Association Between Excessive Daytime Sleepiness and Severe Hypoglycemia in People With Type 2 Diabetes: The Edinburgh Type 2 Diabetes Study

OBJECTIVE

Sleep-disordered breathing and sleepiness cause metabolic, cognitive, and behavioral disturbance. Sleep-disordered breathing is common in type 2 diabetes, a condition that requires adherence to complex dietary, behavioral, and drug treatment regimens. Hypoglycemia is an important side effect of treatment, causing physical and psychological harm and limiting ability to achieve optimal glycemic control. We hypothesized that sleep disorder might increase the risk of hypoglycemia through effects on self-management and glucose regulation.

RESEARCH DESIGN AND METHODS

People with type 2 diabetes (n = 898) completed questionnaires to assess sleep-disordered breathing, daytime sleepiness, and occurrence of severe hypoglycemia.

RESULTS

Subjects who scored highly on the Epworth Sleepiness Scale were significantly more likely to have suffered from severe hypoglycemia. This was a significant predictor of severe hypoglycemia in regression analysis including the variables age, sex, duration of diabetes, HbA_1c, BMI, and treatment type.

CONCLUSIONS

Daytime sleepiness may be a novel risk factor for hypoglycemia.Hypoglycemia is an adverse side effect of insulin and sulfonylurea treatment for type 2 diabetes. Factors influencing risk of severe hypoglycemia (requiring external assistance) include duration of diabetes (1), duration of insulin treatment (2), renal impairment (2), age (1), comorbidities (3), and impaired awareness of hypoglycemia (4). Sleep-disordered breathing with associated daytime somnolence is reported in up to 75% of people with type 2 diabetes (5) and is linked to a range of cardiovascular and metabolic morbidities (6). We hypothesized that sleep disorder and increased daytime sleepiness would be associated with increased frequency of severe hypoglycemia in people with diabetes.     

Hypoglycemia Unawareness in Older Compared With Middle-Aged Patients With Type 2 Diabetes

OBJECTIVE

Older patients with type 2 diabetes are at a particularly high risk for severe hypoglycemic episodes, and experimental studies in healthy subjects hint at a reduced awareness of hypoglycemia in aged humans. However, subjective responses to hypoglycemia have rarely been assessed in older type 2 diabetic patients.

RESEARCH DESIGN AND METHODS

We tested hormonal, subjective, and cognitive responses (reaction time) to 30-min steady-state hypoglycemia at a level of 2.8 mmol/l in 13 older (≥65 years) and 13 middle-aged (39–64 years) type 2 diabetic patients.

RESULTS

Hormonal counterregulatory responses to hypoglycemia did not differ between older and middle-aged patients. In contrast, middle-aged patients showed a pronounced increase in autonomic and neuroglycopenic symptom scores at the end of the hypoglycemic plateau that was not observed in older patients (both P < 0.01). Also, seven middle-aged patients, but only one older participant, correctly estimated their blood glucose concentration to be <3.3 mmol/l during hypoglycemia (P = 0.011). A profound prolongation of reaction times induced by hypoglycemia in both groups persisted even after 30 min of subsequent euglycemia.

CONCLUSIONS

Our data indicate marked subjective unawareness of hypoglycemia in older type 2 diabetic patients that does not depend on altered neuroendocrine counterregulation and may contribute to the increased probability of severe hypoglycemia frequently reported in these patients. The joint occurrence of hypoglycemia unawareness and deteriorated cognitive function is a critical factor to be carefully considered in the treatment of older patients.Hypoglycemia is the limiting factor in the glycemic management of diabetes (1). For a long time hypoglycemia was assumed a major problem only in patients suffering from type 1 diabetes (2); however, there is increasing evidence that hypoglycemic episodes are a critical factor also in type 2 diabetes (3,4). Older subjects aged >65 years, who represent the majority of type 2 diabetic patients, appear at a particularly high risk of experiencing severe hypoglycemia (3,4). Previous studies (5–7) have shown weakened perception of hypoglycemia-related symptoms in healthy older (i.e., nondiabetic older subjects, aged 65–80 years) as compared with younger subjects (aged 24–49 years). Of note, in aged humans, the perception of hypoglycemic symptoms was found to simultaneously occur with the impairment of cognitive functions during a stepwise reduction of blood glucose levels (7), contrasting the well-known hierarchical succession of central nervous responses to hypoglycemia in younger healthy adults who normally perceive hypoglycemic symptoms at higher glucose levels than cognitive dysfunction (4). The concurrence of glycemic thresholds for the onset of symptoms and of cognitive dysfunction may be expected to increase the risk for severe hypoglycemic episodes since it likely prevents behavioral counteractions (e.g., the intake of carbohydrates) (3).To date only one study (8) has assessed subjective responses to standardized hypoglycemia in older type 2 diabetic patients (aged 72 ± 1 years), revealing an impairment in the perception of hypoglycemic symptoms that was comparable to that of age-matched healthy control subjects. Although this finding points to a decrease in hypoglycemia awareness that develops in the course of aging also in type 2 diabetic patients, this assumption has not yet been experimentally elucidated. Moreover, in the previous studies in healthy subjects (5–7), the age gap between experimental groups was rather large, raising the question as to the perception of hypoglycemia in middle-aged subjects. On this background, we examined whether older (aged ≥65 years) as compared with middle-aged (aged 39–64 years) type 2 diabetic patients differ in their subjective response to hypoglycemia and how hypoglycemia awareness in these age-groups relates to hormonal and cognitive effects of hypoglycemia.     

