Type 1 Diabetes Mellitus

Diabetic ketoacidosis (DKA) is the leading cause of morbidity and mortality in children with type 1 diabetes mellitus (TIDM). Mortality is predominantly related to the occurrence of cerebral edema; only a minority of deaths in DKA are attributed to other causes. Cerebral edema occurs in ∼0.3% to 1% of all episodes of DKA, and its etiology, pathophysiology, and ideal method of treatment are poorly understood. There is debate as to whether physicians treating DKA can prevent or predict the occurrence of cerebral edema and the appropriate site(s) for children with DKA to be managed. There is agreement that prevention of DKA and reduction of its incidence should be a goal in managing children with diabetes.To explore these issues, the Lawson Wilkins Pediatric Endocrine Society (LWPES) and the European Society for Pediatric Endocrinology (ESPE) convened a panel‖ of expert physicians for a consensus conference. The meeting was chaired by Mark A. Sperling, MD, representing LWPES, and David B. Dunger, MD, representing ESPE. The Consensus statement was developed with close partnership between the ESPE and LWPES and the International Society for Pediatric and Adolescent Diabetes, all 3 organizations being represented by members who participated in the writing process. The statement also was endorsed by related organizations; the Juvenile Diabetes Research Foundation International, the World Federation of Pediatric Intensive and Critical Care Societies, the European Society for Pediatric Critical Care, the European Society of Pediatric and Neonatal Intensive Care, and the Australian Pediatric Endocrine Group were represented by invited participants.Each of the major topics had a presenter and recorder, responsible for review of the literature and providing evidence-based recommendations according to criteria used by the American Diabetes Association (see Appendix; levels of evidence are indicated in capital letters, in parentheses).1 Type 2 diabetes was not considered. All participants contributed significantly to the development of consensus.This document summarizes the final consensus reached and represents the current "state of the art."DKA is caused by a decrease in effective circulating insulin associated with elevations in counterregulatory hormones including glucagon, catecholamines, cortisol, and growth hormone. This leads to increased glucose production by the liver and kidney and impaired peripheral glucose utilization, with resultant hyperglycemia and hyperosmolality. Increased lipolysis, with ketone body (β-hydroxybutyrate [β-OHB] and acetoacetate) production causes ketonemia and metabolic acidosis. Hyperglycemia and acidosis result in osmotic diuresis, dehydration, and obligate loss of electrolytes. The biochemical criteria for the diagnosis of DKA include hyperglycemia (blood glucose: >11 mmol/L [∼200 mg/dL]) with a venous pH <7.3 and/or bicarbonate <15 mmol/L. There is associated glycosuria, ketonuria, and ketonemia. Rarely, young or partially treated children as well as pregnant adolescents may present with near-normal glucose values ("euglycemic ketoacidosis").2DKA is generally categorized by the severity of the acidosis, varying from mild (venous pH: <7.30; bicarbonate concentration: <15 mmol/L) to moderate (pH: <7.2; bicarbonate: <10) to severe (pH: <7.1; bicarbonate: <5).3,4There is wide geographic variation in the frequency of DKA at diabetes onset, and rates correlate inversely with regional incidence of TIDM. Reported frequencies range between 15% and 67% in Europe and North America and may be more common in developing countries (A).5,6 In Canada and Europe, hospitalization rates for DKA in established and new patients with TIDM have remained stable at ∼10 per 100 000 children over the past 20 years, but severity may be decreasing (B).7,8DKA at onset of TIDM is more common in younger children (<4 years of age), children without a first-degree relative with TIDM, and those from families of lower socioeconomic status (A).4,9 High-dose glucocorticoids, atypical antipsychotics, diazoxide, and some immunosuppressive drugs have been reported to precipitate DKA in individuals not diagnosed previously with TIDM (B).10,11The risk of DKA in established TIDM is 1% to 10% per patient per year (A).12–15 Risk is increased in children with poor metabolic control or previous episodes of DKA, peripubertal and adolescent girls, children with psychiatric disorders (including those with eating disorders), and those with difficult family circumstances (including lower socioeconomic status and lack of appropriate health insurance).16 Inappropriate interruption of insulin-pump therapy also leads to DKA.12,14Children whose insulin is administered by a responsible adult rarely have episodes of DKA (C),17 and 75% of episodes of DKA beyond diagnosis probably are associated with insulin omission or treatment error.17,18 The remainder are due to inadequate insulin therapy during intercurrent illness (B).18–20Reported mortality rates from DKA in national population-based studies are reasonably constant: 0.15% (C) (United States),21 0.18% (C) (Canada),7 0.25% (C) (Canada),22 to 0.31% (B) (United Kingdom).23 In places with less developed medical facilities, the risk of dying from DKA