title: Substitution of night-time continuous subcutaneous insulin infusion therapy for bedtime NPH insulin in a multiple injection regimen improves counterregulatory hormonal responses and warning symptoms of hypoglycaemia in IDDM Assessment of the severity of hypoglycemia and glycemic lability in type 1 diabetic subjects undergoing islet transplantation. Reduced Awareness of Hypoglycemia in Adults With IDDM: A prospective study of hypoglycemic frequency and associated symptoms Blood glucose awareness training and epinephrine responses to hypoglycemia during intensive treatment in type 1 diabetes. Glycaemic control and severe hypoglycaemia following training in flexible, intensive insulin therapy to enable dietary freedom in people with type 1 diabetes: a prospective implementation study Frequency of Severe Hypoglycemia in Patients With Type I Diabetes With Impaired Awareness of Hypoglycemia Use of continuous glucose monitoring system in the management of severe hypoglycemia. Impaired hypoglycaemia awareness and employment in people with Type 1 diabetes. Avoidance of Hypoglycemia Restores Hypoglycemia Awareness by Increasing -Adrenergic Sensitivity in Type 1 Diabetes Optimized basal-bolus therapy using a fixed mixture of 75% lispro and 25% NPL insulin in type 1 diabetes patients: no favorable effects on glycemic control, physiological responses to hypoglycemia, well-being, or treatment satisfaction. Blood glucose awareness training (BGAT-2): long-term benefits. Randomized Controlled Clinical Trial of Blood Glucose Awareness Training (BGAT III) in Switzerland and Germany Intensive versus standard blood glucose awareness training (BGAT) with insulin‐dependent diabetes: mechanisms and ancillary effects. Effect of Automated Bio-Behavioral Feedback on the Control of Type 1 Diabetes Improved Biomedical and Psychological Outcomes 1 Year After Structured Education in Flexible Insulin Therapy for People With Type 1 Diabetes Restoration of Self-Awareness of Hypoglycemia in Adults With Long-Standing Type 1 Diabetes Blood glucose estimation and symptoms during hyperglycemia and hypoglycemia in patients with insulin-dependent diabetes mellitus. Severe hypoglycaemia in patients with type 1 diabetes and impaired awareness of hypoglycaemia: a comparative study of insulin lispro and regular human insulin. A Multicenter Evaluation of Blood Glucose Awareness Training-II Evaluation of a treatment and teaching refresher programme for the optimization of intensified insulin therapy in type 1 diabetes. Does insulin lispro preserve the physiological defences to hypoglycaemia during intensive insulin therapy with a conventional basal bolus regimen? Administration of Neutral Protamine Hagedorn Insulin at Bedtime versus with Dinner in Type 1 Diabetes Mellitus To Avoid Nocturnal Hypoglycemia and Improve Control A randomized pilot study in Type 1 diabetes complicated by severe hypoglycaemia, comparing rigorous hypoglycaemia avoidance with insulin analogue therapy, CSII or education alone. Evaluation of a self-management-based patient education program for the treatment and prevention of hypoglycemia-related problems in type 1 diabetes. Hypoglycemia anticipation, awareness and treatment training (HAATT) reduces occurrence of severe hypoglycemia among adults with type 1 diabetes mellitus Effect of sensor-augmented insulin pump therapy and automated insulin suspension vs standard insulin pump therapy on hypoglycemia in patients with type 1 diabetes: a randomized clinical trial. Evaluation of a self-awareness intervention for adults with type 1 diabetes and hypoglycemia unawareness. Long-term recovery from unawareness, deficient counterregulation and lack of cognitive dysfunction during hypoglycaemia, following institution of rational, intensive insulin therapy in IDDM Propranolol in hypoglycaemia unawareness. The effect of a diabetes education programme (PRIMAS) for people with type 1 diabetes: results of a randomized trial. The effect of an education programme (HyPOS) to treat hypoglycaemia problems in patients with type 1 diabetes. Long-Term Follow-Up Evaluation of Blood Glucose Awareness Training Recovery of epinephrine response but not hypoglycemic symptom threshold after intensive therapy in type 1 diabetes. Recovery of Hypoglycemia Awareness in Long-standing Type 1 Diabetes: A Multicenter 2 × 2 Factorial Randomized Controlled Trial Comparing Insulin Pump With Multiple Daily Injections and Continuous With Conventional Glucose Self-monitoring (HypoCOMPaSS) A Psychoeducational Program to Restore Hypoglycemia Awareness: The DAFNE-HART Pilot Study
abstract: Summary In patients with insulin-dependent diabetes mellitus ( IDDM ) good glycaemic control confers an enhanced risk of hypoglycaemia . Nocturnal hypoglycaemia occurs frequently and contributes to the syndrome of hypoglycaemia unawareness . In order to avoid nocturnal hypoglycaemia we substituted night-time continuous subcutaneous insulin infusion ( CSII ) therapy in 14 patients with well-controlled IDDM using a multiple injection regimen for the more variable bedtime NPH insulin . During a stepwise hypoglycaemic clamp we studied the effect of this regimen on counterregulatory hormonal responses , warning symptoms and cognitive function . In addition , we investigated the incidence of daytime hypoglycaemia and the acceptability of night-time CSII  treatment . CSII was associated with a lower frequency of hypoglycaemia ( mean ± SEM ) : 16.1 ± 3.1 vs 23.6 ± 3.3 ) episodes during the last 6 weeks of treatment , p = 0.03 ( CSII vs NPH ) ) with maintenance of good glycaemic control ( HbA1c 7.2 ± 0.2 vs 7.1 ± 0.2 % , p = 0.2 ) . Hypoglycaemic thresholds for the growth hormone response and for autonomic symptoms were lower for CSII treatment than for NPH treatment . Of 14 patients 6 decided to continue with the nocturnal CSII treatment . In conclusion , nocturnal CSII improves warning symptoms and counterregulatory hormonal responses to hypoglycaemia and is an acceptable treatment strategy for patients suffering from hypoglycaemia unawareness , as demonstrated in this acute feasibility study . [ Diabetologia ( 1998 ) 41 : 322–329 Currently , the major indications for solitary islet transplantation are recurrent severe hypoglycemia and labile glucose control . Quantifying these problems remains subjective . We have developed a scoring system for both hypoglycemia and glycemic lability , established normative data , and used them in patients who have undergone islet transplantation .  A composite hypoglycemic score ( HYPO score ) was devised based on the frequency , severity , and degree of unawareness of the hypoglycemia . In addition , using 4 weeks of glucose records , a lability index ( LI ) was calculated based on the change in glucose levels over time and compared with a clinical assessment of glycemic lability . A mean amplitude of glycemic excursions ( MAGE ) was also calculated based on 2 consecutive days of seven readings each day . These scores were determined in 100 r and omly selected subjects with type 1 diabetes from our general clinic to serve as a control group and in patients before and after islet transplantation . The mean age of the control diabetic subjects was 38.4 + /- 1.3 years ( + /-SE ) , with a duration of diabetes of 21.5 + /- 1.1 years . The median HYPO score in the control subjects was 143 ( 25th to 75th interquartile range : 46 - 423 ) . The LI in the diabetic control subjects was 223 ( 25th to 75th interquartile range : 130 - 329 mmol/l(2)/h.week(-1 ) ) . The LI correlated much more closely than the MAGE with the clinical assessment of lability . A HYPO score of > or = 1,047 ( 90th percentile ) or an LI > or = 433 mmol/l(2)/h.week(-1 ) ( 90th percentile ) indicated serious problems with hypoglycemia or glycemic lability , respectively . The islet transplant patients ( n = 51 ) were 42.1 + /- 1.4 years old , with a duration of diabetes of 25.7 + /- 1.4 years . Islet transplant patients had a mean HYPO score of 1,234 + /- 184 pretransplant , which was significantly higher than that of the control subjects ( P < 0.001 ) , which became negligible posttransplantation with the elimination of hypoglycemia . The median LI pretransplant was 497 mmol/l(2)/h.week(-1 ) ( 25th to 75th interquartile range : 330 - 692 ) , significantly higher than that of control subjects ( P < 0.001 ) , and fell to 40 ( 25th to 75th interquartile range : 14 - 83 ) within a month after the final transplant . In those who had lost graft function , the LI rose again . The HYPO score and LI provide measures of the extent of problems with hypoglycemia and glycemic lability , respectively , complement the clinical assessment of the problems with glucose control before islet transplantation , and will allow comparison of selection of subjects for transplants between centers OBJECTIVE To prospect ively evaluate the frequency and severity of hypoglycemic episodes in IDDM subjects who declare themselves to have reduced awareness of hypoglycemia , to vali date their self- design ations in their natural environment , and to determine objective ly the presence or absence of autonomic and neuroglycopenic symptoms associated with their low blood glucose ( BG ) levels . RESEARCH DESIGN AND METHODS A total of 78 insulin-dependent diabetes mellitus ( IDDM ) subjects ( mean age 38.3 ± 9.2 years ; duration of diabetes 19.3 ± 10.4 years ) completed two sets of assessment s separated by 6 months . The assessment s included reports of frequency and severity of low BG , symptoms associated with low BG , and a  BG symptom/estimation trial using a h and -held computer ( HHC ) . Diaries of hypoglycemic episodes were kept for the intervening 6 months  . HbA1 levels were determined at each assessment . RESULTS Of the subjects , 39 declared themselves as having reduced awareness of hypoglycemia ( reduced-awareness subjects ) . There were no differences between these reduced-awareness subjects and aware subjects with regard to age , sex , disease duration , insulin dose , or HbA1 . During the HHC trials , reduced-awareness subjects were significantly less accurate in detecting BG < 3.9 mmol/l ( 33.2 ± 47 vs. 47.6 ± 50 % detection , P = 0.001 ) and had significantly fewer autonomic ( 0.41 ± 0.82 vs. 1.08 ± 1.22 , P = 0.006 , reduced-awareness vs. aware ) and neuroglycopenic ( 0.44 ± 0.85 vs. 1.18 ± 1.32 , P = 0.004 , reduced-awareness vs. aware ) symptoms per subject . Prospect i ve diary records revealed that reduced-awareness subjects experienced more moderate ( 351 vs. 238 , P = 0.026 ) and severe ( 50 vs. 17 , P = 0.0062 ) hypoglycemic events . The second assessment results were similar to