Unchanged incidence of severe retinopathy in a population of Type 1 diabetic patients with marked reduction of nephropathy

The incidence of nephropathy in Type 1 diabetes mellitus has declined during the past decade, probably as a result of improved glycaemic control. We wanted to investigate whether the incidence of severe retinopathy has changed during the same time period and to evaluate the importance of glycaemic control in relation to the development of severe retinopathy and nephropathy. All 213 patients in whom Type 1 diabetes mellitus was diagnosed before the age of 15 years between 1961 and 1980 in a district in south-eastern Sweden were studied. Ninety-two per cent of the patients were followed from the onset of diabetes to 1991 or to death. The cumulative incidence of severe retinopathy was not significantly different between the patients with diabetes onset 1961–65, 1966–70, 1971–75, and 1976–80. The risk of developing severe retinopathy or nephropathy was higher in patients with very poor glycaemic control (HbA_1c ≥ 8.4 %) vs patients with poor control (HbA_1c ≥ 7.2 < 8.4 %; p < 0.001). Patients with poor control had an increased risk of developing severe retinopathy vs patients with good control (HbA_1c < 7.2 %; p < 0.008) but there was no difference in the risk of nephropathy. No patients with good control developed nephropathy and only one patient developed severe retinopathy during 25 years of diabetes. © 1998 John Wiley & Sons, Ltd.     

Glycaemic control during early pregnancy and fetal malformations in women with Type I diabetes mellitus

Aims/hypothesis. To assess the relation between glycaemic control in early pregnancy and the risk of congenital malformations in offspring of mothers with Type I (insulin-dependent) diabetes mellitus.¶Methods. From 1988–1997, we prospectively collected data from 691 pregnancies and 709 offspring of 488 women with Type I diabetes in a specific geographic area in Southern Finland. Glycated haemoglobin A_{1 c} at less than 14 weeks of gestation was used as the indicator of glycaemic control. The malformations were diagnosed either by ultrasonography in pregnancy or during the neonatal period. We also studied 729 non-selected control pregnancies in women without diabetes.¶Results. The numbers of major fetal malformations were 30 (4.2 %) in patients with Type I diabetes and 10 (1.2 %) in the control subjects (relative risk 3.1; 95 % confidence interval: 1.6 to 6.2). Even women whose HbA_{1 c} was only slightly raised (5.6 to 6.8 %, ie 2.0 to 5.9 standard deviation units) showed a relative risk of 3.0 (95 % confidence interval: 1.2 to 7.5). Haemoglobin A_{1 c} retained its statistically significant association with the occurrence of malformations after adjusting for White's class, age at onset of diabetes, duration of diabetes, parity, smoking and participation in pre-pregnancy counselling.¶Conclusions/interpretation. Even a slightly raised HbA_{1 c} during early pregnancy in women with Type I diabetes carries an increased risk for fetal malformations. Therefore normoglycaemia should be strived for during early pregnancy. [Diabetologia (2000) 43: 79–82]     

Are European standard deviation targets for haemoglobin A1c too strict?

The Diabetes Control and Complications Trial (DCCT) has provided objective evidence for desirable glycaemic control in Type 1 patients and defines the benefits of good glycaemic control in terms of haemoglobin A_1c (HbA_1c) values. However, HbA_1c assays vary, leading to suggestions that glycaemic control be classified according to numbers of standard deviations (SD) from a local non-diabetic population mean. We have classified the glycaemic control of 339 UK Type 1 diabetic patients (182 male, 157 female, median age 36 (range 15–74) years) using the DCCT to set HbA_1c targets and compared this with the SD method. Using age matched controls (mean HbA_1c 4.02 %, SD 0.28 %, n = 106), SD guidelines classified 1 % of patients into good (HbA_1c <3sd from reference mean), 4 % into borderline (3–5SD) and 95 % into poor (>5SD) glycaemic control. When calibrating the same instrument to the DCCT analyser (r = 0.996), 37 % of patients had HbA_1c results lower than the 7 % median value found in the intensively treated DCCT group, while only 12 % of patients had values greater than the 9 % conventionally treated median HbA_1c. DCCT subjects with HbA_1c values of less than 8 % belonged predominantly to the intensively treated group. In this study, 71 % of patients fell into this category. Thus, guidelines based on numbers of SD away from a non-diabetic mean may overestimate the glycaemic control required to reduce microvascular complications in Type 1 patients. Standardizing to DCCT targets is more appropriate. © 1998 John Wiley & Sons, Ltd.     

