Kirsten Nørgaard

Microalbuminuria: Implications for micro- and macrovascular disease

Microalbuminuria is diagnosed when the UAER is > 20 but < 200 μg/min. The prevalence of microalbuminuria among diabetic patients is 15–20%. Persistent microalbuminuria in diabetic patients is a risk marker not only of renal disease, but also of proliferative retinopathy and cardiovascular morbidity and mortality. Even among nondiabetic individuals, those with microalbuminuria tend to have an increased cardiovascular morbidity. The established cardiovascular risk factors, such as smoking, elevated plasma cholesterol, fibrinogen, and hypertension, are seen more frequently in diabetic patients with persistent microalbuminuria than in normoalbuminuric diabetic patients of similar age, sex, and diabetes duration. However, these risk factors cannot by themselves explain the cardiovascular overmortality in these patients. In addition, insulin resistance or genetic disposition to hypertension or cardiovascular disease fails to be the missing link. Accumulating evidence suggests a common pathogenetic mechanism for microalbuminuria and premature atherosclerosis (i.e., qualitative alterations of the extracellular matrix, including decreased density and sulfation of HS-PG). Decreased density of HS in the glomeruli may lead to albuminuria and mesangial proliferation. In the intima of large vessel walls, decreased density and/or sulfation of HS may enhance several of the processes involved in premature atherosclerosis. Diabetes affects the composition and structure of the extracellular matrix in many ways and leads to decreased density and sulfation of HS-PG by several mechanisms. Genetic differences in the sulfation of HS and/or genetic defects in the coordinated biosynthesis of HS-PG might contribute to decreased concentration and sulfation of HS-PG in susceptible individuals. It is hoped that susceptibility genes can be identified soon, thereby making prevention of severe late diabetic complications more successful.

Sensor-augmented pump therapy lowers HbA(1c) in suboptimally controlled Type 1 diabetes; a randomized controlled trial

Diabet. Med. 28, 1158–1167 (2011)

Use of an Automated Bolus Calculator in MDI-Treated Type 1 Diabetes: The BolusCal Study, a randomized controlled pilot study

OBJECTIVE To investigate the effect of flexible intensive insulin therapy (FIIT) and an automated bolus calculator (ABC) in a Danish type 1 diabetes population treated with multiple daily injections. Furthermore, to test the feasibility of teaching FIIT in a 3-h structured course. RESEARCH DESIGN AND METHODS The BolusCal Study was a 16-week randomized, controlled, open-label, three-arm parallel, clinical study of 51 adults with type 1 diabetes. Patients aged 18–65 years in poor metabolic control (HbA1c 8.0–10.5%) were randomized to the Control (n = 8), CarbCount (n = 21), or CarbCountABC (n = 22) arm. During a 3-h group teaching, the Control arm received FIIT education excluding carbohydrate counting. CarbCount patients were taught FIIT and how to count carbohydrates. CarbCountABC group teaching included FIIT and carbohydrate counting and patients were provided with an ABC. RESULTS At 16 weeks, the within-group change in HbA1c was −0.1% (95% CI −1.0 to 0.7%; P = 0.730) in the Control arm, −0.8% (−1.3 to −0.3%; P = 0.002) in the CarbCount arm, and −0.7% (−1.0 to −0.4%; P < 0.0001) in the CarbCountABC arm. The difference in change in HbA1c between CarbCount and CarbCountABC was insignificant. Adjusting for baseline HbA1c in a regression model, the relative change in HbA1c was −0.6% (−1.2 to 0.1%; P = 0.082) in CarbCount and −0.8% (−1.4 to −0.1%; P = 0.017) in CarbCountABC. Treatment satisfaction measured by the Diabetes Treatment Satisfaction Questionnaire (status version) improved in all study arms, but the improvement was significantly greater in CarbCountABC. CONCLUSIONS FIIT and carbohydrate counting were successfully taught in 3 h and improved metabolic control and treatment satisfaction. Concurrent use of an ABC improved treatment satisfaction further.

