Longitudinal associations between depression and diabetes complications: a systematic review and meta-analysis.

To conduct a systematic review and meta-analysis of longitudinal studies assessing the bi-directional association between depression and diabetes macrovascular and microvascular complications. Embase, Medline and PsycINFO databases were searched from inception through 27 November 2017. A total of 4592 abstracts were screened for eligibility. Meta-analyses used multilevel random/mixed-effects models. Quality was assessed using the Newcastle-Ottawa scale. Twenty-two studies were included in the systematic review. Sixteen studies examined the relationship between baseline depression and incident diabetes complications, of which nine studies involving over one million participants were suitable for meta-analysis. Depression was associated with an increased risk of incident macrovascular (HR = 1.38; 95% CI: 1.30-1.47) and microvascular disease (HR = 1.33; 95% CI: 1.25-1.41). Six studies examined the association between baseline diabetes complications and subsequent depression, of which two studies involving over 230 000 participants were suitable for meta-analysis. The results showed that diabetes complications increased the risk of incident depressive disorder (HR = 1.14; 95% CI: 1.07-1.21). The quality analysis showed increased risk of bias notably in the representativeness of selected cohorts and ascertainment of exposure and outcome. Depression in people with diabetes is associated with an increased risk of incident macrovascular and microvascular complications. The relationship between depression and diabetes complications appears bi-directional. However, the risk of developing diabetes complications in depressed people is higher than the risk of developing depression in people with diabetes complications. The underlying mechanisms warrant further research.

Examining the Behaviour subscale of the Hypoglycaemia Fear Survey: an international study.

AIMS: The Hypoglycemia Fear Survey (HFS)-II Behaviour and Worry subscales were developed to measure behaviours and anxiety related to hypoglycaemia in diabetes. However, previous studies found lower reliability in the HFS Behaviour subscale and inconsistent relationships with glucose control. The purpose of this study was to conduct extensive analyses of the internal structure of the HFS Behaviour subscale's internal structure and its relationships with diabetes outcomes, including HbA1c and episodes of severe hypoglycaemia. METHODS: HFS-II survey data from 1460 adults with Type 1 diabetes were collected from five countries. This aggregated sample underwent exploratory factor analysis and item analysis to determine the internal structure of the survey and subscales. RESULTS: A three-factor solution showed the best fit for the HFS, with two subscales emerging from the HFS Behaviour representing tendencies towards (1) maintenance of high blood glucose and (2) avoidance of hypoglycaemic risks by other behaviours, and a third single HFS Worry subscale. Subscale item analysis showed excellent fit, separation and good point-measure correlations. All subscales demonstrated acceptable (0.75) to excellent (0.94) internal reliability. HbA(1c) correlated with Maintain High Blood Glucose subscale scores, r = 0.14, P < 0.001, and severe hypoglycaemia frequency correlated with all subscales. CONCLUSIONS: The HFS Worry subscale measures one construct of anxiety about various aspects of hypoglycaemia. In contrast, the HFS Behaviour subscale appears to measure two distinct aspects of behavioural avoidance to prevent hypoglycaemia, actions which maintain high blood glucose and other behaviours to avoid hypoglycaemic risk. These results demonstrate the clinical importance of the HFS Behaviour subscales and their differential relationships with measures of diabetes outcome such as HbA1c .

Three different premixed combinations of biphasic insulin aspart - comparison of the efficacy and safety in a randomized controlled clinical trial in subjects with type 2 diabetes.

