Risk of Thyroid Cancer in People With Type 1 Diabetes by Autoimmune Thyroid Diseases and Tumor Histology.

Context: Thyroid cancer is the most common endocrine cancer, but little is known about it in type 1 diabetes (T1D) and its potential association with autoimmune diseases. Objective: This study aims to assess the risk of thyroid cancer in adults with long-term T1D compared to individuals without diabetes and the proposed association of thyroid autoimmune diseases with thyroid cancer. Methods: The study included 4758 individuals with T1D participating in the Finnish Diabetic Nephropathy Study and 12 710 controls. Thyroid cancers were obtained from the Finnish Care Registers for Health Care. Results: 27 (0.57%) individuals with T1D had thyroid cancer compared to 27 (0.21%) in the controls (standardized incidence ratio 2.43; 95% confidence interval 1.59-3.56). The absolute increase in incidence was modest, with a 0.36%-unit rise. This translates to 17 additional cases among 4710 individuals with T1D. Cancer type was papillary in 81.5% of individuals with T1D and 88.9% of the controls; the rest were follicular. In T1D the distribution of hypothyreosis was similar between those with (n = 5, 18.5%) and without (18.1%) cancer, but hyperthyreosis was diagnosed more often with thyroid cancer (n = 3, 11.1%) than without (2.3%, P = .003). None of the thyroid cancers were invasive or had metastatic characteristics. Conclusion: Although there is an excess risk of thyroid cancer, it is only marginally increased (0.36%-unit) in individuals with T1D compared to control individuals and was not associated with increased morbidity or mortality. An overdiagnosis effect due to regular health care contacts is the most likely explanation for the higher risk.

Incidence and risk factors for cancer in people with type 1 diabetes, stratified by stages of diabetic kidney disease: a nationwide Finnish cohort study.

Background: Individuals with type 1 diabetes (T1D) have been reported to have increased overall risk of cancer. In addition, individuals with a kidney transplant/transplantation (KT) have markedly increased cancer risk due to chronic use of immunosuppressive agents. However, it has not been elucidated whether the observed excess cancer risk is related to KT or whether diabetic kidney disease (DKD) per se is a risk factor for cancer in individuals with T1D. Methods: The study included 5035 individuals from the Finnish Diabetic Nephropathy Study (FinnDiane) and 14,061 control individuals without diabetes. We assessed the standardized incidence ratios (SIRs) for cancers in individuals with T1D compared to controls according to DKD status. Cox regression analyses were used to identify potential risk factors for cancer in individuals with type 1 diabetes. Findings: The SIR for overall cancer for all participants was 1.14 (1.05-1.24), for participants without KT 0.92 (0.83-1.01) and for participants with KT 4.78 (4.02-5.64). Participants without KT had in fact a reduced risk of prostate cancer with a SIR of 0.54 (0.37-0.76), cancer of urinary organs 0.41 (0.21-0.73) and respiratory and intrathoracic organs, 0.62 (0.38-0.97). Participants with KT had on the contrary an increased risk of non-melanoma skin cancer, SIR 14.50 (10.99-18.86), cancer in the lymphoid and hematopoietic tissue 5.38 (2.99-8.96), mouth or pharynx 5.13 (2.08-10.66), melanoma 5.12 [2.38-9.72]) and respiratory and intrathoracic organs 2.77 (1.21-5.49). The risk of thyroid cancer was increased both in participants without KT, SIR 2.14 (1.39-3.16) and with KT 5.30 (1.68-12.78). Interpretation: The excess overall cancer risk in individuals with type 1 diabetes is only seen in KT recipients and in thyroid cancer. The individuals without KT seem to have a decreased risk of some forms of cancer. Funding: Folkhälsan Research Foundation, Academy of Finland [316664], Wilhelm and Else Stockmann Foundation, Liv och Hälsa Society, Novo Nordisk Foundation [NNF OC0013659], Finnish Foundation for Cardiovascular Research, Finnish Diabetes Research Foundation, Medical Society of Finland, Sigrid Jusélius Foundation, and Helsinki University Hospital Research Funds [TYH2018207 and TYH 2020305].

Every Fifth Individual With Type 1 Diabetes Suffers From an Additional Autoimmune Disease: A Finnish Nationwide Study.