International Consensus on Use of Continuous Glucose Monitoring

Measurement of glycated hemoglobin (HbA1c) has been the traditional method for assessing glycemic control. However, it does not reflect intra- and interday glycemic excursions that may lead to acute events (such as hypoglycemia) or postprandial hyperglycemia, which have been linked to both microvascular and macrovascular complications. Continuous glucose monitoring (CGM), either from real-time use (rtCGM) or intermittently viewed (iCGM), addresses many of the limitations inherent in HbA1c testing and self-monitoring of blood glucose. Although both provide the means to move beyond the HbA1c measurement as the sole marker of glycemic control, standardized metrics for analyzing CGM data are lacking. Moreover, clear criteria for matching people with diabetes to the most appropriate glucose monitoring methodologies, as well as standardized advice about how best to use the new information they provide, have yet to be established. In February 2017, the Advanced Technologies & Treatments for Diabetes (ATTD) Congress convened an international panel of physicians, researchers, and individuals with diabetes who are expert in CGM technologies to address these issues. This article summarizes the ATTD consensus recommendations and represents the current understanding of how CGM results can affect outcomes.

Routine Sensor-Augmented Pump Therapy in Type 1 Diabetes: The INTERPRET Study

BACKGROUND Sensor-augmented pump (SAP) therapy can improve glycemic control, compared with multiple daily insulin injections or with insulin pump therapy alone, without increasing the risk of hypoglycemia. SUBJECTS AND METHODS A 12-month observational study in patients with type 1 diabetes treated with continuous subcutaneous insulin infusion (CSII), upon the introduction of continuous glucose monitoring (CGM), was conducted in 15 countries (in Europe and in Israel) to document the real-life use of SAP and assess which variables are associated with improvement in type 1 diabetes management. RESULTS Data from 263 patients (38% male; mean age, 28.0 ± 15.7 years [range, 1-69 years]; body mass index, 23.3 ± 4.9 kg/m(2); diabetes duration, 13.9 ± 10.7 years; CSII duration, 2.6 ± 3 years) were collected. Baseline mean glycated hemoglobin A1c (HbA1c) was 8.1 ± 1.4%; 82% had suboptimal HbA1c (≥ 7%). The average sensor use for 12 months was 30% (range, 0-94%), and sensor use decreased with time (first 3 months, 37%; last 3 months, 27%). Factors associated with improvement in HbA1c after 12 months in patients with baseline HbA1c ≥ 7% were high baseline HbA1c (P<0.001), older age group (P<0.001), and more frequent sensor use (P = 0.047). Significantly less hospitalization, increased treatment satisfaction, and reduced fear of hypoglycemia were reported after 12 months of SAP. CONCLUSIONS This is the largest and longest multicenter prospective observational study providing real-life data on SAP. These results are consistent with those of controlled trials showing the effectiveness of CGM in pump users.

Obesity, body composition and metabolic disturbances in polycystic ovary syndrome

BACKGROUND We determined the impact of polycystic ovary syndrome (PCOS) and obesity on glucose and lipid metabolism and beta-cell function in women with PCOS. METHODS In 35 women with PCOS (17 lean, lean PCOS and 18 obese, obese PCOS) and 25 control women (9 lean, lean controls and 16 obese, obese controls), beta-cell function was evaluated by the first-phase insulin response after intravenous glucose, acute insulin response to glucose (AIRg); insulin sensitivity, determined as insulin sensitivity index (ISI), was evaluated by the euglycemic hyperinsulinemic clamp. Indirect calorimetry was used for the assessment of glucose and lipid oxidation. Body composition was estimated by dual X-ray absorptiometry scan. RESULTS When adjusted for obesity, PCOS was associated with higher 2-h glucose levels (P < 0.05), higher trunk/periphery fat ratio (P < 0.001), lower ISI (P < 0.001), lower insulin-stimulated glucose oxidation (GOX 2) (P < 0.05) and lower non-oxidative glucose metabolism (P < 0.05), but a normal AIRg compared with control women. Lean women with PCOS had lower ISI (P < 0.001), GOX-2 (P < 0.05) and higher trunk/periphery fat ratio (P < 0.05) than lean control women. In obese women with PCOS, ISI was reduced with 25% compared with obese control women, whereas trunk/peripheral fat ratio did not differ. AIRg was increased in obese groups compared with lean groups (P < 0.05), but was, in all groups, appropriate for the ambient action of insulin. CONCLUSIONS PCOS is associated with a low ISI, which in lean women with PCOS may partly be explained by higher trunk/peripheral fat ratio. AIRg was amplified by obesity, but was, in all groups, appropriate for prevailing insulin sensitivity, suggesting a normal beta-cell adaptation.