the first and verified the reliability of the data . CONCLUSIONS IDDM subjects who believe they have reduced awareness of hypoglycemia are generally correct . They have a history of more moderate and severe hypoglycemia , are less accurate at detecting BG < 3.9 mmol/l , and prospect ively experience more moderate and severe hypoglycemia than do aware subjects . Neither disease duration nor level of glucose control explains their reduced awareness of hypoglycemia . Reduced-awareness individuals may benefit from interventions design ed to teach them to recognize all of their potential early warning symptoms OBJECTIVE To determine the effect of blood glucose awareness training ( BGAT ) on epinephrine and symptom responses to hypoglycemia in patients with type 1 diabetes enrolled in an intensive diabetes treatment ( IDT ) program . RESEARCH DESIGN AND METHODS A total of 47 subjects with uncomplicated diabetes ( duration 9 + /- 3 years : HbA1c 9.0 + /- 1.2 % ; reference range 4 - 6 % ) enrolled in a 4-month outpatient IDT program were r and omized to classes in BGAT ( n = 25 ) ( BGAT group ) or cholesterol awareness ( n = 22 ) ( control group ) . Subjects underwent stepped hypoglycemic clamp studies before and at completion of IDT . Plasma glucose was lowered from 6.7 mmol/l ( baseline ) to 4.4 , 3.9 , 3.3 , 2.8 , and 2.2 mmol/l over 190 min . Symptoms , counterregulatory hormones , and ability of the subject to estimate their glucose level were assessed at each plateau . At home , subjects used a h and held computer to first estimate and then measure and record blood glucose levels for 70 trials over a 4-week period immediately before IDT and again immediately following the educational intervention . RESULTS HbA1c decreased in both BGAT group ( 9.1 + /- 1.4 to 7.9 + /- 1.1 % ; P < 0.001 ) and control group ( 9.0 + /- 1.1 to 7.8 + /- 0.8 % ; P < 0.001 ) ( NS between groups ) . Frequency of hypoglycemia ( < 3.9 mmol/l ) increased in both groups , from 0.45 + /- 0.06 to 0.69 + /- 0.07 episodes per day ( P < 0.001 ) in the BGAT group and from 0.50 + /- 0.08 to 0.68 + /- 0.06 episodes per day ( P < 0.05 ) in the control group NS between groups ) . Epinephrine responses after IDT were greater in the BGAT group ( repeated measure analysis of variance [ ANOVA ] , F = 3.5 , P < 0.05 ) . A separate analysis of subjects n = 26 ) most at risk for hypoglycemia ( HbA1c after IDT < 7.8 % or an HbA1c improvement of > 2 percentage points ) showed that frequency of hypoglycemia increased in both the groups : from 0.50 + /- 0.09 to 0.80 + /- 0.11 episodes per day ( P < 0.01 ) in the BGAT group ( n = 14 ) and from 0.43 + /- 0.11 to 0.75 + /- 0.07 episodes per day ( P < 0.05 ) in the control group ( n = 12 ) ( NS between groups ) . However , the epinephrine response in control subjects decreased with IDT while the response in the BGAT subjects was preserved ( repeated measure ANOVA , F = 4.4 , P < 0.02 ) . CONCLUSIONS BGAT is a useful intervention to decrease blunting of counterregulatory responses associated with improved glycemic control and may modify the severity of hypoglycemia associated with improved glycemic control in type 1 diabetes Aims /hypothesisThe aim of this study was to evaluate the implementation of a course teaching flexible , intensive insulin therapy on glycaemic control and severe hypoglycaemia in routine care . Methods This is a continuous quality -assurance project involving hospital diabetes centres . Every third year each centre re-examines 50 consecutive patients ( evaluation sample ) 1 year after participation in the course . Ninety-six diabetes centres in Germany participated and 9,583 patients with type 1 diabetes ( 190 evaluation sample s ) were re-examined between 1992 and 2004 . The intervention was a 5-day inpatient course for groups of up to ten patients with a fixed curriculum of education and training for dietary flexibility and insulin adjustment . The main outcome measures were HbA1c and severe hypoglycaemia . Results Mean baseline HbA1c was 8.1 % , and had decreased to 7.3 % at follow-up ; incidence of severe hypoglycaemia was 0.37 events per patient per year prior to intervention and 0.14 after intervention . In mixed-effects models adjusted for effects of centres , age and diabetes duration , the mean difference was −0.7 % ( 95 % CI −0.9 to −0.6 % , p<0.0001 ) for HbA1c and −0.21 events per patient per year ( 95 % CI −0.32 to −0.11 , p=0.0001 ) for severe hypoglycaemia , with similar results for evaluation sample s , with a maximum of 10 % of patients lost to follow-up . Before intervention , the incidence of severe hypoglycaemia was three-fold higher in the lowest quartile than in the highest quartile of HbA1c , whereas the risk was comparable across the range of HbA1c values after intervention . Conclusions /interpretationImplemented as part of a continuous quality -assurance programme the self-management programme is effective and safe in routine care . Improvement of glycaemic control can be achieved without increasing the risk of severe hypoglycaemia OBJECTIVE To determine the frequency of hypoglycemia in patients with type I diabetes and impaired awareness of hypoglycemia by prospect i ve assessment . RESEARCH DESIGN AND METHODS A prospect i ve study was undertaken for 12 months in 60 patients with type I diabetes : 29 had impaired awareness of hypoglycemia and 31 retained normal awareness of hypoglycemia . The two groups of patients were matched for age , age at onset of diabetes , duration of diabetes , and glycemic control . Episodes of severe hypoglycemia were recorded within 24 h of the event and verified where possible by witnesses . RESULTS During the 12 months , 19 ( 66 % ) of the patients with impaired awareness had one or more episodes of severe hypoglycemia with an overall incidence of 2.8 episodes · patient–1 · year–1 . By comparison , 8 ( 26 % ) of the patients with normal awareness experienced severe hypoglycemia ( P < 0.01 ) with an annual incidence of 0.5 episode · patient–1 · year–1 ( P < 0.001 ) . Severe hypoglycemia occurred at different times of the day in the two groups : patients with impaired awareness experienced a greater proportion of episodes during the evening ( P = 0.03 ) , and patients with normal awareness experienced a greater proportion in the early morning ( P = 0.05 ) . An assessment of fear of hypoglycemia revealed that patients with impaired awareness of hypoglycemia worried more about hypoglycemia than did patients with normal awareness ( P = 0.008 ) , but did not modify their behavior accordingly . CONCLUSIONS This prospect i ve evaluation demonstrated that impaired awareness of hypoglycemia predisposes to a sixfold increase in the frequency of severe hypoglycemia , much of which occurred at home during waking hours BACKGROUND Severe hypoglycemia can have a dramatic impact on daily life for people with diabetes . Hypoglycemia is quantifiable by the HYPO-Score derived from the frequency of severe hypoglycemia over a year and a component based on 4 weeks of glucose records . The latter gives a modified HYPO-Score as a short-term measure of hypoglycemia . We used a continuous glucose monitoring system ( CGMS ) in patients with severe hypoglycemia to assess if we could decrease hypoglycemia as measured by the modified HYPO-Score . METHODS Sixteen type 1 diabetes subjects , 52.0 + /- 2.3 years old with a diabetes duration of 29.4 + /- 2.8 years having problematic hypoglycemia were enrolled . All used multiple daily insulin injections , and the glycosylated hemoglobin level was 8.4 + /- 0.3 % . After a month of gathering hypoglycemia information for baseline modified HYPO-Score , subjects wore the CGMS for 2 months , and a modified HYPO-Score was repeated . To assess long-term benefit , CGMS was then discontinued for 3 months , and a final modified HYPO-Score was determined . RESULTS The modified HYPO-Score decreased from 857 + /- 184 to 444 + /- 92 ( P = 0.055 ) ( intention-to-treat basis ) . Further analysis of the modified HYPO-Score when the CGMS was actually functioning showed it decreased from 857 + /- 184 to 366 + /- 86 ( P = 0.023 ) . Severe hypoglycemia episodes dropped from 16 at baseline to three when wearing the CGMS . The number of hypoglycemia episodes < 3.0 mmol/L dropped from 8.6 + /- 1.5 to 4.7 + /- 0.9 ( P = 0.01 ) . Subjects expressed less fear of hypoglycemia with CGMS . In 11 who completed modified Final Month HYPO-Scores , the number of severe hypoglycemic events rose to six . At study end , 13 of 16 subjects elected to continue using the CGMS . CONCLUSIONS When the CGMS was worn and functioning there was a significant decrease in the modified HYPO-Score and number of hypoglycemic values < 3.0 BACKGROUND Impaired awareness of hypoglycaemia ( IAH ) is common in adults with Type 1 diabetes mellitus ( T1DM ) and is a major risk factor for severe hypoglycaemia . Little is known about its effect on employment status . AIMS To examine the effect that IAH has on the employment status or employability of people with T1DM . METHODS A r and omly selected cohort of adults of employment age with T1DM completed a question naire detailing the history of their diabetes , their occupational history ( including job and industry type ) and assessing both their hypoglycaemia awareness status and whether in their view their ability to obtain or retain employment had been adversely affected by having diabetes . RESULTS A total of 252 patients participated , with the following characteristics : 135 males , mean HbA1c 8.5 % [ st and ard deviation ( SD ) 1.4 ] , mean age 43.3 years ( SD 13.2 ) , mean duration of diabetes 21.3 years ( SD 12.8 ) and prevalence of IAH 23.4 % . The employment rate was comparable between those with preserved awareness ( 73 % ) and the IAH group ( 66 % ) ( not significant ) . People with IAH were older ( P < 0.05 ) and also more commonly felt that having diabetes affected their ability to work ( P < 0.05 ) . CONCLUSIONS This study is the first to demonstrate that those with T1DM and IAH remain as economically active as those with normal awareness of hypoglycaemia , although subjects with IAH were significantly more likely to feel that having diabetes had adversely affected their capacity for employment Hypoglycemia unawareness is a major limiting factor in the management of type 1 diabetes ( 1 ) . This common problem , reported to occur in about 25 % of patients with type 1 diabetes ( 2 ) , is characterized by loss of autonomic warning symptoms before development of neuroglycopenia ( 2 ) . Hypoglycemia unawareness is associated with a sevenfold increase in the frequency of severe hypoglycemia ( 3 ) , which may be accompanied by seizure and coma . In the past decade , several risk factors for hypoglycemia unawareness have been identified , including long duration of diabetes , tight glycemic control ( low hemoglobin A1c values ) , and repeated episodes of hypoglycemia ( 1 , 2 , 4 - 7 ) . It has been thought that reduced counterregulatory hormone responses to hypoglycemia ( 4 , 5 ) are primarily responsible for hypoglycemia unawareness . However , recent studies suggest that impaired -adrenergic sensitivity ( 8 - 10 ) may also be involved . Patients with type 1 diabetes experience progressive reduction in the plasma catecholamine response to hypoglycemia ( 11 ) . This phenomenon may be an intrinsic element of type 1 diabetes or a consequence of cortisol release during hypoglycemia , which has been shown to blunt catecholamine response during subsequent hypoglycemic episodes ( 12 ) . Hypoglycemia-aware patients with type 1 diabetes who have reduced catecholamine responses during hypoglycemia have increased -adrenergic sensitivity ( 10 ) , perhaps because increases in plasma cortisol during hypoglycemia upregulate -receptors ( 13 , 14 ) . With continued episodes of hypoglycemia , the maximally enhanced -adrenergic sensitivity decreases and hypoglycemia unawareness ensues , probably because of exhausted -receptor upregulation ( 9 ) . Indeed , a single episode of hypoglycemia reduces -adrenergic sensitivity in patients with type 1 diabetes who are already compensating for reduced catecholamine response to hypoglycemia with maximally enhanced -adrenergic sensitivity ( 10 ) . Studies of patients with insulinoma ( 15 ) , those who have had pancreas transplantation ( 16 ) , and those with type 1 diabetes ( 17 - 21 ) indicate that hypoglycemia unawareness can be reversed by avoidance of hypoglycemia . In patients with type 1 diabetes ( 17 - 21 ) , hypoglycemia unawareness has been shown to occur in the absence of improved plasma catecholamine responses ( 20 , 22 ) , suggesting that increased sensitivity to catecholamines may be the primary mechanism . We sought to examine the effect of strict avoidance of hypoglycemia for 4 months in 10 patients with diabetes of long duration , hypoglycemia unawareness , and a history of severe hypoglycemia . Methods Participants The protocol was approved by the Ethical Committee of the University of Tbingen School of Medicine . Ten men with type 1 diabetes who had self-reported reduced awareness of hypoglycemia and a history of severe hypoglycemia as defined by the Diabetes Control and Complications Trial ( 7 , 23 ) ( hypoglycemia result ing in coma or seizure , requiring assistance of another person and treatment with glucagon or intravenous glucose ) were studied . All participants gave written informed consent . Clinical characteristics are shown in the Table . Table . Patient Characteristics and Responses during Hypoglycemic Clamp In all participants , autonomic neuropathy was excluded by st and ard cardiovascular testing ( variation in resting heart rate according to spectral analysis , the Valsalva maneuver , lying-to-st and ing , and deep breathing [ 24 ] ) . All patients were receiving an intensive insulin regimen with injections of long-acting insulin in the morning and at bedtime and short-acting insulin before meals ( usually three times daily ) . We compared the study patients with 10 patients who had type 1 diabetes and hypoglycemia awareness and 10 nondiabetic controls ; data on these 20 persons were published elsewhere ( 10 ) . These 20 persons had been studied by using methods identical to those in the present study . Prevention of Hypoglycemia To avoid hypoglycemia , we followed modifications of the guidelines proposed by Amiel ( 25 ) . Target prepr and ial blood glucose levels were increased from 5.6 mmol/L to 8.3 mmol/L ( 100 mg/dL to 150 mg/dL ) , and target bedtime blood glucose levels were increased from 5.6 mmol/L to 10 mmol/L ( 100 mg/dL to 180 mg/dL ) to avoid nighttime hypoglycemia . To achieve these targets , the dose of long-acting insulin  ( preferably that given at bedtime ) was reduced . The daily short-acting insulin dose was reduced and adjusted individually to the carbohydrate content of the meal to be consumed and the actual blood glucose level . Patients were instructed to measure blood glucose at least five times daily . During the study , participants were contacted at least biweekly for adjustments of insulin dosage intended to prevent blood glucose levels from decreasing to less than 3.9 mmol/L ( 70 mg/dL ) . Patient adherence to the new blood glucose targets was reinforced by discussion with patients of the importance of the problem . Protocol Participants underwent hyperinsulinemic hypoglycemic clamp before and after 4 months of prevention of hypoglycemia . Isoproterenol testing was performed to measure -adrenergic sensitivity before and after 2 and 4 months of prevention of hypoglycemia . Isoproterenol testing was performed approximately 1 week before the corresponding hypoglycemic clamp . For both the hypoglycemic clamp and the isoproterenol test , participants were admitted to the university 's clinical research unit at 8:00 pm . They had been instructed to reduce their insulin dose by 10 % for 3 days before testing to avoid blood glucose lower than 5 mmol/L ( 90 mg/dL ) . They had injected their last regular dose of insulin before dinner on the day before testing . At 11:00 pm , they injected a 10 % reduced dose of neutral protamine Hagedorn insulin to avoid blood glucose levels less than 6.7 mmol/L ( 120 mg/dL ) . During the night , blood glucose was checked every 2 hours . Oral administration of 10 g of glucose was planned if blood glucose levels decreased below 6.7 mmol/L ( 120 mg/dL ) ; this did not occur in any patient . Isoproterenol Testing At 7:00 a.m. , an indwelling catheter was inserted into an antecubital vein for infusion of insulin and injection of isoproterenol . A variable insulin infusion ( 0 to 1 mU/kg/min ) was begun to keep blood glucose levels between 6.7 and 10 mmol/L ( 120180 mg/dL ) during isoproterenol testing . Participants were connected to a computer-assisted electrocardiograph ( NeuroDiag , Munich , Germany ) for determination of cardiovascular responses . Blood pressure was recorded by using an automatic device ( DINAMAP , Critikon , Tampa , Florida ) . Appropriately diluted isoproterenol ( Isuprel , Sanofi , Brussels , Belgium ) was injected as a 5-mL bolus in a forearm vein through a three-way valve in doses of 0 ( 5 mL NaCl , 0.9 % ) , 0.25 , 0.5 , 0.75 , 1.0 , 1.5 , 2.0 , 2.5 , 3.0 , and 4.0 g. The interval between each injection was 20 minutes . An electrocardiogram was recorded online for 1 minute before and 5 minutes after each injection . The basal heart rate was defined as the mean of the rate obtained in the 20 seconds before the first injection . The maximal heart rate was usually reached approximately 30 to 60 seconds after each injection and returned to baseline before the end of the 5-minute recording interval . The maximal heart rate was determined by search ing for the shortest RR interval after injection ; extrasystoles were excluded by graphical analysis of heart rate recordings . Blood pressure was recorded at baseline and at 2 minutes and 5 minutes after injection , by which time heart rate had returned to baseline .  Blood glucose  was measured every 15 minutes . The test was stopped prematurely if the increase in heart rate exceeded 50 beats/min or maximal blood pressure exceeded 170/90 mm Hg . -Adrenergic sensitivity was expressed as the dose of isoproterenol that increased heart rate by 25 beats/min ( IC25 ) . This value was determined by fitting a curve through the change in heart rates plotted over the isoproterenol doses and calculating the intercept , with the change in heart rate equal to 25 beats/min . Hypoglycemic Clamp At 7:00 a.m. , indwelling catheters were inserted into an antecubital vein for infusion of glucose and insulin and into a dorsal h and vein for arterial blood sampling . The h and was kept in a heated chamber during this procedure . An insulin infusion with a constant rate of 1 mU/kg per minute was begun , and blood glucose was clamped at 3 mmol/L ( 54 mg/dL ) for 180 minutes . Afterward , participants received a st and ardized meal containing 48 g of carbohydrates and were discharged as soon as blood glucose levels exceeded 6.7 mmol/L ( 120 mg/dL ) . Symptom Question naire A semiquantitative symptom question naire was administered twice before hypoglycemic clamp and at 30 , 90 , 150 , and 180 minutes during the clamp . Participants scored their symptoms from 0 ( none ) to 7 ( severe ) in response to 9 autonomic symptoms ( tremor , sweating , shivering , hunger , pounding heart , anxiety , nausea , feeling tearful ) , 10 neuroglycopenic symptoms ( difficulty speaking , double vision , headache , drowsiness , blurred vision , tingling around the mouth , inability to concentrate , confusion , tiredness , weakness ) and 10 dummy symptoms . All of these symptoms were presented to patients in r and om order ( 26 ) . Total symptom score and the neuroglycopenic and autonomic symptom scores were calculated for each time point . Blood Sampling and Analysis Plasma epinephrine and norepinephrine levels were measured at 30 and 15 minutes before and 30 , 90 , 150 , and 180 minutes during hypoglycemic clamp . Blood glucose was measured at the bedside by using a Hemocue blood glucose photometer ( Hemocue AB , Angelham , Sweden ) . Catecholamines were measured in ethylenediamine tetraacetic acidtreated plasma by using high-performance liquid chromatography with electrochemical detection ( ClinRep Analysis Kit , Recipe Pharma , Munich , Germany ) . Statistical Analysis Unless otherwise stated , data are given as the mean ( SE ) . For increments of catecholamine OBJECTIVE To investigate the effects of a multiple injection regimen with a mixture of 75 % lispro and 25 % intermediate-acting insulin ( lispro high mixture [ HM ] ) before meals on glycemic control , physiological responses to hypoglycemia , well-being , and treatment satisfaction . RESEARCH DESIGN AND METHODS We studied 35 type 1 diabetes patients . After an 8- to 10-week lead-in period , patients were r and omized to HM or human regular insulin therapy for 12 - 14 weeks . During the lead-in and treatment periods , HbA1c levels and hypoglycemic frequencies were measured , and patients completed the Well-Being Question naire and the Diabetes Treatment Satisfaction Question naire . In 19 patients , responses to hypoglycemia were tested during stepped euglycemic-hypoglycemic clamps . RESULTS