OBJECTIVE: The aim of this study was to quantify the excess risk of autoimmune hypothyroidism and hyperthyroidism, Addison disease, celiac disease, and atrophic gastritis in adults with type 1 diabetes (T1D) compared with nondiabetic individuals in Finland. RESEARCH DESIGN AND METHODS: The study included 4,758 individuals with T1D from the Finnish Diabetic Nephropathy (FinnDiane) Study and 12,710 nondiabetic control individuals. The autoimmune diseases (ADs) were identified by linking the data with the Finnish nationwide health registries from 1970 to 2015. RESULTS: The median age of the FinnDiane individuals at the end of follow-up in 2015 was 51.4 (interquartile range 42.6-60.1) years, and the median duration of diabetes was 35.5 (26.5-44.0) years. Of individuals with T1D, 22.8% had at least one additional AD, which included 31.6% of women and 14.9% of men. The odds ratios for hypothyroidism, hyperthyroidism, celiac disease, Addison disease, and atrophic gastritis were 3.43 (95% CI 3.09-3.81), 2.98 (2.27-3.90), 4.64 (3.71-5.81), 24.13 (5.60-104.03), and 5.08 (3.15-8.18), respectively, in the individuals with T1D compared with the control individuals. The corresponding ORs for women compared with men were 2.96 (2.53-3.47), 2.83 (1.87-4.28), 1.52 (1.15-2.02), 2.22 (0.83-5.91), and 1.36 (0.77-2.39), respectively, in individuals with T1D. Late onset of T1D and aging increased the risk of hypothyroidism, whereas young age at onset of T1D increased the risk of celiac disease. CONCLUSIONS: This is one of the largest studies quantifying the risk of coexisting AD in adult individuals with T1D in the country with the highest incidence of T1D in the world. The results highlight the importance of continuous screening for other ADs in individuals with T1D.

The association between macronutrient intake and the metabolic syndrome and its components in type 1 diabetes.

Diet is a major modifiable lifestyle factor that may affect the components of the metabolic syndrome. We aimed to investigate the association between relative proportions of macronutrients and the components of the metabolic syndrome in a population of individuals with type 1 diabetes. In all, 791 individuals without nephropathy, with plausible energy intake and known metabolic syndrome status, taking part in the Finnish Diabetic Nephropathy Study were included in the analyses. Dietary data were collected with a diet record. The association between the relative macronutrient intake and the outcome variables were analysed using multivariable nutrient density substitution models. The relative proportions of dietary macronutrients or fatty acids were not associated with the presence of the metabolic syndrome. In men, however, favouring carbohydrates over fats was associated with lower odds of the waist component, whereas favouring either carbohydrates or fats over proteins was associated with lower odds of the blood pressure component of the metabolic syndrome. In women, substituting carbohydrates for fats was associated with lower HDL-cholesterol concentration. Substituting carbohydrates or fats for alcohol or protein was, in men, associated with lower systolic blood pressure. To conclude, the relative distribution of macronutrients may have some relevance for the metabolic syndrome.

Association between adherence to dietary recommendations and high-sensitivity C-reactive protein level in type 1 diabetes.

AIMS: Inflammation plays an important role in the pathogenesis of cardiovascular diseases. Diet, as a modifiable risk factor, may in turn impact systemic inflammation. We therefore assessed whether adherence to the dietary recommendations is associated with high-sensitivity C-reactive protein (hs-CRP) concentrations in type 1 diabetes. METHODS: Cross-sectional data from 677 FinnDiane study participants (48% men, mean±standard deviation age 46±13years) were included. Dietary intake was assessed with a self-administered questionnaire. A diet score, with higher values denoting better adherence to the recommendations, was calculated. Serum hs-CRP concentration was measured, and individuals with hs-CRP <1.0mg/l, and hs-CRP >3.0 but ≤10.0mg/l were compared. RESULTS: Men and women with high hs-CRP had higher BMI, waist circumference, and triglyceride concentration, but lower HDL-cholesterol concentration. Adjusted for BMI, mean diet score was higher in the low hs-CRP group, both in men (10.8±3.6 vs. 9.9±3.8, p=0.023) and women (12.7±3.4 vs. 11.6±3.5, p=0.021). After further adjustments with potential confounding factors, the difference remained significant only in men. CONCLUSIONS: A diet that more closely adheres to the dietary recommendations is associated with lower hs-CRP in men. A prudent diet may help reduce systemic inflammation in type 1 diabetes.