is greater, and children may die before receiving treatment.23Cerebral edema accounts for between 57% and 87% of all DKA deaths.24,25 The incidence of cerebral edema has been fairly consistent between national population-based studies: 0.46% (C) (Canada),22 0.68% (B) (United Kingdom),24 and 0.87% (B) (United States).25 Single-center studies often report higher frequencies because of ascertainment bias arising from secondary referral patterns: 1.1% (C) (United States)26 to 4.6% (United States).27Reported mortality rates from cerebral edema in population-based studies are 21% (C),25 25% (C),22 and 24% (B).24 Significant morbidity is evident in 10% (C),22 21% (B),25 and 26% (B)24 of survivors. However, some individual centers have reported markedly lower mortality and serious morbidity after DKA and cerebral edema (B [United States28], C [United States29]).Other possible causes of mortality and morbidity include hypokalemia, hyperkalemia, hypoglycemia, other central nervous system (CNS) complications, hematoma (C),30 thrombosis (C),31 sepsis, infections (including rhinocerebral mucormycosis) (C),32 aspiration pneumonia, pulmonary edema (C),33 adult respiratory distress syndrome (C),34 pneumomediastinum and subcutaneous emphysema (C),35 and rhabdomyolysis (C).36 Late sequelae relate to cerebral edema and other CNS complications including hypothalamopituitary insufficiency,37,38 isolated growth hormone deficiency,39 and combined growth hormone and thyroid-stimulating hormone deficiency.40Cerebral edema typically occurs 4 to 12 hours after treatment is activated25,41 but can be present before treatment has begun (B,23 C,42,43, B25) or may develop any time during treatment for DKA. Symptoms and signs of cerebral edema are variable and include onset of headache, gradual decrease or deterioration in level of consciousness, inappropriate slowing of the pulse rate, and an increase in blood pressure (C).44,45In vitro experiments and studies in animals and humans presenting with cerebral edema due to other causes (eg, trauma or stroke) suggest that the etiopathological mechanisms may be complex. A number of mechanisms have been proposed, including the role of cerebral ischemia/hypoxia and the generation of various inflammatory mediators,46,47 increased cerebral blood flow,48 and disruption of cell membrane ion transport49,50 and aquaporin channels.51 The generation of intracellular organic osmolytes (myoinositol and taurine) and subsequent cellular osmotic imbalance has also been implicated.52 Preliminary imaging studies in children with DKA using ultrasound, computed tomography, or magnetic resonance imaging indicate that some degree of cerebral edema may be present even in patients without clinical evidence of raised intracranial pressure (ICP).53–56Various demographic factors have been associated with an increased risk of cerebral edema including: presentation with new-onset TIDM (B, C)23,44 younger age (C),44 and longer duration of symptoms (C).26 These associations may be a consequence of the greater likelihood of presenting with severe DKA (C).25Several potential risk factors, at diagnosis or during treatment, have been identified through epidemiologic studies.Most studies show no association between the degree of hyperglycemia at presentation of DKA with risk of cerebral edema after correcting for other covariates (C).25,27Children with ketosis and hyperglycemia without vomiting or severe dehydration can be managed at home or in an outpatient health care setting (eg, emergency ward or units with similar facilities), but the level of care needs to be reevaluated frequently and supervised by an experienced diabetes team (C,3,63,64 E).A specialist/consultant pediatrician with training and expertise in the management of DKA should direct inpatient management. The child also should be cared for in a unit that has experienced nursing staff trained in monitoring and management, clear written guidelines, and access to laboratories for frequent evaluation of biochemical variables.Children with signs of severe DKA (long duration of symptoms, compromised circulation, or depressed level of consciousness) or those who are at increased risk for cerebral edema (including <5 years of age and new onset) should be considered immediately for treatment in an intensive care unit (pediatric, if available) or a children's ward specializing in diabetes care with equivalent resources and supervision (C,65 E). If transfer by ambulance to another unit is required, caution should be exercised in the use of sedatives and antiemetics.There should be documentation of hour-by-hour clinical observations, IV and oral medication, fluids, and laboratory results during the entire treatment period (E).Monitoring should include: Those monitoring should be instructed to alert the physician of any of these manifestations, because it may be difficult to clinically discriminate cerebral edema from other causes of altered mental status.The high effective osmolality of the extracellular fluid (ECF) compartment results in a shift of water from the intracellular fluid (ICF) compartment to the ECF. Studies performed in adults with TIDM in whom insulin therapy was withheld have shown fluid deficits of ∼5 L66 together with ∼20% loss of total body