Em humanos, pacientes com diabetes mellitus (DM) podem apresentar aumento da concentração sérica de lactato quando comparados a indivíduos não-diabéticos. Considerando que existem poucas informações quanto aos valores de lactato em cães diabéticos, o objetivo principal desse trabalho foi determinar a concentração do lactato em cães com DM não tratados (ao diagnóstico), cães com DM em tratamento e cães em cetoacidose diabética (CAD), em comparação com cães hígidos. Foram incluídos 86 cães, sendo 25 do grupo controle e 61 diabéticos (14 ao diagnóstico, 24 em tratamento e 23 em cetoacidose diabética), sendo a maioria proveniente da rotina de atendimento do Hospital Veterinário da Faculdade de Medicina Veterinária e Zootecnia USP, e alguns obtidos em Hospital Veterinário privado. Todos os exames foram processados com os mesmos equipamentos. Os cães diabéticos foram selecionados com base em testes de glicemia, exame de urina e hemogasometria. Somente nos animais do grupo em CAD, foram admitidos pacientes com comorbidades graves, uma vez que estas podem ser responsáveis pela descompensação e que nestes animais indica-se a monitoração da concentração de lactato. Foram excluídos animais em sepse/ choque séptico ou choque cardiogênico, considerando que estas condições causam alteração do lactato. Não houve diferença estatística significativa entre os quatros grupos, quando se excluiu CAD, e nem mesmo quando observados pares de grupos isolados (P> 0,05). A existência de correlação positiva do lactato com a concentração de glicose referida por outros autores aumenta a possibilidade da acidose lática na CAD não ser somente causada pela hipoperfusão como também pela alteração do metabolismo da glicose, merecendo maior investigação a respeito do seu papel na fisiopatologia do DM e nas suas complicações. / In humans, diabetes mellitus (DM) patients may present increased lactate levels compared to non-diabetics. Considering that there is little information regarding lactate levels in diabetic dogs, the main goal of this study was the determination of lactate concentration in diabetic dogs at diagnosis, under treatment and in ketoacidosis (DKA), compared to healthy dogs. Eighty six dogs were included: 25 controls and 61 diabetics (14 at diagnosis, 24 under treatment, and 23 in DKA), most patients from the Veterinary Teaching Hospital, School of Veterinary Medicine and Animal Science, University of São Paulo, and a few from a private Veterinary Hospital. All the laboratory analyses were performed with the same equipments. The diabetic dogs were selected based on glycemia levels, urinalysis and blood gas analysis. Only the DKA patients were allowed to have comorbidities, since these may be the cause of decompensation. Patients with sepsis/ septic shock or cardiogenic shock were excluded, as these conditions may lead to lactate changes. There was no difference in lactate levels among groups when compared all together, when excluding DKA group or even when compared as isolated pairs (P>0.05). The existence of a positive correlation between lactate concentration and glycemia referred by other authors, suggests that lactic acidosis seen in DKA may not be only due to poor perfusion, but also due to changes in glucose metabolism, therefore lactate levels deserves further investigation regarding its role in DM pathophysiology and complications.

Em humanos, pacientes com diabetes mellitus (DM) podem apresentar aumento da concentração sérica de lactato quando comparados a indivíduos não-diabéticos. Considerando que existem poucas informações quanto aos valores de lactato em cães diabéticos, o objetivo principal desse trabalho foi determinar a concentração do lactato em cães com DM não tratados (ao diagnóstico), cães com DM em tratamento e cães em cetoacidose diabética (CAD), em comparação com cães hígidos. Foram incluídos 86 cães, sendo 25 do grupo controle e 61 diabéticos (14 ao diagnóstico, 24 em tratamento e 23 em cetoacidose diabética), sendo a maioria proveniente da rotina de atendimento do Hospital Veterinário da Faculdade de Medicina Veterinária e Zootecnia USP, e alguns obtidos em Hospital Veterinário privado. Todos os exames foram processados com os mesmos equipamentos. Os cães diabéticos foram selecionados com base em testes de glicemia, exame de urina e hemogasometria. Somente nos animais do grupo em CAD, foram admitidos pacientes com comorbidades graves, uma vez que estas podem ser responsáveis pela descompensação e que nestes animais indica-se a monitoração da concentração de lactato. Foram excluídos animais em sepse/ choque séptico ou choque cardiogênico, considerando que estas condições causam alteração do lactato. Não houve diferença estatística significativa entre os quatros grupos, quando se excluiu CAD, e nem mesmo quando observados pares de grupos isolados (P> 0,05). A existência de correlação positiva do lactato com a concentração de glicose referida por outros autores aumenta a possibilidade da acidose lática na CAD não ser somente causada pela hipoperfusão como também pela alteração do metabolismo da glicose, merecendo maior investigação a respeito do seu papel na fisiopatologia do DM e nas suas complicações. / In humans, diabetes mellitus (DM) patients may present increased lactate levels compared to non-diabetics. Considering that there is little information regarding lactate levels in diabetic dogs, the main goal of this study was the determination of lactate concentration in diabetic dogs at diagnosis, under treatment and in ketoacidosis (DKA), compared to healthy dogs. Eighty six dogs were included: 25 controls and 61 diabetics (14 at diagnosis, 24 under treatment, and 23 in DKA), most patients from the Veterinary Teaching Hospital, School of Veterinary Medicine and Animal Science, University of São Paulo, and a few from a private Veterinary Hospital. All the laboratory analyses were performed with the same equipments. The diabetic dogs were selected based on glycemia levels, urinalysis and blood gas analysis. Only the DKA patients were allowed to have comorbidities, since these may be the cause of decompensation. Patients with sepsis/ septic shock or cardiogenic shock were excluded, as these conditions may lead to lactate changes. There was no difference in lactate levels among groups when compared all together, when excluding DKA group or even when compared as isolated pairs (P>0.05). The existence of a positive correlation between lactate concentration and glycemia referred by other authors, suggests that lactic acidosis seen in DKA may not be only due to poor perfusion, but also due to changes in glucose metabolism, therefore lactate levels deserves further investigation regarding its role in DM pathophysiology and complications.