Insulins NPH, glargine, and detemir, and risk of severe hypoglycemia among working-age adults.

INTRODUCTION: The longer acting basal insulin analogs glargine and detemir have shown a lower incidence of hypoglycemia compared to insulin NPH in clinical studies. We evaluated the real-life risk of severe hypoglycemia among new users of insulins in the working-age population in Finland. METHODS: All persons aged 18-65 years with diabetes mellitus who were newly prescribed with insulins NPH, glargine, or detemir during 2006-2009, were identified from national registers. Risk of severe hypoglycemia requiring hospital care was compared between insulin types. RESULTS: A total of 16,985 persons initiated basal insulin treatment (5586, 7499, and 3900 patients started NPH, glargine, and detemir, respectively) during follow-up. Five hundred and thirty-six persons were hospitalized because of severe hypoglycemia. Absolute rate (per 1000 patient-years) was 20.6 (95% CI 17.9, 23.8), 17.8 (15.6, 20.3), and 12.4 (9.9, 15.5) for NPH, glargine, and detemir initiators, respectively. With NPH as reference, the adjusted hazard ratio (HR) was 0.92 (95% CI 0.74, 1.15, p = 0.47) for glargine, and 0.70 (0.51, 0.94, p= 0.018) for detemir. The HR for detemir compared to glargine was 0.76 (0.58, 0.99, p = 0.040). CONCLUSIONS: Initiating insulin treatment with detemir, but not with glargine, was associated with a significantly lower risk of severe hypoglycemia compared to NPH, among working-age adults. KEY MESSAGES The comparative safety of modern basal insulins regarding hypoglycemia among the working-age population is unclear. Large reductions in the incidence of severe hypoglycemia were seen among real-life patients who started insulin detemir, as compared to patients who initiated glargine or especially NPH insulin. Given the large amount of patients using insulin, these findings may have considerable clinical consequences at the population level.

Dietary patterns are associated with various vascular health markers and complications in type 1 diabetes.

AIMS: Diet plays an important role in the management of type 1 diabetes. However, the association between dietary intake and health has not been extensively studied in this population. We studied the cross-sectional association between dietary factors, and selected vascular health markers and complications in type 1 diabetes. METHODS: Data from 874 individuals with type 1 diabetes participating in the FinnDiane Study were included. Dietary intake was assessed using a self-reported questionnaire and a diet score, expressing the extent to which individuals adhered to the dietary recommendations, was calculated. Diet questionnaire was also used to reveal dietary patterns using factor analysis. RESULTS: Seven factors with high degree of inter-correlation were formed; healthy, traditional, vegetable, sweets, modern, low-fat cheese, and fish and eggs. In multivariate models, higher diet score and healthy factor score were associated with better glycaemic control. Higher diet score was associated with higher, while sweets, and fish and eggs patterns were associated with lower systolic blood pressure. Healthy, sweets, and fish and eggs factors were additionally associated with lower diastolic blood pressure. CONCLUSIONS: Closer adherence to the dietary recommendations, and a diet high in fresh vegetables, fruits and berries, cooked vegetables, fish dishes, and yoghurt may be beneficial for the glycaemic control in type 1 diabetes. Moreover, a diet pattern with fish and eggs may have beneficial effects for blood pressure.

Fear of hypoglycaemia and self-management in type 1 diabetes.

AIMS: We studied the association between fear of hypoglycaemia (FoH) and various diabetes self-management practices. METHODS: Data from 798 individuals with type 1 diabetes participating in the FinnDiane Study were included. Self-reported questionnaires were used to assess FoH and self-management practices (e.g. dietary intake, insulin administration, physical activity). For glycaemic control, we used both the latest HbA1c measurements and the serial HbA1c measurements from the medical files. Factor analysis was used to reveal underlying constructs within the food frequency section of the diet questionnaire. RESULTS: In all, 44% and 63% of men and women reported FoH, respectively. In men, FoH was associated with higher mean serial HbA1c levels, higher number of reported self-monitoring of blood glucose (SMBG), higher carbohydrate intake, and lower scores in the "high-fat" factor. In women, FoH was associated with a higher number of reported SMBGs and higher energy intake. No difference was observed in physical activity and insulin administration. CONCLUSIONS: FoH has various implications for the self-management of diabetes. More studies are however needed to assess on one hand the association between FoH and diabetes self-management, and on the other hand, FoH and its long term consequences, such as the emergence of diabetic complications and mortality.