2型糖尿病病人发生低血糖的临床分析

2型糖尿病是由多种原因引起的代谢性紊乱综合征。近年来发病率呈上升趋势 ,现发病率为 2 %～ 5 % ,随之而来病人因用药或节食不当而引发的低血糖反应也明显增加。对我院1998年— 2 0 0 2年收治的 12 4例发生低血糖的糖尿病病人进行了临床分析。现报告如下。1　材料与方法1.1　对象　已经确诊的 2型糖尿病病人 ,有低血糖临床表现时立即抽取静脉血 2ml送检 ,检测在 1h内完成。并记录其是否用药及其种类和剂量。1.2　方法　严格按照《临床检验操作规程》进行操作 ;检测仪器为日本TBA— 40FR全自动性化分析仪 ;试剂为保定长城公司出产的葡萄糖…     

Morning Cortisol Levels and Cognitive Abilities in People With Type 2 Diabetes: The Edinburgh Type 2 Diabetes Study

OBJECTIVE

People with type 2 diabetes are at increased risk of cognitive impairment but the mechanism is uncertain. Elevated glucocorticoid levels in rodents and humans are associated with cognitive impairment. We aimed to determine whether fasting cortisol levels are associated with cognitive ability and estimated lifetime cognitive change in an elderly population with type 2 diabetes.

RESEARCH DESIGN AND METHODS

This was a cross-sectional study of 1,066 men and women aged 60–75 years with type 2 diabetes, living in Lothian, Scotland (the Edinburgh Type 2 Diabetes Study). Cognitive abilities in memory, nonverbal reasoning, information processing speed, executive function, and mental flexibility were tested, and a general cognitive ability factor, g, was derived. Prior intelligence was estimated from vocabulary testing, and adjustment for scores on this test was used to estimate lifetime cognitive change. Relationships between fasting morning plasma cortisol levels and cognitive ability and estimated cognitive change were tested. Models were adjusted for potential confounding and/or mediating variables including metabolic and cardiovascular variables.

RESULTS

In age-adjusted analyses, higher fasting cortisol levels were not associated with current g or with performance in individual cognitive domains. However, higher fasting cortisol levels were associated with greater estimated cognitive decline in g and in tests of working memory and processing speed, independent of mood, education, metabolic variables, and cardiovascular disease (P < 0.05).

CONCLUSIONS

High morning cortisol levels in elderly people with type 2 diabetes are associated with estimated age-related cognitive change. Strategies targeted at lowering cortisol action may be useful in ameliorating cognitive decline in individuals with type 2 diabetes.Type 2 diabetes is associated with cognitive impairments, including deficits in processing speed, executive function and declarative memory, and with structural changes in the brain including reductions in hippocampal and amygdalar volumes, which are key areas influencing learning and long-term memory (1,2). Hyperglycemia, cerebral microvascular disease, and recurrent severe hypoglycemic episodes have all been implicated as potential causative factors of cognitive decline (3) but are unlikely to explain the entire effect of diabetes on cognition.Increasing evidence supports a link between elevated plasma glucocorticoids and cognitive dysfunction. Exogenous glucocorticoid administration and elevated endogenous glucocorticoids (as occurs in Cushing''s syndrome) are associated with cognitive impairment in animals and humans. More subtle alterations in hypothalamic-pituitary-adrenal (HPA) axis function have also been linked with cognitive function, with higher plasma cortisol levels at 0900 h being associated with poorer age-related cognitive ability in a small group of elderly, healthy male volunteers (4). Conversely, manipulations that reduce plasma glucocorticoid concentrations or their effects on target tissues can attenuate cognitive decline with ageing in rodents (5,6). Elevated glucocorticoid levels have widespread effects within the central nervous system, including deleterious effects on the structure and function of the hippocampus, a key locus for cognitive function, which also highly expresses glucocorticoid receptors (7,8).Several studies have demonstrated that people with type 2 diabetes have activation of the HPA axis, manifested by elevated basal plasma cortisol levels (9,10), higher late-night salivary cortisol levels (11), elevated ACTH levels (12), increased cortisol levels following overnight dexamethasone suppression (13,14), and impaired habituation of cortisol levels to repeated stress (15). These findings are consistent with a central dysregulation of the HPA axis in type 2 diabetes. The elevated plasma cortisol levels are associated with metabolic abnormalities in diabetes (16) and with complications of diabetes, including retinopathy, neuropathy, and nephropathy (17).Investigators have started to explore whether altered HPA axis activity contributes to cognitive impairment in diabetes. Impaired central negative feedback control of the HPA axis, as indicated by higher cortisol levels after 1.5 mg dexamethasone administration, was related to declarative memory impairments, possibly reflecting hippocampal dysfunction, in 30 individuals with type 2 diabetes compared with age-, sex-, and education-matched control subjects (18). However, the association between cortisol and cognitive function disappeared after adjustment for glycemic control (A1C). The same investigators reported similarly impaired HPA axis feedback control in association with verbal declarative memory deficits in 41 subjects with type 2 diabetes (1). In the latter study, the subjects with type 2 diabetes also had reduced hippocampal and prefrontal volumes, but there were no significant associations between the cortisol measurements and magnetic resonance image findings (1).Despite these findings from animal and human studies, information from large-scale epidemiological studies of representative populations is lacking, which could confirm or refute an association between circulating plasma cortisol levels and age-related cognitive impairment. We therefore examined the relationship between fasting cortisol and both late-life cognitive ability and estimated lifetime cognitive change in a large, representative study population of people with type 2 diabetes (the Edinburgh Type 2 Diabetes Study [ET2DS]). The ET2DS has the advantage over many previous epidemiological studies of having detailed cognitive testing in a range of cognitive domains and very extensive phenotyping for potential confounding or mediating factors.     