Indiana University-Purdue University Indianapolis (IUPUI) / The expression of pyruvate dehydrogenase kinase (PDK) 2 and 4 are increased in the fasted state to inactivate the pyruvate dehydrogenase complex (PDC) by phosphorylation to conserve substrates for glucose production. To assess the importance of PDK2 and PDK4 in regulation of the PDC to maintain glucose homeostasis, PDK2 knockout (KO), PDK4 KO, and PDK2/PDK4 double knockout (DKO) mice were generated. PDK2 deficiency caused higher PDC activity and lower blood glucose levels in the fed state while PDK4 deficiency caused similar effects in the fasting state. DKO intensified these effects in both states. PDK2 deficiency had no effect on glucose tolerance, PDK4 deficiency produced a modest effect, but DKO caused a marked improvement, lowered insulin levels, and increased insulin sensitivity. However, the DKO mice were more sensitive than wild-type mice to long term fasting, succumbing to hypoglycemia, ketoacidosis, and hypothermia. Stable isotope flux analysis indicated that hypoglycemia was due to a reduced rate of gluconeogenesis. We hypothesized that hyperglycemia would be prevented in DKO mice fed a high saturated fat diet for 30 weeks. As expected, DKO mice fed a high fat diet had improved glucose tolerance, decreased adiposity, and were euglycemic due to reduction in the rate of gluconeogenesis. Like chow fed DKO mice, high fat fed DKO mice were unusually sensitive to fasting because of ketoacidosis and hypothermia. PDK deficiency resulted in greater PDC activity which limited the availability of pyruvate for oxaloacetate synthesis. Low oxaloacetate resulted in overproduction of ketone bodies by the liver and inhibition of ketone body and fatty acid oxidation by peripheral tissues, culminating in ketoacidosis and hypothermia. Furthermore, when fed a ketogenic diet consisting of low carbohydrate and high fat, DKO mice also exhibited hypothermia, ketoacidosis, and hypoglycemia. The findings establish that PDK2 is more important in the fed state, PDK4 is more important in the fasted state, survival during long term fasting depends upon regulation of the PDC by both PDK2 and PDK4, and that the PDKs are important for the regulation of glucose and ketone body metabolism.

Aims: The Childhood Diabetes Registry in Saxony, Germany, examined the incidence and metabolic characteristics of childhood diabetes. Methods: In the federal state of Saxony, newly diagnosed cases of diabetes in children and adolescents aged less than 15 years were registered continuously from 1999 until 2008. Family history, date of diagnosis, clinical and laboratory parameters were obtained. Reported cases were ascertained by public health departments as an independent data source and verified using the capture- recapture method. Results: A total of 865 children and adolescents with newly diagnosed diabetes were registered in Saxony. About 96% of them were classified as having type 1 diabetes, 0.6% had type 2 diabetes, 2.4% had maturity-onset diabetes of the young (MODY), and 1.4% had other types of diabetes. The age-standardized incidence rate of type 1 diabetes was estimated at 17.5 per 100,000 children per year. Completeness of ascertainment as calculated by the capture-recapture method amounted to 93.6%. At the time of diagnosis, 27.1% of children with type 1 diabetes had ketoacidosis, 1.5% had a blood pH <7.0, and 1.1% were unconscious. Conclusion: The registry provided data about the incidence rates and clinical presentation of childhood diabetes in a defined German population. We observed higher incidence rates compared to previous surveys. / Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich.