Evaluation of the incidence and risk of hypoglycemic coma associated with selection of basal insulin in the treatment of diabetes: a Finnish register linkage study.

OBJECTIVE: Long-acting basal insulin analogs have demonstrated positive effects on the balance between effective glycemic control and risk of hypoglycemia versus neutral protamine Hagedorn (NPH) insulin in randomized controlled trials. Evidence of severe hypoglycemic risk with insulin detemir, insulin glargine, or NPH insulin is presented from a nationwide retrospective database study. RESEARCH DESIGN AND METHODS: Data from hospital and secondary healthcare visits due to hypoglycemic coma from 75 682 insulin-naïve type 1 or 2 diabetes patients initiating therapy with NPH insulin, insulin glargine, or insulin detemir in Finland between 2000 and 2009 were analyzed. Incidence rates with 95% confidence intervals (CIs) were calculated using Poisson regression. Hazard ratios were estimated using Cox's regression with adjustments for relevant background variables. RESULTS: The adjusted risk of hospital/secondary healthcare visits due to the first severe hypoglycemic event was 21.7% (95% CI 9.6-32.1%, p < 0.001) lower for insulin detemir and 9.9% (95% CI 1.5-17.6%, p = 0.022) lower for insulin glargine versus NPH insulin. Risk of hypoglycemic coma recurrence was 36.3% (95% CI 8.9-55.5%, p = 0.014) lower for detemir and 9.5% but not significantly (95% CI -10.2 to 25.7%, p = 0.318) lower for glargine versus NPH insulin. Risk of all hypoglycemic coma events was 30.8% (95% CI 16.2-42.8%, p-value <0.001) lower for detemir and 15.6% (95% CI 5.1-25.0%, p-value 0.005) lower for glargine versus NPH. Insulin detemir had a significantly lower risk for first (13.1% lower [p = 0.034]), recurrent (29.6% lower [p = 0.021]), and all (17.9% lower [p = 0.016]) severe hypoglycemic events than insulin glargine. CONCLUSIONS: There were considerable differences in risk of hospitalization or secondary healthcare visits due to hypoglycemic coma between basal insulin treatments in real-life clinical practice.

Sense of coherence, food selection and leisure time physical activity in type 1 diabetes.

BACKGROUND: Successful management of type 1 diabetes depends on the self-care practices. Sense of coherence has been associated with various measures of lifestyle choices. We aimed to study the associations between sense of coherence and self-care practices in patients with type 1 diabetes. We hypothesized that patients with weak sense of coherence have less prudent food choices and lower physical activity. METHODS: Cross-sectional data from 1104 patients (44% men, mean age 45±12 years) from the FinnDiane Study were available. Sense of coherence, dietary intake, and leisure time physical activity were evaluated using self-reported questionnaires. Diet score was calculated based on the degree to which food choices complied with dietary guidelines. Weekly metabolic equivalent hours were calculated by multiplying the activity duration by the activity- and intensity-specific metabolic equivalent. RESULTS: The sense of coherence score correlated positively both with the diet score and the weekly metabolic equivalent hours. Those in the lowest sense of coherence tertile had both the lowest diet scores and the lowest weekly metabolic equivalent hours values. Among women, the sense of coherence score was associated with the diet score when adjusted for age, socioeconomic status, received dietary guidance, and nephropathy status. The sense of coherence score independently predicted the metabolic equivalent hours value in men. CONCLUSIONS: A higher sense of coherence score predicted more prudent food choices in women and higher physical activity in men. In the future, the health consequences associated with a weak sense of coherence should be studied prospectively. Also, the possibility to use the sense of coherence questionnaire as a screening instrument to identify patients who could benefit from intensified counseling should be investigated.

Energy and nutrient intakes and adherence to dietary guidelines among Finnish adults with type 1 diabetes.