sodium and potassium.67 At the time of presentation, patients are ECF contracted, and clinical estimates of the deficit are usually in the range of 7% to 10%, although these estimates can be subjective and may overestimate the problem.68 Shock with hemodynamic compromise is a rare event in DKA. The serum sodium measurement is an unreliable measure of the degree of ECF contraction due to the dilutional effect of fluid shift. The effective osmolality (2 [Na + K] + glucose) at the time of presentation is frequently in the range of 300 to 350 mOsm/L. Elevated serum urea nitrogen and hematocrit may be useful markers of severe ECF contraction.28,64The onset of dehydration is associated with a reduction in glomerular filtration rate (GFR), which results in decreased glucose and ketone clearance from the blood. Studies in humans have shown that IV fluid administration alone results in substantial falls in blood glucose levels because of an increase in GFR.69,70 The objectives of fluid and sodium replacement therapy in DKA are 1) restoration of circulating volume, 2) replacement of sodium and the ECF and ICF deficit of water, 3) restoration of GFR with enhanced clearance of glucose and ketones from the blood, and 4) avoidance of cerebral edema.Both animal and human studies have shown that ICP rises as IV fluids are administered.71,72 There are also animal models of DKA that show that the use of hypotonic fluids, compared with isotonic, is associated with greater rises in ICP.71 Although there are no category A studies that demonstrate superiority of any fluid regimen over another, there are category C data that suggest that rapid fluid replacement with hypotonic fluid is associated with an increased risk of cerebral edema (see "Risk Factors" above). There are both adult (category A) and pediatric (level B) studies that show that a less-rapid fluid-deficit correction with isotonic or near-isotonic solutions results in earlier reversal of acidosis.29,73 However, the use of large amounts of 0.9% saline has also been associated with the development of hyperchloremic metabolic acidosis.74,75There are no data to support the use of colloids in preference to crystalloids in the treatment of DKA. There also are no data to support the use of solutions more dilute than 0.45% NaCl; the use of these solutions, which contain a large amount of electrolyte-free water, is likely to lead to a rapid osmolar change and movement of fluid into the ICF compartment.Although rehydration alone causes some decrease in blood glucose concentration, insulin therapy is essential to normalize the blood glucose concentration and suppress lipolysis and ketogenesis. Although different routes (subcutaneous, intramuscular, and IV) and doses have been used, extensive evidence indicates that "low-dose" IV insulin administration should be the standard of care.76Physiologic studies indicate that IV insulin at a dose of 0.1 unit/kg per hour, which achieves steady-state plasma insulin levels of ∼100 to 200 μU/mL within 60 minutes, is effective.77 Such plasma insulin levels are able to offset insulin resistance and, in most circumstances, inhibit lipolysis and ketogenesis, exerting maximal or near-maximal effects on suppression of glucose production and stimulated peripheral glucose uptake.78 The resolution of acidemia invariably takes longer than normalization of blood glucose concentrations.79Adults with DKA have total body potassium deficits on the order of 3 to 6 mmol/kg; data in children are sparse.66,67,82–85 The major loss of potassium is from the intracellular pool as a result of hypertonicity, insulin deficiency, and buffering of hydrogen ions within the cell. Serum potassium levels at the time of presentation may be normal, increased or decreased: Hypokalemia at presentation may be related to prolonged duration of disease, whereas hyperkalemia primarily results from reduced renal function.86 Administration of insulin and the correction of acidosis will drive potassium back into the cells, decreasing serum levels.Depletion of intracellular phosphate occurs and phosphate is lost as a result of osmotic diuresis. In adults, deficits are in the range of 0.5 to 2.5 mmol/kg,66,67,84 but comparable data in children are unavailable. The fall in plasma phosphate levels after starting treatment is exacerbated by insulin administration as phosphate reenters cells.87 Low plasma phosphate levels, when indicative of total body depletion in other conditions, have been associated with a wide array of metabolic disturbances; however, particular interest has focused on erythrocyte 2,3-diphosphoglycerate concentrations and effects on tissue oxygenation.88 Phosphate depletion persists for several days after resolution of DKA.66,82,84 However, prospective studies have failed to show significant clinical benefit from phosphate replacement.89–94 Nevertheless, provided that careful monitoring is performed to avoid hypocalcemia,95,96 potassium phosphate may be used safely in combination with potassium chloride or acetate to avoid hyperchloremia.Even severe acidosis is reversible by fluid and insulin replacement. Administration of insulin stops further ketoacid synthesis and allows excess ketoacids to be metabolized. The metabolism of keto-anion results in