AIM: To evaluate clinical efficacy and safety of biphasic insulin aspart (BIAsp) 30 twice daily (b.i.d.) vs. BIAsp 50 or BIAsp 70 (high-mix regimens) thrice daily (t.i.d.) all in combination with metformin in a 36-week clinical trial in subjects with type 2 diabetes. METHODS: Efficacy measurements included haemoglobin A(1c) (HbA(1c)) and eight-point plasma glucose (PG); safety included adverse events (AEs) and hypoglycaemic episodes. The three treatment groups (approximately 200 subjects in each group) were well matched regarding sex ratio, ethnicity, age and body mass index. RESULTS: After 12 weeks, 43% and 54% in the BIAsp 50 and 70 groups, respectively, switched their dinner insulin to BIAsp 30. Both high-mix regimens were non-inferior to BIAsp 30 b.i.d., as measured by change in HbA(1c), and the BIAsp %50 regimen was superior. The odds for meeting the American Diabetes Association and The American Association of Clinícal Endocrinologist HbA(1c) targets of <7% and < or =6.5%, respectively, were significantly higher with the BIAsp 50 regimen than with BIAsp 30. A significantly lower PG level was achieved from lunch until 02:00 hours with both high-mix regimens compared with BIAsp 30 b.i.d. AEs were mild or moderate with all three regimens. Frequency of hypoglycaemic episodes was comparable for the BIAsp 50 and the BIAsp 30 b.i.d. regimens but was significantly higher with BIAsp 70 t.i.d. CONCLUSIONS: Glycaemic control improved with BIAsp 50 t.i.d. without higher incidence of hypoglycaemia compared with BIAsp 30 b.i.d.; with BIAsp 70 t.i.d. lower PG levels from lunch to 02.00 hours, but more hypoglycaemic episodes were obtained compared with BIAsp 30 b.i.d.

The pharmacokinetic and pharmacodynamic properties of different formulations of biphasic insulin aspart: a randomized, glucose clamp, crossover study.

BACKGROUND: Type 2 diabetes patients on premixed insulin are commonly prescribed biphasic insulin with low prandial insulin content, such as biphasic insulin aspart (BIAsp) 30, comprising 30% insulin aspart (IAsp). The new formulations BIAsp 50 and BIAsp 70 contain 50% and 70% soluble IAsp, respectively. We compared the pharmacodynamics (PD) and pharmacokinetics (PK) of BIAsp 30, 50, and 70 and IAsp in a glucose clamp trial. METHODS: In this randomized, double-blind, crossover study at a clinical research institute, 32 type 1 diabetes patients on basal-bolus therapy each underwent four glucose clamps (clamp level 5 mmol/L, duration 28 h post-dosing [12 h for IAsp]) and received a single dose of 0.4 U/kg BIAsp 30, 50, or 70 and IAsp. Main PD/PK outcome parameters measured were early- and late-phase glucose disposal (area under the curve of glucose infusion rate [AUC(GIR)]), nonesterified fatty acid concentrations, and IAsp concentrations. RESULTS: With increasing proportions of soluble IAsp, the insulin formulations showed significantly higher early metabolic activity (ratio of AUC(GIR) 0-6 h: BIAsp 50/BIAsp 30 = 1.28 [P < 0.001], BIAsp 70/BIAsp 50 = 1.18 [P < 0.001), IAsp/BIAsp 70 = 1.15 [P < 0.01]) and lower late metabolic activity (ratio of AUC(GIR) 12-28 h: BIAsp 50/BIAsp 30 = 0.17 [P < 0.01], BIAsp 70/BIAsp 50 = 0.21 [P < 0.05]). Likewise, early IAsp levels were significantly greater and late PK concentrations were significantly lower with increasing proportion of soluble IAsp. CONCLUSIONS: There are significant differences between the early and late PD and PK effects among BIAsp 30, 50, and 70 and IAsp that should allow tailored treatment with the convenience of prandial and basal insulin in each injection.

Antibody response to insulin in children and adolescents with newly diagnosed Type 1 diabetes.

AIMS: To compare levels of insulin antibodies in children and adolescents after initiation of insulin therapy using either insulin aspart (IAsp) or human insulin (HI) in combination with Neutral Protamine Hagedorn (NPH) insulin, and to investigate the relationships between insulin antibodies and HbA(1c) and insulin dose. METHODS: IAsp-specific antibodies (IAsp-Ab) and antibodies cross-reacting with HI and IAsp (HI-cross-Ab) were analysed by radioimmunoassay at diagnosis of diabetes and every 3-6 months for 30 months. Seventy-two patients (HI = 30, IAsp = 42) with Type 1 diabetes, aged 2-17 years were included. Data on HbA(1c), insulin dose and serious adverse events (SAEs) were collected retrospectively. RESULTS: IAsp-Ab levels remained low throughout the study. After 9 months, the level of HI-cross-Ab increased [mean (SD) HI, 48.8% (21.53); IAsp, 40.2% (17.92)] and remained elevated. Repeated measurement analysis of HI-cross-Ab levels showed no significant difference between treatments (P = 0.16). HI-cross-Ab were significantly associated with total insulin dose (U/kg) (P = 0.001) and time (P < 0.0001), but not with HbA(1c) (P = 0.24). Mean (+/- SD) HbA(1c) was similar at diagnosis (HI 9.5 +/- 1.97%; IAsp 9.6 +/- 1.62%); HbA(1c) then decreased and stabilized to about 6.0% in both groups. Few SAEs were reported, the majority being hypoglycaemic episodes. CONCLUSIONS: Treatment with IAsp and with HI was associated with an increase in HI-cross-Ab in insulin-naive children, but this did not influence treatment efficacy or safety. These results support the safe use of IAsp in children and adolescents with Type 1 diabetes.

