Nocturnal hypoglycemia in patients with insulin-treated diabetes

While use of intensive insulin therapy has proven effective for reducing risk of long-term complications of hyperglycemia in people with diabetes, overnight hypoglycemia remains a significant barrier to intensive therapy. Findings from numerous studies indicate that nocturnal hypoglycemia is a frequent event among patients with type 1 diabetes, while severe hypoglycemic episodes are approximately three times more likely in patients on intensive insulin therapy than in those on conventional therapy. Nocturnal hypoglycemia remains frequent, even when specific approaches-use of short-acting insulin analogues to manage postprandial glucose surges, peakless long-acting insulin analogues as basal therapy, and strategically selected bedtime snacks-aim to avert this problem. Thus, nocturnal hypoglycemia continues to threaten the well-being of patients with diabetes and cause concerns for their family members and caregivers. Continuing research is required to improve methods for detection and prompt correction of hypoglycemia in order to achieve a safe level of euglycemia in people with diabetes.     

Morbidity of hypoglycemia in type 1 diabetes

Hypoglycemia is a common side effect of intensive insulin therapy in patients with type 1 diabetes. Mild hypoglycemia is any episode that can be self-treated, while a severe episode requires external help for recovery. Acute hypoglycemia produces autonomic and neuroglycopenic symptoms, including cognitive impairment and mood changes, while sympathoadrenal stimulation can provoke acute hemodynamic changes with alterations in regional vascular perfusion and a risk of cardiac dysrhythmias. Neurological manifestations include coma, convulsions and focal abnormalities. Long-term morbidities associated with hypoglycemia include impaired awareness of hypoglycemia, counterregulatory hormonal deficiencies, hypoglycemia-associated autonomic failure, and, in rare cases, permanent cognitive impairment. Hypoglycemia affects all aspects of life for the person with type 1 diabetes, including employment, social interactions, driving, sport and leisure activities, and sleep. Appreciation of the potential morbidities of hypoglycemia should encourage physicians to utilize therapeutic regimens that decrease the risk of severe hypoglycemia.     

Nocturnal hypoglycaemia in type 1 diabetes--consequences and assessment

Hypoglycaemia is inevitable when striving for low HbA1c values. Nocturnal hypoglycaemia often occurs without symptoms, but results in diminished next day well-being and hypoglycaemia unawareness. Frequency of nocturnal hypoglycaemia was first assessed in research ward settings, but suffered from insufficient glucose sampling frequency. This may have resulted in overestimation of the duration of hypoglycaemic episodes. The advent of the first continuous glucose sensor, the needle-type MedtronicMiniMed Continuous Glucose Measurement System, revolutionized the assessment of glucose values. However, on scrutiny, the first version of this sensor showed a drift into the hypoglycaemic area and delayed recovery from hypoglycaemia. Using the microdialysis-based GlucoDay system, our group reported a lower frequency of nocturnal hypoglycaemia in type 1 diabetes patients using an insulin pump, than that expected from the existing literature. Today, more than 80 years after the introduction of insulin for the treatment of type 1 diabetes, the associated frequency of nocturnal hypoglycaemia still awaits its definitive assessment.     

Nocturnal hypoglycemia is underdiagnosed in older people with insulin-treated type 2 diabetes: The HYPOAGE observational study

Background

There is a lack of real-life data regarding the frequency and predictive factors of hypoglycemia in older patients with type 2 diabetes (T2D). This study aimed to determine the frequency and predictors of hypoglycemia in older patients with insulin-treated T2D.

Methods

This prospective multicenter study included 155 insulin-treated T2D patients aged 75 years and older with ≥2 self-monitoring of blood glucose (SMBG) daily controls. Participants underwent a geriatric and diabetic assessment and received ambulatory blinded continuous glucose monitoring (CGM) for 28 consecutive days with FreeStyle Libre Pro® sensor. Study population (n = 141) has >70% CGM active time. Multivariable logistic regressions were used to identify factors associated with SMBG confirmed hypoglycemia (≥70 mg/dL) and with nocturnal level 2 time below range (glucose concentration <54 mg/dL during ≥15 consecutive min between 0.00 and 6.00 am).

Results

The mean age of the 141 analyzed patients was 81.5 ± 5.3 years and 56.7% were male. The mean baseline HbA_1c was 7.9% ± 1.0%. After geriatric assessment, 102 participants (72.3%) were considered as complex and 39 (27.7%) as healthy. The primary endpoint (confirmed SMBG <70 mg/dL) occurred in 37.6% patients. In multivariable analysis, the risk of SMBG-confirmed hypoglycemia was positively associated with a longer duration of diabetes (OR (+1 year) =1.04, (1.00–1.08), p = 0.04) and glycemic variability assessed by CGM (CV %) (OR (+1%) = 1.12, [1.05–1.19], p = <0.001). Nighty-two patients (65.2%) experienced nocturnal time in hypoglycemia (i.e., <54 mg/dL during ≥15 consecutive min between midnight and 6 a.m.). In multivariable analyses, cognitive impairment (OR: 9.31 [2.59–33.4]), heart failure (OR: 4.81 [1;48–15.6]), and depressive disorder (OR: 0.19 [0.06–0.53]) were associated with nocturnal time in hypoglycemia.

