Socio-economic status and mortality in people with type 1 diabetes in Scotland 2006-2015: a retrospective cohort study.

AIMS: To describe the association between socio-economic status and mortality in a nation-wide cohort of people with type 1 diabetes in Scotland and to compare patterns over time and with the general population. METHODS: A retrospective cohort study was performed using data for people with type 1 diabetes from a population-based register linked to mortality records. Socio-economic status was derived from quintiles of an area-based measure: the Scottish Index of Multiple Deprivation. Sex-specific directly age-standardized mortality rates for each Scottish Index of Multiple Deprivation quintile and rate ratios comparing the most vs least deprived quintile were calculated for two time periods: 2006-2010 and 2011-2015. Data for the population without type 1 diabetes between 2011 and 2015 were available for comparison. RESULTS: Data for 3802 deaths among 33 547 people with type 1 diabetes were available. The age-standardized mortality rate per 1000 person-years decreased over time (from 2006-2010 to 2011-2015) for men and women with type 1 diabetes: 24.8 to 20.2 and 22.5 to 17.6, respectively. Mortality in populations with and without type 1 diabetes was generally higher for men than women and was inversely associated with socio-economic status. Rate ratios for the most vs least deprived groups increased over time among people with type 1 diabetes (men: 2.49 to 2.81; women: 1.92 to 2.86) and were higher than among populations without type 1 diabetes in 2011-2015 (men: 2.06; women: 1.66). CONCLUSIONS: Socio-economic deprivation was associated with a steeper mortality gradient in people with type 1 diabetes than in the population without type 1 diabetes in Scotland. Age-standardized mortality has decreased over time but socio-economic inequalities may be increasing.

Reducing the burden of hypoglycaemia in people with diabetes through increased understanding: design of the Hypoglycaemia REdefining SOLutions for better liVEs (Hypo-RESOLVE) project.

BACKGROUND: Hypoglycaemia is the most frequent complication of treatment with insulin or insulin secretagogues in people with diabetes. Severe hypoglycaemia, i.e. an event requiring external help because of cognitive dysfunction, is associated with a higher risk of adverse cardiovascular outcomes and all-cause mortality, but underlying mechanism(s) are poorly understood. There is also a gap in the understanding of the clinical, psychological and health economic impact of 'non-severe' hypoglycaemia and the glucose level below which hypoglycaemia causes harm. AIM: To increase understanding of hypoglycaemia by addressing the above issues over a 4-year period. METHODS: Hypo-RESOLVE is structured across eight work packages, each with a distinct focus. We will construct a large, sustainable database including hypoglycaemia data from >100 clinical trials to examine predictors of hypoglycaemia and establish glucose threshold(s) below which hypoglycaemia constitutes a risk for adverse biomedical and psychological outcomes, and increases healthcare costs. We will also investigate the mechanism(s) underlying the antecedents and consequences of hypoglycaemia, the significance of glucose sensor-detected hypoglycaemia, the impact of hypoglycaemia in families, and the costs of hypoglycaemia for healthcare systems. RESULTS: The outcomes of Hypo-RESOLVE will inform evidence-based definitions regarding the classification of hypoglycaemia in diabetes for use in daily clinical practice, future clinical trials and as a benchmark for comparing glucose-lowering interventions and strategies across trials. Stakeholders will be engaged to achieve broadly adopted agreement. CONCLUSION: Hypo-RESOLVE will advance our understanding and refine the classification of hypoglycaemia, with the ultimate aim being to alleviate the burden and consequences of hypoglycaemia in people with diabetes.

Cardiovascular disease prevalence and risk factor prevalence in Type 2 diabetes: a contemporary analysis.

