Tore Julsrud Berg

Clinical, Immunological, and Genetic Features of Autoimmune Primary Adrenal Insufficiency: Observations from a Norwegian Registry

OBJECTIVE Primary adrenal insufficiency [Addisons disease (AD)] is rare, and systematic studies are few, mostly conducted on small patient samples. We aimed to determine the clinical, immunological, and genetic features of a national registry-based cohort. DESIGN Patients with AD identified through a nationwide search of diagnosis registries were invited to participate in a survey of clinical features, health-related quality of life (HRQoL), autoantibody assays, and human leukocyte antigen (HLA) class II typing. RESULTS Of 664 registered patients, 64% participated in the study. The prevalence of autoimmune or idiopathic AD in Norway was 144 per million, and the incidence was 0.44 per 100,000 per year (1993-2007). Familial disease was reported by 10% and autoimmune comorbidity by 66%. Thyroid disease was most common (47%), followed by type 1 diabetes (12%), vitiligo (11%), vitamin B12 deficiency (10%), and premature ovarian insufficiency (6.6% of women). The mean daily treatment for AD was 40.5 mg cortisone acetate and 0.1 mg fludrocortisone. The mean Short Form 36 vitality scores were significantly diminished from the norm (51 vs. 60), especially among those with diabetes. Concomitant thyroid autoimmunity did not lower scores. Anti-21-hydroxylase antibodies were found in 86%. Particularly strong susceptibility for AD was found for the DR3-DQ2/ DRB1*0404-DQ8 genotype (odds ratio, 32; P = 4 x 10(-17)), which predicted early onset. CONCLUSIONS AD is almost exclusively autoimmune, with high autoimmune comorbidity. Both anti-21-hydroxylase antibodies and HLA class II can be clinically relevant predictors of AD. HRQoL is reduced, especially among diabetes patients, whereas thyroid disease did not have an impact on HRQoL. Treatment modalities that improve HRQoL are needed.

Advanced glycation end products in serum predict changes in the kidney morphology of patients with insulin-dependent diabetes mellitus

The biochemical mechanisms that cause the development and progression of diabetic nephropathy are unknown. Advanced glycation end products (AGEs) might play a role, as shown by increased levels of tissue-bound and circulating AGEs that correlate with the severity of diabetic nephropathy. The aim of the present study was to investigate if circulating AGEs predict the progression of morphological pathology in patients with diabetic nephropathy. We have developed an immunoassay to determine serum levels of AGEs. In a prospective clinical trial of young insulin-dependent diabetes mellitus (IDDM) patients with microalbuminuria, kidney biopsies were taken at baseline and after 24 to 36 months. The biopsies were analyzed for structural changes in the glomeruli by quantitative morphometry (electron microscopy). We have retrospectively analyzed serum AGEs. The mean serum level of AGEs at the start of the study was 18.7 U/mL (95% confidence interval [CI], 16.9 to 20.5). A positive correlation between serum AGE levels at the start of study and changes from baseline to follow-up study in basement membrane thickness (r = .56, P < .02) and matrix/glomerular volume fraction (r = .57, P < .02) was demonstrated. In a stepwise regression analysis with changes in the matrix/glomerular volume fraction as the dependent variable, serum AGE levels at the start of the study proved to be a significant independent variable (P < .02), whereas the mean hemoglobin A1c (HbA1c) or HbA1c at the start was not. This study shows that serum AGEs predict the progression of early morphological kidney damage during 2.5 years in patients with IDDM.

High Serum Levels of Advanced Glycation End Products Predict Increased Coronary Heart Disease Mortality in Nondiabetic Women but not in Nondiabetic Men A Population-Based 18-Year Follow-Up Study

Background—Advanced glycation end products (AGEs), modification products of glycation or glycoxidation of proteins and lipids, have been linked to premature atherosclerosis in patients with diabetes as well as in nondiabetic subjects. Methods and Results—Serum levels of AGEs were measured with an immunoassay in samples obtained at baseline examination of a random sample of 1141 nondiabetic individuals (535 men and 606 women), aged 45 to 64 years, living in Kuopio, East Finland, or Turku, West Finland in 1982 to 1984. After 18 years of follow-up, all-cause mortality, cardiovascular disease (CVD), and coronary heart disease (CHD) mortality were registered on the basis of copies of death certificates. Multivariate Cox regression model showed a significant association of serum AGEs with all-cause (P=0.012), CVD (P=0.018), and CHD (P=0.008) mortality in women but not in men. Fasting serum AGEs in the highest quartile were an independent risk factor for all-cause (hazards ratio [HR], 1.90; 95% CI, 1.16 to 3.11; P=0.011) and CHD (HR, 6.51; 95% CI, 1.78 to 23.79; P=0.005) mortality in women, even after the adjustment for confounding factors, including highly sensitive C-reactive protein. Conclusions—The present study is the first to show that serum levels of AGEs can predict total, CVD, and CHD mortality in nondiabetic women.

