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Continuous Glucose Monitoring (CGM) has improved the diabetes follow up. The use of CGM can be expected to reduce the long-term complications of diabetes. To achieve this, education of physicians and diabetic individuals is essential. The latest CGMs have alarms to improve glycemic control by avoiding hypoglycemia and hyperglycemia, hence the importance of proper setting of these alarms. Although useful to signal these events, we have noted that these alarms do not necessarily meet with unanimity in consultations… Are alarms considered a comfort or a possible disturbance ?

Aims/hypothesis: Attenuated counterregulation after recurrent hypoglycaemia is a major complication of diabetes treatment. As there is previous evidence for the relevance of sleep in metabolic control, we assessed the acute contribution of sleep to the counterregulatory adaptation to recurrent hypoglycaemia. Methods: Within a balanced crossover design, 15 healthy, normal-weight male participants aged 18–35 years underwent three hyperinsulinaemic–hypoglycaemic clamps with a glucose nadir of 2.5 mmol/l, under two experimental conditions, sleep and sleep deprivation. Participants were exposed to two hypoglycaemic episodes, followed by a third hypoglycaemic clamp after one night of regular 8 h sleep vs sleep deprivation. The counterregulatory response of relevant hormones (glucagon, growth hormone [GH], ACTH, cortisol, adrenaline [epinephrine] and noradrenaline [norepinephrine]) was measured, and autonomic and neuroglycopenic symptoms were assessed. Results: Sleep deprivation compared with sleep dampened the adaptation to recurrent hypoglycaemia for adrenaline (p=0.004), and this pattern also emerged in an overall analysis including adrenaline, GH and glucagon (p=0.064). After regular sleep, the counterregulatory responses of adrenaline (p=0.005), GH (p=0.029) and glucagon (p=0.009) were attenuated during the 3rd clamp compared with the 1st clamp, but were preserved after sleep deprivation (all p>0.225). Neuroglycopenic and autonomic symptoms during the 3rd clamp compared with the 1st clamp were likewise reduced after sleep (p=0.005 and p=0.019, respectively). In sleep deprivation, neuroglycopenic symptoms increased (p=0.014) and autonomic symptoms were unchanged (p=0.859). Conclusions/interpretation: The counterregulatory adaptation to recurrent hypoglycaemia is compromised by sleep deprivation between hypoglycaemic episodes, indicating that sleep is essential for the formation of a neurometabolic memory, and may be a potential target of interventions to treat hypoglycaemia unawareness syndrome. [ABSTRACT FROM AUTHOR]

The beneficial effects of closed-loop insulin delivery in patients with highly unstable type 1 diabetes eligible for islet transplantation are maintained over 6 months: An extension study of the DBLHU-WP10 trial Prospective analysis of satisfaction and usability of closed-loop Diabeloop DBLHU treatment in patients with highly unstable type 1 diabetes. Keywords: artificial pancreas; brittle diabetes; closed-loop; hypoglycaemia unawareness; problematic hypoglycaemia; severe hypoglycaemia; type 1 diabetes; unstable diabetes EN artificial pancreas brittle diabetes closed-loop hypoglycaemia unawareness problematic hypoglycaemia severe hypoglycaemia type 1 diabetes unstable diabetes 956 961 6 04/07/22 20220501 NES 220501 PEER REVIEW The peer review history for this article is available at https://publons.com/publon/10.1111/dom.14654. Insulin delivery DBLHU system DBLHU is a hybrid, CL insulin delivery system combining a Dexcom G6 CGM device, a Kaleido insulin pump and the investigational DBLHU software into a dedicated controller handset. [Extracted from the article]