Retinopathy in Youth With Type 2 Diabetes Participating in the TODAY Clinical Trial

OBJECTIVE

To determine the prevalence of retinopathy in 517 youth with type 2 diabetes of 2–8 years duration enrolled in the TODAY study.

RESEARCH DESIGN AND METHODS

Retinal photographs were graded centrally for retinopathy using established standards.

RESULTS

Retinopathy was identified in 13.7% of subjects. Prevalence increased with age, diabetes duration, and mean HbA_1c. Subjects in the highest BMI tertile had the lowest prevalence of retinopathy.

CONCLUSIONS

Prevalence of retinopathy and its association with HbA_1c and diabetes duration is similar to that previously reported in youth with type 1 diabetes and in adults with type 2 diabetes of known duration. The mechanism underlying the reduced risk of retinopathy in the most obese individuals is unknown. Follow-up of this cohort will help define the natural history of retinopathy in youth with type 2 diabetes.Characterization of the early course of diabetic retinopathy in adults with type 2 diabetes has been hindered by the long lag time before diagnosis. The TODAY cohort of youth with type 2 diabetes is ideal for examining the prevalence of retinopathy early in the course of the disorder.     

老年2型糖尿病并发低血糖35例分析

对35例老年2型糖尿病患者出现低血糖的临床资料进行分析。结果低血糖病因多种,症状各异,进食或输注葡萄糖治疗效果好。     

Parental Characteristics Associated With Outcomes in Youth With Type 2 Diabetes: Results From the TODAY Clinical Trial

OBJECTIVEThis study examined parental factors associated with outcomes of youth in the Treatment Options for type 2 Diabetes in Adolescents and Youth (TODAY) clinical trial.RESULTSParental diabetes (43.6% of parents) was associated with higher baseline HbA_1c (P < 0.0001) and failure of youths to maintain glycemic control on study treatment (53.6% vs. 38.2% failure rate among those without a diabetic parent, P = 0.0002). Parental hypertension (40.6% of parents) was associated with hypertension in youth during TODAY (40.4% vs. 27.4% of youth with and without parental hypertension had hypertension, P = 0.0008) and with higher youth baseline BMI z scores (P = 0.0038). Parents had a mean baseline BMI of 33.6 kg/m². Parental obesity (BMI >30 kg/m²) was associated with higher baseline BMI z scores in the youth (P < 0.0001). Depressive symptoms in parents (20.6% of parents) were related to youth depressive symptoms at baseline only (P = 0.0430); subclinical BE in parents was related to the presence of subclinical BE (P = 0.0354) and depressive symptoms (P = 0.0326) in youth throughout the study period.CONCLUSIONSParental diabetes and hypertension were associated with lack of glycemic control, hypertension, and higher BMI z scores in youth. Further research is needed to better understand and address parental biological and behavioral factors to improve youth health outcomes.     

Overnight Closed-Loop Insulin Delivery in Young People With Type 1 Diabetes: A Free-Living,Randomized Clinical Trial

OBJECTIVE

To evaluate feasibility, safety, and efficacy of overnight closed-loop insulin delivery in free-living youth with type 1 diabetes.

RESEARCH DESIGN AND METHODS

Overnight closed loop was evaluated at home by 16 pump-treated adolescents with type 1 diabetes aged 12–18 years. Over a 3-week period, overnight insulin delivery was directed by a closed-loop system, and on another 3-week period sensor-augmented therapy was applied. The order of interventions was random. The primary end point was time when adjusted sensor glucose was between 3.9 and 8.0 mmol/L from 2300 to 0700 h.

RESULTS

Closed loop was constantly applied over at least 4 h on 269 nights (80%); sensor data were collected over at least 4 h on 282 control nights (84%). Closed loop increased time spent with glucose in target by a median 15% (interquartile range −9 to 43; P < 0.001). Mean overnight glucose was reduced by a mean 14 (SD 58) mg/dL (P < 0.001). Time when glucose was <70 mg/dL was low in both groups, but nights with glucose <63 mg/dL for at least 20 min were less frequent during closed loop (10 vs. 17%; P = 0.01). Despite lower total daily insulin doses by a median 2.3 (interquartile range −4.7 to 9.3) units (P = 0.009), overall 24-h glucose was reduced by a mean 9 (SD 41) mg/dL (P = 0.006) during closed loop.

CONCLUSIONS

Unsupervised home use of overnight closed loop in adolescents with type 1 diabetes is safe and feasible. Glucose control was improved during the day and night with fewer episodes of nocturnal hypoglycemia.     

Effects of Acute Insulin-Induced Hypoglycemia on Spatial Abilities in Adults With Type 1 Diabetes

OBJECTIVE

To examine the effects of acute insulin-induced hypoglycemia on spatial cognitive abilities in adult humans with type 1 diabetes.