Synergistic effect of angiotensin II type 1 receptor genotype and poor glycaemic control on risk of nephropathy in IDDM

Summary We investigated the contribution of polymorphisms in the angiotensin II type 1 receptor gene (AGTR1) to renal complications in an inception cohort of 152 insulin-dependent diabetic (IDDM) patients examined 15–21 years after diabetes onset. This nested case-control study included 79 normoalbuminuric control subjects and 73 cases with evidence of nephropathy ranging from microalbuminuria to overt proteinuria. Subjects were genotyped for two AGTR1 polymorphisms (T⁵⁷³→C and A¹¹⁶⁶→C), and an adjacent CA repeat microsatellite. Allele C¹¹⁶⁶ and the 140 bp allele of the microsatellite were more frequent among nephropathy cases than normoalbuminuric control subjects (0.322 vs 0.247, and 0.618 vs 0.521, respectively), but these differences were not statistically significant. Although not significant by themselves, the AGTR1 polymorphisms contributed significantly to the risk of diabetic nephropathy when accompanied by poor glycaemic control. Among patients with frequent severe hyperglycaemia during the first decade of diabetes, the relative risk of nephropathy among allele C¹¹⁶⁶ carriers was 12.1 (95 % CI: 3.7–39.8), whereas it was only 1.4 (95 % CI: 0.6–3.5) among allele A¹¹⁶⁶ homozygotes. The difference between relative risks was highly significant (χ ² = 8.25, p = 0.004 with 1 df). A similar pattern of higher risk of microalbuminuria, specifically among those carriers of allele C¹¹⁶⁶ who had poor glycaemic control was also found in an independent study of a cross-sectional sample of 551 IDDM individuals, although the effect was smaller in magnitude. We conclude that DNA sequence differences in the AGTR1 gene may modify the noxious effects of hyperglycaemia on the kidney. Allele C¹¹⁶⁶ carriers might especially benefit from nephropathy prevention programmes. [Diabetologia (1997) 40: 1293–1299] Received: 4 March 1997 and in revised form: 18 June 1997     

Obese Patients with Type 2 Diabetes Poorly Controlled by Insulin and Metformin: Effects of Adjunctive Dexfenfluramine Therapy on Glycaemic Control

Dexfenfluramine is well known for its weight reducing action and has been reported to improve glycaemic control in obese Type 2 diabetic patients not adequately controlled on conventional oral hypoglycaemic therapy. In this double-blind placebo-controlled study, 20 obese Type 2 diabetic patients with mean HbA_1c of 8.8 ± 0.5% (normal range 3.5–6.0%), and mean body mass index (BMI) of 34.4 ± 1.0 kg m^?2, who were poorly controlled on insulin (mean dosage 58.0 ± 6.1 units day^?1) were randomized to receive either additional dexfenfluramine or placebo for 12 weeks. Seventeen of these patients were already taking maximum tolerated metformin therapy (mean dosage 1.6 ± 0.2 g day^?1) and the other three were unable to tolerate any at all. At baseline, the dexfenfluramine and placebo groups were similar in all parameters studied. After the 12-week treatment period, median HbA_1c had fallen in dexfenfluramine treated patients from 8.5 (interquartile range (IR): 7.5–10.3) to 7.1% (IR: 6.7–7.5; p < 0.02). The fall in HbA_1c in individual patients after treatment with dexfenfluramine was strongly associated with weight loss (r = 0.69; p < 0.04), although as a group the changes in weight and BMI were not statistically significant. Placebo was without effect. These results show that in the obese patient with Type 2 diabetes who is poorly controlled despite large daily doses of insulin and metformin, adjunctive dexfenfluramine can improve glycaemic control without exacerbating weight gain.     

Elevated long-term glycated haemoglobin precedes proliferative retinopathy and nephropathy in Type 1 (insulin-dependent) diabetic patients

