Andrew T Hattersley, Siri A W Greeley, Michel Polak, Oscar Rubio-Cabezas, Pål R Njølstad, Wojciech Mlynarski, Luis Castano, Annelie Carlsson, Klemens Raile, Dung V Chi, Sian Ellard, Maria E Craig
ISPAD Clinical Practice Consensus Guidelines 2018: The diagnosis and management of monogenic diabetes in children and adolescents.
Pediatr Diabetes. 2018 Oct;19 Suppl 27:47-63. doi: 10.1111/pedi.12772.
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Maturity-onset diabetes of the young (MODY) is characterized by autosomal dominant inheritance, onset before 25 years of age, absence of β-cell autoimmunity, and sustained pancreatic β-cell function. To date, mutations have been identified in at least 14 different genes, including six genes encoding proteins that, respectively, correspond to MODY subtypes 1-6: hepatocyte nuclear factor (HNF) 4α (HNF4α), glucokinase (GCK), HNF1α (HNF1α), pancreatic and duodenal homeobox 1 (PDX1), HNF1β (HNF1β), and neurogenic differentiation 1 (NEUROD1). Diagnostic tools based on currently available genetic tests can facilitate the correct diagnosis and appropriate treatment of patients with MODY. Candidates for genetic testing include nonobese subjects with hyperglycemia, no evidence of β-cell autoimmunity, sustained β-cell function, and a strong family history of similar-type diabetes among first-degree relatives. Moreover, identification of the MODY subtype is important, given the subtype-related differences in the age of onset, clinical course and progression, type of hyperglycemia, and response to treatment. This review discusses the current perspectives on the diagnosis and treatment of MODY, particularly with regard to the six major subtypes (MODY 1-6).
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STUDY OBJECTIVE: Although adjunctive intravenous bicarbonate therapy is commonly recommended for children with severe diabetic ketoacidosis (DKA), no studies assessing clinical outcome with this therapy have ever been performed. Our objective was to determine whether bicarbonate therapy influenced outcome for pediatric DKA.
METHODS: The study was a retrospective consecutive case series of 147 admissions for severe DKA (initial pH < or = 7.15 and glucose concentration > or = 300 mg/dL [16.7 mmol/L]) in 106 children during a 16-year period at a tertiary university medical center. Descriptive statistics were applied to the 147 admissions. The first patient admitted with DKA was then selected for each of the 106 children, and clinical and laboratory data were compared between subjects who did and did not receive bicarbonate. Multivariate and matched pair analyses were performed to control potentially confounding variables.
RESULTS: Fifty-seven of the 147 patients admitted with DKA (39%) were successfully treated without bicarbonate, including 9 with a pH of 7.00 or less and one with a pH of 6.73. The frequency of complications was comparable between bicarbonate and nonbicarbonate groups (4% versus 2%, P = 1.00). The mean duration of hospitalization for children receiving bicarbonate was 23% (16 hours) longer than children who did not receive bicarbonate in the multivariate analysis (P = .07) and 37% (22 hours) longer in the matched pair analysis (P = .01). The mean rate of metabolic recovery by three distinct measures was similar between groups, and the sample had 80% power to detect differences of 14% to 29% in these measures.
CONCLUSION: We found no evidence that adjunctive bicarbonate improved clinical outcome in children with severe DKA. The rate of metabolic recovery and complications were similar in patients treated with and without bicarbonate, and prolonged hospitalizations were noted in the bicarbonate group. We conclude that adjunctive bicarbonate is unnecessary and potentially disadvantageous in severe pediatric DKA.
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AIMS/HYPOTHESIS: Cerebral oedema complicating diabetic ketoacidosis (DKA) remains the major cause of morbidity and mortality in children with type 1 diabetes, but its aetiology remains unknown. Our objective was to determine the impact of baseline biochemical factors and of treatment-related variables on risk of the development of cerebral oedema in children with DKA.
MATERIALS AND METHODS: This was a national UK case-control study. Through the British Paediatric Surveillance Unit we identified 43 cases of cerebral oedema. Through a parallel reporting system, we also identified 2,940 episodes of DKA and selected 169 control subjects on the basis of comparable age, sex, numbers of new or known cases of diabetes and date of admission. Baseline biochemical data and treatment-related variables were extracted from the clinical notes of cases and control subjects.