Reproducibility of the insulin tolerance test (ITT) for assessment of growth hormone and cortisol secretion in normal and hypopituitary adult men.

OBJECTIVE: The within subject variability of the insulin tolerance test (ITT) for assessment of growth hormone (GH) status and cortisol reserve has rarely been examined, particularly in patients with hypopituitarism. This becomes important when biochemical criteria are used to determine which adults with hypopituitarism should receive GH and/or cortisol replacement. In the present study we assessed the reproducibility of GH and cortisol responses in repeated ITTs. Baseline insulin-like growth factor 1 (IGF-1) levels were also assessed for reproducibility on each occasion. DESIGN AND PATIENTS: Three consecutive ITTs were performed in seven normal adult men (ages 22-27 years) and two ITTs in 11 men with hypopituitarism and suspected GH deficiency (ages 23-48 years). MEASUREMENTS: Serum GH and IGF-1 were measured by immunoradiometric and cortisol by immunofluorimetric assays. RESULTS: In normal men group peak GH responses did not differ between the three tests. There was no correlation between individual peak values. The within subject peak GH variability was between 4.6 and 59.3%, and the overall variability in 21 tests was 35%. The lowest peak GH concentration was 70 mU/l (27 microg/l). All hypopituitary men had severe GH deficiency (all peak GH concentrations < 4 mU/l (1.5 microg/l) in both tests). There was a highly significant correlation between individual peak GH values (r = 0.95, P < 0.0001). Basal IGF-1-values in normal and hypopituitary men were highly correlated between tests (r = 0.98, P < 0.0001). The overall within subject variability of IGF-1-values was 11.9% in normal and 22.7% in hypopituitary men. In normal men group peak cortisol responses were not different between the three tests. There was a good correlation between individual peak cortisol responses in the three ITTs. The within subject peak cortisol variability (median 8.3%; range 0.7-21.5%) was significantly less than that of GH (P < 0.03) in two of three test comparisons. In hypopituitary men the within subject peak cortisol variability (median 41.6%; range 3.5-92.7%) was significantly greater (P < 0.001) than in normal men. All patients were correctly classified as cortisol deficient or normal in both ITTs. CONCLUSION: The cortisol response to repeated hypoglycaemia is very reproducible in normal men but the GH response is less so. In hypopituitary men the reproducibility of the GH response is good while that of the cortisol response is poor. However, a single ITT did not misclassify hypopituitary patients who are severely GH and/or ACTH deficient and was therefore adequate for clinical decisions regarding GH and/or cortisol replacement. Nevertheless, it remains possible that a single ITT could misclassify some hypopituitary patients with partial GH or ACTH deficiency.

Symptomatic and counterregulatory hormonal responses to acute hypoglycaemia induced by insulin aspart and soluble human insulin in Type 1 diabetes.

BACKGROUND: The aim of this study was to assess hypoglycaemia awareness with the insulin analogue, insulin aspart. The counterregulatory hormonal and symptomatic responses to hypoglycaemia induced by insulin aspart were compared with soluble human insulin in a double-blind, randomised, two-period crossover trial in patients with Type 1 diabetes. The primary objective was to compare the blood glucose threshold for autonomic activation during hypoglycaemia induced by insulin aspart and soluble human insulin. Secondary objectives were to compare the counterregulatory, symptomatic and physiological responses to hypoglycaemia. METHODS: 20 patients were screened, 17 were randomised and 16 completed the study. Acute hypoglycaemia was induced by intravenous infusion of insulin aspart or soluble human insulin (100 U ml(-1) at a rate of 2 mU kg(-1) min(-1)). RESULTS: No statistical difference between insulin aspart and soluble human insulin was shown for the primary blood glucose endpoint; mean arterialised blood glucose concentrations (+/-SD) at the onset of autonomic activation were 1. 88+/-0.39 mmol L(-1) for insulin aspart and 1.89+/-0.43 mmol L(-1) for soluble human insulin (not significant). No statistical differences were observed between the two insulins for the secondary endpoints: counterregulatory hormonal responses, autonomic responses, hypoglycaemia symptom scores, cognitive function and blood glucose responses. No serious adverse events were reported during the study. CONCLUSIONS: Insulin aspart and soluble human insulin elicit the same counterregulatory and symptomatic responses to acute hypoglycaemia in patients with Type 1 diabetes.