Summary The importance of glycaemic control for the development of proliferative retinopathy and nephropathy was assessed by monitoring glycated haemoglobin for 5 years or more before the diagnosis of these complications. The study comprised Type 1 (insulin-dependent) diabetic patients diagnosed at an age less than 31 years, and with diabetes duration 25 years or less. They were followed for an average of 7.9 years with 3.3 measurements per year. Of 172 patients screened for retinopathy 60 had no retinopathy, 104 had background retinopathy, and 8 had proliferative retinopathy. The mean HbA_1c (95% confidence intervals) of the groups was 6.4% (6.2–6.7%), 7.3% (7.1–7.5%) and 8.9% (8.1–9.6%), respectively (p<0.0001); the mean duration of diabetes was 12, 18, and 17 years. Of 186 patients 7 had nephropathy (albuminuria>200 mg/l). Mean HbA_1c in patients without nephropathy was 7.0% (6.8–7.1%) and in patients with nephropathy 8.8% (7.8–9.9%,p<0.001). Mean diabetes duration was 16 years in both groups. Multiple logistic regression including mean HbA₁₀, age at onset, duration, sex, and hypertension, was for both proliferative retinopathy and nephropathy significant only for mean HbA_1c. In all cases, proliferative retinopathy and nephropathy were preceded by poor glycaemic control over several years, suggesting that these complications are caused by poor glycaemic control.     

Insulin pump use in pregnancy is associated with lower HbA1c without increasing the rate of severe hypoglycaemia or diabetic ketoacidosis in women with type 1 diabetes

Aims/hypothesis

The aim of this study was to compare glycaemic control and maternal–fetal outcomes in women with type 1 diabetes managed on insulin pumps compared with multiple daily injections of insulin (MDI).

Methods

In a retrospective study, glycaemic control and outcomes of 387 consecutive pregnancies in women with type 1 diabetes who attended specialised clinics at three centres 2006–2010 were assessed.

Results

Women using insulin pumps (129/387) were older and had a longer duration of diabetes, more retinopathy, smoked less in pregnancy, and had more preconception care (p?<?0.01 for each). Among 113 pregnancies >20 weeks’ gestation in women on insulin pumps and 218 in women on MDI, there was a significant difference in HbA_1c in the first trimester (mean HbA_1c 6.90?±?0.71% (52?±?7.8 mmol/mol) vs 7.60?±?1.38% (60?±?15.1 mmol/mol), p?<?0.001), which persisted until the third trimester (mean HbA_1c 6.49?±?0.52% (47?±?5.7 mmol/mol) vs 6.81?±?0.85% (51?±?9.3 mmol/mol), p?=?0.002). Rates of diabetic ketoacidosis were similar in women on insulin pumps vs MDI (1.8% vs 3.0%, p?=?0.72). Despite lower HbA_1c, women on insulin pumps did not have an increased incidence of severe hypoglycaemia (8.0% vs 7.6%, p?=?0.90) or more weight gain (16.3?±?8.7 vs 15.2?±?6.2 kg, p?=?0.18). More large-for-gestational-age infants in the pump group (55.0% vs 39.2%, p?=?0.007) may have resulted from confounding by parity.

Conclusions/interpretation

In this large multicentre study, women using insulin pumps in pregnancy had lower HbA_1c without increased risk of severe hypoglycaemia or diabetic ketoacidosis but no improvement in other pregnancy outcomes. This information can help inform care providers and patients about the glycaemic effectiveness and safety of insulin pumps in pregnancy.     

Gene transfer of endothelial nitric oxide synthase alters endothelium-dependent relaxations in aortas from diabetic rabbits

Aims/hypothesis. Cardiovascular disease is the leading cause of death in diabetes mellitus. Abnormal endothelium-dependent relaxation is observed both in humans and in animal models of diabetes mellitus and decreased bioavailability of nitric oxide (NO) is thought to be involved in this defect. Therefore, the aim of this study was to test whether adenovirus-mediated gene transfer of endothelial nitric oxide synthase (eNOS) alters vascular reactivity of diabetic vessels.¶Methods. Vascular reactivity was first assessed in thoracic aortas and carotid arteries from nine alloxan-induced diabetic (plasma glucose, 26.5 ± 1.2 mmol/l; HbA_{1 c}, 6.4 ± 0.3 %) and nine control rabbits (plasma glucose, 11.1 ± 1.3 mmol/l; HbA_{1 c}, 2.1 ± 0.1 %). Vascular reactivity was next examined in thoracic aortas of diabetic animals after ex vivo transduction with replication-deficient adenovirus encoding gene for eNOS (AdeNOS) or β-galactosidase (Adβ gal).¶Results. After 10 weeks of hyperglycaemia, endothelium-dependent relaxation to acetylcholine was impaired in diabetic aorta, but was normal in carotid arteries from diabetic rabbits. In contrast, responses of both vessels to calcium ionophore and nitric oxide donor were normal. Histochemical staining for β-galactosidase and immunohistochemistry for eNOS showed transgene expression in the endothelium and adventitia in Adβ gal and AdeNOS transduced vessels, respectively. During submaximum contractions with phenylephrine, relaxations to low concentrations of acetylcholine (3 × 10^–8 to 10^–7 mol/l) were augmented in AdeNOS transduced diabetic vessels.¶Conclusion/interpretation. These findings suggest that adenovirus-mediated gene transfer of eNOS to diabetic aorta alters vascular reactivity. [Diabetologia (2000) 43: 340–347]     