BACKGROUND: Patients with type 1 diabetes are instructed to eat a healthy, balanced diet. Implementation of diet is an under-studied phenomenon. We aimed to describe the nutrient intake of a large sample of adult Finnish patients with type 1 diabetes and assess whether they meet the recommendations. METHODS: Cross-sectional data from a total of 817 patients are presented. Data on food intake were collected with a 3-day food record completed twice with a 2-3-month interval. Compliance with dietary guidance was self-reported. RESULTS: Patients frequently reported a diet low in carbohydrates and fibre but high in fat. Only 28% restricted saturated fatty acid to less than 10% of their daily energy intake. One-fourth of the patients reported higher than recommended sucrose intake. Salt recommendations were frequently exceeded. Of the micronutrients, the recommendations for vitamin A, vitamin D, folate, and iron were most frequently unmet. Although self-reported compliance was associated with a higher frequency of meeting the recommendations for some of the macronutrients, the actual frequencies were modest. In general, those compliant were observed to consume more vitamin and mineral-dense food. CONCLUSION: Dietary intake among patients with type 1 diabetes does not, for many nutrients, meet the recommendations.

Many patients with Type 1 diabetes estimate their prandial insulin need inappropriately.

BACKGROUND: Many factors contribute to the need for prandial insulin in Type 1 diabetes. However, patients' success in achieving normal postprandial glucose concentration is understudied. The aim of the present study was to determine how often patients with Type 1 diabetes achieve normal postprandial glucose concentrations and to evaluate factors associated with postprandial hypo- and hyperglycemia. METHODS: Data on food intake, physical activity, insulin administration, and blood glucose concentration were collected using a self-administered questionnaire from 331 patients with Type 1 diabetes (43% men; mean age 49 ± 12 years; mean diabetes duration 32 ± 13 years). Of these, 179 provided data on blood glucose concentrations measured 110-150 min postprandially. One such meal per patient was randomized for analyses. RESULTS: Hypoglycemia (< 4.0 mmol/L), normoglycemia (4.0-7.9 mmol/L), and hyperglycemia (≥ 8.0 mmol/L) were observed after 23%, 36%, and 41% of meals, respectively. The three postprandial glycemia groups did not differ with respect to the meal composition or the timing of the postprandial blood glucose measurement. In women, postprandial hyperglycemia was associated with shorter diabetes duration and higher preprandial blood glucose concentration, whereas postprandial hypoglycemia was associated with higher physical activity. No single factor explained the postprandial glycemic state in men. CONCLUSIONS: A total of 64% of patients estimated their prandial insulin need inappropriately, suggesting that estimation of the optimal prandial insulin dose is not easy, even after a long duration of diabetes.

Evidence for abnormal glucose uptake or metabolism in thalamus during acute hyperglycaemia in type 1 diabetes--a 1H MRS study.

Acute hyperglycaemia impairs cognitive function. It is however not known, whether different brain regions are equally exposed to glucose during acute hyperglycemia or whether the brain is able to adjust its glucose uptake or metabolism in response to blood glucose fluctuation. We studied the effect of acute hyperglycaemia on the brain glucose concentration in seven men with type 1 diabetes with daily glucose fluctuations of 11 +/- 3 mmol/l, and in eleven age-matched non-diabetic men. Glucose was quantified with proton magnetic resonance spectroscopy in three different brain regions at baseline (fasting glycaemia) and twice during a 2 h hyperglycaemic clamp with plasma glucose increase of 12 mmol/l. The increase in brain glucose during acute hyperglycaemia in the non-diabetic group was: cortex (2.7 +/- 0.9 mmol/l) > thalamus (2.3 +/- 0.7 mmol/l) > white matter (1.7 +/- 0.7 mmol/l, P = 0.021 vs. cortex) and in the diabetic group: cortex (2.0 +/- 0.7 mmol/l) > white matter (1.3 +/- 0.7 mmol/l) > thalamus (1.1 +/- 0.4 mmol/l, P = 0.010 vs. cortex). In the diabetic group, the glucose increase in the thalamus was attenuated compared to the non-diabetic participants (P = 0.011). In conclusion, the increase of glucose during acute hyperglycaemia seems to be dependent on the brain tissue type. The high exposure of cortex to excess glucose and the altered glucose uptake or metabolism in the thalamus may thus contribute to hyperglycaemia related cognitive dysfunction.