A cetoacidose diabética (CAD) é uma das complicações mais graves do diabetes mellitus (DM) em pequenos animais. A CAD é uma emergência médica caracterizada por alterações metabólicas extremas, incluindo hiperglicemia, acidose metabólica, cetonemia, desidratação e perda de eletrólitos. Embora seja um distúrbio comum e de alta mortalidade, os padrões dos distúrbios ácido-base de cães com CAD ainda não foram avaliados objetivamente. Muitas das assunções sobre a CAD em cães são generalizadas com base em dados de pacientes humanos e estudos experimentais em cães. O objetivo do presente estudo foi descrever os distúrbios ácido-base e eletrolíticos de cães com CAD e cetose diabética (CD) e caracterizá-los segundo a freqüência de ocorrência, adequação dos mecanismos de compensação e ocorrência de distúrbios mistos. Foram avaliados 40 cães diabéticos (22 animais recém diagnosticados e 18 cães em tratamento com insulina) atendidos apresentando cetonúria e hiperglicemia (&gt;250 mg/dL). De acordo com critérios clínicos, esses cães foram distribuídos em dois subgrupos: (CAD, n=22 e CD n=18) e foram determinados o pH e a hemogasometria arteriais e eletrólitos plasmáticos (sódio, cloro, potássio, cálcio ionizado) e o magnésio total e o fósforo inorgânico séricos. As alterações do equilíbrio ácido-base foram avaliadas sistematicamente pelo método de Van Slyke-Henderson-Hasselbalch. Os resultados foram comparados com os obtidos a partir de 37 cães clinicamente hígidos. Com relação aos distúrbios ácido-base, a acidose metabólica foi o mais comumente identificado (n = 27). A maior parte dos animais apresentava acidose normoclorêmica. A acidose hiperclorêmica foi observada em sete pacientes. Dos cães com acidose metabólica, 15 apresentavam alcalose respiratória concomitante. A distribuição dos valores de eletrólitos foi diferente entre o grupo de estudo e o controle, com exceção do magnésio. Não houve diferença na distribuição dos valores dos eletrólitos entre os subgrupos, com exceção do potássio plasmático. A hiponatremia e a hipocloremia foram os distúrbios eletrolíticos mais comumente observados nos 40 cães com DM. A hipocalemia ocorreu com maior freqüência no subgrupo CAD e a hipercalemia no subgrupo CD. Os valores do fósforo inorgânico sérico foram semelhantes entre os subgrupos de estudo. A hiperfosfatemia foi comum em ambos os subgrupos e nenhum paciente apresentou hipofosfatemia. A hipermagnesemia foi observada em sete pacientes com CAD e em apenas um com CD. A maior parte dos pacientes tinha hipocalcemia por ocasião do atendimento inicial. Distúrbios ácido-base mistos, principalmente a acidose metabólica normoclorêmica associada a alcalose respiratória são comuns em cães com cetose ou cetoacidose diabética, assim como distúrbios eletrolíticos como hiponatremia, a hipocloremia e hipocalemia e hiperfosfatemia. / Diabetic ketoacidosis (DKA) is one of the most serious complications of diabetes mellitus (DM) in small animals. DKA is a medical emergency characterized by extreme metabolic abnormalities, including hyperglycemia, metabolic acidosis, ketonemia, dehydration, and electrolyte losses. Despite it is a common disorder and with high mortality, the patterns of the acid-base disturbances in dogs with DKA were not evaluated objectively. Many of the assumptions about DKA in dogs are derived from studies in human beings and experimental studies in dogs. The objective of the present study was to describe the acid-base and electrolytic disturbances in dogs with DKA and diabetic ketosis (DK) according to their frequency, adequacy of the compensatory mechanisms e occurrence of mixed disturbances. Forty dogs with DM (22 with new onset diabetes and 18 insulin-treated dogs) with ketonuria and hyperglycemia (&gt; 250 mg/dL) were enrolled. On the basis of clinical criteria, the dogs were assigned to one of two subgroups: (DKA, n=22 e DK n =18). Arterial blood gases and plasma electrolytes (sodium, chloride, potassium and, ionized calcium), and serum total magnesium and inorganic phosphorus were determined in all dogs. The acid base abnormalities were evaluated systematically by the Van Slyke-Henderson-Hasselbalch method and the results compared to those obtained from 37 healthy dogs (control group). Metabolic acidosis was the most common acid-base disorder identified (n = 27) and most of the dogs had normochloremic acidosis. Hyperchloremic acidosis was observed in seven patients. Fifteen of the dogs with metabolic acidosis had coexisting respiratory alkalosis. The distribuition of the electrolytes values was different between the study group and the control group, with the exception of serum magnesium. The distribution of the electrolytes values was similar between the subgroups, with the exception of plasma potassium. Hyponatremia and hypochloremia were the most common observed electrolyte abnormalities showed in dogs with DK or DKA. Hypokalemia occurred more frequently in dogs with DKA and hyperkalemia in dogs with DK. Serum inorganic phosphorus values were similar between the subgroups. Hyperphosphatemia was a common finding and hypophosphatemia was not observed. Hypermagnesemia was detected in seven patients with DKA and in only one with DK. Most of the dogs were hypocalcemic on admission. Mixed acid-base disorders, mainly metabolic normochloremic acidosis with coexisting respiratory alkalosis are common in dogs with diabetic ketosis or ketoacidosis and electrolytic disturbances, mostly hyponatremia, hypochloremia, hypokalemia, and hyperphosphatemia, were also common.

A cetoacidose diabética (CAD) é uma das complicações mais graves do diabetes mellitus (DM) em pequenos animais. A CAD é uma emergência médica caracterizada por alterações metabólicas extremas, incluindo hiperglicemia, acidose metabólica, cetonemia, desidratação e perda de eletrólitos. Embora seja um distúrbio comum e de alta mortalidade, os padrões dos distúrbios ácido-base de cães com CAD ainda não foram avaliados objetivamente. Muitas das assunções sobre a CAD em cães são generalizadas com base em dados de pacientes humanos e estudos experimentais em cães. O objetivo do presente estudo foi descrever os distúrbios ácido-base e eletrolíticos de cães com CAD e cetose diabética (CD) e caracterizá-los segundo a freqüência de ocorrência, adequação dos mecanismos de compensação e ocorrência de distúrbios mistos. Foram avaliados 40 cães diabéticos (22 animais recém diagnosticados e 18 cães em tratamento com insulina) atendidos apresentando cetonúria e hiperglicemia (&gt;250 mg/dL). De acordo com critérios clínicos, esses cães foram distribuídos em dois subgrupos: (CAD, n=22 e CD n=18) e foram determinados o pH e a hemogasometria arteriais e eletrólitos plasmáticos (sódio, cloro, potássio, cálcio ionizado) e o magnésio total e o fósforo inorgânico séricos. As alterações do equilíbrio ácido-base foram avaliadas sistematicamente pelo método de Van Slyke-Henderson-Hasselbalch. Os resultados foram comparados com os obtidos a partir de 37 cães clinicamente hígidos. Com relação aos distúrbios ácido-base, a acidose metabólica foi o mais comumente identificado (n = 27). A maior parte dos animais apresentava acidose normoclorêmica. A acidose hiperclorêmica foi observada em sete pacientes. Dos cães com acidose metabólica, 15 apresentavam alcalose respiratória concomitante. A distribuição dos valores de eletrólitos foi diferente entre o grupo de estudo e o controle, com exceção do magnésio. Não