RESEARCH DESIGN AND METHODS

Sixteen adults with type 1 diabetes underwent two counterbalanced experimental sessions: euglycemia (blood glucose 4.5 mmol/l [81 mg/dl]) and hypoglycemia (2.5 mmol/l [45 mg/dl]). Arterialized blood glucose levels were maintained using a hyperinsulinemic glucose clamp technique. During each session, subjects underwent detailed assessment of spatial abilities from the Kit of Factor-Referenced Cognitive Tests and two tests of general cognitive function.

RESULTS

Spatial ability performance deteriorated significantly during hypoglycemia. Results for the Hidden Patterns, Card Rotations, Paper Folding, and Maze Tracing tests were all impaired significantly (P ≤ 0.001) during hypoglycemia, as were results for the Cube Comparisons Test (P = 0.03). The Map Memory Test was not significantly affected by hypoglycemia.

CONCLUSIONS

Hypoglycemia is a common side effect of insulin therapy in individuals with type 1 diabetes, and spatial abilities are of critical importance in day-to-day functioning. The deterioration in spatial abilities observed during modest experimental hypoglycemia provides novel information on the cerebral hazards of hypoglycemia that has potential relevance to everyday activities.Hypoglycemia is a common side effect of insulin treatment of diabetes. Strict glycemic control limits the development and severity of vascular complications of diabetes, but hypoglycemia is a frequent consequence. Strict glycemic control can increase the incidence of severe hypoglycemia by threefold (1). Hypoglycemia has an adverse effect on cognitive functions, as the human brain relies solely on glucose as its source of energy (2). It has a pronounced effect on complex cognitive tasks both in diabetic and nondiabetic individuals, whereas simple mental tasks are relatively unaffected (2). Cognitive function deteriorates when arterialized blood glucose concentrations decline to <3.0 mmol/l (3–6). Simple and choice reaction times, speed of mathematical calculation, verbal fluency, attention, memory, and psychomotor function have all been demonstrated to be affected during hypoglycemia (7–10). The recovery of different aspects of cognitive function may vary from between 40 and 90 min after restoration of blood glucose to normal (2,11).Whereas hypoglycemia impairs many domains of cognitive function, the effect of hypoglycemia on spatial cognitive abilities has not been investigated in detail, although spatial ability is undoubtedly a component of some of the tests used to assess other aspects of cognition (12). Spatial abilities may be defined as the ability to generate, retain, retrieve, and transform or manipulate structured visual images to orientate and interpret the surrounding environment. In real-life terms, spatial ability is concerned with how human beings deal with issues concerning two- and three-dimensional objects, space, navigation, and pathfinding. Practical daily cognition often involves inferring how shapes and objects will appear and function when they are rotated or otherwise oriented or viewed differently. In everyday interactions with the environment, this process is very important, with particular relevance for complex tasks such as driving and map reading. A large variety of mental tests are available for the assessment of spatial abilities. Largely, these tests can be separated into tests of spatial perception, namely the ability to determine spatial relations despite distracting information; spatial visualization, which is the ability to manipulate complex, multistep spatial information; and mental rotation, which is the ability to rotate two- or three-dimensional figures in one''s mind (13). The present study was designed to investigate the effects of acute insulin-induced hypoglycemia on spatial abilities in adults with type 1 diabetes, using a well-characterized battery of spatial tests that incorporate all of these components of spatial cognition.     

2型糖尿病无症状低血糖患者膳食结构分析

目的 了解2型糖尿病患者无症状低血糖与膳食结构的关系.方法 对46例2型糖尿病患者采用动态血糖监测系统,筛查出无症状低血糖患者63例次(无症状低血糖组),与63例次患者(非低血糖组)前1 d或后1 d相应时间段未发生低血糖时三大产能营养素实际摄人量进行分析比较,分析比较使用营养计算器V1.6.结果 无症状低血糖63例次,发生在晚夜间31例次,占49%;年龄>60岁者 39例次,占62%;非低血糖组碳水化合物的摄入量高于无症状低血糖组(P相似文献   

A Randomized Trial of a Home System to Reduce Nocturnal Hypoglycemia in Type 1 Diabetes

OBJECTIVE

Overnight hypoglycemia occurs frequently in individuals with type 1 diabetes and can result in loss of consciousness, seizure, or even death. We conducted an in-home randomized trial to determine whether nocturnal hypoglycemia could be safely reduced by temporarily suspending pump insulin delivery when hypoglycemia was predicted by an algorithm based on continuous glucose monitoring (CGM) glucose levels.

RESEARCH DESIGN AND METHODS

Following an initial run-in phase, a 42-night trial was conducted in 45 individuals aged 15–45 years with type 1 diabetes in which each night was assigned randomly to either having the predictive low-glucose suspend system active (intervention night) or inactive (control night). The primary outcome was the proportion of nights in which ≥1 CGM glucose values ≤60 mg/dL occurred.

RESULTS

Overnight hypoglycemia with at least one CGM value ≤60 mg/dL occurred on 196 of 942 (21%) intervention nights versus 322 of 970 (33%) control nights (odds ratio 0.52 [95% CI 0.43–0.64]; P < 0.001). Median hypoglycemia area under the curve was reduced by 81%, and hypoglycemia lasting >2 h was reduced by 74%. Overnight sensor glucose was >180 mg/dL during 57% of control nights and 59% of intervention nights (P = 0.17), while morning blood glucose was >180 mg/dL following 21% and 27% of nights, respectively (P < 0.001), and >250 mg/dL following 6% and 6%, respectively. Morning ketosis was present <1% of the time in each arm.