the regeneration of bicarbonate (HCO3−) and spontaneous correction of acidemia. Also, treatment of hypovolemia will improve decreased tissue perfusion and renal function, thus increasing the excretion of organic acids (see "Fluids and Salt") and reversing any lactic acidosis, which may account for 25% of the acidemia.In DKA, there is an increased anion gap. The major retained anions are β-OHB and acetoacetate. \batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \[anion\ gap{=}{[}Na^{{+}}{]}{-}({[}Cl^{{-}}{]}{+}{[}HCO_{3}^{{-}}{]}):\ normally\ 12\ {\pm}\ 2\ mmol/L\] \end{document}The indications for bicarbonate therapy in DKA are unclear. Several controlled trials of sodium bicarbonate in small numbers of children and adults (B, C) have been unable to demonstrate clinical benefit or any important difference in the rate of rise in the plasma bicarbonate concentration (C).25,97–100There are potential arguments against the use of bicarbonate.25,97,101,102 Of concern is that bicarbonate therapy may cause paradoxical CNS acidosis and that rapid correction of acidosis caused by bicarbonate will result in hypokalemia and may accentuate sodium load and contribute to serum hypertonicity. In addition, alkali therapy may increase hepatic ketone production, thus slowing the rate of recovery from the ketosis.These findings, however, do not address the issue that there may be select patients who may benefit from cautious alkali therapy, including those with severe acidemia (arterial pH: <6.9) in whom decreased cardiac contractility and peripheral vasodilatation can further impair tissue perfusion and patients with potentially life-threatening hyperkalemia.Treatment should be initiated as soon as the condition is suspected. The rate of fluid administration should be reduced. Although mannitol has been shown to have possible beneficial effects in case reports,103–105 there has been no definite beneficial or detrimental effect in retrospective epidemiologic studies.106 The response may be altered by timing of administration, delayed administration being less effective. IV mannitol should be given (0.25–1.0 g/kg over 20 minutes) in patients with signs of cerebral edema before impending respiratory failure (C, E). Repeat in 2 hours if there is no initial response. Hypertonic saline (3%), 5 to 10 mL/kg over 30 minutes, may be an alternative to mannitol (C).107Intubation and ventilation may be necessary. However, aggressive hyperventilation has been associated with poor outcome in one retrospective study of DKA-related cerebral edema106; similarly detrimental effects have been reported in numerous other conditions such as head trauma and high-altitude exposure.62 There are no data regarding glucocorticoid use in DKA-related cerebral edema.Earlier diagnosis through genetic and immunologic screening of high-risk children such as in the recent DPT-1 study108 decrease DKA incidence at diabetes onset (A).14,109 High levels of awareness related to the existence of other members of families with TIDM also reduce the risk of DKA. A school and physician awareness campaign, targeted at 6- to 14-year-olds, reduced rates of DKA from 78% to almost 0% over a 6-year period (B).110 Increased public awareness of signs and symptoms of diabetes should lead to earlier diagnosis, particularly in children <5 years; checking urine or blood for glucose may prevent misdiagnosis (E). Although such strategies are intuitively obvious, programs to decrease DKA at onset need to be designed and evaluated in diverse populations and age groups.Studies of the effects of comprehensive diabetes programs and telephone help lines report a reduction in the rates of DKA from 15–60 to 5–5.9/100 patient-years (B).19,111,112 In patients on continuous subcutaneous insulin pumps, episodes of DKA can be reduced with the introduction of educational algorithms (E). Therefore, it is likely that episodes of DKA after diagnosis could be reduced if all children with diabetes receive comprehensive diabetes health care and education and have access to a 24-hour diabetes telephone help line (A).19 The value of home measurement of β-OHB as a mechanism for earlier diagnosis and thus prevention of hospitalization needs to be assessed.Multiple episodes of recurrent DKA are more problematic: In a recent United Kingdom study, 4.8% of patients accounted for 22.5% of all episodes over a 3-year period.24 Insulin omission has been identified as the major factor in most of these cases and may be confirmed by finding low free-insulin levels on admission (C).13,113 There is no evidence that mental health interventions alone can impact on the frequency of DKA in these children (B),14,17,111 but insulin omission can be prevented by sequential schemes providing education, psychosocial evaluation, and treatment combined with adult supervision of insulin administration (B).17 When responsible adults administer insulin, a 10-fold reduction in episodes of DKA has been reported (B).17The LWPES and ESPE gratefully acknowledge Aventis Pharmaceuticals, Novo Nordisk, and the Society for Endocrinology for support of the consensus conference; Sten Renstad of Semser for organizing the conference; and Emily Knight and Kathy Wypychowski for assistance with preparing the consensus statement.