HM treatment improved postpr and ial glycemia but had no effect on HbA1c , frequency of hypoglycemia , well-being , or treatment satisfaction . During experimental hypoglycemia , HM therapy was associated with a slightly lower total adrenaline response and a higher autonomic symptom threshold ( i.e. , the autonomic symptom response occurred at a lower blood glucose level ) than human regular insulin therapy . We speculate that this effect result ed from an accumulation of insulin during the night . CONCLUSIONS Multiple injection therapy with HM rather than human regular insulin before meals does not offer advantages regarding glycemic control , frequency of hypoglycemia , well-being , or treatment satisfaction . In addition , this regimen causes an attenuation of the adrenaline and autonomic symptom responses to hypoglycemia OBJECTIVE Blood glucose awareness training ( BGAT ) has been shown to improve awareness of blood glucose ( BG ) fluctuations among adults with type 1 diabetes . This study investigates the long-term ( 12-month ) benefits of BGAT-2 . RESEARCH DESIGN AND METHODS A total of 73 adults with type 1 diabetes participated in a 6-month repeated baseline design with a 12-month follow-up . At 6 months and 1 month before BGAT-2 and at 1,6 , and 12 months after BGAT-2 , subjects used a h and held computer for 50 trials and completed psychological tests . Throughout assessment , subjects completed diaries , recording occurrences of diabetic ketoacidosis , severe hypoglycemia , and motor vehicle violations During follow-up , 50 % of the subjects received booster training . RESULTS During the first and last halves of both the baseline period and the follow-up period , dependent variables were generally stable . However , from baseline to follow-up , BGAT-2 led to 1 ) improved detection of hypoglycemia and hyperglycemia ; 2 ) improved judgment regarding when to lower high BG , raise low BG , and not drive while hypoglycemic ; 3 ) reduction in occurrence of diabetic ketoacidosis , severe hypoglycemia , and motor vehicle violations ; and 4 ) improvement in terms of worry about hypoglycemia , quality of life , and diabetes knowledge . Reduction in severe hypoglycemia was not associated with a worsening of metabolic control ( HbA1 ) . The presence or absence of booster training did not differentially affect these benefits . CONCLUSION BGAT has sustained broad-ranging benefits , independent of booster intervention Although both diabetes and the efficacy of medical management are international issues , psycho-educational interventions might be culturally bound . Blood Glucose Awareness Training ( BGAT ) is a psycho-educational program for patients with type 1 diabetes mellitus . It is focused on improving recognition and management of extreme blood glucose levels , and is the best documented American psycho-educational program for this purpose . A r and omized controlled clinical trial of BGAT 's long-term benefits in a non-American setting has been lacking . One hundred and eleven adults with type 1 diabetes mellitus from Switzerl and and Germany participated . After a 6 months baseline assessment , subjects were r and omly assigned to receive either 2 months of BGAT ( n = 56 ) or a physician-guided self-help control intervention ( n = 55 ) . BGAT  improved recognition of low ( p = 0.008 ) , high ( p = .03 ) , and overall blood glucose ( p = 0.001 ) , and reduced frequency of severe hypoglycemia ( p = 0.04 ) , without compromising metabolic control .  BGAT reduced both the external locus of control ( p < 0.02 ) and fear of hypoglycemia ( p < 0.02 ) . BGAT was efficacious in reducing adverse clinical events and achieving clinical ly desirable goals in a European , as well as American setting & NA ; Insulin‐dependent diabetes mellitus ( IDDM ) patients make critical daily self‐care decisions on the basis of what they estimate their blood glucose ( BG ) levels to be . This study : a ) replicated efficacy of St and ard Blood Glucose Awareness Training ( BGAT ) , b ) evaluated the relative efficacy of an Intensive Blood Glucose Awareness Training ( BGAT ) to enhance patient accuracy of BG estimation , and c ) evaluated the mechanisms and ancillary effects of BGAT . Thirty‐nine subjects were r and omly assigned to one of three groups . Compared with Control , both St and ard and Intensive BGAT  improved accuracy ( p less than 0.001 ) . Intensive BGAT post‐treatment accuracy relative to St and ard BGAT did not reach statistical significance ( p = 0.177 ) . Greater improvement in accuracy was associated with poorer pretreatment accuracy . Only Intensive BGAT improved metabolic control ( glycosylated hemoglobin ) , and this improvement was associated with poorer pretreatment control . The effects of BGAT were highly specific , affecting only accuracy and metabolic control , and not affecting fear of hypoglycemia , diabetes knowledge , of frequency of blood glucose monitoring OBJECTIVE To test the effect of an automated system providing real-time estimates of HbA1c , glucose variability , and risk for hypoglycemia . RESEARCH DESIGN AND METHODS For 1 year , 120 adults with type 1 diabetes ( 69 female/51 male , age = 39.1 [ 14.3 ] years , duration of diabetes 20.3 [ 12.9 ] years , HbA1c = 8.0 [ 1.5 ] ) , performed self-monitoring of blood glucose ( SMBG ) and received feedback at three increasingly complex levels , each continuing for 3 months : level 1—routine SMBG ; level 2—adding estimated HbA1c , hypoglycemia risk , and glucose variability ; and level 3—adding estimates of symptoms potentially related to hypoglycemia . The subjects were r and omized to feedback sequences of either levels 1 - 2 - 3 or levels 2 - 3 - 1 . HbA1c , symptomatic hypoglycemia , and blood glucose awareness were evaluated at baseline and at the end of each level . RESULTS For all subjects , HbA1c was reduced from 8.0 to 7.6 from baseline to the end of study ( P = 0.001 ) . This effect was confined to subjects with baseline HbA1c > 8.0 ( from 9.3 to 8.5 , P < 0.001 ) . Incidence of symptomatic moderate/severe hypoglycemia was reduced from 5.72 to 3.74 episodes/person/month ( P = 0.019 ) , more prominently for subjects with a history of severe hypoglycemia ( from 7.20 to 4.00 episodes , P = 0.008 ) and for those who were hypoglycemia unaware ( from 6.44 to 3.71 episodes , P = 0.045 ) . The subjects ’ ratings of the feedback were positive , with up to 89 % approval of the provided features . CONCLUSIONS Feedback of SMBG data and summary SMBG-based measures result ed in improvement in average glycemic control and reduction in moderate/severe hypoglycemia . These effects were most prominent in subjects who were at highest risk at the baseline OBJECTIVE DAFNE ( Dose Adjustment For Normal Eating ) , a structured education program in flexible insulin therapy , has been widely adopted in the U.K. after validation in a r and omized trial . To determine benefits in routine practice , we collected biomedical and psychological data from all participants attending during a 12-month period . RESEARCH DESIGN AND METHODS HbA1c , weight , self-reported hypoglycemia awareness , severe hypoglycemia frequency , PAID ( Problem Areas In Diabetes ) , HADS ( Hospital Anxiety and Depression Scale ) , and EuroQol Group 5-Dimension Self-Report  Question naire scores were recorded prior to DAFNE and after 1 year . RESULTS Complete baseline and follow-up HbA1c data were available for 639 ( 54.9 % ) of 1,163 attendees . HbA1c fell from 8.51 ± 1.41 ( mean ± SD ) to 8.24 ± 1.29 % ( difference 0.27 [ 95 % CI 0.16–0.38 ] ; P < 0.001 ) , with a greater mean fall of 0.44 % from baseline HbA1c > 8.5 % . Severe hypoglycemia rate fell from 1.7 ± 8.5 to 0.6 ± 3.7 episodes per person per year ( 1.1 [ 0.7–1.4 ] ) and hypoglycemia recognition improved in 43 % of those reporting unawareness . Baseline psychological distress was evident , with a PAID score of 25.2 and HADS scores of 5.3 ( anxiety ) and 4.8 ( depression ) , falling to 16.7 ( 8.5 [ 6.6–10.4 ] ) , 4.6 ( 0.7 [ 0.4–1.0 ] ) , and 4.2 ( 0.6 [ 0.3–0.8 ] ) , respectively ( all P < 0.001 at 1 year ) . Clinical ly relevant anxiety and depression ( HADS ≥8 ) fell from 24.4 to 18.0 % and 20.9 to 15.5 % , respectively . CONCLUSIONS A structured education program delivered in routine clinical practice not only improves HbA1c while reducing severe hypoglycemia rate and restoring hypoglycemia awareness but also reduces psychological distress and improves perceived well-being OBJECTIVE Impaired awareness of hypoglycemia ( IAH ) and defective counterregulation significantly increase severe hypoglycemia risk in type 1 diabetes ( T1D ) . We evaluated restoration of IAH/defective counterregulation by a treatment strategy targeted at hypoglycemia avoidance in adults with T1D with IAH ( Gold score ≥4 ) participating in the U.K.-based multicenter HypoCOMPaSS r and omized controlled trial . RESEARCH DESIGN AND METHODS Eighteen subjects with T1D and IAH ( mean ± SD age 50 ± 9 years , T1D duration 35 ± 10 years , HbA1c 8.1 ± 1.0 % [ 65 ± 10.9 mmol/mol ] ) underwent stepped hyperinsulinemic-hypoglycemic clamp studies before and after a 6-month intervention . The intervention comprised the HypoCOMPaSS education tool in all and r and omized allocation , in a 2 × 2 factorial study design , to multiple daily insulin analog injections or continuous subcutaneous insulin infusion therapy and conventional glucose monitoring or real-time continuous glucose monitoring  . Symptoms , cognitive function , and counterregulatory hormones were measured at each glucose plateau ( 5.0 , 3.8 , 3.4 , 2.8 , and 2.4 mmol/L ) , with each step lasting 40 min with subjects kept blinded to their actual glucose value throughout clamp studies . RESULTS After intervention , glucose concentrations at which subjects first felt hypoglycemic increased ( mean ± SE from 2.6 ± 0.1 to 3.1 ± 0.2 mmol/L , P = 0.02 ) , and symptom and plasma metanephrine responses to hypoglycemia were higher ( median area under curve for symptoms , 580 [ interquartile range { IQR } 420–780 ] vs. 710 [ 460–1,260 ] , P = 0.02 ; metanephrine , 2,412 [ −3,026 to 7,279 ] vs. 5,180 [ −771 to 11,513 ] , P = 0.01 ) . Glycemic threshold for deterioration of cognitive function measured by four-choice reaction time was unchanged , while the color-word Stroop test showed a degree of adaptation . CONCLUSIONS Even in long-st and ing T1D , IAH and defective counterregulation may be improved by a clinical strategy aim ed at hypoglycemia avoidance PURPOSE To investigate hypoglycemic and hyperglycemic symptoms , accuracy of estimating blood glucose , and their relation to glycemic control and