CONCLUSIONS

Use of a nocturnal low-glucose suspend system can substantially reduce overnight hypoglycemia without an increase in morning ketosis.     

Effect of Culturally Tailored Diabetes Education in Ethnic Minorities With Type 2 Diabetes: A Meta-analysis

BACKGROUND:: Diabetes is a major cause of cardiovascular morbidity and mortality. Ethnic minorities experience a disproportionate burden of diabetes; however, few studies have critically analyzed the effectiveness of a culturally tailored diabetes intervention for these minorities. OBJECTIVE:: The aim of this study was to evaluate the effectiveness of a culturally tailored diabetes educational intervention (CTDEI) on glycemic control in ethnic minorities with type 2 diabetes. METHOD:: We searched databases within PubMed, Cumulative Index to Nursing and Allied Health Literature (CINAHL), Education Resources Information Center (ERIC), PsycINFO, and ProQuest for randomized controlled trials (RCTs). We performed a meta-analysis for the effect of diabetes educational intervention on glycemic control using glycosylated hemoglobin (HbA1c) value in ethnic minority groups with type 2 diabetes. We calculated the effect size (ES) with HbA1c change from baseline to follow-up between control and treatment groups. RESULTS:: The 12 studies yielded 1495 participants with a mean age of 63.6 years and a mean of 68% female participants. Most studies (84%) used either group education sessions or a combination of group sessions and individual patient counseling. The duration of interventions ranged from 1 session to 12 months. The pooled ES of glycemic control in RCTs with CTDEI was -0.29 (95% confidence interval, -0.46 to -0.13) at last follow-up, indicating that ethnic minorities benefit more from CTDEI when compared with the usual care. The effect of intervention was greatest and significant when HbA1c level was measured at 6 months (ES, -0.41; 95% confidence interval, -0.61 to -0.21). The ES also differed by each participant's baseline HbA1c level, with lower baseline levels associated with higher ESs. CONCLUSIONS:: Based on this meta-analysis, CTDEI is effective for improving glycemic control among ethnic minorities. The magnitude of effect varies based on the settings of intervention, baseline HbA1c level, and time of HbA1c measurement. More rigorous RCTs that examine tailored diabetes education, ethnically matched educators, and more diverse ethnic minority groups are needed to reduce health disparities in diabetes care.     

All-Cause and Cardiovascular Mortality in Middle-Aged People With Type 2 Diabetes Compared With People Without Diabetes in a Large U.K. Primary Care Database

OBJECTIVE

Middle-aged people with diabetes have been reported to have significantly higher risks of cardiovascular events than people without diabetes. However, recent falls in cardiovascular disease rates and more active management of risk factors may have abolished the increased risk. We aimed to provide an up-to-date assessment of the relative risks associated with type 2 diabetes of all-cause and cardiovascular mortality in middle-aged people in the U.K.

RESEARCH DESIGN AND METHODS

Using data from the General Practice Research Database, from 2004 to 2010, we conducted a cohort study of 87,098 people, 40–65 years of age at baseline, comparing 21,798 with type 2 diabetes and 65,300 without diabetes, matched on age, sex, and general practice. We produced hazard ratios (HRs) for mortality and compared rates of blood pressure testing, cholesterol monitoring, and use of aspirin, statins, and antihypertensive drugs.

RESULTS

People with type 2 diabetes, compared with people without diabetes, had a twofold increased risk of all-cause mortality (HR 2.07 [95% CI 1.95–2.20], adjusted for smoking) and a threefold increased risk of cardiovascular mortality (3.25 [2.87–3.68], adjusted for smoking). Women had a higher relative risk than men, and people <55 years of age had a higher relative risk than those >55 years of age. Monitoring and medication rates were higher in those with diabetes (all P < 0.001).

CONCLUSIONS

Despite efforts to manage risk factors, administer effective treatments, and develop new therapies, middle-aged people with type 2 diabetes remain at significantly increased risk of death.In the U.K., cardiovascular disease (CVD) mortality rates in adults have fallen dramatically in recent years (1), by >40% in those 35–69 years of age during 2000–2010 alone (2). The fall in the rates of CVD in the general adult U.K. population may be attributed in part to using aspirin, hydroxymethylglutaryl-CoA reductase inhibitors (statins), and antihypertensive drugs and successfully incorporating lifestyle interventions, in particular reducing smoking (3). In people with type 2 diabetes, who are at increased risk of death from CVD, evidence has shown that statins, antihypertensive drugs (4), and smoking cessation (3,5) reduce the incidence of CVD (6,7). Consequently, these interventions, in addition to weight management strategies to target obesity, a known risk factor for CVD events (3), have been incorporated into the various clinical guidelines, national standards, and incentives relating to managing diabetes (8–10) and implemented by general practitioners with the aim of reducing the risk of complications.The magnitude of the increase in risk of CVD and all-cause mortality in middle-aged people with diabetes, compared with those without diabetes, has been reported at two to four times higher, but these estimates are largely based on data from the 1990s or earlier (11–16). Given that the rates of CVD mortality in the general population have rapidly fallen in recent years (2), and since 2004, the remuneration for general practice actively rewards intensive management for cardiovascular risk factors in people with diabetes (10), the differences may have narrowed even in the past 8 years. Most studies with post-2000 data on relative risk have not distinguished type 1 from type 2 diabetes (17–20), or have been restricted to newly diagnosed type 2 diabetes (21,22). One exception, reporting relative risks for prevalent type 2 diabetes, was the National Diabetes Audit in England (23). Using follow-up data from 2008 to 2009, they presented standardized mortality ratios in the absence of a nondiabetic comparator group; the report’s authors proposed that their results need replicating using survival analysis methods. Using data from the General Practice Research Database (GPRD), we aimed to provide a more up-to-date assessment of the risk of mortality in middle-aged people with prevalent type 2 diabetes in England, overcoming the acknowledged limitation of the National Diabetes Audit study and additionally considering mortality from CVD.     