Increased Serum Levels of Advanced Glycation End Products (AGEs) in Children and Adolescents With IDDM

OBJECTIVE To investigate whether the serum levels of advanced glycation end products (AGEs) are increased in IDDM children and adolescents and to study the effect of puberty on serum levels of AGEs (S-AGEs). RESEARCH DESIGN AND METHODS A total of 68 children and adolescent IDDM patients (age, 13.3 ± 4.0 years; duration of diabetes, 5.0 ± 3.6 years; HbA1c, 8.2 ± 2.0%; Tanner stage [public hair], 1 vs. 2–5, 24/42) recruited from the pediatric outpatient clinic at Aker University Hospital were compared with 25 healthy nondiabetic control subjects. S-AGEs were measured by a fluoremetric immunoassay. RESULTS S-AGEs were significantly elevated in the diabetic group when compared with the control group (14.4 ± 3.5 vs. 11.7 ± 3.0 U/ml, P < 0.002). A significant correlation (r = 0.26, P < 0.04) was found between S-AGEs and HbA1c in the diabetic group but not in the control group. No significant correlation was found between S-AGEs and the duration of diabetes in the diabetic group or S-AGEs and blood glucose concentration or age in either group. We found no difference between S-AGEs in boys and girls and in prepubertal and pubertal diabetic or control subjects. CONCLUSIONS S-AGEs are increased in young patients with diabetes before puberty. Since AGEs are linked to the pathogenesis of vascular complications, this observation suggests that the pathological processes leading to diabetic late complications start even before puberty.

Hydroperoxides in plasma are reduced by intensified insulin treatment. A randomized controlled study of IDDM patients with microalbuminuria.

OBJECTIVE An association between reactive oxygen species and diabetic micro- and macrovascular complications has been proposed. In the present study, we have examined the effect of an improved blood glucose control on plasma levels of hydroperoxides in patients with IDDM. RESEARCH DESIGN AND METHODS Subjects included 30 young IDDM patients with microalbuminuria who were randomized to receive either continuous subcutaneous insulin infusion (CSII) by a portable insulin pump (n = 15) or conventional insulin treatment (CIT) (n = 15) for 24 months. Plasma levels of hydroperoxides were measured by the ferrous oxidation with Xylenol Orange, version 2 (FOX2) assay. This method measures total lipid hydroperoxides and, unlike other methods, does not suffer from extraction losses. RESULTS The mean HbA1c level was lower in the CSII group at the end of the study than in the CIT group: (mean [95% CI]) 8.6 (8.1–9.1) vs. 9.6 (9.0–10.3)%, respectively (P < 0.002). The level of plasma hydroperoxides was very similar at the start of the study but was significantly lower in the CSII group compared with the CIT group at the end of the study: 2.9 (2.1–3.7) vs. 4.3 (3.2–5.4) μmol/l, respectively (P < 0.02). In the CSII group, hydroperoxides were reduced by 31% from baseline (P < 0.001), whereas there was no change in levels of hydroperoxides in the CIT group. Mean hydroperoxide levels correlated with mean HbA1c during the study (r = 0.39, P < 0.04). Hydroperoxide levels were associated with the levels of microalbuminuria (r = 0.45, P < 0.02). CONCLUSIONS This study provides support for the hypothesis that hyperglycemia is an important factor in the generation of hydroperoxides, and, thus, reactive oxygen species, in the circulation of IDDM patients.

No increase in new users of blood glucose-lowering drugs in Norway 2006–2011: a nationwide prescription database study

BackgroundNational estimates for the occurrence of diabetes are difficult to obtain, particularly time trends in incidence. The aim was to describe time trends in prevalent and incident use of blood glucose-lowering drugs by age group and gender in Norway during 2005–2011.MethodsData were obtained from the nationwide Norwegian Prescription Database. We defined prevalent users of “insulins only” as individuals having no oral antidiabetic drugs (OAD) dispensed from a pharmacy during the previous 24 months or in the subsequent 12 months. Incident users had no blood glucose-lowering drugs dispensed in the previous 24 months; incident “insulins only” users also had no OAD in the subsequent 12 months.ResultsIn 2011, 3.2% of the population had blood glucose-lowering drugs dispensed, and the incidence rate was 313 per 100,000 person years. The prevalence of OAD use increased from 1.8% in 2005 to 2.4% in 2011; however a decreasing trend in incidence of OAD use was observed, particularly in those aged 70 years and older. In 2010, 0.64% of the population had insulins only dispensed, with an overall incidence rate in the total population of 33 per 100,000 person years which was stable over time.ConclusionsIn this nationwide study, we found that although the prevalent use of OAD had increased in recent years, incident use was stable or had decreased. This may indicate that the increase in diabetes occurrence in Norway is levelling off, at least temporarily.