Substitution of night-time continuous subcutaneous insulin infusion therapy for bedtime NPH insulin in a multiple injection regimen improves counterregulatory hormonal responses and warning symptoms of hypoglycaemia in IDDM.

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.

Metabolic efficacy of preprandial administration of Lys(B28), Pro(B29) human insulin analog in IDDM patients. A comparison with human regular insulin during a three-meal test period.

OBJECTIVE: The objective of this study was to compare the efficacy of the rapid-acting Lys(B28), Pro(B29) human insulin analog, insulin lispro, with currently available short-acting human insulin in a multiple injection therapy (MIT) regimen with respect to blood glucose and plasma insulin profiles and to serum metabolites (lactate, free fatty acids, glycerol, and beta-hydroxybutyrate) in 12 well-controlled type 1 diabetic subjects (8 male, HbA1c 6.8 +/- 0.9% [mean +/- SD]). RESEARCH DESIGN AND METHODS: After a run-in period of 4 weeks, patients were treated with either lispro at mealtime or human insulin 30 min before the meal for two periods of 4 weeks in a randomized open-label crossover study. Intermediate-acting insulin (NPH insulin) was given at bedtime. At the end of both study periods, metabolic profiles were assessed from 10:00 P.M. to 7:00 P.M. the next day. RESULTS: During the treatment periods, glycemic control was stable during lispro but improved during human insulin (delta HbA1c lispro 0.1 +/- 0.48, NS; human insulin -0.41 +/- 0.34%, P < 0.05). Glucose excursions, as measured by the incremental AUC, during the day and for the 2-h postprandial periods, were lower, although not significantly, for lispro. Insulin profiles demonstrated a faster rise after administration of lispro as compared with human insulin, peaking at 61 +/- 11.9 and 111 +/- 48.1 min (P < 0.01). Glycerol levels showed a slight increase before lunch and dinner, suggestive of enhanced lipolytic activity and compatible with the lower insulin levels. CONCLUSIONS: Lispro insulin applied in an MIT regimen creates more physiologic insulin profiles and tends to lower the glycemic excursions during the day compared with short-acting insulin. The analog can be applied safely in an MIT regimen, with mealtime intervals up to 5 h.

Hypoglycaemia induces emotional disruption.

UNLABELLED: This study investigated how hypoglycaemia affects mood, whether psychological characteristics mediate an emotional disturbance during hypoglycaemia. Ten IDDM patients (1 female) were studied, aged [mean (range)] 28 (20-37) years, body mass index (BMI) 23.4 (19.6-25.7) kg/m2, diabetes duration 11 (7-15) years, HbA1c 7.5 (6.0-8.7)%. Patients underwent a standardized stepwise, hypoglycaemic, hyperinsulinaemic clamp, performed in steps of 0.5 mmol/l from 4.0 mmol/l to a glucose nadir of 2.0 mmol/l. At euglycaemia, the Symptom Checklist-90 (SCL-90) was administered. The Profile of Mood States (POMS) was completed at 4.0 and 2.5 mmol/l, while the feelings chart of the COOP/WONCA was filled out at euglycaemia and all hypoglycaemic steps. RESULTS: The t-test for the POMS demonstrated a significant increase for anger (P < 0.05). COOP/WONCA scores displayed a progressive negative change in mood for each hypoglycaemic step, albeit with a large interindividual variability. Hostility (SCL-90) significantly interacted with anger (POMS) at 2.5 mmol/l (P < 0.05). CONCLUSIONS: Progression of hypoglycaemia negatively alters the overall mood state. IDDM patients characterised by high scores on hostility (SCL-90) apparently are more prone to experience an increase in anger (POMS) during hypoglycaemia.