Evaluation of risk factors for the development of nephropathy in patients with IDDM: insertion/deletion angiotensin converting enzyme gene polymorphism, hypertension and metabolic control

Summary Diabetic nephropathy represents a major complication in patients with insulin-dependent diabetes mellitus (IDDM). Intervention trials using angiotensin-converting enzyme (ACE) inhibitors have pointed towards the important pathogenetic role of the renin-angiotensin system. Recently an insertion/deletion (I/D) polymorphism for the gene encoding the ACE has been described, the deletion type being associated with higher plasma ACE levels. As the intrarenal renin-angiotensin system might also be activated in this setting, we determined the ACE genotype together with other risk factors for the development of diabetic nephropathy in 122 patients with IDDM from a single centre with (n = 63) and without (n = 59) nephropathy. Long-term glycaemic control was evaluated using mean HbA_1c values from the last 10 years. The two patient group were comparable with regard to duration of diabetes and glycaemic control as assessed by current HbA_1c values. However, mean long-term HbA_1c values were significantly higher in patients with diabetic nephropathy as was systemic blood pressure. The DD genotype was more prevalent in patients with renal disease. In the subgroup of patients who had had diabetes for more than 20 years (n = 90), the DD genotype was even more frequent in patients with nephropathy, and blood pressure and long-term HbA_1c values were also higher in patients with renal disease. Logistic regression analysis revealed long-term glycaemic control, blood pressure and the ACE genotype to be independent risk factors for the prevalence of diabetic nephropathy. [Diabetologia (1997) 40: 327–331] Received: 1 July 1996 and in final revised form: 20 November 1996     

Sex differences in the risk of stroke and HbA1c among diabetic patients

Aims/hypothesis

Sex differences in macrovascular disease, especially in stroke, are observed across studies of epidemiology. We studied a large sample of patients with type 2 diabetes to better understand the relationship between glycaemic control and stroke risk.

Methods

We prospectively investigated the sex-specific association between different levels of HbA_1c and incident stroke risk among 10,876 male and 19,278 female patients with type 2 diabetes.

Results

During a mean follow-up of 6.7 years, 2,949 incident cases of stroke were identified. The multivariable-adjusted HRs of stroke associated with different levels of HbA_1c at baseline (HbA_1c <6.0% [<42 mmol/mol], 6.0–6.9% [42–52 mmol/mol] [reference group], 7.0–7.9% [53–63 mmol/mol], 8.0–8.9% [64–74 mmol/mol], 9.0–9.9% [75–85 mmol/mol] and ≥10.0% [≥86 mmol/mol]) were 0.96 (95% CI 0.80, 1.14), 1.00, 1.04 (0.85, 1.28), 1.11 (0.89, 1.39), 1.10 (0.86, 1.41) and 1.22 (0.92, 1.35) (p for trend?=?0.66) for men, and 1.03 (0.90, 1.18), 1.00, 1.09 (0.94, 1.26), 1.19 (1.00, 1.42), 1.32 (1.09, 1.59) and 1.42 (1.23, 1.65) (p for trend <0.001) for women, respectively. The graded association between HbA_1c during follow-up and stroke risk was observed among women (p for trend?=?0.066). When stratified by race, whether with or without glucose-lowering agents, this graded association of HbA_1c with stroke was still present among women. When stratified by age, the adjusted HRs were significantly higher in women older than 55 years compared with younger women.

Conclusions/interpretation

The current study suggests a graded association between HbA_1c and the risk of stroke among women with type 2 diabetes. Poor control of blood sugar has a stronger effect in diabetic women older than 55 years.     