Approximately 20% of type 1 diabetes (T1D) patients have an impaired awareness of hypoglyceamia (IAH). IAH represents a risk factor for severe and recurrent hypoglycaemic events, which can lead to brain damage. Because no effective treatments are currently available to prevent IAH in this population, characterising the set of brain alterations associated with IAH may reveal novel preclinical diagnostic or therapeutic strategies. Using state‐of‐the art neuroimaging techniques, we compared 18F‐fluorodeoxyglucose‐positron emission tomography (FDG‐PET) uptake at rest between 10 T1D patients with IAH and nine patients with normal awareness of hypoglycaemia (NAH). T1D‐IAH patients showed a pattern of increased FDG‐PET uptake with respect to NAH patients (P <.05 corrected). Topographically, glucose metabolism was increased in the frontal and precuneus regions. Importantly, within the IAH group, this abnormal hypermetabolism correlated with IAH severity. This hypermetabolic state appeared to be unrelated to compensatory mechanisms as a result of reduced grey matter density or a neuroinflammatory state. We observed an abnormal increase in FDG‐uptake in T1D patients with IAH in brain regions strongly related to cognition. Because this hypermetabolic state correlated with IAH severity, its biological characterisation could reveal new preventive or therapeutic strategies. A possible mechanism could be that glucose transport is increased in hypoglycaemia unawareness to compensate for recurrent hypoglycaemia, although this need to be confirmed in further research. [ABSTRACT FROM AUTHOR]

Introduction: Clarke, Gold and Pedersen are validated methods to assess awareness of hypoglycaemia. Identifying impaired awareness of hypoglycaemia (IAH) is critical for supporting people with structured education and diabetes technologies, to reduce harm of hypoglycaemia. This study compares the Clarke score, Gold score and Pedersen methods and their correlations with features of hypoglycaemia unawareness and patient characteristics, to evaluate the accuracy of the methods in identifying IAH. Methods: This retrospective, observational questionnaire-based study collected routine clinical data from 100 people with type 1 diabetes. The questionnaire included the three validated scoring methods, frequency of severe and nocturnal hypoglycaemia, knowledge and worry of hypoglycaemia and hypoglycaemia symptom scores using the Edinburgh Hypoglycaemia Scale. Data were analysed for IAH prevalence and the associations with features of IAH. The concordance of Clarke, Gold and Pedersen methods was evaluated using Spearman's correlation coefficient. Results: The prevalence of IAH in this cohort identified by Clarke, Gold and Pedersen methods was 18%, 19% and 61% respectively. The mean autonomic symptom score in people with IAH was significantly reduced using the Clarke method (P = 0.0002) but not on Gold (P = 0.12) and Pedersen methods (P = 0.79). For people with IAH assessed using the Clarke method, scores for night-time worry regarding hypoglycaemia (P = 0.04) and self-reported frequency of nocturnal hypoglycaemia (P = 0.001) were increased. Spearman's correlation coefficients between Pedersen and Clarke and Pedersen and Gold were Rs = 0.555 (P < 0.001) and Rs = 0.645 (P < 0.001) respectively. A moderate association was observed between Clarke and Gold Rs = 0.5669 (P < 0.001). Conclusion: Whilst Clarke and Gold methods determined a similar prevalence of IAH, people identified with IAH assessed by the Clarke method had a significant association with the features and characteristics of IAH, including reduced autonomic symptoms. This study suggests that performing more than one score is important for a reliable risk assessment of IAH. [ABSTRACT FROM AUTHOR]

Objectives: Management of diabetes is a balancing act of preventing a state of hyperglycaemia while avoiding episodes of hypoglycaemia. Limited information is currently available on the incidence of hypoglycaemia in South African people diagnosed with diabetes. Data regarding the management of diabetes and incidence of hypoglycaemia in the South African population was collected as part of Wave 7 of the International Diabetes Management Practices Study (IDMPS). Design and methods: During this observational study the first 10 adult individuals with type 2 diabetes and the first five adult individuals with type 1 diabetes presenting to a study site during the two-week study period were enrolled. Setting: Patients were enrolled from the private healthcare sector in South Africa only. Subjects: A total of 445 individuals (49 diagnosed with T1D, 396 diagnosed with T2D) were included. Outcome measures: Glycated haemoglobin and hypoglycaemia data were recorded for each patient. Results: Of the patients who reported experiencing hypoglycaemia, 48.6% (17/35) among T1D individuals and 67.8% (40/71) among T2D individuals experienced hypoglycaemia over a four-week period. Furthermore, in patients who discontinued insulin treatment (n = 11), fear of hypoglycaemia was reported to influence adherence to insulin treatment by 27.3% in T1D and T2D individuals. Of the 148 patients not achieving their HbA1c target, 23.0% reported fear of hypoglycaemia as a reason. Conclusions: This report demonstrates the need to address hypoglycaemia and fear of hypoglycaemia in the South African diabetes population. [ABSTRACT FROM AUTHOR]