BackgroundTechnology in Diabetes has been rapidly evolving in order to help optimize blood glucose(BG) control in diabetic patients.ObjectivesAnalysis of glycemic control(GC) in children and young people with Type 1 Diabetes...

Type 1 diabetes mellitus (T1DM) causes cognitive changes in children, which may be due to deficits in brain functions. It is unclear whether T1DM children will have brain functional changes during the initial stage of the disease. We aimed to investigate the changes in the functional brain network topology in children with new-onset T1DM. In this study, 35 new-onset T1DM children and 33 age-, sex-matched healthy controls underwent resting-state fMRI. The whole brain functional connectivity density (FCD) analysis and seed-based functional connectivity (FC) analysis were performed to investigate the changes in functional brain networks in new-onset T1DM children when compared with the controls. Pearson correlational analysis was used to explore the correlation between FCD value of differential brain areas and clinical variables in T1DM children. Compared with the controls, children with new-onset T1DM exhibited significantly decreased FCDs of the right inferior temporal gyrus (ITG) and the right posterior cingulate cortex (PCC). In the subsequent FC analysis, decreased FC was found between right PCC and right cuneus and increased FC was found between right ITG and left orbital part of inferior frontal gyrus in children with new-onset T1DM compared to the controls. The FCD values of right ITG and PCC did not correlate with HbA1c, blood glucose level before imaging, and full-scale intelligence quotient (IQ) in T1DM children. These results revealed that T1DM affect the functional activity of the immature brain at the initial stage. These findings also indicate a decrease in regional brain function and abnormalities in temporal-frontal and limbic-occipital circuitry in children with new-onset T1DM, and highlight the effects of T1DM on children's brain networks involved in visual process and memory, which may contribute to the cognition impairments observed in children with T1DM.

Objective To evaluate the efleet of continuous subcutaneous insulin infusion (CSII)combined with mefformin hydroehloride( Met H)on type 2 diabetic patients. Methods 240 patients with type 2 diabetes melli-tus (T2DM) were divided into 3 groups randomly: CSII combined with Met H ( A group: n=80) ; simple CSII ( B group:n=80) ; multiple deliver insulin (MDI) ( C group: n=80). The levels of blood glucose, HbA1 e, therapeutic time, a-mount of insulin, Fins ,C-P, HOMA-IR and IAI were compared among them before and after 10d of treatment. Results GroupA, B eornpared with group C, the levels of HbA1 e significantly deeroased in other two groups [ ( 8.0±3.2)%vs. (6.9±1.4)% and(7.0±1.2)% ] (aU P<0.05),so did the therapeutic time[(6.0±1.9)d vs. (3.0±1.4) and(3.5±1.5) d] and insulin dose[ (55.0±17.0) U/d vs. (38.0±15.0) U/d and(45.0±16) U/d] (all P<0.05). The insulin dose was much less in group A than in group B. Versus group B and C,the HOMA-IR of group A (0.8±0.3 vs. 1.5±0.4 and 1.6±0.4)decreased(P<0.05) ,and IAI(-2.0±4.3 vs. -3.6±4. 2 and -4.1±4.3) increased (all P<0.05), without the function impairments of heart, liver or kidney. Conclusion CSII in combi-nation with mefformin hydreehloride can significantly enhance the treatment effect of the patients with type 2 diabetes mellitns; reduce blood glucose and HbA1 e, improve insulin resistenee,lessen insulin need. Key words: Diabetes mellitus,type2; Insulin infusion systems; Insulin resistanee; Mefformin