Area‐under‐the‐HbA1c‐curve above the normal range and the prediction of microvascular outcomes: an analysis of data from the Diabetes Control and Complications Trial

Aims In the Diabetes Control and Complications Trial, mean updated HbA_1c accounted for most of the differential risk of microvascular complications between intensive and conventional insulin therapy. We hypothesized, however, that a more precise measure of chronic hyperglycaemic exposure may be the incremental area‐under‐the‐HbA_1c‐curve above the Diabetes Control and Complications Trial‐standardized normal range for HbA_1c (iAUC_HbA1c>norm). Methods Using the Principal Diabetes Control and Complications Trial data set, we compared the following three measures of chronic glycaemic exposure for their capacity to predict retinopathy, nephropathy and neuropathy during the Diabetes Control and Complications Trial: mean updated HbA_1c, iAUC_HbA1c>norm, and total area‐under‐the‐HbA_1c‐curve (tAUC_HbA1c). For each outcome, models using each of these three glycaemic measures were compared in the following three ways: hazard or odds ratio, χ² statistic, and Akaike information criterion. Results The three glycaemic measures did not differ in their prediction of neuropathy. iAUC_HbA1c>norm was modestly superior to mean updated HbA_1c for predicting nephropathy (χ²P = 0.017, Akaike P = 0.032). In contrast, for predicting retinopathy, both iAUC_HbA1c>norm (χ²P = 0.0005, Akaike P = 0.0005) and tAUC_HbA1c (χ²P = 0.004, Akaike P = 0.004) were significantly better than mean updated HbA_1c. Varying its HbA_1c threshold incrementally between 37 and 53 mmol/mol (5.5–7.0%), inclusive, did not improve the prediction of retinopathy by iAUC_{HbA1c>threshold} beyond that of tAUC_HbA1c,consistent with the concept of a continuous relationship between glycaemia and retinopathy, with no glycaemic threshold. Conclusions Both iAUC_HbA1c>norm and tAUC_HbA1c were superior to mean updated HbA_1c for predicting retinopathy. Optimal assessment of chronic glycaemic exposure as a determinant of retinopathic risk may require consideration of both the degree of hyperglycaemia and its duration.     

Pre-eclampsia is a potent risk factor for deterioration of retinopathy during pregnancy in type 1 diabetic patients

The aim of the present study was to examine the influence of pregnancy on deterioration of retinopathy in patients with Type 1 diabetes mellitus. Sixty-five pregnant Type 1 diabetic women attending the University Hospital in Lund were studied retrospectively. The degree of retinopathy, and levels of HbA_1c and blood pressure 12 months before, during, and 6 months after pregnancy were compared of those of 56 non-pregnant Type 1 diabetic women matched for age and duration of diabetes. For all patients, sight-threatening deterioration of retinopathy did not differ between the pregnancy group (9/65) and the control group (6/56). Over time, pregnant patients had lower HbA_1c levels than controls (p < 0.001). Pregnant patients with sight-threatening deterioration of retinopathy had higher HbA_1c levels than those without (p = 0.028 and the decrement in HbA_1c between the 6–14th and the 20th week of gestation was more pronounced (p = 0.006). In those patients who developed pre-eclampsia during pregnancy, deterioration of retinopathy ocurred more frequently compared to those without pre-eclampsia (4/8 vs 5/65; p = 0.005). In conclusion, sight-threatening deterioration of retinopathy was not more common during pregnancy in IDDM patients than among age- and duration-matched control patients. In pregnant patients, deterioration of retinopathy was associated with the pregestational degree of metabolic control as well as with a rapidly improved glycaemic control acheived during pregnancy. Among those in whom deterioration occurred during pregnancy, pre-eclampsia was a potent risk factor. © 1997 John Wiley & Sons, Ltd.     

Functional and structural abnormalities in the nerves of Type I diabetic baboons: aminoguanidine treatment does not improve nerve function

Aims/hypothesis. To improve understanding of the pathophysiology of diabetic neuropathy and to establish a primate model for experimental studies, we examined nerve changes in baboons with Type I (insulin-dependent) diabetes mellitus. We also examined the effect of aminoguanidine (an inhibitor of the formation of advanced glycation end products) on nerve function.¶Methods. Male baboons (Papio hamadryas) were assigned to four groups; control, diabetic, control and diabetic treated with aminoguanidine. Diabetes was induced with streptozotocin (60 mg/kg, intravenous). Insulin and aminoguanidine (10 mg/kg) were injected subcutaneously daily. Motor and sensory nerve conduction velocity was measured using standard techniques. Autonomic function was examined by measuring heart rate response to positional change. Sural nerve morphometry was analysed in the diabetic group (mean duration 5.5 years) along with their age-matched controls.¶Results. The diabetic groups were smaller in size with a mean HbA_{1 c} of 8.9 ± 1.2 %. The nerve conduction velocity and heart rate response was reduced in the diabetic groups. Morphometric analysis of the diabetic sural nerve showed smaller axon diameter (2.99 ± 0.06 μm vs 3.29 ± 0.06 μm; p < 0.01) accompanied by thinner myelin (1.02 ± 0.02 μm vs 1.15 ± 0.02 μm, p < 0.01) with no change in the axon density. Treatment with aminoguanidine for 3 years had no effect on glycaemic control and did not restore conduction velocity or autonomic dysfunction in the diabetic animals, contrary to the studies in rats.¶Conclusions/interpretation. These results show that the primate is a good model to study diabetic neuropathy and suggest that the accumulation of advanced glycation end products are not an early mechanism of nerve damage in this disorder. [Diabetologia (2000) 43: 110–116]     