Copyright of Pediatric Endocrinology, Diabetes & Metabolism is the property of Termedia Publishing House and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Aims Many people with type 1 diabetes do not achieve optimal treatment targets despite high patient and professional input. To investigate the reasons underlying suboptimal control we have studied clinical characteristics and self-management behaviours in adults with type 1 diabetes attending a large treatment centre. Methods A questionnaire-based enquiry into self-care behaviours of 380 patients with type 1 diabetes (mean age: 48 (±15) years and mean duration of diabetes: 26 (±15) years), linked with validated measures of impact of treatment on perceived health and hypoglycaemia recognition ( Insulin Treatment Satisfaction Questionnaire; and EuroQoL EQ-5D, Gold score) and retrospective case note review of biomedical parameters . The data were analysed using chi-square test, ANOVA, ANCOVA and post-hoc procedures (Tukey's-b) in SPSS-version 18. The minimum significance level was accepted as 0.05. Results Sixty three percent of participants used multiple daily injections; 36% continuous subcutaneous insulin infusion. Mean HbA 1c was 7.7% (±1.2) [61 ± −10 mmol/mol]; 30% had impaired hypoglycaemia awareness (IHA). Factors significantly related to poor glycaemic control with IHA were longer duration of diabetes ( p = 0.01); less frequent glucose self-monitoring ( p = 0.05); and low level of patient-set glucose targets ( p < 0.001). Patients with IHA and poorer control had significantly lower insulin treatment satisfaction ( p < 0.001); and perceived health ( p < 0.001). Conclusions Suboptimal biomedical outcomes in adults with type 1 diabetes attending a specialist intensified insulin therapy clinic are associated with longer duration of diabetes, fewer self-management behaviours and a trend towards poorer perceived health. These data suggest a need for greater emphasis on integration of psychological and self-management support with intensive medical management of type 1 diabetes. [ABSTRACT FROM AUTHOR]

Aims/hypothesis. High serum angiotensin-converting enzyme (ACE) activity is associated with increased risk of severe hypoglycaemia (SH) within 1 year in type 1 diabetes. We wanted to find out whether ACE activity is stable over time and predicts SH beyond 1 year, and if gender differences exist in the association between ACE activity and risk of SH. Methods. A follow-up study of 128 adult patients with type 1 diabetes was conducted. At entry, ACE activity was measured. For 12 months, patients prospectively recorded events of severe hypoglycaemia (SH). At a median of 40 months, ACE activity was measured again and participants recalled the number of SH in the last year. Results. ACE activity is reproducible over 40 months ( p < 0.00001). Patients with SH during the baseline study also had SH during follow-up ( p < 0.00001). Serum ACE activity measured at baseline was positively associated with the rate of SH at follow-up ( p == 0.0003) with a 3.2-fold increased rate of SH in subjects belonging to the upper ACE quartile compared to subjects in the three lowest quartiles ( p < 0.00001). The association between high serum ACE activity and increased risk of SH did not differ significantly in women and men. Conclusion. In type 1 diabetes individual serum ACE activity is reproducible over time. High ACE activity predicts recurrent SH over at least 40 months with no differences between genders. [ABSTRACT FROM AUTHOR]