LV systolic impairment in patients with asymptomatic coronary heart disease and type 1 diabetes is related to coronary atherosclerosis, glycaemic control and advanced glycation endproducts

To evaluate whether heart failure in type 1 diabetes is linked to poor glycaemic control, coronary atherosclerosis or advanced glycation endproducts (AGEs).

Renal tubulointerstitial expansion is associated with endothelial dysfunction and inflammation in type 1 diabetes

Objective. Diabetic nephropathy has been considered to be primarily of glomerular origin, but there is now compelling evidence that disruption of the tubulointerstitial architecture determines the outcome of diabetic nephropathy in interplay with the glomerular damage. We investigated whether reactive oxidative species, pro‐inflammatory cytokines and endothelial dysfunction were implicated in the progression of tubulointerstitial damage in young subjects with type 1 diabetes. Material and methods. In a prospective study, we investigated 18 young subjects (mean age 21 years) with type 1 diabetes and microalbuminuria. Quantitative morphometry concerning glomerular and tubulointerstitial changes was performed at baseline (i.e. mean duration of diabetes 10 years) and 2.5 and 8 years later. Markers of endothelial activation and inflammation, intercellular adhesion molecule‐1, vascular cell adhesion molecule‐1, tumour necrosis factor‐α, interleukin‐6, interleukin‐8 and highly sensitive C‐reactive protein were measured at baseline and after 8 years. Tissue plasminogen activator antigen and plasminogen activator inhibitor (PAI‐1 activity) and asymmetric dimethylargine (ADMA) were measured at baseline and after 2.5 years. Results. PAI‐1 activity at baseline was a significant independent variable of the 8‐year increment in interstitial volume fraction (Vv(Int/cortex)). ADMA/L‐arginine ratio at baseline was associated with the increment in Vv(Int/cortex) during 2.5 years (p<0.01), still significant after adjustment for covariates (p = 0.02). No associations between Vv(Int/cortex) and glomerular parameters, HaemoglobinA1c and urinary albumin excretion were observed. Conclusions. Biomarkers involved in interstitial volume expansion seem to be different from those of mesangial expansion in early diabetic nephropathy. PAI‐1 activity may have a predictive role in the development of the tubulointerstitial expansion.

A novel technique of Roux-en-Y gastric bypass reversal for postprandial hyperinsulinemic hypoglycaemia: A case report

Highlights • Postprandial hypoglycemia may be a serious adverse effect following Roux-en-Y gastric bypass surgery.• Most patient can be treated with diet and pharmacological agents, but some patients need surgical reversals.• This Roux-en-Y gastric bypass reversal alleviates severe postprandial hyperinsulinaemic hypoglycaemia.• The technique retains some component of rapid transit of food into a shorter alimentary limb in an attempt to reduce weight regain.• This new surgical procedure also attenuates s-GLP-1 and s-insulin responses along with improved p-glucose.

Sources of error when using haemoglobin A1c

BACKGROUND Measurement of glycated haemoglobin A1 in whole blood (b-HbA1c) can be used in both diagnosing and following up patients with diabetes. Correct interpretation of analytical results is contingent on agreement between average plasma glucose (p-glucose) and b-HbA1c. This article provides an overview of factors that may result in a discrepancy between average glucose concentration and b-HbA1c. METHOD Literature search in PubMed to identify scientific articles that describe strengths and weaknesses of b-HbA1c. RESULTS The b-HbA1c reading usually provides a good picture of average p-glucose for the preceding two to three months. Patients who are being treated with iron/vitamin B12 supplements, have liver failure, haemolytic anaemia or bleeding usually have a lower b-HbA1c than their p-glucose level would suggest. With increasing patient age, B12 deficiency or iron deficiency anaemia, higher values of b-HbA1c are seen for the same p-glucose level. Some ethnic groups have a higher b-HbA1c than their average p-glucose would suggest, but the risk of long-term complications appears generally to be more closely associated with b-HbA1c than with the glucose level. Pregnancy, renal failure or haemoglobinopathies may make the b-HbA1c value unreliable as an expression of average p-glucose. INTERPRETATION Correct interpretation of b-HbA1c is conditional on the requisitioner being aware of possible sources of error. If the patient is suspected to have a condition that leads to lack of consistency between b-HbA1c and average p-glucose, glucose-based criteria must be used in diagnosing diabetes.