reviewed the results and approved the final version of the manuscript.

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All methods were performed in accordance with the Declaration of Helsinki. informed consent was obtained from parent and/or legal guardian in all experiments involving human children and was written, the study was submitted and approved by Istanbul S.B.Ü Kanuni Sultan Süleyman Training and Research Hospital Ethics Committee. The reference number of the committee is 2020.06.84 dated 24/06/2020.

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Gözüküçük, D., İleri, B.A., Başkan, S.K. et al. Evaluation of cardiac autonomic dysfunctions in children with type 1 diabetes mellitus. BMC Pediatr 24 , 229 (2024). https://doi.org/10.1186/s12887-024-04644-y

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DOI : https://doi.org/10.1186/s12887-024-04644-y

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