Copyright of Diabetes & Metabolism is the property of Masson Editeur and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Impaired awareness of hypoglycaemia affects approximately 25% of all patients with type 1 diabetes (T1D). Duration of diabetes and tight glycaemic control represent the main risk factors for hypoglycaemia unawareness. However, even among patients with good glycaemic control and longstanding T1D, awareness of hypoglycaemia may be intact. Genetic factors might explain some of this remaining variability, and genes involved in central glucose sensing should represent plausible candidates. Some evidence indicates that ventromedial hypothalamus glucose-responsive neurons require the potassium inward rectifier (KIR) 6.2 subunit of the KATP channel to sense glucose. Therefore, the effects of the Glu23Lys polymorphism in the KCNJ11 ( KIR6.2) gene (potassium inwardly rectifying channel, subfamily J, member 11) on impaired hypoglycaemia awareness in 217 patients with T1D were studied. Hypoglycaemia awareness status was determined using standardized questionnaires. Genotyping of the Glu23Lys in a cohort of T1D subjects was done using the TaqMan allelic discrimination assay (frequency of the Lys-allele=0.35; P=0.57 for Hardy–Weinberg equilibrium). The study confirms that diabetes duration, C-peptide, and HbA1c represent risk factors for impaired hypoglycaemia awareness. However, no significant effect of the Glu23Lys polymorphism on impaired hypoglycaemia awareness was observed with or without adjustment for age, diabetes duration, C-peptide, and HbA1c. Even though the study provides a relatively large dataset, it is possible that small differences may have been missed. [ABSTRACT FROM AUTHOR]

Aims/hypothesis: Hypoglycaemia unawareness in type 1 diabetes increases the risk of severe hypoglycaemia and impairs quality of life for people with diabetes. To explore the central mechanisms of hypoglycaemia awareness, we used [11C]-3-O-methyl-D-glucose (CMG) positron emission tomography (PET) to measure changes in global and regional brain glucose metabolism between euglycaemia and hypoglycaemia in aware and unaware diabetic subjects. Materials and methods: Twelve men with type 1 diabetes, of whom six were characterised as aware and six as unaware of hypoglycaemia, underwent two CMG-PET brain scans while plasma glucose was controlled by insulin and glucose infusion either at euglycaemia (5 mmol/l) or at hypoglycaemia (2.6 mmol/l) in random order. Results: With hypoglycaemia, symptoms and sweating occurred only in the aware group. Brain glucose content fell in both groups (p=0.0002; aware, 1.18± 0.45 to 0.02±0.2 mmol/l; unaware, 1.07±0.46 to 0.19±0.23 mmol/l), with a relative increase in tracer uptake in prefrontal cortical regions, including the anterior cingulate. No detectable differences were found between groups in global brain glucose transport parameters (K1, k2). The cerebral metabolic rate for glucose (CMRglc) showed a relative rise in the aware subjects (11.839±2.432 to 13.958± 2.372) and a fall in the unaware subjects (from 12.457± 1.938 to 10.16±0.801 μmol 100 g-1 min-1, p=0.043). Conclusions/interpretation: Hypoglycaemia is associated with reduced brain glucose content in aware and unaware subjects, with a relative preservation of metabolism in areas associated with sympathetic activation. The relative rise in global glucose metabolic rate seen in aware subjects during hypoglycaemia contrasted with the relative fall in the unaware subjects and suggests that cortical neuronal activation is a necessary correlate of the state of hypoglycaemia awareness. [ABSTRACT FROM AUTHOR]

Copyright of Diabetes & Metabolism is the property of Masson Editeur and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Aims/hypothesis. The role of glucose sensing cells in the human hepatic portal system in the initiation of the neuroendocrine responses to acute hypoglycaemia is not known. We investigated the effect of raising blood glucose concentrations in the hepatic-portal vein on neurohumoral responses during induction of systemic hypoglycaemia in nine healthy male volunteers. Methods. Each subject received an insulin infusion (3 mU·kg–1·min–1) on two occasions, in random order. Variable rate glucose infusion was used to maintain plasma glucose at 5 mmol/l for 60 min, then 3.2 mmol/l for 60 min. At 20 min prior to hypoglycaemia, subjects drank 20 g of glucose in water or water sweetened with saccharin. In five of the volunteers, the oral glucose was labelled with U-13C6 glucose, which showed peak systemic glucose absorption between 90 and 110 min. Five volunteers also repeated the study with a euglycaemic clamp. Results. Oral glucose was associated with a reduction in the early adrenaline response to hypoglycaemia, the area under the curve from 90 to 110 min falling from 24.02±20.84 (means ± SD) to 15.26±13.65 nmol/l per 20 min, p<0.05. Symptom scores (area under curve) decreased from 99.72±91.86 to 16.39±94.71, p=0.008 (total), 51.8±68.61 to 7.78±41.61, p=0.03 (autonomic) and 54.17±50.61 to 8.6±57.99 with oral glucose, p=0.001 (neuroglycopenic). Oral glucose did not influence symptoms during euglycaemia. Conclusion/Interpretation. Our data are compatible with the hypothesis that centrally mediated symptomatic and neuroendocrine responses are attenuated by glucose detection in the hepatic portal vein in humans. [ABSTRACT FROM AUTHOR]