Conclusion

Nocturnal hypoglycemia is very common and largely underdiagnosed in older patients with insulin-treated T2D. CGM is a promising tool to better identify hypoglycemia and adapt diabetes management in this population.     

Regional brain activation during hypoglycemia in type 1 diabetes

CONTEXT: Mechanisms underlying the brain response to hypoglycemia are not well understood. OBJECTIVE: Our objective was to determine the blood glucose level at which the hypothalamus and other brain regions are activated in response to hypoglycemia in type 1 diabetic patients and control subjects. DESIGN: This was a cross-sectional study evaluating brain activity using functional magnetic resonance imaging in conjunction with a hyperinsulinemic hypoglycemic clamp to lower glucose from euglycemia (90 mg/dl) to hypoglycemia (50 mg/dl). Setting: The study was performed at the Brain Imaging Center in the McLean Hospital. STUDY PARTICIPANTS: Seven type 1 diabetic patients between 18 and 50 yr old and six matched control subjects were included in the study. Intervention: Hyperinsulinemic hypoglycemic clamp was performed. MAIN OUTCOME MEASURES: Blood glucose level at peak hypothalamic activation, amount of regional brain activity during hypoglycemia in both groups, and difference in regional brain activation between groups were calculated. RESULTS: The hypothalamic region activates at 68 +/- 9 mg/dl in control subjects and 76 +/- 8 mg/dl in diabetic patients during hypoglycemia induction. Brainstem, anterior cingulate cortex, uncus, and putamen were activated in both groups (P < 0.001). Each group also activated unique brain areas not active in the other group. CONCLUSIONS: This application of functional magnetic resonance imaging can be used to identify the glucose level at which the hypothalamus is triggered in response to hypoglycemia and whether this threshold differs across patient populations. This study suggests that a core network of brain regions is recruited during hypoglycemia in both diabetic patients and control subjects.     

Recent advances in the prevention of hypoglycemia in type 1 diabetes

Iatrogenic hypoglycemia is one of the chief barriers to optimal glycemic control in people with type 1 diabetes (T1D). As a common contributor to morbidity and mortality in T1D, severe hypoglycemia (SH) is also a major fear for people with T1D and their families. Consequently, fear of hypoglycemia and hypoglycemia-avoidant behaviors are predominant limiting factors in achieving euglycemia in people with T1D. Nocturnal SH and hypoglycemia unawareness are prevalent obstacles in the detection of hypoglycemia which further impair the prevention and treatment of SH. Various strategies and technologies have already been developed to help detect and prevent hypoglycemia, including improved patient education, frequent self-monitoring of blood glucose levels, the use of rapid-acting and basal insulin analogs, continuous subcutaneous insulin infusion therapy, exercise-related insulin modifications, and continuous glucose monitors. The efficacy of these methods is well established, but further advances are still needed. The purpose of this review is to describe these currently available methods and to emphasize recent progress related to the prevention of hypoglycemia in T1D.     

Nocturnal growth hormone surges in type 1 diabetes mellitus are both sleep- and glycemia-dependent: assessment under continuous sleep monitoring

Our work has studied the relationship between nocturnal growth hormone (GH) surges, sleep and glycemia in seven conventionally treated type 1 diabetic patients under continuous sleep monitoring and the results were compared to those found in five age-matched healthy controls. On the experimental day, sleep was monitored from 24.00 to 07.00. Blood glucose levels and GH were assayed in both groups. As a group the diabetics had nocturnal GH responses higher than those in controls. However, the sleep-related GH release is not abnormally high in patients who maintain strict normoglycemia. Early-night hypoglycemia and/or rapidly decreasing blood glucose concentrations enhance sleep-related GH secretion in diabetics, whereas hypoglycemia not associated with slow-wave sleep (SWS) causes a moderate increase in GH. Late-onset nocturnal hypoglycemia is not potent enough to stimulate GH. It is proposed that in diabetics sleep-related GH production is probably not abnormally elevated within a wide range of stable glucose levels, but when these thresholds are crossed or when there is a rapid decrease in blood glucose, then GH secretion is inversely related to the changing blood glucose. Therefore, our study supports the conclusion that sleep-related GH secretion is finely modulated by the actual glycemic fluctuations in diabetic patients.     