counterregulatory hormone levels in insulin-dependent diabetes mellitus . PATIENTS AND METHODS During r and omly ordered stepped hypoglycemic and hyperglycemic insulin clamps on two separate days , 42 patients with insulin-dependent diabetes mellitus rated the intensity of 40 moods and symptoms when glucose was 8.9 , 5.6 and 2.2 mmol/L , and 8.9 , 14.4 and 21.1 mmol/L. The subjects were blinded to their actual glucose levels and asked to estimate them at each step . Epinephrine , norepinephrine , cortisol , growth hormone , and glucagon were measured at each glucose plateau . RESULTS Cluster analysis yielded five symptom groups during hypoglycemia : autonomic symptoms , negative moods , positive moods , feeling weak/dizzy , and feeling relaxed . At 2.2 mmol/L , mean scores for all five symptom groups and 11 of 17 unclustered symptoms differed from those reported at the baseline glucose of 8.9 mmol/L ( P < or = 0.05 ) , but 34 % of patients reported no awareness of autonomic symptoms . The intensity of autonomic symptoms correlated positively with HbA1 ( r = .43 , P < 0.01 ) , epinephrine ( r = .59 , P < 0.001 ) , norepinephrine ( r = .45 , P < 0.01 ) and cortisol ( r = .62 , P < 0.001 ) , and negatively with glucose estimation error ( r = -.45 , P = 0.01 ) . Six patients ( 15 % ) were unaware of both autonomic and neuroglycopenic symptoms during hypoglycemia . At 21.1 mmol/L , only 5 of 40 symptoms differed ( P < 0.05 ) from baseline . Seventeen percent of subjects made potentially serious errors when estimating glucose at 2.2 mmol/L , and 66 % at 21.1 mmol/L. Many patients experienced symptoms different from those they reported as their usual manifestations of changing glucose levels . CONCLUSIONS Since the majority of patients made clinical ly serious errors in glucose estimation , and many used symptoms that did not discriminate hyperglycemia and hypoglycemia , individualized training to increase awareness of glucose-related symptoms and glucose levels may help patients reduce the frequency or severity of hyperglycemic and hypoglycemic events OBJECTIVE To assess the potential of insulin lispro to limit the frequency of severe hypoglycaemia without compromising glycaemic control in a cohort of patients with type 1 diabetes who are at a high risk of severe hypoglycemia . Research design and methods An open-label , r and omised , 12-month comparative crossover study of insulin lispro and regular human insulin was performed in 33 patients with type 1 diabetes with impaired hypoglycaemia awareness . The efficacy of each treatment was evaluated by glycaemic control ( HbA(1c ) ) , eight-point home blood glucose profiles , and the frequency and severity of hypoglycaemic episodes and quality of life . RESULTS Eighteen ( 55 % ) patients experienced one or more episodes of severe hypoglycaemia in the 48 weeks of study . There was a trend to a lower incidence of severe hypoglycaemia during treatment with insulin lispro in comparison with regular human insulin ( 55 vs 84 episodes , p=0.087 ) . This result ed principally from a 47 % lower incidence of nocturnal severe hypoglycaemia with insulin lispro ( 25 vs 47 episodes , p=0.11 ) . The lower frequency of severe hypoglycaemia associated with insulin lispro was not explained by differences in glycated haemoglobin between insulin treatments ( HbA(1c ) 9.1 % insulin lispro vs 9.3 % regular human insulin ) . CONCLUSIONS In individuals with type 1 diabetes , who have impaired awareness of hypoglycaemia , treatment with insulin lispro may be associated with a lower incidence of severe hypoglycaemia manifested predominantly through less frequent nocturnal episodes . Insulin lispro may have a beneficial role in the management of patients with diabetes at risk of severe hypoglycaemia , although a larger study is required to confirm these findings OBJECTIVE Blood glucose awareness training ( BGAT ) teaches individuals with insulin-dependent diabetes to more accurately estimate/detect their blood glucose ( BG ) fluctuations . It has not , however , consistently result ed in improved ability to detect low BG . To assess an enhanced version of BGAT ( BGAT-II ) , with more focus on increasing sensitivity to low BG events , a multicenter study was undertaken . Following up on previous findings that BGAT is most effective with individuals who are least accurate in estimating BG , this study explicitly recruited subjects who did and did not report reduced awareness of hypoglycemia . RESEARCH DESIGN AND METHODS Seventy-eight subjects from three research sites participated in a repeated baseline design . Subjects ' BG estimation accuracy and BG profiles were assessed 6 months before , immediately before , and immediately after BGAT-II . RESULTS Post-treatment , BGAT-II led to better overall accuracy in detecting BG fluctuations and better detection of both low and high BG levels . This was achieved while the number of low readings of self-monitoring of blood glucose ( SMBG ) was reduced . Reduction in the number of low SMBG events was significant only for subjects reporting awareness of hypoglycemia . Detection of low BG was significant only for subjects reporting reduced awareness of hypoglycemia . Both groups demonstrated equivalent improvements in detection of high BG levels .  CONCLUSIONS BGAT may be an eﬀective behavioral strategy for reversing hypoglycemic unawareness and an adjunct to intensive insulin therapy to reduce the occurrence of severe hypoglycemia OBJECTIVE Evaluation of an ambulatory diabetes teaching and treatment refresher programme ( DTTP ) for the optimization of intensified insulin therapy in patients with type 1 diabetes ( refresher course ) . METHODS 85 out patients took part in this prospect i ve multicentre trial . Metabolic and psychosocial data were analyzed at baseline ( V1 ) , 6 weeks ( V2 ) and 12 months after DTTP ( V3 ) . RESULTS In patients with baseline HbA1c>7 % ( 88 % ) , HbA1c decreased by 0.36 % ( p=0.004 ) . The percentage of patients with HbA1c≤7 % increased from 21.3 to 34.9 % and with HbA1c above 10 % decreased from 6.6 to 1.6 % at V3 . The incidence of hypoglycaemia decreased significantly : non severe hypoglycaemia from 3.31 to 1.39 episodes/pat/week ( p=0.001 ) and severe hypoglycaemia from 0.16 to 0.03 episodes/pat/year ( p=0.02 ) . The treatment satisfaction increased by + 10 of maximal ±18 points . The negative influence of diabetes on quality of life decreased from -1.93 to -1.69 points ( p=0.031 ) . CONCLUSION In a group of patients with moderately controlled diabetes type 1 who were already treated with intensified insulin therapy , metabolic control , treatment satisfaction and quality of life were improved after participation in an ambulatory DTTP without increasing insulin dosage , number of injections or insulin species . PRACTICE IMPLICATION S This DTTP is effective for the optimization of intensified insulin therapy Aim : Insulin lispro used in an intensive basal/bolus regimen produces equivalent glycaemic control to human‐soluble insulin but reduces rates of hypoglycaemia . We tested the hypothesis that the use of rapid‐acting analogues might prevent the development of defective hypoglycaemic counterregulation during intensive insulin therapy Context Clinicians often split evening insulin dosing ( short-acting insulin at dinner and long-acting insulin at bedtime rather than both types with dinner ) to avoid nocturnal hypoglycemia in patients with type 1 diabetes mellitus . Although split dosing makes sense theoretically , no rigorous studies have examined its effects on glycemic control . Contribution In this r and omized , controlled crossover trial , episodes of nocturnal hypoglycemia were less frequent and fasting blood glucose and hemoglobin A1c levels were lower with split evening insulin than with mixed dosing at dinner . Clinical Implication s This study supports splitting evening insulin dosing to improve glycemic control in patients with intensively treated type 1 diabetes . The Editors Nocturnal hypoglycemia is common in patients with type 1 diabetes mellitus ( 1 - 7 ) . When insulin treatment is intensified to achieve near-normoglycemia , the frequency of hypoglycemia increases ; approximately half of these episodes occur at night ( 2 , 3 ) . Unrecognized nocturnal hypoglycemia is common ( 1 , 3 - 8 ) . Overtreatment of symptomatic nocturnal hypoglycemia with snacks often results in hyperglycemia the next day ( 9 - 11 ) . Asymptomatic nocturnal hypoglycemia can cause morning headache and malaise and may result in diminished awareness , reduced responses of adrenaline , and adaptation of cognitive function during the episode ( 12 - 15 ) . Recurrent nocturnal hypoglycemia may contribute to the vicious cycle of hypoglycemia unawareness and impaired hormonal counterregulation in patients with type 1 diabetes , leading to increased risk for severe hypoglycemia ( 16 ) . The nonphysiologic pharmacokinetics and pharmacodynamics of insoluble , intermediate-acting insulin preparations , such as neutral protamine Hagedorn ( NPH ) insulin , play a central role in inducing nocturnal hypoglycemia in type 1 diabetes ( 4 ) . When injected at dinner , NPH insulin results in excess plasma insulin bioavailability at approximately midnight , a time at which patients with type 1 diabetes are more insulin sensitive ( 17 , 18 ) ; thus , the risk for hypoglycemia increases between midnight and 3:00 a.m. Later , insulin deficiency develops at dawn ( 4 , 18 ) and contributes to fasting hyperglycemia . When the nocturnal peak plasma level of insulin produced by an evening injection of intermediate-acting ( NPH ) insulin is postponed by 3 to 4 hours as a result of injecting NPH insulin at bedtime instead of at dinner , fasting and postbreakfast blood glucose levels decrease ( 19 ) . Although the pharmacokinetics and pharmacodynamics of NPH insulin would suggest that splitting of the evening insulin regimen ( administering short-acting insulin at dinner and NPH insulin at bedtime ) should decrease the risk for nocturnal hypoglycemia , to the best of our knowledge no data indicate this in patients with type 1 diabetes mellitus . W e tested the hypothesis that in intensive treatment of type 1 diabetes , splitting the evening insulin administration rather than mixing short-acting and NPH insulin at dinner reduces the risk for nocturnal hypoglycemia and improves glycemic control , awareness of hypoglycemia , and counterregulation to hypoglycemia . Although split dosing makes sense theoretically , no rigorous studies have examined its effects on glycemic control . Methods Patients We recruited 22 patients ( 10 women , 12 