Relationship between mean blood glucose and glycated haemoglobin in Type 2 diabetic patients

Aims To correlate the values of MBG to HbA_1c in Greek patients with Type 2 diabetes and/or metabolic syndrome. Methods We followed up 140 Greek adult patients: 92 patients with Type 2 diabetes treated with insulin or oral glucose‐lowering medication, and 48 patients with newly diagnosed Type 2 diabetes or metabolic syndrome not receiving any treatment. MBG was calculated for each patient from self‐measurements of blood glucose using a portable glucometer, made six times a day (before eating and 2 h after a meal), three times a week for 1 month. HbA_1c was determined by HPLC at 0 and 12 weeks. Results HbA_1c at 0 (x) and 12 weeks (y) correlated strongly (y = 0.790x + 1.115, r = 0.92), confirming that the patient's glycaemic status remained stable during the whole period of follow‐up. Linear regression was performed on MBG values; HbA_1c at 12 weeks, sex, age, body mass index (BMI) and patient status (Type 2 diabetes treated or not) were used as independent variables. None of the independent variables reached statistical significance in the model, with the exception of HbA_1c at 12 weeks. The final model was: MBG (mg/dl) = (34.74 × HbA_1c) – 79.21, r = 0.93; or MBG (mmol/l) = 1.91 × HbA_1c – 4.36, r = 0.93. Conclusions Our results establish for the first time a strong correlation between MBG and HbA_1c in Type 2 diabetic patients and support the idea of expressing HbA_1c results as MBG. This will help patients to gain a clearer interpretation of the result, with less confusion. This simplification will allow every person with diabetes using home glucose‐monitoring to understand his or her own target level.     

HbA1c levels in non‐diabetic Dutch children aged 8–9 years: the PIAMA birth cohort study

Aim Glycated haemoglobin (HbA_1c) is considered the best index of glycaemic control in established diabetes. It may also be useful in the diagnosis of diabetes and as a screening tool. Little is known about the distribution of HbA_1c in healthy children and its predictors. The aim of this study is to describe the distribution of HbA_1c in non‐diabetic Dutch children aged 8–9 years and to investigate potential associations of HbA_1c in this group. Methods HbA_1c was measured in 788 non‐diabetic children aged 8–9 years participating in the PIAMA birth cohort study. Data on parents and children were collected prospectively by questionnaires. Weight, height and waist and hip circumference of the children were measured when blood samples were taken. Results Mean (sd ) HbA_1c was 4.9 ± 0.33%, range 3.5–6.0%. HbA_1c was significantly higher in boys (4.9 ± 0.31 vs. 4.9 ± 0.33%) and in children of mothers with gestational diabetes (5.0 ± 0.37 vs. 4.9 ± 0.32%). We found a significant inverse association between HbA_1c and haemoglobin (regression coefficient: ?0.169 (95% CI ?0.221 to ?0.118), P < 0.001). HbA_1c was not significantly associated with age, body mass index, waist circumference, parental diabetes or maternal body mass index. Conclusions We found no significant relation between known risk factors for Type 2 diabetes and HbA_1c at age 8–9 years. Moreover, there was a significant inverse association between haemoglobin and HbA_1c. These results suggest that HbA_1c may not only reflect the preceding blood glucose levels, but seems to be determined by other factors as well.     

Prevalence of retinopathy differs with age at onset of diabetes in a population of patients with Type 1 diabetes.