Aims: We aimed to analyze incidence and characteristics of patients with diabetic ketosis (DK) and diabetic ketoacidosis (DKA) in Caucasian adults with type 2 diabetes mellitus (T2DM). Methods: Studied population included 261, 749 adults. DK criteria included plasma glucose >13.9 mmol/L and ketonuria >2, while in DKA bicarbonate <18 mEq/L or pH<7.30 was also required. Hyperglycemic crises without these criteria were defined as non-ketotic hyperglycemia (NKH). Results: During a 5-year period, we observed 630 episodes of DK and 215 episodes of DKA. Only 8.6% of DK episodes and 34.4% of DKA were attributed to type 1 diabetes mellitus (T1DM). Patients with T1DM were younger, leaner, majority had newly diagnosed disease, and hyperglycemia was the main cause of admission. Standardized incidence ratio for DK was 48.1 (95% confidence interval [CI] 44.5-52.1) and 17.0 (95% CI 14.9-19.4) for DKA. Incidence for both DK and DKA was increasing with age. In patients younger than 50, the incidence of DK and DKA was similar. However, dramatic rise in the incidence of DK was observed in both sexes after the age of 50. When compared with patients with NKH, the patients with DK had higher serum pH and bicarbonates. Patients with T2DM had a risk of 0.8% for developing DKA and 2.9% for DK over 5- year period. Conclusions: Our study showed that DK and DKA are not uncommon in Caucasian adults and the majority of episodes were contributed to T2DM. Incidence of DK is far more higher than the incidence of DKA in patients older than 50, who predominantly have T2DM. Moreover, patients with DK have higher serum pH and bicarbonates, both of which imply that DK and DKA are distinct clinical entities in patients with T2DM. Further studies are needed to assess the impact of these clinical entities.

SGLT2 INHIBITOR-INDUCED EUGLYCEMIC DIABETIC KETOACIDOSIS

Type 1 and type 2 diabetes in children and young people: updated <scp>NICE</scp> guidance

Some people with type 2 diabetes mellitus (T2DM) and cirrhosis tend to have fluctuating glucose values usually uncontrolled with conventional therapy. The aim of this case series was to retrospectively analyze the effect of continuous subcutaneous insulin infusion (CSII) on four patients with cirrhosis and poorly controlled T2DM. The four patients in this case series presented with chronic cirrhosis with no ascitis, preexisting T2DM, and inadequate blood glucose (BG) control with conventional insulin therapy. After initiation of CSII, patients' BG values were monitored at regular intervals, and basal and bolus doses were adjusted. Fasting BG, postprandial BG, and glycated hemoglobin A1c (HbA1c) values were monitored while the patient was in the hospital, upon discharge, and at one follow-up visit. The daily dose of insulin was reduced in three patients. Fasting and postprandial BG values returned to normal ranges for all four patients. HbA1c was reduced in all four patients and reduced to normal ranges in two patients. There were no recorded incidents of severe hypoglycemia, diabetic ketoacidosis, or weight gain associated with the use of CSII. Initiation of CSII in patients with T2DM and cirrhosis was beneficial in controlling BG values in the four patients studied in this case series.

Introduction: Diabetic ketoacidosis (DKA) is a serious acute metabolic complication of diabetes. Rare DKA events have occurred in patients taking sodium glucose co-transporter 2 inhibitors (SGLT2i). This study evaluated the risk of DKA in patients with type 2 diabetes mellitus (T2DM) taking SGLT2i versus other antihyperglycemic agents (AHAs) in clinical practice. Methods: This study, per protocol reviewed and approved by the European Medicines Agency, identified patients from 4 large US claims databases using broad and narrow definitions of T2DM; the broad definition captured all patients with a T2DM diagnosis and the narrow definition was intended to exclude T1DM misclassified as T2DM. DKA was identified from diagnosis codes in inpatient or emergency room claims. Eligible new users of SGLT2i and 7 groups of AHA comparators were matched (1:1) on exposure propensity scores (PS) to adjust for imbalances in baseline covariates. Cox proportional hazard models conditioned on PS-matched pairs were used to estimate hazard ratios (HR) of DKA risk for new users of SGLT2i versus other AHAs. P values were calibrated using negative control outcomes to address potential residual bias. Pooled HRs were calculated when I 2 was &lt;40% across 4 databases. Results: The number of new users of SGLT2i in each database ranged from 11,141 to 152,728 using the broad T2DM definition and from 7,779 to 130,708 using the narrow definition. Across databases, the unadjusted incidence rates of DKA (events per 1000 patient-years) ranged from 2.75 to 8.84 with SGLT2i and 1.38 to 15.82 with other AHAs using the broad T2DM definition and from 1.15 to 3.91 with SGLT2i and 0.75 to 7.94 with other AHAs using the narrow definition. Using the broad T2DM definition, a significantly increased risk of DKA was observed among new users of SGLT2i versus 5 groups of other AHAs; when using the narrow definition, an increased risk of DKA with SGLT2i was observed only compared with sulfonylureas ( Figure ). Conclusion: In this claims database study, an increased risk of DKA was observed for new users of SGLT2i versus new users of several non-SGLT2i AHAs when T2DM was defined broadly. When T2DM was defined narrowly to exclude possible misdiagnosed T1DM patients, an increased risk of DKA with SGLT2i was observed compared to sulfonylureas.