houve diferença na distribuição dos valores dos eletrólitos entre os subgrupos, com exceção do potássio plasmático. A hiponatremia e a hipocloremia foram os distúrbios eletrolíticos mais comumente observados nos 40 cães com DM. A hipocalemia ocorreu com maior freqüência no subgrupo CAD e a hipercalemia no subgrupo CD. Os valores do fósforo inorgânico sérico foram semelhantes entre os subgrupos de estudo. A hiperfosfatemia foi comum em ambos os subgrupos e nenhum paciente apresentou hipofosfatemia. A hipermagnesemia foi observada em sete pacientes com CAD e em apenas um com CD. A maior parte dos pacientes tinha hipocalcemia por ocasião do atendimento inicial. Distúrbios ácido-base mistos, principalmente a acidose metabólica normoclorêmica associada a alcalose respiratória são comuns em cães com cetose ou cetoacidose diabética, assim como distúrbios eletrolíticos como hiponatremia, a hipocloremia e hipocalemia e hiperfosfatemia. / Diabetic ketoacidosis (DKA) is one of the most serious complications of diabetes mellitus (DM) in small animals. DKA is a medical emergency characterized by extreme metabolic abnormalities, including hyperglycemia, metabolic acidosis, ketonemia, dehydration, and electrolyte losses. Despite it is a common disorder and with high mortality, the patterns of the acid-base disturbances in dogs with DKA were not evaluated objectively. Many of the assumptions about DKA in dogs are derived from studies in human beings and experimental studies in dogs. The objective of the present study was to describe the acid-base and electrolytic disturbances in dogs with DKA and diabetic ketosis (DK) according to their frequency, adequacy of the compensatory mechanisms e occurrence of mixed disturbances. Forty dogs with DM (22 with new onset diabetes and 18 insulin-treated dogs) with ketonuria and hyperglycemia (&gt; 250 mg/dL) were enrolled. On the basis of clinical criteria, the dogs were assigned to one of two subgroups: (DKA, n=22 e DK n =18). Arterial blood gases and plasma electrolytes (sodium, chloride, potassium and, ionized calcium), and serum total magnesium and inorganic phosphorus were determined in all dogs. The acid base abnormalities were evaluated systematically by the Van Slyke-Henderson-Hasselbalch method and the results compared to those obtained from 37 healthy dogs (control group). Metabolic acidosis was the most common acid-base disorder identified (n = 27) and most of the dogs had normochloremic acidosis. Hyperchloremic acidosis was observed in seven patients. Fifteen of the dogs with metabolic acidosis had coexisting respiratory alkalosis. The distribuition of the electrolytes values was different between the study group and the control group, with the exception of serum magnesium. The distribution of the electrolytes values was similar between the subgroups, with the exception of plasma potassium. Hyponatremia and hypochloremia were the most common observed electrolyte abnormalities showed in dogs with DK or DKA. Hypokalemia occurred more frequently in dogs with DKA and hyperkalemia in dogs with DK. Serum inorganic phosphorus values were similar between the subgroups. Hyperphosphatemia was a common finding and hypophosphatemia was not observed. Hypermagnesemia was detected in seven patients with DKA and in only one with DK. Most of the dogs were hypocalcemic on admission. Mixed acid-base disorders, mainly metabolic normochloremic acidosis with coexisting respiratory alkalosis are common in dogs with diabetic ketosis or ketoacidosis and electrolytic disturbances, mostly hyponatremia, hypochloremia, hypokalemia, and hyperphosphatemia, were also common.

Contextualização: As complicações agudas do diabetes, embora em grande parte evitáveis, apresentavam considerável mortalidade em diversas localidades do mundo no século passado. No Brasil, a organização do Sistema Único de Saúde pode ter resultado em importante queda na mortalidade por esta causa. Objetivos: Descrever a mortalidade por complicações agudas do diabetes no Brasil entre 1991 e 2010. Métodos: Os óbitos declarados no Sistema de Informações sobre Mortalidade por complicações agudas do diabetes (CID-9 249 e 250, seguidos pelos dígitos 1, 2 ou 3, e CID-10 E10 a E14, seguidos pelos dígitos 0 ou 1) foram corrigidos para causas mal definidas e sub-registro. A partir da população obtida do Instituto Brasileiro de Geografia e Estatística, foram calculadas taxas de mortalidade padronizadas de acordo com a população mundial. Correlações lineares foram realizadas para descrever a relação entre mortalidade e idade, e regressões Joinpoint foram utilizadas para descrever tendências. Resultados: Houve queda de 70,9% na mortalidade por complicações agudas do diabetes no Brasil entre 1991 e 2010, de 8,42 para 2,45 óbitos por 100.000 habitantes. A redução ocorreu em ambos os sexos, todas as faixas etárias, todas as regiões e quase todas as unidades federativas. O declínio foi menor nos últimos anos, quando as taxas já estavam bem mais baixas. A mortalidade aumentou exponencialmente com a idade e foi maior nas regiões Norte e Nordeste. Conclusões: A marcante redução na mortalidade por complicações agudas do diabetes no Brasil nas últimas duas décadas indica que a cobertura ampla e gratuita adotada pelo sistema nacional de saúde do Brasil, com disponibilização de insulina e organização do cuidado, foi capaz de reduzir substancialmente as complicações agudas dessa doença. Entretanto, considerando especialmente as iniquidades regionais existentes, ainda há espaço para redução na mortalidade por essas complicações no Brasil. / Background: Acute complications of diabetes, though largely preventable, presented considerable mortality in various locations around the world in the 20th Century. In Brazil, the organization of the national health system may have resulted in an important decline in this cause of mortality. Objectives: To describe mortality rates from acute complications of diabetes in Brazil from 1991 to 2010. Methods: The deaths reported in the Mortality Information System for acute complications of diabetes (ICD-9 249 and 250, followed by the digits 1, 2 or 3, and ICD-10 E10 to E14, followed by the digits 0 or 1) were corrected for ill-defined and under-reporting. Using the population obtained from national censuses, we calculated mortality rates standardized to the world population. Linear correlations were performed to describe the relationship between mortality and age, and Joinpoint regressions were used to characterize trends. Results: Mortality from acute complications of diabetes decreased 70.9%, from 8.42 to 2.45 deaths / 100000 inhabitants, in Brazil from 1991 to 2010. The reduction occurred in both sexes, all ages, all regions and almost all states. The decline was less marked in recent years. Mortality rates increased exponentially with age and were higher in the North and Northeast regions. Conclusions: The marked reduction in mortality from acute complications of diabetes in Brazil over the last two decades suggests that the universal coverage adopted by the national health system of Brazil, provided without charge and in an increasingly organized fashion, coupled with greater availability of insulin, was able to substantially reduce deaths due to the acute complications of diabetes. However, especially considering regional inequities, much room still exists for further reduction in mortality from these complications in Brazil.