AIMS: To describe the prevalence of major cardiovascular disease (CVD) and risk factor control in a contemporary population with Type 2 diabetes. METHODS: We used data from the national registry in Scotland, Scottish Care Information-Diabetes, linked to hospital admissions. Using descriptive statistics and logistic regression we described associations of risk factors with CVD. CVD was defined based on diagnostic codes in primary or secondary care data for ischaemic heart disease, cerebrovascular disease peripheral arterial disease, heart failure, cardiac arrhythmia, hypertensive heart disease and revascularization procedures. RESULTS: Among 248 400 people with Type 2 diabetes with a median age of 67.5 years (IQR 58.2, 76.1) and median diabetes duration of 7.8 years (3.8, 13.0), 32% had prior CVD (35% of men, 29% of women). Median HbA1c overall was 55 mmol/mol (7.2%), median SBP was 132 mmHg, median total cholesterol was 4.1 mmol/l and mean BMI was 32 kg/m2 . Overall two-thirds (65% of men, 68% of women) have two or more of the following CVD risk factor thresholds: HbA1c ≥ 53 mmol/mol (7%), SBP > 130 mmHg or DBP > 80 mmHg, total cholesterol ≥ 5 mmol/l or BMI ≥ 30 kg/m2 , or were currently smoking. Overall 84% were taking anti-hypertensives and 75% a statin. Use of metformin was common at 58%, but other diabetes drugs that reduce CVD were rarely used. CONCLUSIONS: There continues to be a high prevalence of CVD among people with Type 2 diabetes and a high level of unmet need for risk factor control. This implies substantial scope for reducing the excess risk of CVD in diabetes through improved management of known risk factors.

Incident ischaemic stroke and Type 2 diabetes: trends in incidence and case fatality in Scotland 2004-2013.

AIM: To describe trends in first ischaemic stroke incidence and case fatality in adults with and without a diagnosis of Type 2 diabetes prior to their ischaemic stroke event in Scotland between 2004 and 2013. METHODS: Using population-wide hospital admission, death and diabetes datasets, we conducted a retrospective cohort study. Negative binomial and logistic regression models were used to calculate year-specific incidence and case-fatality rates for people with Type 2 diabetes and for people without diabetes. RESULTS: During 41.0 million person-years of follow-up there were 69 757 ischaemic stroke events. Type 2 diabetes prevalence among patients who experienced ischaemic stroke increased from 13.5% to 20.3% between 2004 and 2013. Stroke incidence rates declined by 2.7% (95% CI 2.4, 3.0) annually for people with and without diabetes [diabetes/year interaction: rate ratio 0.99 (95% CI 0.98, 1.01)]. Type 2 diabetes was associated with an increased risk of ischaemic stroke in men [rate ratio 1.23 (95% CI 1.17, 1.30)] and women [rate ratio 1.41 (95% CI 1.35, 1.48)]. Case-fatality rates were 14.2% and 12.7% in people with Type 2 diabetes and without diabetes, respectively. Case fatality declined by 3.5% (95% CI 2.7, 4.5) annually [diabetes/year interaction: odds ratio 1.01 (95% CI 0.98, 1.02)]. CONCLUSIONS: Ischaemic stroke incidence declined no faster in people with a diagnosis of Type 2 diabetes than in people without diabetes. Increasing prevalence of Type 2 diabetes among stroke patients may mean that declines in case fatality over time will be less marked in the future.

RD Lawrence Lecture 2015 Old habits are hard to break: lessons from the study of hypoglycaemia.

Despite the introduction of newer technologies and improved insulin formulations, recurrent hypoglycaemia continues to affect the lives of many people with Type 1 and Type 2 diabetes. Developing strategies or therapies designed to prevent or minimize hypoglycaemia risk is of utmost importance to help individuals safely achieve glycaemic targets. Novel, educational or behavioural approaches need to be based on a clear understanding of the mechanisms underpinning both the detection of hypoglycaemia and why repeated exposure to hypoglycaemia leads to the development of a clinical syndrome referred to as impaired awareness of hypoglycaemia. In the present review, I propose that impaired awareness of hypoglycaemia may represent a form of learning called habituation, a response that, at a cellular level, represents a biological adaptation designed to protect the organism from future exposure to that stressor. In diabetes, this survival response to low glucose is, however, overwhelmed by high systemic insulin levels resulting from exogenous insulin therapy, leading to progressively more severe hypoglycaemia. A recognition of the underlying mechanism means that the development of impaired awareness of hypoglycaemia can perhaps be better understood and explained to individuals with diabetes, and novel therapeutic approaches such as dishabituation or cognitive behavioural therapies can be considered.

Saxagliptin co-therapy in C-peptide negative Type 1 diabetes does not improve counter-regulatory responses to hypoglycaemia.