Association of Clinical Symptomatic Hypoglycemia With Cardiovascular Events and Total Mortality in Type 2 Diabetes: A nationwide population-based study

OBJECTIVE

Hypoglycemia is associated with serious health outcomes for patients treated for diabetes. However, the outcome of outpatients with type 2 diabetes who have experienced hypoglycemia episodes is largely unknown.

RESEARCH DESIGN AND METHODS

The study population, derived from the National Health Insurance Research Database released by the Taiwan National Health Research Institutes during 1998–2009, comprised 77,611 patients with newly diagnosed type 2 diabetes. We designed a prospective study consisting of randomly selected hypoglycemic type 2 diabetic patients and matched type 2 diabetic patients without hypoglycemia. We investigated the relationships of hypoglycemia with total mortality and cardiovascular events, including stroke, coronary heart disease, cardiovascular diseases, and all-cause hospitalization.

RESULTS

There were 1,844 hypoglycemic events (500 inpatients and 1,344 outpatients) among the 77,611 patients. Both mild (outpatient) and severe (inpatient) hypoglycemia cases had a higher percentage of comorbidities, including hypertension, renal diseases, cancer, stroke, and heart disease. In multivariate Cox regression models, including diabetes treatment adjustment, diabetic patients with hypoglycemia had a significantly higher risk of cardiovascular events during clinical treatment periods. After constructing a model adjusted with propensity scores, mild and severe hypoglycemia still demonstrated higher hazard ratios (HRs) for cardiovascular diseases (HR 2.09 [95% CI 1.63–2.67]), all-cause hospitalization (2.51 [2.00–3.16]), and total mortality (2.48 [1.41–4.38]).

CONCLUSIONS

Symptomatic hypoglycemia, whether clinically mild or severe, is associated with an increased risk of cardiovascular events, all-cause hospitalization, and all-cause mortality. More attention may be needed for diabetic patients with hypoglycemic episodes.Hypoglycemia is a major side effect of glucose-lowering therapy in patients with type 1 or type 2 diabetes. Patients with type 2 diabetes are usually believed to have less frequent hypoglycemia episodes than type 1 diabetic patients (1). Prodromal symptoms of hypoglycemia, including tremor, diaphoresis, tachycardia, and anxiety, are sometimes noticed by the patient; consequently, severe complications can be avoided. If left untreated, however, neuroglycopenia may develop, resulting in neurologic damage (2,3).Hypoglycemia has also been associated with adverse cardiovascular events in type 2 diabetic patients beyond hypoglycemic episodes themselves (4). The surge of sympathetic activity during hypoglycemic episodes has been suggested to be the underlying mechanism leading to destabilization of atherosclerotic plaques (5), increased arrhythmia attributable to increased corrected QT interval (6), and induction of cardiac and cerebral ischemia. Studies including epidemiological cohort studies and clinical trials (7–10) have already suggested that hypoglycemia also is a risk factor for cardiovascular outcomes. However, some patients in these studies had comorbidities on admission, such as unstable angina and acute myocardial infarction (11–14). Recently, the ADVANCE study suggested that hypoglycemia is associated with increased risks of a range of adverse clinical outcomes, and it is considered to be a marker for vulnerability to such events for type 2 diabetic patients (15).Whether hypoglycemia is a risk factor or a marker, it is important to evaluate the possible correlates to both hypoglycemia and serious health conditions, including hepatic disease, malignancy, renal disease, and use of various medications. Furthermore, in real-world clinical practice, it is intriguing to identify hypoglycemic events based solely on symptoms or a physician’s diagnosis rather than on glucose levels, as most previous studies have. Moreover, patient selection bias, especially the Berkson bias, in hospital-based observational or case-control studies probably confounds and casts doubt on the associations between hypoglycemia and clinical outcomes. Finally, the clinical impact of mild self-reported hypoglycemic episodes is largely unknown. We therefore conducted this nationwide random-sampling cohort study of type 2 diabetic patients to characterize their comorbidities and evaluate the influences of mild and severe hypoglycemia and their outcomes.     