INTRODUÇÃO: a ação dos hormônios contrarreguladores da insulina na cetoacidose diabética tem sido estudada desde a década 1970-80, e é sabido que seus níveis elevados, aumentando a resistência à insulina, têm papel importante na gênese da CAD. Leptina e ghrelina foram mais recentemente associadas à homeostase da glicose, no entanto, seu papel na CAD ainda é controverso. Os objetivos deste estudo foram: avaliar as alterações nas concentrações séricas de leptina e ghrelina presentes ao diagnóstico da CAD durante os primeiros três dias de seu tratamento e após a estabilização completa do quadro, as correlações com a insulina e outros contrarreguladores, comparando com indivíduos saudáveis. MÉTODOS: foram analisados 25 episódios de cetoacidose diabética em 22 pacientes admitidos no setor de emergência pediátrica de um hospital terciário em São Paulo, Brasil, entre março de 2010 e julho de 2013. Os episódios de cetoacidose foram manejados com reposição endovenosa de fluidos e eletrólitos e análogos de ação ultrarrápida de insulina subcutânea intermitente. Amostras para glicose, insulina, leptina, ghrelina, GH, cortisol e catecolaminas foram obtidas no momento da admissão (T0), durante o tratamento da cetoacidose (após 2, 4, 6, 12, 24 e 72 horas) e em um momento estável após a alta (TE). Os dados foram analisados utilizando-se os testes ANOVA ou Kruskal-Wallis para a comparação de variáveis contínuas durante o tratamento, Teste t de Student ou Mann Whitney para a comparação entre pacientes e grupo controle, e testes de Pearson ou Spearman para correlação entre as variáveis; p < 0.05 foi considerado significativo. RESULTADOS: observamos três fases distintas (a): o diagnóstico de CAD (T0) em que prevalecem hiperglicemia, insulinopenia e elevação de hormônios contrarreguladores; nesse momento, as concentrações de leptina foram menores que no grupo controle, provavelmente relacionadas à insuficiência de energia, estado hipercatabólico e elevação dos hormônios contrarreguladores; as concentrações de ghrelina foram menores que no grupo controle, apesar do hipercatabolismo, da hipoinsulinemia e da hiperglucagonemia, todas situações que fisiologicamente elevariam seus níveis, possivelmente devido à hiperglicemia marcante do momento; (b) durante o tratamento da CAD (T2 a T72): com redução gradual da glicemia até T24, elevação gradual da insulina, redução de glucagon, GH, cortisol e norepinefrina; nesse período, ocorreu elevação gradual da leptina após o início do tratamento com insulina, que atingiu níveis comparáveis ao GC no T72; redução da ghrelina (T4 menor que T72), provavelmente inibida pela hiperglicemia e por doses suprafisiológicas de insulina; e (c) após a resolução da CAD (TE): com hiperinsulinização; GH, cortisol e norepinefrina comparáveis ao GC, glucagon reduzido em relação ao GC, possivelmente supresso pelos altos níveis de insulina; as concentrações de leptina foram maiores que em T0 e comparáveis ao GC; os níveis de ghrelina, comparáveis ao diagnóstico e durante o tratamento da CAD, ainda significativamente menores que no GC, provavelmente influenciados pela hiperglicemia, hiperinsulinemia e baixos níveis de glucagon. CONCLUSÕES: as concentrações de leptina diminuídas ao diagnóstico de CAD tornam-se semelhantes em pacientes com DM1 estáveis em relação a indivíduos saudáveis, podendo ser um marcador de hipercatabolismo. As concentrações de ghrelina permaneceram baixas durante todo o estudo em pacientes diabéticos, independentemente da descompensação / INTRODUCTION: The role of glucoregulatory hormones in diabetic ketoacidosis have been investigated since 1970-80s and the elevation of growth hormone, cortisol and norepinephrine reduce the sensitivity to insulin. Leptin and Ghrelin have more recently been shown to regulate glucose and insulin metabolism; however, their functions in DKA are still controversial. The aims of this study were to analyze leptin, ghrelin and their relationships with other glucoregulatory hormones on diagnosis of diabetic ketoacidosis, during the first 72 hours of treatment and after recovery compared with healthy subjects. METHODS: We examined 25 DKA episodes in 22 patients who were admitted to the pediatric emergency department of a tertiary hospital in São Paulo, Brazil, from March 2010 to July 2013. These episodes were managed with fluids and electrolytes replacement and intermittent subcutaneous fast-acting insulin analogues. Samples for blood glucose, insulin, leptin, ghrelin, GH, cortisol, and catecholamines were obtained on admission (T0), during treatment (after 2, 4, 6, 12, 24 and 72 hours) and after discharge (TS). The control group (CG) was comprised by 21 healthy subjects, who submitted a single blood sample. Data were analyzed by ANOVA or Kruskal-Wallis to compare continuous variables during