RESULTS: Allowing for differences in age, sex and new or known diabetes, cases were more acidotic at diagnosis of DKA (odds ratio [OR] for events in the least acidotic compared with the most acidotic tertile=0.02 [95% CI: 0.002-0.15], p<0.001). In addition, cases had higher potassium and urea levels at baseline. Calculated osmolality and baseline glucose were not significantly different. After allowing for severity of acidosis, insulin administration in the first hour (OR 12.7 [1.41-114.5], p=0.02) and volume of fluid administered over the first 4 h (OR 6.55 [1.38-30.97], p=0.01) were associated with risk. Low baseline plasma sodium and an elevated p(a)CO(2) also contributed to risk in the final regression model. Bicarbonate administration was not associated with increased risk of an event when corrected for acidosis.
CONCLUSIONS/INTERPRETATION: In this case-control study of DKA, baseline acidosis and abnormalities of sodium, potassium and urea concentrations were important predictors of risk of cerebral oedema. Additional risk factors identified were early administration of insulin and high volumes of fluid. These observations should be taken into account when designing treatment protocols.
N Glaser, P Barnett, I McCaslin, D Nelson, J Trainor, J Louie, F Kaufman, K Quayle, M Roback, R Malley, N Kuppermann, Pediatric Emergency Medicine Collaborative Research Committee of the American Academy of Pediatrics
Risk factors for cerebral edema in children with diabetic ketoacidosis. The Pediatric Emergency Medicine Collaborative Research Committee of the American Academy of Pediatrics.
N Engl J Med. 2001 Jan 25;344(4):264-9. doi: 10.1056/NEJM200101253440404.
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BACKGROUND: Cerebral edema is an uncommon but devastating complication of diabetic ketoacidosis in children. Risk factors for this complication have not been clearly defined.
METHODS: In this multicenter study, we identified 61 children who had been hospitalized for diabetic ketoacidosis within a 15-year period and in whom cerebral edema had developed. Two additional groups of children with diabetic ketoacidosis but without cerebral edema were also identified: 181 randomly selected children and 174 children matched to those in the cerebral-edema group with respect to age at presentation, onset of diabetes (established vs. newly diagnosed disease), initial serum glucose concentration, and initial venous pH. Using logistic regression we compared the three groups with respect to demographic characteristics and biochemical variables at presentation and compared the matched groups with respect to therapeutic interventions and changes in biochemical values during treatment.
RESULTS: A comparison of the children in the cerebral-edema group with those in the random control group showed that cerebral edema was significantly associated with lower initial partial pressures of arterial carbon dioxide (relative risk of cerebral edema for each decrease of 7.8 mm Hg [representing 1 SD], 3.4; 95 percent confidence interval, 1.9 to 6.3; P<0.001) and higher initial serum urea nitrogen concentrations (relative risk of cerebral edema for each increase of 9 mg per deciliter [3.2 mmol per liter] [representing 1 SD], 1.7; 95 percent confidence interval, 1.2 to 2.5; P=0.003). A comparison of the children with cerebral edema with those in the matched control group also showed that cerebral edema was associated with lower partial pressures of arterial carbon dioxide and higher serum urea nitrogen concentrations. Of the therapeutic variables, only treatment with bicarbonate was associated with cerebral edema, after adjustment for other covariates (relative risk, 4.2; 95 percent confidence interval, 1.5 to 12.1; P=0.008).
CONCLUSIONS: Children with diabetic ketoacidosis who have low partial pressures of arterial carbon dioxide and high serum urea nitrogen concentrations at presentation and who are treated with bicarbonate are at increased risk for cerebral edema.
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BACKGROUND: Long-term microvascular and neurologic complications cause major morbidity and mortality in patients with insulin-dependent diabetes mellitus (IDDM). We examined whether intensive treatment with the goal of maintaining blood glucose concentrations close to the normal range could decrease the frequency and severity of these complications.