Cerebellar glucose during fasting and acute hyperglycemia in nondiabetic men and in men with type 1 diabetes.

In diabetic patients, proton magnetic resonance spectroscopy (¹H MRS) has revealed increased brain glucose concentration and metabolite alterations that indicate neuronal damage and glial cell activation. Cerebellum is known to be more resistant to hypoglycemia than cerebrum, but the effects of both chronic and acute hyperglycemia on the cerebellum are less well known. ¹H MRS was used to quantify brain glucose and metabolite levels in the cerebellum, cerebral cortex, cerebral white matter, and the thalamus of diabetic and nondiabetic men after an overnight fast and during a hyperglycemic normoinsulinemic clamp with blood glucose 12 mmol/l above baseline. Fasting glucose levels were twice as high in the cerebellum than in the cerebrum. During acute hyperglycemia, the cerebellar glucose concentration increased by 3.0 mmol/l, which equals that in the cortex, but is 35% more than in the thalamus and 173% more than in the white matter. Acute hyperglycemia also increased the cerebellar tissue water content by 10%. There were no differences between diabetic and nondiabetic participants. Notably, the patients with complication free type 1 diabetes showed brain metabolite alterations in the cerebral cortex and the white matter but not in the cerebellum. Our study suggests that diabetes does not alter glucose content or uptake in the cerebellum. The increase in tissue water during acute hyperglycemia may serve to protect the cerebellum from the potentially deleterious effects of the excess glucose.

Risk for metabolic syndrome predisposes to alterations in the thalamic metabolism.

Risk factors for the metabolic syndrome (MetS) affect brain function and associate with asymptomatic brain infarctions in healthy individuals. We studied whether MetS risk factors alter cerebral metabolism. Eighteen non-smoking men (36 +/- 6years) were stratified into two groups according to their risk of developing the MetS. Individuals in the Risk group had a family history of type 2 diabetes, were pre-obese, had mild hypertension and higher fasting plasma glucose and serum insulin compared to the Control group with no risk factors. N-acetyl aspartate, choline, total creatine (tCr), myo-inositol, and glucose were studied in the thalamus, frontal cortex, and frontal white matter with proton magnetic resonance spectroscopy. The plasma glucose was 13% higher (p < 0.01) in the Risk group, but the brain glucose levels were comparable between the groups. In the Control group, the thalamic tCr correlated with the thalamic glucose level (r = 0.81, p = 0.015). In the Risk group, the tCr was 17% higher (p = 0.006) and correlated with the fasting plasma glucose concentration (r = 0.78, p = 0.013), but not with the thalamic glucose level. In conclusion, the increased tCr level in the Risk group suggests that a family history of type 2 diabetes together with MetS risk factors alters thalamic energy metabolism.

Acquired obesity is associated with increased liver fat, intra-abdominal fat, and insulin resistance in young adult monozygotic twins.

We determined whether acquired obesity is associated with increases in liver or intra-abdominal fat or impaired insulin sensitivity by studying monozygotic (MZ) twin pairs discordant and concordant for obesity. We studied nineteen 24- to 27-yr-old MZ twin pairs, with intrapair differences in body weight ranging from 0.1 to 24.7 kg [body mass index (BMI) range 20.0-33.9 kg/m2], identified from a population-based FinnTwin16 sample. Fat distribution was determined by magnetic resonance imaging, percent body fat by dual-energy X-ray absorptiometry, liver fat by proton spectroscopy, insulin sensitivity by measuring the fasting insulin concentration, and whole body insulin sensitivity by the euglycemic insulin clamp technique. Intrapair differences in BMI were significantly correlated with those in intra-abdominal fat (r = 0.82, P < 0.001) and liver fat (r = 0.57, P = 0.010). Intrapair differences in fasting insulin correlated with those in subcutaneous abdominal (r = 0.60, P = 0.008), intra-abdominal (r = 0.75, P = 0.0001) and liver (r = 0.49, P = 0.048) fat. Intrapair differences in whole body insulin sensitivity correlated with those in subcutaneous abdominal (r = -0.72, P = 0.001) and intra-abdominal (r = -0.55, P = 0.015) but not liver (r = -0.20, P = 0.20) fat. We conclude that acquired obesity is associated with increases in intra-abdominal and liver fat and insulin resistance, independent of genetic factors.