Aim The VISS study (Vascular complications in South‐east Sweden) investigates prevalence and incidence of vascular complications in a population with Type 1 diabetes, from a well‐defined geographical area and followed from diagnosis with HbA_1c measurement. Method The study population comprised all 440 patients with Type 1 diabetes onset before the age of 36 years, onset during 1983–1987, and at the time of onset living within the counties of Jönköping, Kalmar or Östergötland. Retinopathy was examined with fundus photography 1994–1995, and classified according to a modified Airlie House protocol. Results Fundus photographs from 390 patients were evaluated. In 277 (71%) patients no retinopathy was seen. The prevalence of retinopathy increased from 11% among patients < 5 years old at diabetes onset, to 48% among those 15–19 years old at diabetes onset, and then decreased to 30% for patients 30–35 years old at diabetes onset (P for χ² for linear trend for all ages 0.017, for age at onset 0–19 years P = 0.0003), without corresponding differences in duration or HbA_1c between patients with different onset age. Patients with HbA_1c in the highest quartile (> 8.3% HbA_1c) had a relative risk of 2.4 (95% confidence interval (CI) 1.7–3.2) of having any retinopathy compared with patients with lower HbA_1c, and a relative risk of 7.1 (95% CI 3.0–16.7) of having other forms of retinopathy than microaneurysms. Conclusion In patients with diabetes duration of 6–13 years, the prevalence of retinopathy is clearly related to glycaemic control. Furthermore, the risk of retinopathy varies with different age at onset, independently of differences in duration or glycaemic control. Diabet. Med. 19, 924–931 (2002)     

Long-term glycaemic control directly correlates with glomerular filtration rate in early Type 1 diabetes mellitus before the onset of microalbuminuria

Hyperfiltration occurs early in diabetes mellitus and has been implicated in the development of microalbuminuria. Our aim was to re-examine the controversial relationship between glycaemic control and glomerular filtration (GFR) in normoalbuminuric, normotensive, non-obese patients with short duration Type 1 diabetes mellitus (DM). We studied 75 Type 1 DM patients, 35 male, aged 18–42 years, with a duration of diabetes of 4–8 years. GFR was determined by inulin clearance; hyperfiltration was defined as above 145 ml min⁻¹ 1.73 m⁻² (equivalent to 2 SD above mean for a control population). Analysis was by paired Student’s t-testing and linear regression. GFR correlated significantly with HbA_1c (r = 0.47, p < 0.0001) and fructosamine (r = 0.24, p = 0.035). Mean HbA_1c and fructosamine in the 13 patients with hyperfiltration was significantly higher than in the rest of the group (HbA_1c: 9.2 % (95 % C.I. 7.9–10.4 %) vs 7.6 % (7.2–7.9), p = 0.002; fructosamine: 479 μmol l⁻¹ (450–507) vs 410 μmol l⁻¹ (388–432), p = 0.009. This significant difference persisted even when the two highest values of HbA_1c or fructosamine were removed from analysis. Effective renal plasma flow, assessed by PAH clearance, also correlated in all patients with HbA_1c (r = 0.31, p = 0.039). We conclude that poor glycaemic control directly correlates with hyperfiltration and renal hyperperfusion in early Type 1 DM. Copyright © 1998 John Wiley & Sons, Ltd.     

Comparison of progression of macrovascular diseases after kidney or pancreas and kidney transplantation in diabetic patients with end-stage renal disease

Aims/hypothesis . The aim of the study was to examine the effect of pancreas-kidney transplantation on the progression of macrovascular diseases in Type I diabetic patients with end-stage renal disease.¶Methods . The progression of cerebrovascular disease, coronary heart disease and peripheral vascular disease in uraemic patients with Type I (insulin-dependent) diabetes mellitus and who had had simultaneous pancreas-kidney transplantation was compared with that of recipients of a kidney transplant alone. Between 1986 and 1998 a total of 11 uraemic diabetic patients received a simultaneous pancreas-kidney transplantation and 10 diabetic patients a kidney transplant alone. All transplants functioned for at least 24 months, the mean observation period was 69 ± 37 compared with 70 ± 33 months in both patient groups. Macroangiopathic diseases were classified in four stages as described earlier.¶Results. In the group with simultaneous pancreas-kidney transplantation progression of cerebrovascular and coronary heart disease was observed in four patients (36 %) and progression of peripheral vascular disease in five subjects (45 %). In the cohort with kidney transplant alone four patients (40 %) showed progression of cerebrovascular and coronary heart disease and five progression of peripheral vascular disease (50 %); the difference is not significant. Mean values of HbA_{1 c} (5.8 ± 0.2 vs 7.5 ± 0.6 %, p < 0.001) and serum triglycerides (1.2 ± 0.4 vs 2.0 ± 1.0 mmol/l, p < 0.05) were significantly lower in the patients with pancreas-kidney transplantation than in the patient group with kidney transplant alone. Serum cholesterol concentrations and blood pressures were similar in both cohorts.¶Conclusion/interpretation. From our results we concluded that pancreas-kidney transplantation reduces risk factors for the development of macroangiopathy but fails to halt progression of macrovascular diseases similar to Type I diabetic patients with kidney transplant alone. [Diabetologia (2000) 43: 231–234]     