Effect of insulin analogues on risk of severe hypoglycaemia in patients with type 1 diabetes prone to recurrent severe hypoglycaemia (HypoAna trial): a prospective, randomised, open-label, blinded-endpoint crossover trial

BACKGROUND Insulin analogues have been developed to reduce the risk of hypoglycaemia in patients with diabetes who require insulin-based treatment, but their effect on this endpoint in patients with type 1 diabetes complicated by recurrent severe hypoglycaemia is unknown. We compared the occurrence of severe hypoglycaemic episodes in such patients during treatment with insulin analogues or human insulin. METHODS In this investigator-initiated, prospective, randomised, open-label, blinded-endpoint crossover trial at seven medical centres in Denmark, we recruited patients (aged ≥18 years) with type 1 diabetes (diagnosed for >5 years) who had reported two or more episodes of severe hypoglycaemia in the preceding year. Patients were randomly assigned (1:1) using computer-generated site-specific randomisation lists in blocks of four to treatment with basal-bolus therapy with either analogue insulin (detemir and aspart) or human insulin (human neutral protamine Hagedorn and human regular) in a balanced crossover design. A 1-year plus 1-year treatment period was specified, consisting of two 3-month run-in periods, each followed by a 9-month maintenance period. The primary endpoint was the number of validated episodes of severe hypoglycaemia (defined by need for treatment assistance from others) reported during the maintenance periods, analysed by intention to treat. The study is registered with ClinicalTrials.gov, number NCT00346996. FINDINGS Between May 9, 2007, and Oct 30, 2009, 159 patients were randomly assigned. 18 patients discontinued during the first run-in period, leaving 141 patients in the intention-to-treat population. 136 severe hypoglycaemic episodes were reported during treatment with human insulin and 105 episodes were reported during treatment with insulin analogues, resulting in an absolute rate reduction of 0.51 episodes (95% CI 0.19-0.84) per patient-year with insulin analogues. This result corresponds to a relative rate reduction of 29% (95% CI 11-48; p=0.010). INTERPRETATION Treatment with insulin detemir and aspart in patients with type 1 diabetes and recurrent severe hypoglycaemia resulted in a clinically significant reduced rate of severe hypoglycaemia compared with human insulin. Patients with the greatest chance of benefitting from improved insulin therapy should be offered treatment with insulin analogues and be included in future trials of new insulins. FUNDING Novo Nordisk A/S.

Insulin analogues and severe hypoglycaemia in type 1 diabetes

INTRODUCTION The effect of insulin analogues on glycaemic control is well-documented, whereas the effect on avoidance of severe hypoglycaemia remains tentative. We studied the frequency of severe hypoglycaemia in unselected patients with type 1 diabetes treated with insulin analogues, human insulin, or mixed regimens. METHODS A questionnaire was posted from six Danish diabetes clinics to 6112 unselected patients with type 1 diabetes and filled in by 3861 patients (63.2%). Primary endpoint was number of episodes of severe hypoglycaemia in the preceding year. Mild hypoglycaemia was also reported. RESULTS The frequency of severe hypoglycaemic episodes per patient-year in patients receiving long-acting insulin analogues was 1.47±0.18 versus 1.09±0.10 in patients on long-acting human insulin (p=0.01). The frequency of severe hypoglycaemic episodes per patient-year was 1.09±0.11 in patients on short-acting insulin analogues versus 1.26±0.13 in patients on short-acting human insulin (p=0.15), which was statistically significant in an adjusted analysis. CONCLUSIONS Severe hypoglycaemia is more frequent in patients with type 1 diabetes treated with long-acting insulin analogues. Confounding by indication may be involved. Clinical intervention trials using insulin analogues in patients prone to severe hypoglycaemia are highly needed.