METHODS: A total of 1441 patients with IDDM--726 with no retinopathy at base line (the primary-prevention cohort) and 715 with mild retinopathy (the secondary-intervention cohort) were randomly assigned to intensive therapy administered either with an external insulin pump or by three or more daily insulin injections and guided by frequent blood glucose monitoring or to conventional therapy with one or two daily insulin injections. The patients were followed for a mean of 6.5 years, and the appearance and progression of retinopathy and other complications were assessed regularly.
RESULTS: In the primary-prevention cohort, intensive therapy reduced the adjusted mean risk for the development of retinopathy by 76 percent (95 percent confidence interval, 62 to 85 percent), as compared with conventional therapy. In the secondary-intervention cohort, intensive therapy slowed the progression of retinopathy by 54 percent (95 percent confidence interval, 39 to 66 percent) and reduced the development of proliferative or severe nonproliferative retinopathy by 47 percent (95 percent confidence interval, 14 to 67 percent). In the two cohorts combined, intensive therapy reduced the occurrence of microalbuminuria (urinary albumin excretion of > or = 40 mg per 24 hours) by 39 percent (95 percent confidence interval, 21 to 52 percent), that of albuminuria (urinary albumin excretion of > or = 300 mg per 24 hours) by 54 percent (95 percent confidence interval 19 to 74 percent), and that of clinical neuropathy by 60 percent (95 percent confidence interval, 38 to 74 percent). The chief adverse event associated with intensive therapy was a two-to-threefold increase in severe hypoglycemia.
CONCLUSIONS: Intensive therapy effectively delays the onset and slows the progression of diabetic retinopathy, nephropathy, and neuropathy in patients with IDDM.
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BACKGROUND: Intensive diabetes therapy aimed at achieving near normoglycemia reduces the risk of microvascular and neurologic complications of type 1 diabetes. We studied whether the use of intensive therapy as compared with conventional therapy during the Diabetes Control and Complications Trial (DCCT) affected the long-term incidence of cardiovascular disease.
METHODS: The DCCT randomly assigned 1441 patients with type 1 diabetes to intensive or conventional therapy, treating them for a mean of 6.5 years between 1983 and 1993. Ninety-three percent were subsequently followed until February 1, 2005, during the observational Epidemiology of Diabetes Interventions and Complications study. Cardiovascular disease (defined as nonfatal myocardial infarction, stroke, death from cardiovascular disease, confirmed angina, or the need for coronary-artery revascularization) was assessed with standardized measures and classified by an independent committee.
RESULTS: During the mean 17 years of follow-up, 46 cardiovascular disease events occurred in 31 patients who had received intensive treatment in the DCCT, as compared with 98 events in 52 patients who had received conventional treatment. Intensive treatment reduced the risk of any cardiovascular disease event by 42 percent (95 percent confidence interval, 9 to 63 percent; P=0.02) and the risk of nonfatal myocardial infarction, stroke, or death from cardiovascular disease by 57 percent (95 percent confidence interval, 12 to 79 percent; P=0.02). The decrease in glycosylated hemoglobin values during the DCCT was significantly associated with most of the positive effects of intensive treatment on the risk of cardiovascular disease. Microalbuminuria and albuminuria were associated with a significant increase in the risk of cardiovascular disease, but differences between treatment groups remained significant (P< or =0.05) after adjusting for these factors.
CONCLUSIONS: Intensive diabetes therapy has long-term beneficial effects on the risk of cardiovascular disease in patients with type 1 diabetes.
Copyright 2005 Massachusetts Medical Society.
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BACKGROUND: An impaired glomerular filtration rate (GFR) leads to end-stage renal disease and increases the risks of cardiovascular disease and death. Persons with type 1 diabetes are at high risk for kidney disease, but there are no interventions that have been proved to prevent impairment of the GFR in this population.