men ; mean age [ SD ] , 29 3 years ) with type 1 diabetes mellitus ( mean duration of diagnosed diabetes [ SD ] , 14 2 years ) receiving long-term intensive insulin treatment ( multiple insulin injections with regular human insulin before meals and NPH insulin at bedtime ) from the outpatient Diabetes Clinic of the Department of Internal Medicine at the University of Perugia . At baseline , the mean ( SD ) body mass index of the cohort was 23 1 kg/m2 , and the mean ( SD ) hemoglobin A1c value was 6.7 % 0.4 % . Patients had no detectable microangiopathic complications ; autonomic neuropathy , as assessed by using a st and ard battery of cardiovascular tests [ 20 ]  ; peripheral neuropathy ; or microalbuminuria . The patients had no history or clinical evidence of hypertension and were taking no medications other than insulin . We excluded 1 ) patients with hypoglycemia unawareness , defined as an absence of symptoms while the blood glucose level is approximately 2.5 to 2.8 mmol/L [ 45 to 50 mg/dL ] and 2 ) patients with a history of severe hypoglycemia , defined as episodes of hypoglycemia requiring assistance from another person in the previous year . All patients in the study gave informed consent . The Institutional Review Board of University of Perugia in Perugia , Italy , approved this study . Study Design After a 1-month run-in period , during which patients continued their usual regimen of multiple daily insulin injections , we r and omly assigned patients to receive one of the two following treatment regimens for the first 4-month treatment period : 1 ) a continued regimen of four daily insulin injections ( evening split treatment)that is , administration of regular insulin before dinner and NPH insulin at bedtime [ usually between 10:30 p.m. and 11:00 p.m. ] or 2 ) a regimen of regular insulin at breakfast and lunch and a mixture of regular and NPH insulins at dinner ( evening mixed treatment ) . Thereafter , the patients were switched to the other treatment for an additional 4 months . Insulin ( short-acting and NPH ) was administered with syringes to achieve the target values for fasting blood glucose of 5.0 to 6.7 mmol/L ( 90 to 120 mg/dL ) before meals and at bedtime [ 2 ] . The dose of mealtime regular insulin was titrated on the basis of the blood glucose measurement obtained 1 ) before the meal and 2 ) on the previous day , 4 to 5 hours after that meal , or , in the case of the evening meal , at bedtime . The dose of NPH insulin given at dinner or at bedtime was titrated on the basis of the predinner or bedtime blood glucose level , respectively . The patients were instructed to measure capillary blood glucose levels by using Reflolux S ( Boehringer Mannheim , Mannheim , Germany ) before each insulin injection , at bedtime , and every other day at 3:00 a.m. The patients were also asked to skip no more than one of their daily capillary glucose measurements and to keep diaries of blood glucose values , insulin dosage , and hypoglycemic episodes ( blood glucose level 4.0 mmol/L [ 72 mg/dL ] ) occurring any time during the day . To prevent nocturnal hypoglycemia , the patient instructions included a suggestion to consume a snack containing approximately 20 g of carbohydrates ( approximately 20 g of bread and approximately 60 mL of 2 % milk ) when the capillary blood glucose level at bedtime was less than 7.0 mmol/L ( < 126 mg/dL ) with the evening mixed treatment and less than 6.0 mmol/L ( < 108 mg/dL ) with the evening split treatment . We also suggested that patients have a similar snack if the blood glucose level at 3:00 a.m. was 4.0 mmol/L or less ( 72 mg/dL ) at any time during the night . If such a snack did not relieve hypoglycemic symptoms in approximately 10 minutes , patients were told to have another snack ( for a total of 40 g of carbohydrates ) . Throughout the study , patients visited the outpatient clinic monthly to su bmi t their diaries and had frequent telephone contacts ( every 3 to 6 days ) with the investigators . At the end of each treatment period , patients were admitted to the clinical research unit of the hospital , where blood glucose was monitored overnight ; the next morning , counterregulatory and symptomatic responses to hypoglycemia and cognitive performance were evaluated during a hyperinsulinemic , stepped hypoglycemic clamp study . Hemoglobin A1c values were measured before r and omization and at the end of both treatment periods . In-Hospital Evaluation Overnight Testing Patients were admitted for overnight evaluations after dinner ( and , thus , after premeal insulin administration ) , at approximately 9:00 p.m. A h and vein of the nondominant arm was cannulated retro grade ly , and the h and was maintained in a hot pad ( approximately 60 C ) for sampling of arterialized-venous blood ( 21 ) . A second venous line of the ipsilateral arm was cannulated for intravenous infusion of glucose whenever an infusion was needed to prevent hypoglycemia ( that is , to prevent a decrease in plasma glucose level to 4.0 mmol/L [ 72 mg/dL ] ) . Glucose was infused whenever the plasma glucose level decreased to less than 4.4 mmol/L ( < 80 mg/dL ) . On overnight stays , patients were allowed to watch television until 11:00 p.m. , at which time patients receiving the evening split regimen had their bedtime injection of NPH insulin . Overnight , patients gave blood sample s for measurement of plasma glucose and insulin levels every 30 minutes . Stepped Hypoglycemic Clamp Studies At 8:30 a.m. on the following morning , a variable intravenous infusion of human regular insulin ( diluted to 1 U/mL in 2 mL of the patient 's blood and sodium chloride [ NaCl 0.9 % ] to a final volume of 100 mL ) was begun to maintain a plasma glucose level of 5.0 mmol/L ( 90 mg/dL ) . Infusion continued until 10:00 a.m. For this procedure , which was done according to a previously described algorithm ( 22 ) , we used an intravenous syringe pump ( Harvard Apparatus , Ealing , South Natick , Massachusetts ) . At 10:00 a.m. , the rate of  intravenous insulin infusion  was increased to 1 mU/kg 1 min 1 until 2:30 p.m. ( 270 minutes ) , followed by 2 mU/kg 1 min 1 for an additional 90 minutes , until 4:00 p.m. ( time , 360 minutes ) . Plasma glucose was clamped by variable glucose infusion at sequential target glucose values of 4.3 , 3.7 , 3.0 , and 2.3 mmol/L ( 78 , 66 , 54 , and 42 mg/dL ) ; at each target level , blood was drawn to measure hormone and metabolite levels , and patients were assessed for symptoms of hypoglycemia and for cognitive function ( 23 - 25 ) . Symptoms were quantified by asking the patients to score ( on a scale in which 0 = none and 5 = severe ) each of the following symptoms : dizziness , tingling , blurred vision , difficulty in thinking , faintness , anxiety , palpitations , hunger , sweating , irritability , AIM To determine potential for amelioration of recurrent severe hypoglycaemia without worsening in overall control in individuals with long-st and ing Type 1 diabetes ( T1DM ) . METHODS Twenty-one people with T1DM characterized by altered hypoglycaemia awareness and debilitating severe hypoglycaemia were r and omized in a pilot 24-week prospect i ve study to optimized analogue therapy ( ANALOGUE ; lispro/glargine ) ; continuous subcutaneous insulin infusion therapy ( CSII ; lispro ) ; or re-education with relaxation of blood glucose targets on existing conventional insulin regimen ( EDUCATION ) .  Glycaemic profiles and duration of biochemical hypoglycaemia were measured by continuous subcutaneous glucose monitoring and self-monitored blood glucose . RESULTS Further severe hypoglycaemia was prevented in five participants ( 71 % ) in each group ( P = 0.06 ) . Incidence of severe hypoglycaemia was : 0.6 ( ANALOGUE ) , 0.9 ( CSII ) , and 3.7 ( EDUCATION ) episodes per patient year . Restoration of hypoglycaemia awareness was confirmed by vali date d question naire in three ( 43 % ) ANALOGUE , four ( 57 % ) CSII and five ( 71 % ) EDUCATION patients . Glycated haemoglobin ( HbA1c ) was significantly improved in the ANALOGUE group between weeks 0 and 24 ( 8.6 + /- 1.1 vs. 7.6 + /- 0.8 % ; P = 0.04 for change ) . Non-significant improvement was seen in the CSII group ( 8.5 + /- 1.9 vs. 7.4 + /- 1.0 % ; P = 0.06 ) . No change in HbA1c was seen in the EDUCATION group ( 8.5 + /- 1.1 vs. 8.3 + /- 1.0 % ; P = 0.54 ) . There were no episodes of diabetic ketoacidosis or any other adverse events in any group . CONCLUSIONS In this pilot r and omized trial comparing optimized ANALOGUE , CSII or EDUCATION alone in unselected individuals with recurrent severe hypoglycaemia , we show potential for restoring hypoglycaemia awareness and preventing further severe hypoglycaemia with concomitant improvement in glycaemic control in ANALOGUE and CSII groups OBJECTIVE Aim of this study was to investigate the effectiveness of a patient education program for the treatment of  hypoglycemia-associated problems in type 1 diabetic in patients . METHODS In this observational controlled pre-post study , the intervention group ( IG ; N = 105 ) participated in the new program ,  controls ( control group CG ; N = 102 ) received conventional patient education on hypoglycemia . RESULTS Follow-up data ( mean follow-up : 6.63 months ) were obtained from 177 patients ( 85.6 % ) . Though severe hypoglycemia also decreased in CG to some degree , the decrease in IG was higher than in CG , but fails to reach significance between groups . Hypoglycemia awareness remained constant in IG , whereas some deterioration was observed in CG ( p = 0.06 ) . Prevalence of hypoglycemia-related problems decreased in IG , whereas in CG it remained constant . No differential effects with regard to psychological well being , fear of hypoglycemia and late complications , and control beliefs were observed . CONCLUSION The results suggest that the new intervention program is an effective treatment . The effectiveness should be confirmed , however , in a r and omized controlled trial , also incorporating outpatient setting s. PRACTICE IMPLICATION S A self-management intervention targeting the patients ' health beliefs and attitudes towards hypoglycemia and their diabetes self-management , rather than knowledge-centered patient education , can help to ameliorate or even prevent hypoglycemia-associated problems Severe hypoglycemia ( SH ) can be a significant problem for patients around the world with Type 1 Diabetes Mellitus ( T1DM ) . To avoid SH , patients need to better manage , and reduce the occurrence of , preceding mild hypoglycemia . Hypoglycemia Anticipation , Awareness and Treatment Training ( HAATT ) , developed in the United States specifically to address such issues , was evaluated at short- and long-term follow-up in a medically , economically and culturally different setting ; Bulgaria . Sixty adults with T1DM and a history of recurrent SH ( 20 each from Sofia , Russe , and Varna , Bulgaria ) were r and omized to Self-Monitoring of Blood Glucose ( SMBG ) or SMBG+ HAATT . For 6 months before and 1 to 6 and 13 to 18 months after intervention , participants recorded occurrence of moderate , severe , and nocturnal hypoglycemia . For 1-month pre- and post-intervention , participants completed daily diaries concerning their diabetes management . Relative to SMBG , HAATT produced significant improvement in occurrence of low BG , moderate , severe , and nocturnal hypoglycemia , and detection and treatment of low BG ( p values < .05 to < .001 ) , with no compromise in metabolic control . At long-term follow-up , HAATT participants continued to have significantly fewer episodes of moderate and severe hypoglycemia . These findings suggest that a structured , specialized psycho-educational treatment program ( HAATT ) can be highly effective in managing hypoglycemia IMPORTANCE Hypoglycemia is a critical obstacle to the care of patients with type 1 diabetes .  