Departments of Anesthesiology and Pain Medicine and Pediatrics, University of Washington, Seattle, WA * See also p. 694. Supported, in part, by grant NINDS R01-NS072308 03. Dr. Vavilala received support for article research from the National Institutes of Health.

The National Institute for Health and Clinical Excellence (NICE) was reviewing its previous guidance on continuous subcutaneous insulin infusion (CSII). The review provided an assessment of evidence which had been published since the previous NICE appraisal (TA 151) in 2007. To examine the clinical effectiveness and cost-effectiveness of using CSII to treat diabetes. To update the previous assessment report by reviewing evidence that has emerged since the last appraisal, and to take account of developments in alternative therapies, in particular the long-acting analogue insulins, which cause fewer problems with hypoglycaemia. A systematic review of the literature and an economic evaluation were carried out. The bibliographic databases used were MEDLINE and EMBASE, 2002 to June 2007. The Cochrane Library (all sections), the Science Citation Index (for meeting abstracts only) and the website of the 2007 American Diabetes Association were also searched. The primary focus for type 1 diabetes mellitus (T1DM) was the comparison of CSII with multiple daily injection (MDI), based on the newer insulin analogues, but trials of neutral protamine Hagedorn (NPH)-based MDI that had been published since the last assessment were identified and described in brief. For type 2 diabetes mellitus (T2DM), all trials of MDI versus CSII were included, whether the long-acting insulin was analogue or not, because there was no evidence that analogue-based MDI was better than NPH-based MDI. Trials that were shorter than 12 weeks were excluded. Information on the patients' perspectives was obtained from four sources: the submission from the pump users group--Insulin Pump Therapy (INPUT); interviews with parents of young children who were members of INPUT; some recent studies; and from a summary of findings from the previous assessment report. Economic modelling used the Center for Outcomes Research (CORE) model, through an arrangement with the NICE and the pump manufacturers, whose submission also used the CORE model. The 74 studies used for analysis included eight randomised controlled trials (RCTs) of CSII versus analogue-based MDI in either T1DM or T2DM, eight new (since the last NICE appraisal) RCTs of CSII versus NPH-based MDI in T1DM, 48 observational studies of CSII, six studies of CSII in pregnancy, and four systematic reviews. The following benefits of CSII were highlighted: better control of blood glucose levels, as reflected by glycated haemoglobin (HbA1c) levels, with the size of improvement depending on the level before starting CSII; reduction in swings in blood glucose levels, and in problems due to the dawn phenomenon; fewer problems with hypoglycaemic episodes; reduction in insulin dose per day, thereby partly off-setting the cost of CSII; improved quality of life, including a reduction in the chronic fear of severe hypoglycaemia; more flexibility of lifestyle--no need to eat at fixed intervals, more freedom of lifestyle and easier participation in social and physical activity; and benefits for the patients' family. The submission from INPUT emphasised the quality of life gains from CSII, as well as improved control and fewer hypoglycaemic episodes. Also, there was a marked discrepancy between the improvement in social quality of life reported by successful pump users, and the lack of convincing health-related quality of life gains reported in the trials. With regard to economic evaluation, the main cost of CSII is for consumables, such as tubing and cannulas, and is about 1800-2000 pounds per year. The cost of the pump, assuming 4-year life, adds another 430-720 pounds per annum. The extra cost compared with analogue-based MDI averages 1700 pounds. Most studies, assuming a reduction in HbA1c level of 1.2%, found CSII to be cost-effective. The most important weakness of the evidence was the very small number of randomised trials of CSII against the most modern forms of MDI, using analogue insulins. Based on the totality of evidence, using observational studies to supplement the limited data from randomised trials against best MDI, CSII provides some advantages over MDI in T1DM for both children and adults. However, there was no evidence that CSII is better than analogue-based MDI in T2DM or in pregnancy. Further trials with larger numbers and longer durations comparing CSII and optimised MDI in adults, adolescents and children are needed. In addition, there should be a trial of CSII versus MDI with similar provision of structured education in both arms. A trial is also needed for pregnant women with pre-existing diabetes, to investigate using CSII to the best effect.