AIMS: To test the hypothesis that dipeptidyl peptidase-4 inhibition in C-peptide negative Type 1 diabetes would reduce glucose variability and exposure to hypoglycaemia and therefore may indirectly enhance counter-regulatory responses to subsequent hypoglycaemia. METHODS: We conducted a 12-week double-blind, randomized, placebo-controlled crossover study. The study was conducted in a tertiary hospital outpatient clinic, with additional studies performed in a clinical research centre. After obtaining informed consent, we recruited 14 subjects with moderately well controlled Type 1 diabetes (HbA1c 64 ± 2 mmol/mol) of long duration (20.5 ± 2.7 years). The subjects received 12 weeks' therapy with oral saxagliptin (5 mg) or placebo. Glucose variability, assessed via continuous glucose monitoring, together with frequency of hypoglycaemia, hypoglycaemia awareness and symptomatic, cognitive and counter-regulatory hormone responses to experimental hypoglycaemia, were assessed. Additional outcome measures included HbA1c level, weight, total daily insulin dose and adverse events. RESULTS: Saxagliptin co-therapy did not reduce glucose variability (low blood glucose index, average daily risk range), hypoglycaemia frequency or awareness and did not improve counter-regulatory hormonal responses during experimental hypoglycaemia (area under the curve for adrenaline 25 775 vs. 24 454, for placebo vs saxagliptin, respectively; P = 0.76). CONCLUSIONS: No additional benefit of dipeptidyl peptidase-4 inhibition co-therapy with saxagliptin in the management of Type 1 diabetes was observed.

Potential role of non-insulin adjunct therapy in Type 1 diabetes.

Despite improvements in the pharmacodynamics of injectable insulin and better insulin delivery systems, glucose control remains suboptimal in the majority of individuals with Type 1 diabetes. Profound defects in the physiological processes that normally maintain glucose homeostasis contribute to the difficulty in achieving glycaemic targets. Non-insulin-based adjunct treatments offer a potential means of complementing intensive insulin therapy in Type 1 diabetes through addressing some of the physiological disturbances that result from endogenous ß-cell destruction, particularly through preservation of ß-cell mass and prevention of apoptosis, and suppression of α-cell glucagon release in the postprandial state. The former approach applies most readily to newly diagnosed C-peptide-positive Type 1 diabetes, while the latter to established C-peptide-negative Type 1 diabetes. This review focuses primarily on the clinical trial data available on the use of non-insulin-based therapies in longer-duration Type 1 diabetes. We conclude that metformin may prove useful in macrovascular disease reduction, while pramlintide, glucagon-like peptide-1 agonists, dipeptidyl peptidase-4 inhibitors and leptin co-therapies may reduce HbA(1c) , glucose variability, postprandial glucose excursions and body weight. These early studies are encouraging and offer novel and potentially very effective approaches to the treatment of Type 1 diabetes, but the evidence is largely restricted to small, often uncontrolled trials. As such, these therapies cannot be currently recommended for routine clinical practice. There is a clear need to support large, multi-centre randomized controlled trials designed to establish whether adjunct insulin therapy has a place in the modern management of Type 1 diabetes.

Mouse hypothalamic GT1-7 cells demonstrate AMPK-dependent intrinsic glucose-sensing behaviour.

AIMS/HYPOTHESIS: Hypothalamic glucose-excited (GE) neurons contribute to whole-body glucose homeostasis and participate in the detection of hypoglycaemia. This system appears defective in type 1 diabetes, in which hypoglycaemia commonly occurs. Unfortunately, it is at present unclear which molecular components required for glucose sensing are produced in individual neurons and how these are functionally linked. We used the GT1-7 mouse hypothalamic cell line to address these issues. METHODS: Electrophysiological recordings, coupled with measurements of gene expression and protein levels and activity, were made from unmodified GT1-7 cells and cells in which AMP-activated protein kinase (AMPK) catalytic subunit gene expression and activity were reduced. RESULTS: Hypothalamic GT1-7 neurons express the genes encoding glucokinase and ATP-sensitive K(+) channel (K(ATP)) subunits K ( ir ) 6.2 and Sur1 and exhibit GE-type glucose-sensing behaviour. Lowered extracellular glucose concentration hyperpolarised the cells in a concentration-dependent manner, an outcome that was reversed by tolbutamide. Inhibition of glucose uptake or metabolism hyperpolarised cells, showing that energy metabolism is required to maintain their resting membrane potential. Short hairpin (sh)RNA directed to Ampkα2 (also known as Prkaa2) reduced GT1-7 cell AMPKα2, but not AMPKα1, activity and lowered the threshold for hypoglycaemia-induced hyperpolarisation. shAmpkα1 (also known as Prkaa1) had no effect on glucose-sensing or AMPKα2 activity. Decreased uncoupling protein 2 (Ucp2) mRNA was detected in AMPKα2-reduced cells, suggesting that AMPKα2 regulates UCP2 levels. CONCLUSIONS/INTERPRETATION: We have demonstrated that GT1-7 cells closely mimic GE neuron glucose-sensing behaviour, and reducing AMPKα2 blunts their responsiveness to hypoglycaemic challenge, possibly by altering UCP2 activity. These results show that suppression of AMPKα2 activity inhibits normal glucose-sensing behaviour and may contribute to defective detection of hypoglycaemia.