AbstractThe symptoms of hypoglycaemia are fundamental to the early detection and treatment of this side-effect of insulin and oral hypoglycaemic therapy in people with diabetes. The physiology of normal responses to hypoglycaemia is described and the importance of symptoms of hypoglycaemia is discussed in relation to the treatment of diabetes. The symptoms of hypoglycaemia are described in detail. The classification of symptoms is considered and the usefulness of autonomic and neuroglycopenic symptoms for detecting hypoglycaemia is discussed. The many external and internal factors involved in the perception of symptoms are reviewed, and symptoms of hypoglycaemia experienced by people with Type 2 diabetes are addressed. Age-specific differences in the symptoms of hypoglycaemia have been identified, and are important for clinical and research practice, particularly with respect to the development of acquired hypoglycaemia syndromes in people with Type 1 diabetes that can result in impaired awareness of hypoglycaemia. In addition, the routine assessment of hypoglycaemia symptoms in the diabetic clinic is emphasized as an important part of the regular review of people with diabetes who are treated with insulin. Diabet. Med. 18, 690–705 (2001). [ABSTRACT FROM AUTHOR]

The majority of the impaired symptoms in hypoglycaemia unawareness, such as palpitations, tachycardia and tremor, are caused by increased release of adrenaline (ADR) and noradrenaline (NA), and induced by stimulation of β-adrenergic receptors. Binding of ADR or NA to the β-adrenergic receptor generates a signal, transmitted via a guanine nucleotide binding protein complex (G-protein), which in turn activates adenylate cyclase with increased production of cAMP. The aim of this study was to show whether IDDM-patients with hypoglycaemia unawareness had deficient coupling between β-adrenergic receptors and G-proteinscompared to IDDM-patients with hypoglycaemia awareness and healthy controls. The IDDM-patients were subgrouped as hypoglycaemia aware or unaware based on questionnaire answers, clinical information and the results of isoprenaline sensitivity tests. Mononuclear leukocytes (MNL) were isolated from venous blood. By saturation binding experiments, using [I]-(-)-iodopindolol ((-)-IPIN), total receptor number (B) and affinity (K) were determined. By displacement experiments the relative number of low-and high-affinity receptors for the β-adrenergic agonist (-)-isoprenaline ((-)-ISO) were determined. We found no difference in B- or K-values for (-)-IPIN between the subgroups. However, there was a reduced capability to form high-affinity binding complexes with (-)-ISO in MNL from IDDM-patients with hypoglycaemia unawareness. It was concluded that hypoglycaemia unawareness in IDDM was associated with dysfunction of the proximal β-adrenergic signal pathway. [ABSTRACT FROM AUTHOR]

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] [ABSTRACT FROM AUTHOR]