METHODS: In the Diabetes Control and Complications Trial (DCCT), 1441 persons with type 1 diabetes were randomly assigned to 6.5 years of intensive diabetes therapy aimed at achieving near-normal glucose concentrations or to conventional diabetes therapy aimed at preventing hyperglycemic symptoms. Subsequently, 1375 participants were followed in the observational Epidemiology of Diabetes Interventions and Complications (EDIC) study. Serum creatinine levels were measured annually throughout the course of the two studies. The GFR was estimated with the use of the Chronic Kidney Disease Epidemiology Collaboration formula. We analyzed data from the two studies to determine the long-term effects of intensive diabetes therapy on the risk of impairment of the GFR, which was defined as an incident estimated GFR of less than 60 ml per minute per 1.73 m(2) of body-surface area at two consecutive study visits.
RESULTS: Over a median follow-up period of 22 years in the combined studies, impairment of the GFR developed in 24 participants assigned to intensive therapy and in 46 assigned to conventional therapy (risk reduction with intensive therapy, 50%; 95% confidence interval, 18 to 69; P=0.006). Among these participants, end-stage renal disease developed in 8 participants in the intensive-therapy group and in 16 in the conventional-therapy group. As compared with conventional therapy, intensive therapy was associated with a reduction in the mean estimated GFR of 1.7 ml per minute per 1.73 m(2) during the DCCT study but during the EDIC study was associated with a slower rate of reduction in the GFR and an increase in the mean estimated GFR of 2.5 ml per minute per 1.73 m(2) (P<0.001 for both comparisons). The beneficial effect of intensive therapy on the risk of an impaired GFR was fully attenuated after adjustment for glycated hemoglobin levels or albumin excretion rates.
CONCLUSIONS: The long-term risk of an impaired GFR was significantly lower among persons treated early in the course of type 1 diabetes with intensive diabetes therapy than among those treated with conventional diabetes therapy. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others; DCCT/EDIC ClinicalTrials.gov numbers, NCT00360815 and NCT00360893.).
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BACKGROUND: Among patients with type 1 diabetes mellitus, intensive therapy (with the aim of achieving near-normal blood glucose and glycosylated hemoglobin concentrations [hemoglobin A1c]) markedly reduces the risk of microvascular complications as compared with conventional therapy. To assess whether these benefits persist, we compared the effects of former and intensive conventional therapy on the recurrence and severity of retinopathy and nephropathy for four years after the end of the Diabetes Control and Complications Trial (DCCT).
METHODS: At the end of the DCCT, the patients in the conventional-therapy group were offered intensive therapy, and the care of all patients was transferred to their own physicians. Retinopathy was evaluated on the basis of centrally graded fundus photographs in 1208 patients during the fourth year after the DCCT ended, and nephropathy was evaluated on the basis of urine specimens obtained from 1302 patients during the third or fourth year, approximately half of whom were from each treatment group.
RESULTS: The difference in the median glycosylated hemoglobin values between the conventional-therapy and intensive-therapy groups during the 6.5 years of the DCCT (average, 9.1 percent and 7.2 percent, respectively) narrowed during follow-up (median during 4 years, 8.2 percent and 7.9 percent, respectively, P<0.001). Nevertheless, the proportion of patients who had worsening retinopathy, including proliferative retinopathy, macular edema, and the need for laser therapy, was lower in the intensive-therapy group than in the conventional-therapy group (odds reduction, 72 percent to 87 percent, P<0.001). The proportion of patients with an increase in urinary albumin excretion was significantly lower in the intensive-therapy group.
CONCLUSIONS: The reduction in the risk of progressive retinopathy and nephropathy resulting from intensive therapy in patients with type 1 diabetes persists for at least four years, despite increasing hyperglycemia.
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The American Diabetes Association (ADA) "Standards of Medical Care in Diabetes" includes the ADA's current clinical practice recommendations and is intended to provide the components of diabetes care, general treatment goals and guidelines, and tools to evaluate quality of care. Members of the ADA Professional Practice Committee, a multidisciplinary expert committee (https://doi.org/10.2337/dc20-SPPC), are responsible for updating the Standards of Care annually, or more frequently as warranted. For a detailed description of ADA standards, statements, and reports, as well as the evidence-grading system for ADA's clinical practice recommendations, please refer to the Standards of Care Introduction (https://doi.org/10.2337/dc20-SINT). Readers who wish to comment on the Standards of Care are invited to do so at professional.diabetes.org/SOC.
© 2019 by the American Diabetes Association.