The mechanisms that underlie glucose sensing during hypoglycaemia in diabetes.

Hypoglycaemia is a frequent and greatly feared side-effect of insulin therapy, and a major obstacle to achieving near-normal glucose control. This review will focus on the more recent developments in our understanding of the mechanisms that underlie the sensing of hypoglycaemia in both non-diabetic and diabetic individuals, and how this mechanism becomes impaired over time. The research focus of my own laboratory and many others is directed by three principal questions. Where does the body sense a falling glucose? How does the body detect a falling glucose? And why does this mechanism fail in Type 1 diabetes? Hypoglycaemia is sensed by specialized neurons found in the brain and periphery, and of these the ventromedial hypothalamus appears to play a major role. Neurons that react to fluctuations in glucose use mechanisms very similar to those that operate in pancreatic B- and A-cells, in particular in their use of glucokinase and the K(ATP) channel as key steps through which the metabolic signal is translated into altered neuronal firing rates. During hypoglycaemia, glucose-inhibited (GI) neurons may be regulated by the activity of AMP-activated protein kinase. This sensing mechanism is disturbed by recurrent hypoglycaemia, such that counter-regulatory defence responses are triggered at a lower glucose level. Why this should occur is not yet known, but it may involve increased metabolism or fuel delivery to glucose-sensing neurons or alterations in the mechanisms that regulate the stress response.

Symptoms of hypoglycemia in children with IDDM.

OBJECTIVE: To examine the symptoms of hypoglycemia in children with insulin-dependent diabetes, from the perspective both of the child and of the child's parents, and to compare the symptom reporting of the diabetic children with that of adult diabetic patients. RESEARCH DESIGN AND METHODS: Interviews were conducted with 100 parents and 43 of their children. The frequency and intensity of symptoms of hypoglycemia were documented using a structured interview and classified into groups using Principal Components Analysis (PCA). RESULTS: Diabetic children and their parents showed close agreement concerning the relative frequency and the intensity of symptoms reported. PCA of the symptom reports showed that diabetic children and their parents identified the same distinct subgroups of hypoglycemia-related symptoms: behavioral disturbance and autonomic-neuroglycopenic subgroups. CONCLUSIONS: Hypoglycemic symptoms in children with diabetes clearly differ from those experienced by insulin-treated adults and, in particular, include behavioral changes as primary features of a low blood glucose. These observations have important implications for parental education on hypoglycemia.

Auditory information processing during acute insulin-induced hypoglycaemia in non-diabetic human subjects.

Acute insulin-induced hypoglycaemia impairs performance on tests of general mental ability in humans. It is recognized that different brain functions vary in their sensitivity to neuroglycopenia, but little is known about the effects of neuroglycopenia on specific brain processes. The effect of controlled hypoglycaemia on two aspects of auditory information processing (auditory temporal processing and simple auditory processing) was examined in a homogeneous group of 20 healthy non-diabetic human subjects. Auditory temporal processing (temporal order discrimination) and simple auditory processing (pitch discrimination, single-tone duration and single-tone loudness discrimination) tests were part of the Test of Basic Auditory Capabilities (TBAC). Two tests of general cognitive performance (Digit Symbol Substitution and Trail Making B) were included to provide a measure of general brain functioning during hypoglycaemia. Hypoglycaemia lead to a significant deterioration in auditory temporal processing (P < 0.01), and a deterioration in one of three tasks of simple auditory processing (discrimination of single-tone loudness, P < 0.05). Significant disruptions also occurred in both tests of general brain functioning. These results are congruent with other studies in human subjects, showing a disruptive effect of hypoglycaemia on visual information processing when examined under conditions of limited perceptual time, and they provide further evidence of the importance of sensory processing speed in basic perceptual and cognitive functions. The disruptive effect of moderate insulin-induced hypoglycaemia on auditory perception may have implications for insulin-treated diabetic humans exposed to this metabolic stress, because of the importance of hearing in everyday life.