Sensor-augmented insulin pump with automated low-glucose insulin suspension has the potential to reduce the incidence of major hypoglycemic events . OBJECTIVE To determine the incidence of severe and moderate hypoglycemia with sensor-augmented pump with low-glucose suspension compared with st and ard insulin pump therapy . DESIGN , SETTING , AND PARTICIPANTS A r and omized clinical trial involving 95 patients with type 1 diabetes , recruited from December 2009 to January 2012 in Australia . INTERVENTIONS Patients were r and omized to insulin pump only or automated insulin suspension for 6 months . MAIN OUTCOMES AND MEASURES The primary outcome was the combined incidence of severe ( hypoglycemic seizure or coma ) and moderate hypoglycemia ( an event requiring assistance for treatment ) . In a subgroup , counterregulatory hormone responses to hypoglycemia were assessed using the hypoglycemic clamp technique . RESULTS Of the 95 patients r and omized , 49 were assigned to the st and ard-pump ( pump-only ) therapy and 46 to the low-glucose suspension group . The mean ( SD ) age was 18.6 ( 11.8 ) years ; duration of diabetes , 11.0 ( 8.9 ) years ; and duration of pump therapy , 4.1 ( 3.4 ) years . The baseline rate of severe and moderate hypoglycemic events in the pump-only group was 20.7 vs 129.6 events per 100 patient months in the low-glucose suspension group . After 6 months of treatment , the event rates decreased from 28 to 16 in the pump-only group vs 175 to 35 in the low-glucose suspension group . The adjusted incidence rate per 100 patient-months was 34.2 ( 95 % CI , 22.0 - 53.3 ) for the pump-only group vs 9.5 ( 95 % CI , 5.2 - 17.4 ) for the low-glucose suspension group . The incidence rate ratio was 3.6 ( 95 % CI , 1.7 - 7.5 ; P < .001 ) . There was no change in glycated hemoglobin in either group : mean , 7.4 ( 95 % CI , 7.2 - 7.6 ) to 7.4 ( 95 % CI , 7.2 - 7.7 ) in the pump-only group vs mean , 7.6 ( 95 % , CI , 7.4 - 7.9 ) to 7.5 ( 95 % CI , 7.3 - 7.7 ) in the low-glucose suspension group . Counterregulatory hormone responses to hypoglycemia were not changed . There were no episodes of diabetic ketoacidosis or hyperglycemia with ketosis . CONCLUSIONS AND RELEVANCE Sensor-augmented pump therapy with automated insulin suspension reduced the combined rate of severe and moderate hypoglycemia in patients with type 1 diabetes . TRIAL REGISTRATION anzctr.org.au Identifier : ACTRN12610000024044 The purpose of this prospect i ve before- and -after study was to determine whether there are psychosocial and physical benefits of a self-awareness intervention for adults with type 1 diabetes and hypoglycemia unawareness ( HU ) . A total of 29 adults participated in the self-awareness intervention of 8 sessions , each lasting 3 hours . Psychosocial ( integration , diabetes quality of life ) and physical ( number of body cues , HU-related events , HbA1c ) measures were taken at baseline and at 6 , 12 , and 18 months post-intervention . Post-intervention the participants detected more cues of euglycemia and hypoglycemia and experienced significant increases in integration and metabolic control ( HbA1c ) . The number of HU-related events was not decreased and diabetes quality -of-life results were unstable . A self-awareness intervention can have physical and psychosocial benefits and has implication s for diabetes education . This intervention needs to be tested in a multi-centre r and omized control trial Summary Hypoglycaemia unawareness , is a major risk factor for severe hypoglycaemia and a contraindication to the therapeutic goal of near-normoglycaemia in IDDM . We tested two hypotheses , first , that hypoglycaemia unawareness is reversible as long as hypoglycaemia is meticulously prevented by careful intensive insulin therapy in patients with short and long IDDM duration , and that such a result can be maintained long-term . Second , that intensive insulin therapy which strictly prevents hypoglycaemia , can maintain long-term near-normoglycaemia . We studied 21 IDDM patients with hypoglycaemia unawareness and frequent mild/severe hypoglycaemia episodes while on “ conventional ” insulin therapy , and 20 nondiabetic control subjects . Neuroendocrine and symptom responses , and deterioration in cognitive function were assessed in a stepped hypoglycaemia clamp before , and again after 2 weeks , 3 months and 1 year of either intensive insulin therapy which meticulously prevented hypoglycaemia ( based on physiologic insulin replacement and continuous education , experimental group , EXP , n=16 ) , or maintenance of the original “ conventional ” therapy ( control group , CON , n=5 ) . At entry to the study , all 21 IDDM- patients had subnormal neuroendocrine and symptom responses , and less deterioration of cognitive function during hypoglycaemia . After intensive insulin therapy in EXP , the frequency of hypoglycaemia decreased from 0.5±0.05 to 0.045±0.02 episodes/patient-day ; HbA1C increased from 5.83±0.18 to 6.94±0.13 % ( range in non-diabetic subjects 3.8–5.5 % ) over a 1-year period ; all counterregulatory hormone and symptom responses to hypoglycaemia improved between 2 weeks and 3 months , with the exception of glucagon which improved at 1 year ; and cognitive function deteriorated further as early as 2 weeks ( p<0.05 ) . The improvement in responses was maintained at 1 year . The improvement in plasma adrenaline and symptom responses inversely correlated with IDDM duration . In contrast , in CON , neither frequency of hypoglycaemia , nor neuroendocrine responses to hypoglycaemia improved . Thus , meticulous prevention of hypoglycaemia by intensive insulin therapy reverses hypoglycaemia unawareness even in patients with long-term IDDM , and is compatible with long-term near-normoglycaemia . Because carefully conducted intensive insulin therapy reduces , not increases the frequency of moderate/severe hypoglycaemia , intensive insulin therapy should be extended to the majority of IDDM patients in whom it is desirable to prevent/delay the onset/progression of microvascular complications The effect of propranolol on the occurrence of hypoglycaemic symptoms was assessed in insulin-dependent diabetic patients with hypoglycaemia unawareness . A double-blind , r and omised parallel group study ( 2:1 fashion ) was conducted over 4-week period . The propranolol group ( n = 9 ) received 20 mg ( week 1 and 2 ) and 30 mg ( week 3 and 4 ) twice daily , and the other group ( n = 5 ) a matched placebo for 4 weeks . Patients included had experienced at least two severe hypoglycaemic episodes ( coma or seizures ) during the previous year , which were characterised by a lack of adrenergic symptoms and required the assistance of another person . The mean number of hypoglycaemias during the study period was similar in both groups ( placebo : 13 + /- 2 propranolol : 11 + /- 1 ) , whereas the number of totally asymptomatic hypoglycaemias ( < 0.6 g/l ) was lower on propranolol than on placebo ( 3 + /- 1 vs 8 + /- 3 , NS ) and the number of symptomatic hypoglycaemias was higher ( 7.2 + /- 2 vs 4.6 + /- 1 , NS ) . Subjective evaluation of treatment by the investigators showed 0/5 successes in the placebo group and 5/9 in the propranolol group ( chi2 = 4.32 , p = 0.038 ) . The main advantage of propranolol over placebo was an increased incidence of sweating . The ratio [ number of hypoglycaemias with sweating/total number of hypoglycaemias ] being higher with propranolol ( 0.28 + /- 0.08 vs 0.06 + /- 0.02 , p = 0.06 ) . This pilot study suggests that beta-blockers may be useful in restoring adrenergic symptoms during hypoglycaemia in insulin-dependent diabetic patients without warning symptoms of hypoglycaemia . This beneficial effect seems to be predominantly related to an increase in hypoglycaemia-induced sweating . A larger study is needed to confirm or invali date these preliminary results OBJECTIVE In a r and omized , multi-centre trial , the efficacy of a self-management-oriented education programme ( PRIMAS ) for people with type 1 diabetes was compared with an established education programme as control group ( CG ) . Primary outcome was the effect on glycaemic control in a 6-month follow-up . Secondary outcomes were the impact on emotional aspects , self-management related aspects and hypoglycaemia problems . METHODS The study was conducted in an outpatient setting . 160 participants were r and omized . Baseline characteristics in PRIMAS and CG were similar ( age 45.1±13.5 vs. 45.9±13.1 years , p=.716 ; diabetes duration 18.8±12.3 vs. 19.8±13.4 years , p=.615 ; BMI 26.5±4.6 vs. 27.5±5.0kg/m(2 ) , p=.236 ; HbA1c 8.3±1.1 vs. 8.1±1.0 % , p=.236 ) . RESULTS At follow-up there was a significant 0.4 percentage points greater reduction of HbA1c in PRIMAS compared to CG ( Δ -0.4±1.0 % vs. Δ 0.0±0.6 % ; p=.012 ) . Also , diabetes-related distress ( Δ -0.3±0.7 vs. -0.1±0.4 , p=.032 ) and dissatisfaction with diabetes treatment ( Δ -3.3±6.9 vs. -1.9±5.6 , p=.024 ) decreased more in PRIMAS . Diabetes empowerment ( Δ 2.6±5.9 vs. 0.8±5.1 , p=.037 ) and diabetes self-efficacy ( Δ 1.4±3.6 vs. 0.2±4.0 , p=.013 ) increased in PRIMAS . Incidence of severe hypoglycemia , hypoglycemia awareness , diabetes knowledge , and self-care behaviour improved in both groups with no significant differences between groups . CONCLUSION PRIMAS is more effective in lowering HbA1c than a previously established education programmes and also showed superiority in reducing diabetes-related distress and increasing diabetes empowerment , diabetes self-efficacy and satisfaction with insulin therapy BACKGROUND In a r and omized , prospect i ve multi-centre trial , the effect of a specific training programme ( HyPOS ) for patients with hypoglycaemia problems was compared with a control group ( CG ) , receiving a st and ardized education programme aim ing at avoidance of hypoglycaemia by optimization of insulin therapy . METHODS A total of 164 type 1 diabetes patients ( age 46.0 + /- 12.5 yrs , HbA(1c ) 7.3 + /- 1.0 % , 50 % male ) were r and omized .  