treatment, student t-test or Mann Whitney for comparisons between patients and controls, and Pearson or Spearman correlations between variables; p < 0.05 was considered to be significant. RESULTS: we observed three distinct phases: (a) on diagnosis of DKA (T0) where hyperglycemia, insulinopenia, and elevated glucoregulatory hormones prevail; leptin concentrations were lower than CG at this moment, probably related to energy insufficiency, hypercatabolic state, and elevated glucoregulatory hormones; ghrelin concentrations were lower than CG at this moment, despite hypercatabolism, hypoinsulinemia and hyperglucagonemia, situations that physiologically would increase them, possibly related to marked hyperglycemia at T0; (b) during DKA treatment (T2 to T72): with gradual reduction of blood glucose until T24, gradual rise of insulin; reduction of glucagon, GH, cortisol and norepinephrine. Leptin levels rises gradually after the start of insulin treatment and is comparable to control group at T72; reduction of ghrelin (T4 lower than T72), possibly inhibited by hyperglycemia and supraphysiological doses of insulin, all lower than CG; and (c) After DKA (TS), in an outpatient setting: with marked hyperinsulinization, GH, cortisol and norepinephrine were comparable to CG. Glucagon was lower than CG, possibly suppressed by high insulin levels; leptin was higher than T0 and comparable to CG; ghrelin levels were comparable to all samples during DKA treatment, and still significantly lower than CG, probably influenced by hyperglycemia, hyperinsulinemia and low glucagon levels. CONCLUSIONS: Low leptin levels were a marker of hypercatabolic state, with normalization of its concentrations with DKA resolution. Ghrelin was low in diabetic patients independent of metabolic derangements

INTRODUÇÃO: a ação dos hormônios contrarreguladores da insulina na cetoacidose diabética tem sido estudada desde a década 1970-80, e é sabido que seus níveis elevados, aumentando a resistência à insulina, têm papel importante na gênese da CAD. Leptina e ghrelina foram mais recentemente associadas à homeostase da glicose, no entanto, seu papel na CAD ainda é controverso. Os objetivos deste estudo foram: avaliar as alterações nas concentrações séricas de leptina e ghrelina presentes ao diagnóstico da CAD durante os primeiros três dias de seu tratamento e após a estabilização completa do quadro, as correlações com a insulina e outros contrarreguladores, comparando com indivíduos saudáveis. MÉTODOS: foram analisados 25 episódios de cetoacidose diabética em 22 pacientes admitidos no setor de emergência pediátrica de um hospital terciário em São Paulo, Brasil, entre março de 2010 e julho de 2013. Os episódios de cetoacidose foram manejados com reposição endovenosa de fluidos e eletrólitos e análogos de ação ultrarrápida de insulina subcutânea intermitente. Amostras para glicose, insulina, leptina, ghrelina, GH, cortisol e catecolaminas foram obtidas no momento da admissão (T0), durante o tratamento da cetoacidose (após 2, 4, 6, 12, 24 e 72 horas) e em um momento estável após a alta (TE). Os dados foram analisados utilizando-se os testes ANOVA ou Kruskal-Wallis para a comparação de variáveis contínuas durante o tratamento, Teste t de Student ou Mann Whitney para a comparação entre pacientes e grupo controle, e testes de Pearson ou Spearman para correlação entre as variáveis; p < 0.05 foi considerado significativo. RESULTADOS: observamos três fases distintas (a): o diagnóstico de CAD (T0) em que prevalecem hiperglicemia, insulinopenia e elevação de hormônios contrarreguladores; nesse momento, as concentrações de leptina foram menores que no grupo controle, provavelmente relacionadas à insuficiência de energia, estado hipercatabólico e elevação dos hormônios contrarreguladores; as concentrações de ghrelina foram menores que no grupo controle, apesar do hipercatabolismo, da hipoinsulinemia e da hiperglucagonemia, todas situações que fisiologicamente elevariam seus níveis, possivelmente devido à hiperglicemia marcante do momento; (b) durante o tratamento da CAD (T2 a T72): com redução gradual da glicemia até T24, elevação gradual da insulina, redução de glucagon, GH, cortisol e norepinefrina; nesse período, ocorreu elevação gradual da leptina após o início do tratamento com insulina, que atingiu níveis comparáveis ao GC no T72; redução da ghrelina (T4 menor que T72), provavelmente inibida pela hiperglicemia e por doses suprafisiológicas de insulina; e (c) após a resolução da CAD (TE): com hiperinsulinização; GH, cortisol e norepinefrina comparáveis ao GC, glucagon reduzido em relação ao GC, possivelmente supresso pelos altos níveis de insulina; as concentrações de leptina foram maiores que em T0 e comparáveis ao GC; os níveis de ghrelina, comparáveis ao diagnóstico e durante o tratamento da