糖尿病性低血糖危象19例临床分析

糖尿病性低血糖危象为糖尿病的急性并发症之一,对机体的危害较高血糖更为严重。其临床表现复杂多变,有时容易误诊误治,一旦处置失当将给病人造成不可逆的脑损害乃至死亡。我院2000年1月~2005年8月收治19例糖尿病性低血糖危象,现分析报告如下。1临床资料1·1一般资料本组19例,均为我院急诊科收住的糖尿病性低血糖危象,男10例,女9例;年龄32~75岁,60岁以上17例。全部为临床诊断的2型糖尿病。15例病程2~20年,4例病程1日~3个月。15例合并糖尿病慢性并发症,其中合并高血压病7例,糖尿病肾病8例,糖尿病周围神经病变3例,糖尿病足1例。发病前患急性胃…     

The Effect of Walking on Postprandial Glycemic Excursion in Patients With Type 1 Diabetes and Healthy People

OBJECTIVE

Physical activity (PA), even at low intensity, promotes health and improves hyperglycemia. However, the effect of low-intensity PA captured with accelerometery on glucose variability in healthy individuals and patients with type 1 diabetes has not been examined. Quantifying the effects of PA on glycemic variability would improve artificial endocrine pancreas (AEP) algorithms.

RESEARCH DESIGN AND METHODS

We studied 12 healthy control subjects (five males, 37.7 ± 13.7 years of age) and 12 patients with type 1 diabetes (five males, 37.4 ± 14.2 years of age) for 88 h. Participants performed PA approximating a threefold increase over their basal metabolic rate. PA was captured using a PA-monitoring system, and interstitial fluid glucose concentrations were captured with continuous glucose monitors. In random order, one meal per day was followed by inactivity, and the other meals were followed by walking. Glucose and PA data for a total of 216 meals were analyzed from 30 min prior to meal ingestion to 270 min postmeal.

RESULTS

In healthy subjects, the incremental glucose area under the curve was 4.5 mmol/L/270 min for meals followed by walking, whereas it was 9.6 mmol/L/270 min (P = 0.022) for meals followed by inactivity. The corresponding glucose excursions for those with type 1 diabetes were 7.5 mmol/L/270 min and 18.4 mmol/L/270 min, respectively (P < 0.001).

CONCLUSIONS

Walking significantly impacts postprandial glucose excursions in healthy populations and in those with type 1 diabetes. AEP algorithms incorporating PA may enhance tight glycemic control end points.Diabetes has reached epidemic proportions, especially in the U.S., and is classified mainly into type 1 and type 2 (1). Although type 2 diabetes constitutes ∼90% of the population burden of diabetes and is classically associated with a BMI that is >27 kg/m², modern society and improvements in multiple technologies have transformed type 1 diabetes into a disorder that is increasingly associated with obesity (2).Glycemic control remains a challenge in type 1 diabetes and is associated with extreme glucose variability of hypo- and hyperglycemia (3). An artificial endocrine pancreas (AEP) would represent a significant advance for patients with type 1 diabetes. Closed-loop algorithms for type 1 diabetes are currently being developed (4). Two major reasons for glucose excursions are food and physical activity (PA). How these factors interrelate, especially on an hour-to-hour basis and postprandially, is poorly documented. Incorporation of data from PA sensors into the AEP has the potential to improve the efficacy and safety of the system. Therefore, we examined the impact of levels of PA akin to activities of daily living on glycemic excursions.Low-cost motion sensors, such as accelerometers, exploit micro-electromechanical systems technology, making it possible to measure daily PA using miniature sensors worn underneath regular clothing. These accelerometers have been proven valid when compared with measurements of total daily energy expenditure performed using doubly labeled water (5). PA data thus captured along with the daily glucose profiles recorded by continuous glucose monitoring (CGM) sensors would enable us to better understand the underlying relationship.We studied healthy control subjects and patients with type 1 diabetes with the hypothesis that in patients with type 1 diabetes, glucose excursions are blunted by low-intensity PA.     

Association Between the CYP2C9 Genotype and Hypoglycemia Among Patients With Type 2 Diabetes Receiving Sulfonylurea Treatment: A Meta-analysis

PurposeTwo common variants, CYP2C9*2 (Arg144Cys, rs1799853) and CYP2C9*3 (Ile359Leu, rs1057910), are known to reduce the catalytic function of the CYP2C9 enzyme. Because impaired catalytic function is likely to affect sulfonylurea metabolism, it is predictable that CYP2C9 loss-of-function alleles may increase the risk of sulfonylurea-induced hypoglycemia. This systematic review and meta-analysis aimed to assess the association between CYP2C9 genotype and hypoglycemia among patients with type 2 diabetes mellitus (T2DM) receiving sulfonylurea.MethodsWe searched for studies on the association between CYP2C9 genotype and sulfonylurea-induced hypoglycemia among patients with T2DM, published through August 7, 2020, using PubMed, Web of Science, and EMBASE. Odds ratios (ORs) and 95% CIs were calculated.FindingsFive cohort studies and 2 case-control studies were included, and the total number of patients analyzed in this meta-analysis was 2769. The CYP2C9 variant alleles were associated with an increase in sulfonylurea-induced hypoglycemia compared with wild-type homozygote (OR = 1.24; 95% CI, 1.03–1.48). Compared with CYP2C9 wild-type homozygotes, CYP2C9*2 allele was associated with increased incidence of hypoglycemia (OR = 1.85; 95% CI, 1.18–2.89), whereas the CYP2C9*3 allele failed to show the statistical significance (OR = 1.67; 95% CI, 0.40–6.86; P = 0.48).ImplicationsOn the basis of these results, CYP2C9 genotyping may be useful for predicting the risk of hypoglycemia during sulfonylurea treatment for T2DM.     