Hypoglycaemia awareness was measured by the  hypoglycaemia awareness question naire ( HAQ ) and by a  visual analogue scale ( VAS ) . There were no baseline differences . RESULTS After a 6-month follow-up , hypoglycaemia awareness significantly improved in HyPOS compared to that in the CG ( Delta HAQ 0.7 [ 95 % CL 0.1 - 1.2 ] , p = 0.024 , Delta VAS 0.8 [ 95 % CL 0.2 - 1.2 ] , p = 0.015 ) . In HyPOS , the threshold for detection of low blood glucose ( Delta 0.2 mmol/L [ 95 % CL 0.03 - 0.04 ] , p = 0.02 ) and the treatment of low blood glucose ( Delta 4.6 g [ 95 % CL 1.6 - 7.6 ] , p = 0.03 ) increased significantly . The number of undetected hypogylcaemic episodes ( Delta - 1.4 episodes per week [ 95 % CL 0.4 - 2.5 ] , p = 0.01 ) and the rate of mild hypoglycaemia dropped significantly in HyPOS ( Delta 2.1 % [ 95 % CL 0.5 - 5.3 ] , p = 0.015 ) . The numbers of severe ( Delta 0.3 events per patient per year [ 95 % CL - 0.04 - 1.0 ] , p = 0.037 ) and very severe hypoglycaemic episodes ( Delta 0.3 events per patient per year [ 95 % CL - 0.1 - 0.7 ] , p = 0.09 ) were lower in HyPOS , but these differences were not significant . CONCLUSION Compared to the CG , HyPOS demonstrates additional benefits in terms of improving impaired hypoglycaemia awareness , reducing mild hypoglycaemia , detecting low blood glucose , and treating low blood glucose OBJECTIVE Blood glucose awareness training ( BGAT ) has been found effective in teaching individuals with insulin-requiring diabetes to improve their ability to better recognize blood glucose ( BG ) fluctuations . This study investigated whether subjects who underwent BGAT a mean of 4.9 years previously were superior to past control subjects in terms of their ability to recognize BG fluctuations , and whether past BGAT subjects had fewer automobile crashes and lost work days and better glycosylated hemoglobin than control subjects . Additionally , the beneficial effects of providing booster training to past BGAT subjects also was evaluated . RESEARCH DESIGN AND METHODS This study followed up 28 past BGAT subjects . Half of these subjects ( n = 14 ) received a simple booster-training program . Twelve previous control subjects also were evaluated . Booster subjects were given a BGAT diary to complete for 2 weeks before evaluation . Evaluation for all subjects included completion of a retrospective question naire on work and driving history , blood drawing for a glycosylated hemoglobin analysis , and having subjects estimate and measure their BG levels 50–80 times during a 3- to 4-week period during their daily routine . RESULTS At long-term follow-up , BGAT subjects had significantly fewer automobile crashes than control subjects . BGAT subjects receiving booster training were significantly more accurate at estimating their BG levels and were more aware of hypoglycemia . Post hoc analyses indicated that the ability to accurately estimate BG fluctuations correlated positively with follow-up glycosylated hemoglobin and the number of hypoglycemic and hyperglycemic symptoms participants demonstrated . Both BGAT and control subjects demonstrated significantly improved glycosylated hemoglobin relative to baseline measures . CONCLUSIONS These data suggest that BGAT has long-term benefits , which can be enhanced with booster training . Specifically , BGAT and simple booster training may result in reduction of severe hypoglycemic episodes and automobile crashes in the long term PURPOSE Patients with intensively treated insulin-dependent diabetes mellitus ( IDDM ) exhibit more severe defects in counterregulatory hormone secretion and symptom recognition during hypoglycemia than do conventionally treated patients . In this prospect i ve study in patients with preexisting defects in counterregulation , we examined the induction and reversibility of impaired symptomatic and adrenomedullary responses to hypoglycemia in 5 patients with IDDM ( diabetes duration of 2 to 16 years ; aged 19 to 36 years ; 3 women , 2 men ) who were receiving intensive therapy .  METHODS Counterregulatory responses were assessed by using a single-step ( approximately 2.8 mmol/L plasma glucose ) and multiple-step ( from approximately 5 mmol/L to 2.2 mmol/L plasma glucose ) clamped hypoglycemia procedure . Patients were first studied after a stable period of conventional insulin therapy ( glycosylated hemoglobin [ HbA1c ] 9.5 + /- 1.2 % ) , then after 3 to 5 months of intensive therapy ( HbA1c 6.6 + /- 0.2 % ) , and a third time after resuming conventional therapy ( HbA1c 8.7 + /- 0.9 % ) . RESULTS Intensive therapy was associated with a 44 % decline ( P < 0.01 ) in the average plasma epinephrine increase during hypoglycemia , and the plasma glucose level required to stimulate epinephrine secretion fell from 3.7 + /- 0.2 to 3.0 + /- 0.1 mmol/L ( P < 0.01 ) . The threshold , but not the magnitude , of the plasma norepinephrine response was similarly altered . Hypoglycemic symptoms also decreased in intensity ( by 67 % , P < 0.01 ) , and the glucose level required for symptom activation fell from 3.4 + /- 0.3 to 2.7 + /- 0.2 mmol/L , P < 0.01 ) . When conventional therapy was resumed , the abnormalities in the epinephrine response due to intensive therapy were almost completely reversed . However , the reduction in symptoms and the altered thresholds for plasma norepinephrine were not reversed . CONCLUSIONS There is dissociation between the treatment-associated defects in hypoglycemia counterregulation in IDDM , and an increase in average glycemia produced by a return to conventional insulin therapy is not sufficient to reverse hypoglycemia unawareness worsened by intensive therapy OBJECTIVE To determine whether impaired awareness of hypoglycemia ( IAH ) can be improved and severe hypoglycemia ( SH ) prevented in type 1 diabetes , we compared an insulin pump ( continuous subcutaneous insulin infusion [ CSII ] ) with multiple daily injections ( MDIs ) and adjuvant real-time continuous glucose monitoring ( RT ) with conventional self-monitoring of blood glucose ( SMBG ) . RESEARCH DESIGN AND METHODS A 24-week 2 × 2 factorial r and omized controlled trial in adults with type 1 diabetes and IAH was conducted . All received comparable education , support , and congruent therapeutic targets aim ed at rigorous avoidance of biochemical hypoglycemia without relaxing overall control . Primary end point was between-intervention difference in 24-week hypoglycemia awareness ( Gold score ) . RESULTS A total of 96 participants ( mean diabetes duration 29 years ) were r and omized . Overall , biochemical hypoglycemia ( ≤3.0 mmol/L ) decreased ( 53 ± 63 to 24 ± 56 min/24 h ; P = 0.004 [ t test ] ) without deterioration in HbA1c . Hypoglycemia awareness improved ( 5.1 ± 1.1 to 4.1 ± 1.6 ; P = 0.0001 [ t test ] ) with decreased SH ( 8.9 ± 13.4 to 0.8 ± 1.8 episodes/patient-year ; P = 0.0001 [ t test ] ) . At 24 weeks , there was no significant difference in awareness comparing CSII with MDI ( 4.1 ± 1.6 vs. 4.2 ± 1.7 ; difference 0.1 ; 95 % CI −0.6 to 0.8 ) and RT with SMBG ( 4.3 ± 1.6 vs. 4.0 ± 1.7 ; difference −0.3 ; 95 % CI −1.0 to 0.4 ) . Between-group analyses demonstrated comparable reductions in SH , fear of hypoglycemia , and insulin doses with equivalent HbA1c . Treatment satisfaction was higher with CSII than MDI ( 32 ± 3 vs. 29 ± 6 ; P = 0.0003 [ t test ] ) , but comparable with SMBG and RT ( 30 ± 5 vs. 30 ± 5 ; P = 0.79 [ t test ] ) . CONCLUSIONS Hypoglycemia awareness can be improved and recurrent SH prevented in long-st and ing type 1 diabetes without relaxing HbA1c . Similar biomedical outcomes can be attained with conventional MDI and SMBG regimens compared with CSII/RT , although satisfaction was higher with CSII OBJECTIVE To develop and pilot a novel intervention addressing motivational and cognitive barriers to avoiding hypoglycemia in people with type 1 diabetes and persistent impaired awareness of hypoglycemia ( IAH ) despite training in flexible insulin therapy . RESEARCH DESIGN AND METHODS A 6-week intervention using motivational interviewing and cognitive behavioral techniques was design ed . Diabetes educators were trained and supported in its delivery to 23 people with IAH ( Gold score ≥4 ) . RESULTS Twelve months postcourse , hypoglycemia awareness had improved ( P < 0.001 ) . Median ( range ) rates of severe hypoglycemia ( SH ) fell from 3 ( 0–104 ) to 0 ( 0–3 ) per person per year ( P < 0.0001 ) and moderate from 14 ( 0–100 ) to 0 ( 0–18 ) per person per 6 weeks ( P < 0.001 ) . Worry and behavior around hyperglycemia improved . HbA1c was unchanged . CONCLUSIONS A pilot intervention targeting motivation and cognitions around hypoglycemia engaged patients with resistant IAH and recurrent SH and was associated with significant improvement , supporting the hypothesis that these factors underpin problematic hypoglycemia
target: These were able to reduce SH and improve glycemic control , with greater benefit from the latter two techniques in improving IAH .
  Technological interventions ( insulin pump therapy , continuous glucose monitoring , and sensor-augmented pump ) reduced SH , improved glycemic control , and restored awareness when used in combination with structured education and frequent contact .
  This review provides evidence for the effectiveness of a stepped-care approach in the management of patients with IAH  , initially with structured diabetes education in flexible insulin therapy , which may incorporate psychotherapeutic and behavioral therapies , progressing to diabetes technology , incorporating sensors and insulin pumps , in those with persisting need
background: OBJECTIVE Impaired awareness of hypoglycemia ( IAH ) increases the risk of severe hypoglycemia ( SH ) sixfold and affects 30 % of adults with type 1 diabetes ( T1D ) .
  This systematic review and meta- analysis looks at the educational , technological , and pharmacological interventions aim ed at restoring hypoglycemia awareness ( HA ) in adults with T1D .