Restoration of Self-Awareness of Hypoglycemia in Adults With Long-Standing Type 1 Diabetes Phase 3 Trial of Transplantation of Human Islets in Type 1 Diabetes Complicated by Severe Hypoglycemia A Psychoeducational Program to Restore Hypoglycemia Awareness: The DAFNE-HART Pilot Study 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) Frequency of Severe Hypoglycemia in Patients With Type I Diabetes With Impaired Awareness of Hypoglycemia Role of Mobile Technology to Improve Diabetes Care in Adults with Type 1 Diabetes: The Remote-T1D Study iBGStar® in Type 1 Diabetes Management Hypoglycemia anticipation, awareness and treatment training (HAATT) reduces occurrence of severe hypoglycemia among adults with type 1 diabetes mellitus Evaluation of a self-awareness intervention for adults with type 1 diabetes and hypoglycemia unawareness. Impaired hypoglycaemia awareness and employment in people with Type 1 diabetes. Blood glucose awareness training (BGAT-2): long-term benefits. Decrease in clinical hypoglycemia in young children with type 1 diabetes treated with free-mixed aspart and detemir insulin: an open labeled randomized trial. Switching from twice-daily glargine or detemir to once-daily degludec improves glucose control in type 1 diabetes. An observational study. A pilot program for physical exercise promotion in adults with type 1 diabetes: the PEP-1 program. Reduced Awareness of Hypoglycemia in Adults With IDDM: A prospective study of hypoglycemic frequency and associated symptoms Severe sulfonylurea-induced hypoglycemia: a problem of uncritical prescription and deficiencies of diabetes care in geriatric patients Evaluation of a self-management-based patient education program for the treatment and prevention of hypoglycemia-related problems in type 1 diabetes. Randomized Controlled Clinical Trial of Blood Glucose Awareness Training (BGAT III) in Switzerland and Germany 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 Blood glucose awareness training and epinephrine responses to hypoglycemia during intensive treatment in type 1 diabetes. Avoidance of Hypoglycemia Restores Hypoglycemia Awareness by Increasing -Adrenergic Sensitivity in Type 1 Diabetes Poor Cognitive Function and Risk of Severe Hypoglycemia in Type 2 Diabetes A Multicenter Evaluation of Blood Glucose Awareness Training-II
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 OBJECTIVE Impaired awareness of hypoglycemia ( IAH ) and severe hypoglycemic events ( SHEs ) cause substantial morbidity and mortality in patients with type 1 diabetes ( T1D ) . Current therapies are effective in preventing SHEs in 50–80 % of patients with IAH and SHEs , leaving a substantial number of patients at risk . We evaluated the effectiveness and safety of a st and ardized human pancreatic islet product in subjects in whom IAH and SHEs persisted despite medical treatment . RESEARCH DESIGN AND METHODS This multicenter , single-arm , phase 3 study of the investigational product purified human pancreatic islets ( PHPI ) was conducted at eight centers in North America . Forty-eight adults with T1D for > 5 years , absent stimulated C-peptide , and documented IAH and SHEs despite expert care were enrolled . Each received immunosuppression and one or more transplants of PHPI , manufactured on-site under good manufacturing practice conditions using a common batch record and st and ardized lot release criteria and test methods . The primary end point was the achievement of HbA1c < 7.0 % ( 53 mmol/mol ) at day 365 and freedom from SHEs from day 28 to day 365 after the first transplant . RESULTS The primary end point was successfully met by 87.5 % of subjects at 1 year and by 71 % at 2 years . The median HbA1c level was 5.6 % ( 38 mmol/mol ) at both 1 and 2 years . Hypoglycemia awareness was restored , with highly significant improvements in Clarke and HYPO scores ( P > 0.0001 ) . No study -related deaths or disabilities occurred . Five of the enrollees ( 10.4 % ) experienced bleeds requiring transfusions ( corresponding to 5 of 75 procedures ) , and two enrollees ( 4.1 % ) had infections attributed to immunosuppression . Glomerular filtration rate decreased significantly on immunosuppression , and donor-specific antibodies developed in two patients . CONCLUSIONS Transplanted PHPI provided glycemic control , restoration of hypoglycemia awareness , and protection from SHEs in subjects with intractable IAH and SHEs . Safety events occurred related to the infusion procedure and immunosuppression , including bleeding and decreased renal function .  