Praise and brickbats: the latest results of National Diabetes Audits for England and Wales

Advances in exercise, physical activity, and diabetes mellitus.

In recent years, continuous subcutaneous insulin infusion (CSII) using a rapid-acting insulin analog (Ra) has increasingly been utilized for young children with type 1 diabetes mellitus (T1DM). Blood glucose levels are highly variable, and achieving adequate diabetes control is quite difficult for this age group with T1DM. Studies have demonstrated CSII using Ra to be useful for improving glycemic control and making insulin delivery more convenient (1,2,3,4,5,6). This treatment option seems more suited than any other insulin regimen for young children with T1DM. Recent insulin pumps used for CSII allow programming of various basal insulin rates at different times of day to accommodate changes in the required insulin level. Nevertheless, the children themselves or their parents need to push a button to administer insulin boluses before each meal. Accordingly, administration of the boluses is very difficult for children attending a kindergarten or day nursery because neither kindergarten teachers nor nurses can give the boluses in place of a child’s parents. Therefore, we introduced an increment in the insulin basal rate during a one-hour mealtime in place of pre-meal boluses in 4 preschoolers with T1DM using CSII.

Type 1 diabetes mellitus (T1DM) is frequently associated with other autoimmune disorders that are characterized by the presence of organ-specific autoantibodies. Autoimmune thyroid disease (AIT) is the most frequent autoimmune disorder associated with T1DM. Thyroid peroxidase antibodies (TPOAb) serve as a marker for diagnosing AIT. Prior research indicates that thyroid dysfunction can negatively impact linear growth and glycemic control in subjects with T1DM. The present study was done to determine the impact of thyroid autoimmunity on the clinical and biochemical characteristics of patients with newly diagnosed T1DM. In this single-center, hospital-based, observational cross-sectional study, we enrolled 70 patients with newly diagnosed T1DM ≤18 years of age. Type 1 diabetes mellitus was diagnosed based on the acute onset of osmotic symptoms with or without diabetic ketoacidosis (DKA), severe hyperglycemia (blood glucose >13.9 mmol/l (>250 mg/dl)), and insulin requirement from the onset of diabetes. Secondary diabetes, pancreatic diabetes (Type 3c), and maturity-onset diabetes of the young (MODY) were excluded. Participants were screened for AIT disease using TPOAb testing. Based on the presence or absence of TPOAb, the participants were categorized into two groups: Group A comprised individuals with T1DM who tested positive for TPOAb, while Group B consisted of those who tested negative for TPOAb. Out of 70 patients, 41.4% were girls and 58.6% were boys, with a mean age of 9.8±4.4 years. The prevalence of TPOAb among the cohort was 18.6%. A significant majority of patients (71.4%), presented with DKA. Group A showed significantly lower mean height standard deviation scores (SDS) compared to Group B (-0.3±0.6 vs. -0.8±0.5, p = 0.004), but no differences in weight SDS or BMI SDS. Hemoglobin A1C (HbA1c) levels, C-peptide levels, and frequency of DKA did not differ between groups. Group A had higher mean thyroid-stimulating hormone (TSH) levels (4.8±3.7 µU/ml vs. 2.6±1.5 µU/ml, p = 0.001) and a greater proportion of patients with TSH levels above the upper limit of normal compared to Group B (38.4% vs. 7.1%, p = 0.008). Additionally, Group A exhibited a higher frequency of glutamic acid decarboxylase antibody (GADA) positivity compared to Group B (46.1% vs. 17.5%, p = 0.04). Patients positive for TPOAb exhibited significantly lower height SDS compared to TPOAb-negative patients. Additionally, T1DM patients with TPOAb positivity showed an increased frequency of GADA compared to those without TPOAb. However, no significant differences were found in HbA1c levels, C-peptide levels, or hematological parameters between TPOAb-positive and TPOAb-negative patients. These findings emphasize the impact of TPOAb on growth parameters in T1DM and advocate for routine screening of TPOAb in all T1DM patients, starting at the time of diabetes diagnosis.