CAD, ainda significativamente menores que no GC, provavelmente influenciados pela hiperglicemia, hiperinsulinemia e baixos níveis de glucagon. CONCLUSÕES: as concentrações de leptina diminuídas ao diagnóstico de CAD tornam-se semelhantes em pacientes com DM1 estáveis em relação a indivíduos saudáveis, podendo ser um marcador de hipercatabolismo. As concentrações de ghrelina permaneceram baixas durante todo o estudo em pacientes diabéticos, independentemente da descompensação / INTRODUCTION: The role of glucoregulatory hormones in diabetic ketoacidosis have been investigated since 1970-80s and the elevation of growth hormone, cortisol and norepinephrine reduce the sensitivity to insulin. Leptin and Ghrelin have more recently been shown to regulate glucose and insulin metabolism; however, their functions in DKA are still controversial. The aims of this study were to analyze leptin, ghrelin and their relationships with other glucoregulatory hormones on diagnosis of diabetic ketoacidosis, during the first 72 hours of treatment and after recovery compared with healthy subjects. METHODS: We examined 25 DKA episodes in 22 patients who were admitted to the pediatric emergency department of a tertiary hospital in São Paulo, Brazil, from March 2010 to July 2013. These episodes were managed with fluids and electrolytes replacement and intermittent subcutaneous fast-acting insulin analogues. Samples for blood glucose, insulin, leptin, ghrelin, GH, cortisol, and catecholamines were obtained on admission (T0), during treatment (after 2, 4, 6, 12, 24 and 72 hours) and after discharge (TS). The control group (CG) was comprised by 21 healthy subjects, who submitted a single blood sample. Data were analyzed by ANOVA or Kruskal-Wallis to compare continuous variables during treatment, student t-test or Mann Whitney for comparisons between patients and controls, and Pearson or Spearman correlations between variables; p < 0.05 was considered to be significant. RESULTS: we observed three distinct phases: (a) on diagnosis of DKA (T0) where hyperglycemia, insulinopenia, and elevated glucoregulatory hormones prevail; leptin concentrations were lower than CG at this moment, probably related to energy insufficiency, hypercatabolic state, and elevated glucoregulatory hormones; ghrelin concentrations were lower than CG at this moment, despite hypercatabolism, hypoinsulinemia and hyperglucagonemia, situations that physiologically would increase them, possibly related to marked hyperglycemia at T0; (b) during DKA treatment (T2 to T72): with gradual reduction of blood glucose until T24, gradual rise of insulin; reduction of glucagon, GH, cortisol and norepinephrine. Leptin levels rises gradually after the start of insulin treatment and is comparable to control group at T72; reduction of ghrelin (T4 lower than T72), possibly inhibited by hyperglycemia and supraphysiological doses of insulin, all lower than CG; and (c) After DKA (TS), in an outpatient setting: with marked hyperinsulinization, GH, cortisol and norepinephrine were comparable to CG. Glucagon was lower than CG, possibly suppressed by high insulin levels; leptin was higher than T0 and comparable to CG; ghrelin levels were comparable to all samples during DKA treatment, and still significantly lower than CG, probably influenced by hyperglycemia, hyperinsulinemia and low glucagon levels. CONCLUSIONS: Low leptin levels were a marker of hypercatabolic state, with normalization of its concentrations with DKA resolution. Ghrelin was low in diabetic patients independent of metabolic derangements

Σκοπός. Η διαβητική κετοξέωση (ΔΚ) και η υπεργλυκαιμική υπερωσμωτική κατάσταση (ΥΥΚ) είναι δύο από τις πιο σοβαρές οξείες επιπλοκές του Σακχαρώδη διαβήτη, που εξακολουθούν να αποτελούν σημαντική αιτία νοσηρότητας και θνητότητας μεταξύ των διαβητικών. Οι λοιμώξεις, συχνός εκλυτικός παράγων και επιπλοκή της ΔΚ και ΥΥΚ, αποτελούν την κύρια αιτία θανάτου και η έγκαιρη διάγνωση και αντιμετώπιση της σήψης είναι κριτικής σημασίας για την επιβίωση των ασθενών. Διερευνήσαμε την επίδραση των ανωτέρω καταστάσεων στην ανοσοποιητική απόκριση, μελετώντας τους υποπληθυσμούς των Τ λεμφοκυττάρων – παραμέτρους οξείας φάσης και την ιντερλευκίνη 6 (IL-6) στο περιφερικό αίμα των ασθενών μας, σε μια προσπάθεια να διαπιστώσουμε τυχόν υποκείμενες διαταραχές και να προσδιορίσουμε πιθανόν διαγνωστικούς και προγνωστικούς δείκτες για τη σήψη. Μέθοδος. Η μελέτη μας περιέλαβε 61 διαβητικούς ασθενείς με ΔΚ ή ΥΥΚ. Ξεχωρίσαμε μια ομάδα ασθενών που είχαν συμπτώματα Συνδρόμου συστηματικής φλεγμονώδους αντίδρασης (SIRS). Προσδιορίσαμε στον ορό όλων των ασθενών τις συγκεντρώσεις των παραγόντων οξείας φάσης (συμπεριλαμβανομένης της C αντιδρώσας πρωτεΐνης ,CRP) και της IL-6 (ως κύρια κυτταροκίνη για την παραγωγή πρωτεϊνών οξείας φάσης), κατά την εισαγωγή και στην