Pre-eclampsia and pregnancy-induced hypertension are associated with severe diabetic retinopathy in type 1 diabetes later in life

To investigate whether pre-eclampsia (PE) or pregnancy-induced hypertension (PIH) predicts the development of severe diabetic retinopathy (SDR) in type 1 diabetes. Altogether, 203 women with type 1 diabetes who were followed during pregnancy were re-examined within the Finnish Diabetic Nephropathy Study. After excluding patients with pre-pregnancy hypertension and those who had had laser treatment or whose retinopathy was graded as proliferative at the index pregnancy, 158 were prospectively studied. As a surrogate marker for SDR, retinal laser photocoagulation was used. The time from pregnancy to SDR (N = 21) or follow-up was 16 years (interquartile range, 11–19). HbA_1c was repeatedly measured both during pregnancy and follow-up. Women with prior PE (26 % vs. 6 %, P = 0.003) or PIH (24 % vs. 6 %, P = 0.008) had more often incident SDR during follow-up compared to those with normotensive pregnancy. The hazard ratios (HR) remained associated with the progression to SDR after adjustment for duration of diabetes and diabetic nephropathy in a Cox regression analysis [PE: 3.5 (95 % CI 1.1–10.9); P = 0.03 and for PIH: 3.2 (1.1–9.8); P = 0.04]. The association between PIH and incident SDR did not change after inclusion of mean HbA_1c, measured during pregnancy (all 3 trimesters) and serial HbA_1c measurements during follow-up, 3.5 (1.1–11.8; P = 0.03). However, in a similar model, the HR for PE was no more significant 2.0 (0.6–6.8; P = NS). The results suggest that women with type 1 diabetes and a hypertensive pregnancy have an increased risk of severe diabetic retinopathy later in life.     

The Effect of Glycaemic Control and the Introduction of Insulin Therapy on Retinopathy in Non-insulin-dependent Diabetes Mellitus

To study the progression of diabetic retinopathy in relation to diabetes treatment and glycaemic control in patients with non-insulin dependent (Type 2) diabetes mellitus (NIDDM), we performed a prospective study in a cohort of 1378 diabetic patients, aged ⩾40 years at diagnosis, of whom 333 were treated with insulin, and 1045 with oral antihyperglycaemic agents or diet alone. In the latter group 174 patients changed to insulin therapy during follow-up. We used the Wisconsin scale to grade retinopathy, recorded blindness (visual acuity ⩽0.1) and visual impairment (visual acuity 0.2–0.4), and measured the average HbA_1c for each patient during a mean 3.1-year study period. In a multivariate analysis, patients who changed treatment from oral agents or diet alone to insulin therapy had a relative risk of 2.0 (95 % confidence interval 1.7–2.3) for progression of retinopathy ⩾3 levels compared with all other patients in the study. The increase in risk remained even after controlling for mean HbA_1c (relative risk 1.6; 95 % confidence interval 1.3–1.9). Progression ⩾3 levels was significantly associated with a higher incidence of macular oedema and deterioration of visual acuity (p < 0.001). The relative risk for blindness/visual impairment due to retinopathy was 2.7 (95 % confidence interval 1.8–4.0) in the group with changed treatment compared with all the other patients in the study. Poor glycaemic control (HbA_1c %) before the start of insulin therapy and any retinopathy at baseline were significant risk factors for progression in the group with changed treatment (both p < 0.01). In the whole study group, poor glycaemic control was significantly associated with retinopathy progression ⩾3 levels; the relative risk for those having mean HbA_1c above the median being 1.7 (95 % confidence interval 1.4–2.1), compared to those with a HbA_1c value below the median. Moderate non-proliferative diabetic retinopathy at baseline was also associated with progression (relative risk 2.5; 95 % confidence interval 1.4–4.5). In contrast, insulin treatment at baseline was not associated with an increased risk of retinopathy progression. In conclusion, while hyperglycaemia was a risk factor for the progression of retinopathy in all patients, change of treatment from oral drugs to insulin was associated with a 100 % increased risk of retinopathy progression and a 3-fold increased risk of blindness/visual impairment. © 1997 by John Wiley & Sons, Ltd.