Model-Based Closed-Loop Glucose Control in Type 1 Diabetes: The DiaCon Experience

Background: To improve type 1 diabetes mellitus (T1DM) management, we developed a model predictive control (MPC) algorithm for closed-loop (CL) glucose control based on a linear second-order deterministic-stochastic model. The deterministic part of the model is specified by three patient-specific parameters: Insulin sensitivity factor, insulin action time, and basal insulin infusion rate. The stochastic part is identical for all patients but identified from data from a single patient. Results of the first clinical feasibility test of the algorithm are presented. Methods: We conducted two randomized crossover studies. Study 1 compared CL with open-loop (OL) control. Study 2 compared glucose control after CL initiation in the euglycemic (CL-Eu) and hyperglycemic (CL-Hyper) ranges, respectively. Patients were studied from 22:00–07:00 on two separate nights. Results: Each study included six T1DM patients (hemoglobin A1c 7.2% ± 0.4%). In study 1, hypoglycemic events (plasma glucose < 54 mg/dl) occurred on two OL and one CL nights. Average glucose from 22:00–07:00 was 90 mg/dl [74–146 mg/dl; median (interquartile range)] during OL and 108 mg/dl (101–128 mg/dl) during CL (determined by continuous glucose monitoring). However, median time spent in the range 70–144 mg/dl was 67.9% (3.0–73.3%) during OL and 80.8% (70.5–89.7%) during CL. In study 2, there was one episode of hypoglycemia with plasma glucose <54 mg/dl in a CL-Eu night. Mean glucose from 22:00–07:00 and time spent in the range 70–144 mg/dl were 121 mg/dl (117–133 mg/dl) and 69.0% (30.7–77.9%) in CL-Eu and 149 mg/dl (140–193 mg/dl) and 48.2% (34.9–72.5%) in CL-Hyper, respectively. Conclusions: This study suggests that our novel MPC algorithm can safely and effectively control glucose overnight, also when CL control is initiated during hyperglycemia.

A Comparison of Spirapril and Isradipine in Patients with Diabetic Nephropathy and Hypertension

The effects of spirapril and isradipine on blood pressure, urinary albumin excretion and sodium-volume homeostasis in hypertensive insulin-dependent diabetic patients with nephropathy were assessed. Fifteen Type 1 diabetic patients aged 28-53 years with a diabetes duration of 19-37 years were studied. All had hypertension and diabetic nephropathy with a urinary albumin excretion of more than 300 mg/24 h. After a single blind placebo treatment period of 4 weeks the patients were randomly assigned to treatment with the calcium antagonist isradipine SRO 5 mg once daily or the ACE inhibitor spirapril 6 mg once daily for 6 months in a double-blind design. Isradipine lowered ambulatory systolic blood pressure from 152 +/- 12 to 141 +/- 11 mmHg (p < 0.05) and ambulatory diastolic pressure from 91 +/- 9 to 86 +/- 8 mmHg (p < 0.05). The blood pressure lowering effect of spirapril was similar: 156 +/- 13 vs 143 +/- 11 mmHg (p < 0.01) and 90 +/- 4 vs 84 +/- 4 mmHg (p < 0.05). The fractional albumin clearance was unchanged on isradipine but decreased after 6 months treatment with spirapril with on average 20% (p < 0.05). Total body exchangeable sodium decreased on spirapril treatment: 2994 +/- 296 vs 2636 +/- 194 meq/1.73 m2 (p < 0.05) and extracellular volume tended to do so (p = 0.12). On isradipine treatment these parameters remained unchanged. In conclusion both isradipine and spirapril lowered blood pressure in patients with diabetic nephropathy. Only the ACE inhibitor had demonstrable beneficial effects on urinary albumin excretion rate and the sodium-volume expansion seen in these patients.