Acute Hypoglycemia Impairs Executive Cognitive Function in Adults With and Without Type 1 Diabetes

OBJECTIVE

Acute hypoglycemia impairs cognitive function in several domains. Executive cognitive function governs organization of thoughts, prioritization of tasks, and time management. This study examined the effect of acute hypoglycemia on executive function in adults with and without diabetes.

RESEARCH DESIGN AND METHODS

Thirty-two adults with and without type 1 diabetes with no vascular complications or impaired awareness of hypoglycemia were studied. Two hyperinsulinemic glucose clamps were performed at least 2 weeks apart in a single-blind, counterbalanced order, maintaining blood glucose at 4.5 mmol/L (euglycemia) or 2.5 mmol/L (hypoglycemia). Executive functions were assessed with a validated test suite (Delis-Kaplan Executive Function). A general linear model (repeated-measures ANOVA) was used. Glycemic condition (euglycemia or hypoglycemia) was the within-participant factor. Between-participant factors were order of session (euglycemia-hypoglycemia or hypoglycemia-euglycemia), test battery used, and diabetes status (with or without diabetes).

RESULTS

Compared with euglycemia, executive functions (with one exception) were significantly impaired during hypoglycemia; lower test scores were recorded with more time required for completion. Large Cohen d values (>0.8) suggest that hypoglycemia induces decrements in aspects of executive function with large effect sizes. In some tests, the performance of participants with diabetes was more impaired than those without diabetes.

CONCLUSIONS

Executive cognitive function, which is necessary to carry out many everyday activities, is impaired during hypoglycemia in adults with and without type 1 diabetes. This important aspect of cognition has not received previous systematic study with respect to hypoglycemia. The effect size is large in terms of both accuracy and speed.The human brain depends on glucose as its energy source; acute hypoglycemia results in neuroglycopenia with subsequent cognitive impairment. Individuals with type 1 diabetes are exposed to an average of two episodes of self-treated hypoglycemia per week (1). In general, performance on complex cognitive tasks deteriorates when blood glucose declines to <3.0 mmol/L (54 mg/dL) (2,3). Previous studies have demonstrated that for complex tasks, accuracy often is preserved at the expense of speed (4). The impairment of cognitive function is reversible, although full recovery requires between 20 and 75 min after the restoration of euglycemia (5,6). Acute hypoglycemia has been shown to impair various cognitive domains, including memory, attention, information processing, psychomotor function, and spatial ability (7–10). However, the effect of hypoglycemia on executive cognitive function, which is important for everyday functioning, has received little systematic study.Executive function incorporates a number of complex, interdependent cognitive processes that allow an individual to plan, initiate, sequence, monitor, and inhibit complex behavior (11), allowing one to organize thoughts, prioritize tasks, manage time efficiently, and make decisions. Executive function, therefore, is vital for the performance of many everyday activities, and in children, inadequate executive functioning has been linked to poor adherence to treatment (12). Executive function is not localized to one particular area of the brain (13), although evidence from neuroimaging studies suggests that the frontal lobes of the brain (and their connections to other regions) are closely associated with this cognitive domain (14).The current study examined the effects of acute hypoglycemia on executive function in adult humans with and without type 1 diabetes with use of a well-validated test battery (15–18). Performance was examined in a counterbalanced design under euglycemic and hypoglycemic conditions.     

Effect of Ranolazine Monotherapy on Glycemic Control in Subjects With Type 2 Diabetes

OBJECTIVE

Ranolazine is an antianginal drug that mediates its effects by inhibition of cardiac late sodium current. Although ranolazine is not approved for the treatment of type 2 diabetes, in post hoc analyses of pivotal angina trials, ranolazine was associated with reductions in percent glycosylated hemoglobin (HbA_1c) in subjects with type 2 diabetes. The study prospectively assessed the safety and efficacy of ranolazine in subjects with type 2 diabetes with inadequate glycemic control managed by lifestyle alone.

RESEARCH DESIGN AND METHODS

The study was conducted worldwide in 465 subjects, with baseline HbA_1c of 7–10% (53–86 mmol/mol) and fasting serum glucose of 130–240 mg/dL, randomized to placebo versus ranolazine.

RESULTS

Compared with placebo, there was a greater decline in HbA_1c at week 24 from baseline (primary end point) in subjects taking ranolazine (mean difference −0.56% [−6.1 mmol/mol]; P < 0.0001). Moreover, the proportion of subjects achieving an HbA_1c <7.0% was greater with ranolazine (25.6% vs. 41.2%; P = 0.0004). Ranolazine was associated with reductions in fasting (mean difference −8 mg/dL; P = 0.0266) and 2-h postprandial glucose (mean difference −19 mg/dL; P = 0.0008 vs. placebo). Subjects taking ranolazine trended toward a greater decrease from baseline in fasting insulin (P = 0.0507), a greater decrease in fasting glucagon (P = 0.0003), and a lower postprandial 3-h glucagon area under the curve (P = 0.0031 vs. placebo). Ranolazine was safe and well tolerated.

CONCLUSIONS

Compared with placebo, use of ranolazine monotherapy over 24 weeks, in subjects with type 2 diabetes and inadequate glycemic control on diet and exercise alone, significantly reduced HbA_1c and other measures of glycemic control.