Appraisal of mood and personality during hypoglycaemia in human subjects.

This study used the biological model of experimental hypoglycaemia to examine the effect of a manipulation in mood-state on appraisal. Controlled hypoglycaemia was achieved using the hyperinsulinaemic glucose clamp technique. Mood, appraisal, and personality traits were assessed using well validated questionnaires. Our findings 1) reaffirm the existence of multiple arousal systems in the generation of moods, 2) show that the induction of a negative mood state does lead to more negative appraisals of a life situation, and 3) show that personality traits remain stable during the experience of negative emotions and cognitions. We conclude that hypoglycaemia, by inducing a state of tense tiredness in some individuals, may lead to more negative appraisals of a life situation but does not alter people's reporting of behavioural dispositions.

Effect of acute hypoglycemia on visual information processing in adults with type 1 diabetes mellitus.

Acute hypoglycemia in people with type 1 (insulin-dependent) diabetes mellitus causes general impairment in cognitive performance. The effects on more specific cognitive processes are less well defined. Acute hypoglycemia has been shown to impair visual information processing in nondiabetic human subjects and has now been examined in 16 adult subjects with type 1 diabetes. All subjects had normal visual acuity and no diabetic retinopathy, and their median (range) age was 24 (18-47) years with a median (range) duration of type 1 diabetes of 8 (2-18) years and a mean (SD) HbA1c of 8.5 (1.3)%. A hyperinsulinemic glucose clamp technique was used to maintain arterialized blood glucose at 5.0 mmol l(-1), and on separate test days, either euglycemia was continued or hypoglycemia (2.6 mmol l(-1)) was induced. During each condition subjects performed tests of visual processing and cognitive function. Hypoglycemia caused a significant disruption in general cognitive ability as assessed by digit symbol (p < 0.001) and trail-making B (p < 0.05) tasks. Conventional measures of visual acuity were unaffected by hypoglycemia, but visual information processing deteriorated significantly as indexed by inspection time (p < 0.005) and visual change detection (p < 0.01). Contrast sensitivity tended to deteriorate during hypoglycemia (p = 0.06). In conclusion, hypoglycemia impairs important aspects of early visual information processing and contrast sensitivity in adults with type 1 diabetes. Further research is needed to evaluate the functional relevance of such changes for everyday tasks that require the intake of visual information at speed and under conditions of low contrast.

Anger state during acute insulin-induced hypoglycaemia.

This study sought to examine the effects of insulin-induced hypoglycaemia on anger state, and to describe the associations between change in the anger state and measures of anger trait and anger expression (assessed using the State-Trait Anger Expression Inventory). A hyperinsulinaemic glucose clamp was used to achieve controlled euglycaemia (5.0 mmol/L) and hypoglycaemia (2.6 mmol/L) in 18 nondiabetic subjects and 30 people with insulin-dependent diabetes mellitus (IDDM). Subjects underwent both hypoglycaemic and euglycaemic conditions, separated by 2 weeks, in a counterbalanced order. During each study condition subjects were asked to complete a questionnaire on anger state. Results at euglycaemia and hypoglycaemia were compared, and differences between the conditions were correlated with measures of anger trait and anger expression. Hypoglycaemia caused both nondiabetic and IDDM subjects to report a significant increase in feelings of anger, despite being in a nonconfrontational setting. However, there were no clear associations between an individual's change in reported anger and measures of anger trait and anger expression. No association was found between the change in anger state and the intensity of an individual's symptomatic response to hypoglycaemia.

Hypothalamic AMP-activated protein kinase activation with AICAR amplifies counterregulatory responses to hypoglycemia in a rodent model of type 1 diabetes.