Maternal hypoglycemia during pregnancy in type 1 diabetes: maternal and fetal consequences

There is strong evidence that the avoidance of hyperglycemia is essential inoptimizing pregnancy outcome in type 1 diabetes. The price to pay is a striking increase in severe hypoglycemia (SH), defined as episodes requiring help from another person. During type 1 diabetic pregnancy, occurrence rates of SH up to 15 times higher as in the intensively treated group of the Diabetes Control and Complications Trial (DCCT) are reported. Blood glucose (BG) treatment targets differ considerably between clinics; some authors advocate lower limits as low as 3.3 mmol/l. Improved glycemic control and/or recurrent hypoglycemia (i.e. BG <3.9 mmol/l) may result in impairment of glucose counterregulatory responses. Also, glucose counterregulation may be altered by pregnancy itself. Short-acting insulin analogs may help reduce hypoglycemia with preservation of good glycemic control, but their use during pregnancy has yet to be proven safe.Several clinical studies did not establish an association between maternal hypoglycemia and diabetic embryopathy. However, animal studies clearly indicate that hypoglycemia is potentially teratogenic during organogenesis. Increased rates of macrosomia continue to be observed despite near normal HbA(1c) levels. This may, at least in part, be the result of rebound hyperglycemia elicited by hypoglycemia. Exposure to hypoglycemia in utero may have long-term effects on offspring including neuropsychological defects. It is yet unclear to what extent the benefits of tight glycemic control balance with the increased risk of (severe) hypoglycemia during type 1 diabetic pregnancy. Efforts must be made to avoid low BG, i.e. <3.9 mmol/l, when tightening glycemic control.     

Classification of hypoglycemia awareness in people with type 1 diabetes in clinical practice

AimNo consensus exists on classification of hypoglycemia awareness. We compared three methods for assessment of hypoglycemia awareness in a clinical setting.MethodsA questionnaire including the three methods was filled in by 372 outpatients with Type 1 diabetes [43% women, age 51±14 years (mean±S.D.)], duration of diabetes 24±13 years, and hemoglobin A1c 8.2±1.0%). Method A (Diabetes Care, 17, 697–703) and B (Diabetes Care, 18, 517-522) classify into two degrees of awareness, while Method C (Diabetes/Metabolism Research and Reviews, 19, 232-240) includes three classes.ResultsNormal awareness was reported in 75%, 51%, and 41% (A, B, C); 25% and 28% had impaired awareness (A, B); and 13% were unaware (C); 46% belonged to the intermediate class of impaired awareness (C), while 21% were not classifiable (B). Higher rates of severe hypoglycemic events were reported by patients with impaired awareness (A, B) and unawareness (C) compared to aware patients. Patients with impaired awareness (C) had more severe hypoglycemia than aware patients and less severe hypoglycemia than unaware patients. A lower rate of severe hypoglycemia was reported by aware patients classified by Method C than A. Fractions of patients with normal awareness without an event of severe hypoglycemia were 0.81, 0.86, and 0.91 (A, B, C).ConclusionAll three methods for assessment of hypoglycemia awareness are feasible in clinical practice since the degree of awareness is associated with risk of severe hypoglycemia. The trisected method (C) identifies an intermediate group with impaired awareness and with a risk of severe hypoglycemia that is significantly different from those of aware and unaware patients.     

老年2型糖尿病低血糖反应的特点与预防

目的加强对老年2型糖尿病的低血糖反应特点的认识及预防措施的探讨。方法回顾性分析58例老年2型糖尿病低血糖反应患者的临床资料。结果老年2型糖尿病低血糖反应具有临床症状不典型、低血糖持续时间长、恢复慢等特点，其诱因主要与饮食不规律有关，医源性因素也是另一重要原因。结论老年2型糖尿病患者应加强健康宣教和血糖监测，对其血糖的控制要相对放宽标准。     

Motor activity during asymptomatic nocturnal hypoglycemia in adolescents with type 1 diabetes mellitus

Abstract. Nocturnal hypoglycemia is reported in 13%–56% of adolescents with type 1 diabetes mellitus. It may be asymptomatic in more than 50% of patients. No noninvasive method for detecting asymptomatic nocturnal hypoglycemia (ANH) has so far proven successful. The aim of the present study was to evaluate quantitative changes of motor activity by actigraphy during episodes of ANH in adolescents with type 1 diabetes mellitus. A total of 18 patients aged 10–16 years with a history of ANH were investigated. Blood was sampled at half-hourly intervals between 22.30 and 06.00 hours with a micropump, and an actigraph was fastened to the right wrist. Blood glucose concentrations were measured and compared to motor activity. Nocturnal hypoglycemia was recorded in 10 patients (55%), with blood glucose during periods of hypoglycemia of 3.00+0.17 mmol/l (range, 1.2–3.4 mmol/l), and duration of hypoglycemia of 1.95+1.34 hours (range, 0.5–5.0 hours). All periods of hypoglycemia were clinically asymptomatic. Regression analysis revealed a statistically significant linear correlation (p=0.03) between blood glucose concentration and the respective 30-min activity counts. Activity counts in patients with nocturnal hypoglycemia were significantly (ANOVA, p<0.02) higher than in patients with normoglycemia. We conclude that low blood glucose was significantly correlated with an increase in motor activity as detected by actigraphy. This implies the possibility of noninvasive screening of asymptomatic nocturnal hypoglycemia.