ύφεση (μετά τη βελτίωση των συμπτωμάτων και σε κατάσταση ευγλυκαιμίας). Σε μια ομάδα 28 ασθενών με ΔΚ ή ΥΥΚ (σε σύγκριση και με αντίστοιχη ομάδα ελέγχου) μελετήσαμε επιπλέον υποπληθυσμούς των Τ λεμφοκυττάρων, τα ολικά (CD3) / τα βοηθητικά (CD4) / τα κατασταλτικά (CD8) Τ κύτταρα και τα κύτταρα φυσικοί φονείς (ΝΚ) χρησιμοποιώντας μονοκλωνικά αντισώματα και μικροσκόπιο ανοσοφθορισμού, προ και αμέσως μετά τη διόρθωση της μεταβολικής διαταραχής. Αποτελέσματα. Παρατηρήσαμε ότι οι υποπληθυσμοί των Τ λεμφοκυττάρων ήταν σημαντικά ελαττωμένοι κατά την εισαγωγή, συγκρινόμενοι με τους υγιείς μάρτυρες (ενώ οι περισσότερες μελέτες διαβητικών τύπου 1 καταγράφουν αυξημένα βοηθητικά Τ κύτταρα) και παρέμειναν και αμέσως μετά τη διόρθωση της μεταβολικής διαταραχής. Οι ασθενείς που τελικά απεβίωσαν είχαν σημαντικά ελαττωμένους τους υποπληθυσμούς των Τ λεμφοκυττάρων (εκτός των ΝΚ κυττάρων) συγκρινόμενοι και με τους υγιείς μάρτυρες και με όσους ασθενείς επιβίωσαν. Από τους 61 ασθενείς της μελέτης με ΔΚ ή ΥΥΚ, οι 49 ασθενείς είχαν συμπτώματα SIRS. Οι 27 ασθενείς είχαν SIRS χωρίς στοιχεία λοίμωξης, ενώ οι 22 ασθενείς είχαν SIRS με αποδεδειγμένη λοίμωξη. Διαπιστώσαμε σημαντικά αυξημένες συγκεντρώσεις CRP και IL-6 στον ορό των σηπτικών διαβητικών ασθενών συγκριτικά με όσους ασθενείς μας είχαν SIRS χωρίς λοίμωξη. Οι ασθενείς που τελικά απεβίωσαν είχαν σημαντικά πιο αυξημένες συγκεντρώσεις CRP και IL-6 κατά την εισαγωγή, που μειώθηκαν σημαντικά στην ύφεση. Συμπεράσματα. Η διαβητική κετοξέωση και η υπεργλυκαιμική υπερωσμωτική κατάσταση προκαλούν συχνά κλινικό σύνδρομο που ομοιάζει με σύνδρομο συστηματικής φλεγμονώδους αντίδρασης. Διαταραχές στην ισορροπία των υποπληθυσμών των Τ λεμφοκυττάρων, κυρίως η ελάττωση των βοηθητικών Τ κυττάρων μπορεί να συμβάλλουν στην υψηλή θνησιμότητα αυτών των μεταβολικών διαταραχών. Οι μετρήσεις των συγκεντρώσεων C αντιδρώσας πρωτεΐνης και ιντερλευκίνης 6 στον ορό αυτής της ομάδας των διαβητικών ασθενών, είναι ένας χρήσιμος τρόπος αποκλεισμού λοίμωξης και επιβεβαίωσης και παρακολούθησης της σήψης. / Aims / hypothesis. Diabetic ketoacidosis (DKA) and hyperglycemic hyperosmolar state (HHS) are two of the most serious acute complications of diabetes mellitus, being important causes of morbidity and mortality among patients with diabetes. Infection is a common precipitating event in DKA and HHS and the major cause of death. An early diagnosis of sepsis in patients with DKA and HHS is crucial and life saving. We studied the immune responses in these states, investigating the peripheral T lymphocyte subsets, acute phase reactants and interleukin 6 (IL-6) to find out how useful these might be for identifying sepsis. Methods. Sixty one diabetic patients with DKA or HHS were enrolled. Patients with signs and symptoms of systemic inflammatory response syndrome (SIRS) were identified. Acute phase reactants, including serum C-reactive protein (CRP) and IL-6, the main cytokine responsible for the induction of acute phase proteins, were measured (concentrations in peripheral blood) on admission and when patients were clinically improved and were euglycaemic. Peripheral T lymphocyte subsets including total (CD3), helper (CD4) and suppressor (CD8) T cells and natural killer (NK) cells, were studied in twenty one patients with DKA plus seven patients with HHS and twenty eight healthy matched control (using monoclonal antibodies), prior to and after treatment of metabolic disorders. Results. Peripheral T lymphocyte subsets were decreased in the twenty eight patients with DKA and HHS in admission compared to healthy controls (while helper T cells are mostly increased in diabetics type 1), and remained so after treatment of metabolic disorders. Patients who finally died had significantly decreased T lymphocyte subsets (except NK cells) compared with both healthy controls and patients who survived. A total of forty nine out of sixty one patients with DKA and HHS had signs of SIRS. Twenty seven patients had SIRS and no signs of infection and twenty two patients had SIRS due to proven infection. We detected a significant increase in serum CRP and IL-6 values in patients infected compared to patients with no septic SIRS. Patients who finally died had much higher levels of these proteins, while there was a prompt reduction of serum CRP and IL-6 early during remission. Conclusion / interpretation. Diabetic ketoacidosis and hyperglycemic hyperosmolar state can often cause a clinical syndrome resembling systemic inflammatory response syndrome. An imbalance of subpopulations of T lymphocytes, especially decreased helper T cells (CD4), may be correlated with the high morbidity and mortality in these states. Determination of serum C-reactive protein and interleukin-6 is a useful way of early excluding an underlying infection as well as confirming and monitoring sepsis.