In nondiabetic rodents, AMP-activated protein kinase (AMPK) plays a role in the glucose-sensing mechanism used by the ventromedial hypothalamus (VMH), a key brain region involved in the detection of hypoglycemia. However, AMPK is regulated by both hyper- and hypoglycemia, so whether AMPK plays a similar role in type 1 diabetes (T1DM) is unknown. To address this issue, we used four groups of chronically catheterized male diabetic BB rats, a rodent model of autoimmune T1DM with established insulin-requiring diabetes (40 +/- 4 pmol/l basal c-peptide). Two groups were subjected to 3 days of recurrent hypoglycemia (RH), while the other two groups were kept hyperglycemic [chronic hyperglycemia (CH)]. All groups subsequently underwent hyperinsulinemic hypoglycemic clamp studies on day 4 in conjunction with VMH microinjection with either saline (control) or AICAR (5-aminoimidazole-4-carboxamide) to activate AMPK. Compared with controls, local VMH application of AICAR during hypoglycemia amplified both glucagon [means +/- SE, area under the curve over time (AUC/t) 144 +/- 43 vs. 50 +/- 11 ng.l(-1).min(-1); P < 0.05] and epinephrine [4.27 +/- 0.96 vs. 1.06 +/- 0.26 nmol.l(-1).min(-1); P < 0.05] responses in RH-BB rats, and amplified the glucagon [151 +/- 22 vs. 85 +/- 22 ng.l(-1).min(-1); P < 0.05] response in CH-BB rats. We conclude that VMH AMPK also plays a role in glucose-sensing during hypoglycemia in a rodent model of T1DM. Moreover, our data suggest that it may be possible to partially restore the hypoglycemia-specific glucagon secretory defect characteristic of T1DM through manipulation of VMH AMPK.

Symptomatic and physiological responses to hypoglycaemia induced by human soluble insulin and the analogue Lispro human insulin.

The aim of this study was to compare the glycaemic threshold for onset of the clinically detectable sympatho-adrenal (autonomic) reaction (defined as 'R') to hypoglycaemia induced by Lispro human insulin, with that induced by human soluble insulin (HS). The hypoglycaemia symptom profile, counterregulatory hormonal responses, and cognitive performance at R were also compared. Sixteen patients with IDDM, aged 32.5 (20-45) (median (range)) years and duration of IDDM 3.0 (0.5-4.5) years participated in a randomized, double-blind study during which intravenous infusions of either Lispro or HS insulin (2.0 mU kg(-1) min(-1)) were used on separate occasions to lower the blood glucose to the level at which R was induced. For both HS and Lispro, significant increments in systolic blood pressure (p<0.05), heart rate (p<0.05), and in autonomic (p<0.05) and neuroglycopenic symptom scores (p<0.05) occurred at R, and a significant deterioration was observed in cognitive performance (p<0.05). In response to hypoglycaemia, a significant increase from baseline occurred in plasma concentrations of all of the counterregulatory hormones (p<0.01) and the magnitude of response and temporal pattern did not differ, nor were any significant differences apparent between HS and Lispro insulins for any of the variables studied. The autonomic reaction occurred at a blood glucose (mean +/- SD) of 2.0 (+/- 0.6) mmol(-1) for Lispro and 1.9 (+/- 0.6) mmol(-1) for HS, which did not differ significantly. Thus, at the autonomic reaction to hypoglycaemia no significant differences were evident in the glycaemic threshold, symptom profile, physiological responses, and counterregulatory hormonal responses between Lispro and human soluble insulin in IDDM patients.

Hypoglycaemia, the most feared complication of insulin therapy.

Insulin-induced hypoglycaemia, the most frequent side-effect of insulin-therapy, is a potential source of considerable morbidity and has a recognised mortality. Acute hypoglycaemia produces an intense physiological stress with profound sympathoadrenal stimulation and widespread activation of hormonal counterregulatory systems, leading to secondary haemodynamic and haemorheological changes. The clinical effects of acute and recurrent severe hypoglycaemia are associated with significant morbidity including reversible, and permanent, abnormalities of cardiovascular, neurological and cognitive function, in addition to trauma and road traffic accidents. Comprehension of the morbidity of hypoglycaemia is important when designing insulin regimens and determining therapeutic goals for individual patients if the frequency and adverse effects of this dangerous side-effect of insulin therapy are to be limited.