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 .
Administration of Neutral Protamine Hagedorn Insulin at Bedtime versus with Dinner in Type 1 Diabetes Mellitus To Avoid Nocturnal Hypoglycemia and Improve Control
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 ,
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 .