Islet transplantation should be considered for patients with T1D and IAH in whom other , less invasive current treatments have been ineffective in preventing SHEs 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 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 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 Introduction The role of mobile technology in patient-reported outcomes ( PRO ) and glycemic control in adults with type 1 diabetes ( T1D ) needs further evaluation . Methods The single-center , prospect i ve , 6-month , open-label , investigator-initiated study r and omized 100 subjects with T1D in a 1:1 fashion to a  control group using self-monitoring of blood glucose ( SMBG ) with Accu-Chek Nano ® and an intervention group using SMBG with iPhone plus glucose meter ( iBGStar ® ) . The primary endpoint was the change in PRO ( hypoglycemia fear score , behavior and worry subscores ) . Secondary outcomes were the improvement in glycemic variability indices and the reduction in A1c values . Results Baseline demographics and glycosylated hemoglobin ( A1c ) values were similar in the two groups . There was a significant decrease in A1c value at 6 months in iBGStar ® group compared to the control group ( −0.16 vs. −0.51 , p = 0.04 ) . The total insulin dose increased significantly in the iBGStar ® group at 3 months but did not change at 6 months . The hypoglycemia fear scale ( PRO ) improved in both groups at 6 months ( −1.4 ± 10.0 vs. −3.9 ± 12.5 , p = 0.32 ) . Conclusion The use of iBGStar ® result ed in better glycemic control and improvement in some PRO ( hypoglycemia fear and behavior scores ) compared to the control group at 6 months with no increased risk of hypoglycemia . Clinical trial registration Clinical Trials.gov : NCT01825382 . Funding Sanofi 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 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 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 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 OBJECTIVE To compare the effectiveness of a free-mix of aspart ( A ) and detemir ( D ) insulins ( ADIM ) with a commonly used premixed fixed-ratio aspart and neutral protamine Hagedorn ( NPH ) insulin mixture ( ANIM ) in young children with type 1 diabetes ( T1D ) treated with twice-daily injections . The trial thus compares not only D vs. NPH , but also flexible , personalized insulin preparations vs. a fixed premixed preparation . RESEARCH DESIGN AND METHODS This single-center , open-label , r and omized trial included 82 children with T1D . Patients stayed on ANIM for 1 yr of optimization of disease management , then were r and omized to either ANIM ( N = 41 ) or ADIM ( N = 41 ) for another year . OUTCOMES Frequency of severe or symptomatic episodes , glycated hemoglobin A1c ( HbA1c ) , and blood glucose ( BG ) values . RESULTS Compared with ANIM , ADIM  decreases symptomatic hypoglycemia by approximately 2 fold ( p < 0.001 ) and severe hypoglycemia by 7 - 10 fold ( p = 0.04 ) . ADIM somewhat reduced BG variation . Mean HbA1c was comparable on ADIM ( 7.9 ± 0.8 % ; 63 ± 9 mmol/mol ) and ANIM ( 8.2 ± 0.7 % ; 66 ± 8 mmol/mol ) . CONCLUSIONS Using a free-mixing preparation of aspart and detemir insulin decreases hypoglycemia in young children with type 1 diabetes BACKGROUND AND AIMS Degludec is an ultralong-acting insulin analogue with a flat and reproducible pharmacodynamic profile . As some patients with type 1 diabetes ( T1D ) fail to achieve 24-h coverage with glargine or detemir despite twice-daily injections , we studied the effect of switching T1D patients from twice-daily glargine or detemir to degludec . METHODS AND RESULTS In this prospect i ve observational study , T1D patients on twice-daily glargine or detemir were enrolled . At baseline and 12 weeks after switching to degludec , we recorded HbA1c , insulin dose , 30-day blood glucose self monitoring ( SMBG ) or 14-day continuous glucose monitoring ( CGM ) , treatment satisfaction ( DTSQ ) , fear of hypoglycemia ( FHS ) . We included 29 patients ( mean age 34 ± 11 years ; diabetes duration 18 ± 10 years ) . After switching to degludec  , HbA1c decreased from 7.9 ± 0.6 % ( 63 ± 6 mmol/mol ) to 7.7 ± 0.6 % ( 61 ± 6 mmol/mol ; p = 0.028 ) . SMBG showed significant reductions in the percent and number of blood glucose values < 70 mg/dl and in the low blood glucose index ( LBGI ) during nighttime . CGM showed a significant reduction of time spent in hypoglycemia , an increase in daytime spent in target 70 - 180 mg/dl , and a reduction in glucose variability . Total insulin dose declined by 17 % ( p < 0.001 ) , with 24 % reduction in basal and 10 % reduction in pr and ial insulin . DTSQ and FHS significantly improved . CONCLUSION Switching from twice-daily glargine or detemir to once daily degludec  improved HbA1c , glucose profile , hypoglycemia risk and treatment satisfaction , while insulin doses decreased . Clinical Trials.govNCT02360254 Physical inactivity is highly common in adults with type 1 diabetes ( T1D ) as specific barriers ( i.e. , hypoglycemia ) may prevent them from being active . The objective of this study was to examine the efficacy of the Physical Exercise Promotion program in type 1 diabetes ( PEP-1 ) program , a group program of physical activity ( PA ) promotion ( intervention ) compared with an information leaflet ( control ) , to improve total energy expenditure ( TEE ) in adults with T1D after 12 weeks . TEE was measured with a motion sensor over a 7-day period at inclusion , after the program ( 12 weeks ) and 1-year after inclusion . The 12 weekly sessions of the program included a 30-min information session ( glycemic control and PA ) and 60 min of PA .  