The present studies were designed to assess the percentage of HbA, frequency, and awareness of hypoglycaemia (H) during long-term intensive therapy (IT) of insulin-dependent diabetes mellitus (IDDM). From 1981 to 1994, 112 IDDM patients were on IT. HbA was 7.17±0.16% (non-diabetic subjects 3.8-5.5%), the frequency of severe H 0.01±0.009 episodes/patient-year, frequency of mild symptomatic H 35.6±2.9 episodes/patient-year. IDDM patients with HbA ≤ 5.5% (Group I, n=10), between 6.1-7.0% (Group II, n=12), and ≥ 7.6% (Group III, n=11) were studied to assess responses of counterregulatory hormones, symptoms and cognitive function during experimental, stepped H. Compared to 18 non-diabetic subjects, Group I exhibited high thresholds (plasma glucose had to decrease more than normal to evoke responses), and impaired responses of adrenaline, unawareness of H and delayed onset of cognitive dysfunction at the lowest glycaemic plateau (2.3 mmol/l). Group II had normal thresholds and responses, whereas Group III had low thresholds. Frequency of mild H was higher in Group I (54.5±1.9 episodes/patient-year) than in Group II and III (33.7±3.5 and 20.4±2.5 episodes/ patient-year, respectively, p<0.001) and correlated with percentage of HbA ( r=−0.82). In conclusion: IT can maintain near-normal HbA and is compatible with low frequency of severe H. However, if HbA is less than 6.0%, mild, symptomatic H is excessively frequent and causes impaired counterregulation and H unawareness. Efforts should be made not only to maintain HbA ≤ 7.0%, but also to prevent, recognize and reverse iatrogenic H unawarenes during long-term IT of IDDM by maintaining HbA>6.0%. [ABSTRACT FROM AUTHOR]

Recent studies have reported reduced endocrine and symptomatic responses to hypoglycaemia 18-24 h after antecedent hypoglycaemia in both non-diabetic subjects and those with insulin-dependent diabetes mellitus. We examined these and peripheral physiological responses in eight nondiabetic subjects aged 23-35 years in the week following antecedent hypoglycaemia. Blood glucose levels were held at plateaus of 5 mmol/l and 2.5 mmol/l for 30 min during hyperinsulinaemic (60 mU · m · min) morning clamps on days 1, 3 and 8 of two study periods separated by at least 4 weeks. Measurements were made at time 0, 15 and 30 min of each plateau on each day. On the afternoon of Day 1 we also induced either euglycaemia with a blood glucose level of 5 mmol/l (control week) or hypoglycaemia of 2.9 mmol/l (hypo week) for 2 h in random order. The adrenaline response to morning hypoglycaemia ( p<0.01 on all days) was attenuated on Day 3 ( p<0.05) and Day 8 ( p<0.05) compared to Day 1 of hypo week only. Sweating was also attenuated on Day 3 ( p<0.05) and Day 8 ( p<0.02) of hypo week only. Noradrenaline levels and tremor increased during hypoglycaemia on each study day ( p<0.05) but did not differ between days in either week. During hypo week only, the total symptom score response to hypoglycaemia was attenuated on Day 3 ( p<0.03) but not Day 8 ( p=0.10). Autonomic symptoms were similarly affected. In summary, the physiological responses to hypoglycaemia are affected differentially by antecedent hypoglycaemia with sweating and adrenaline responses remaining impaired for at least 5 days. [ABSTRACT FROM AUTHOR]

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; HbA 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. [ABSTRACT FROM AUTHOR]

The aim of our study was to evaluate the frequency of hypoglycaemia unawareness and the continuous glucose profile in a group of subjects with Type 1 diabetes (T1D) with repeated non-severe/severe hypoglycaemia. Twenty patients (aged 35.2 ± 7.6 years, duration of disease 16.4 ± 6.4 years) were included. Hypoglycaemia awareness was evaluated using questionnaires and after an acute-induced hypoglycaemia. Glucose profile was studied using 72-h continuous glucose monitoring (CGM). All subjects were classified as having hypoglycaemia unawareness by questionnaires. Four patients displayed a “normal” signs/symptoms response to hypoglycaemia. The CGM revealed 18% of the measurements <70 mg/dl and this percentage was correlated with questionnaire score ( r = 0.55, P < 0.035) and with the increase in the percentage of signs/symptoms during the induced hypoglycaemia ( r = −0.57, P < 0.015). In patients exhibiting an “abnormal” response during hypoglycaemia, CGM values <70 mg/dl was higher (22.6 ± 8.4%) than in those with a “normal” response (10.2 ± 9.0%; P < 0.028). Summarising, in subjects with T1D and repeated hypoglycaemia the frequency of impaired awareness is substantially common. Its presence is related to a high proportion of ambulatory glycaemic profile below the desirable range. [ABSTRACT FROM AUTHOR]