A total of 48 adults , aged 18 to 65 years with a reported PA practice < 150 min per week , were recruited ( 45.8 % men ; aged 44.6 ± 13.3 years ; 8.0 % ± 1.1 % glycated hemoglobin ( A1c ) ) and r and omized in this pilot trial . Ninety percent of participants completed the program and 88 % completed the 1-year follow-up . No change was observed for TEE and A1c in both groups . After the 12-week program , the mean peak oxygen uptake increased ( 14 % ; p = 0.003 ) in the intervention group ; however , at the 1-year follow-up , it was no longer different from baseline . In the control group , no difference was observed for the peak oxygen uptake . These results suggest that the PEP-1 pilot program could increase cardiorespiratory fitness . However , this benefit is not sustained over a long-term period . The PEP-1 program did not increase TEE in patients with T1D and other strategies remain necessary to counteract physical inactivity in this population 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 : Severe sulfonylurea-induced hypoglycemia ( SH ) remains a life-threatening and under-reported condition . We investigated the incidence of SH and clinical characteristics of patients with type 2 diabetes mellitus ( T2DM ) to demonstrate typical risk constellations . Methods : In a prospect i ve population -based observational study , all consecutive cases of SH in the period 2000 – 2009 in a German area with 200,000 inhabitants were registered .  Severe hypoglycemia was defined as a symptomatic event requiring treatment with intravenous glucose and was confirmed by a blood glucose measurement of < 50 mg/dl . Results : A mean incidence of seven episodes of SH per year and 100,000 inhabitants was registered . The 139 hypoglycemic individuals had been treated with glimepiride ( n = 98 ) , glibenclamide ( n = 40 ) or gliquidone ( n = 1 ) . No preparation showed a constant dose – effect relationship , SH occurring within a wide dose range . The patients were characterized as follows : age 77.5 ± 9.4 years , duration of diabetes 11 ± 7 years , body mass index 26.3 ± 4.9 kg/m2 , HbA1c 6.6 ± 1.3 % , creatinine clearance 46 ± 24 ml/min with renal insufficiency in 73 % and co-medication 7 ± 3 drugs . Two-thirds of all subjects lived independently at home whereas a third were cared for by a home nursing service or received care in nursing homes . In all , 30 % had participated in diabetes education programs . In 31 % , systematic blood glucose monitoring was performed . Conclusions : Uncritical prescription of sulfonylureas neglecting crucial contraindications – particularly renal insufficiency – and deficiencies of diabetes care contributed substantially to the risk of SH in the mainly geriatric patients . There is a need for alternative therapeutic concepts that minimize the risk of hypoglycemia in geriatric patients with T2DM 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 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 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 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 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 Self-management of type 2 diabetes including avoidance of hypoglycemia is complex , but the impact of cognition on safe self-management is not well understood . This study aim ed to assess the effect of baseline cognitive function and cognitive decline on subsequent risk of severe hypoglycemia and to assess the effect of different glycemic strategies on these relationships . RESEARCH DESIGN AND METHODS Prospect i ve cohort analysis of data from the ACCORD trial included 2,956 adults aged ≥55 years with type 2 diabetes and additional cardiovascular risk factors .  Cognitive tests ( Digit Symbol Substitution Test [ DSST ] , Rey Auditory Verbal Learning Test , Stroop Test , and Mini Mental Status Examination )  were conducted at baseline and 20 months . Study outcomes were incident confirmed severe hypoglycemia requiring medical assistance ( HMA ) and hypoglycemia requiring any assistance ( HAA ) . RESULTS After a median 3.25-year follow-up , a 5-point-poorer baseline score on the DSST was predictive of a first episode of HMA ( hazard ratio 1.13 [ 95 % CI 1.08–1.18 ] ) . Analyses of the other cognitive tests and of HAA were consistent with the DSST results . Cognitive decline over 20 months increased the risk of subsequent hypoglycemia to a greater extent in those with lower baseline cognitive function ( Pinteraction = 0.037 ) . R and omization to an intensive versus st and ard glycemic strategy had no impact on the relationship between cognitive function and the risk of severe hypoglycemia . CONCLUSIONS Poor cognitive function increases the risk of severe hypoglycemia in patients with type 2 diabetes . Clinicians should consider cognitive function in assessing and guiding their patients regarding safe diabetes self-management regardless of their glycemic targets 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
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
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 .