Brain metabolic alterations in patients with type 1 diabetes-hyperglycemia-induced injury.

Microangiopathic end-organ injury is common in type 1 diabetes. However, the pathophysiology of diabetic encephalopathy is poorly understood. The authors studied 10 normotensive patients with type 1 diabetes with retinopathy, autonomic neuropathy, but without nephropathy, and 10 healthy subjects. Proton magnetic resonance spectroscopy was performed at 1.5 T in the frontal cortex, thalamus, and posterior frontal white matter. There was no change in N-acetyl-containing compounds (NA), but choline-containing compounds (Cho) were increased in the white matter and in the thalamus; myo-inositol was increased in the white matter, glucose excess was found in all brain, and water intensity was increased in the cortical voxel in the patients. Calculated lifetime glycemic exposure correlated inversely with Cho and NA in white matter and with Cho in thalamus. Concentrations of soluble intercellular adhesion molecules and vascular cell adhesion molecules were increased in the patients. In conclusion, in patients with type 1 diabetes, the increase in adhesion molecules and an association between altered brain metabolites and glycemic exposure suggest the presence of a vascularly mediated, progressive metabolic disturbance in the brain.

Effects of rosiglitazone and metformin on liver fat content, hepatic insulin resistance, insulin clearance, and gene expression in adipose tissue in patients with type 2 diabetes.

Both rosiglitazone and metformin increase hepatic insulin sensitivity, but their mechanism of action has not been compared in humans. The objective of this study was to compare the effects of rosiglitazone and metformin treatment on liver fat content, hepatic insulin sensitivity, insulin clearance, and gene expression in adipose tissue and serum adiponectin concentrations in type 2 diabetes. A total of 20 drug-naive patients with type 2 diabetes (age 48 +/- 3 years, fasting plasma glucose 152 +/- 9 mg/dl, BMI 30.6 +/- 0.8 kg/m2) were treated in a double-blind randomized fashion with either 8 mg rosiglitazone or 2 g metformin for 16 weeks. Both drugs similarly decreased HbA1c, insulin, and free fatty acid concentrations. Body weight decreased in the metformin (84 +/- 4 vs. 82 +/- 4 kg, P < 0.05) but not the rosiglitazone group. Liver fat (proton spectroscopy) was decreased with rosiglitazone by 51% (15 +/- 3 vs. 7 +/- 1%, 0 vs. 16 weeks, P = 0.003) but not by metformin (13 +/- 3 to 14 +/- 3%, NS). Rosiglitazone (16 +/- 2 vs. 20 +/- 1 ml.kg(-1).min(-1), P = 0.02) but not metformin increased insulin clearance by 20%. Hepatic insulin sensitivity in the basal state increased similarly in both groups. Insulin-stimulated glucose uptake increased significantly with rosiglitazone but not with metformin. Serum adiponectin concentrations increased by 123% with rosiglitazone but remained unchanged during metformin treatment. The decrease of serum adiponectin concentrations correlated with the decrease in liver fat (r = -0.74, P < 0.001). Rosiglitazone but not metformin significantly increased expression of peroxisome proliferator-activated receptor-gamma, adiponectin, and lipoprotein lipase in adipose tissue. In conclusion, rosiglitazone but not metformin decreases liver fat and increases insulin clearance. The decrease in liver fat by rosiglitazone is associated with an increase in serum adiponectin concentrations. Both agents increase hepatic insulin sensitivity, but only rosiglitazone increases peripheral glucose uptake.

Impaired responsiveness to NO in newly diagnosed patients with rheumatoid arthritis.

OBJECTIVE: Cardiovascular disease is the major cause of excessive mortality in patients with rheumatoid arthritis (RA). We determined whether endothelial dysfunction characterizes patients with newly diagnosed RA (n=10) compared with normal subjects (control group, n=33) and whether it is reversible with 6 months of anti-inflammatory therapy. METHODS AND RESULTS: Endothelial function was determined by measuring vasodilatory responses to intrabrachial artery infusions of acetylcholine (ACh at 7.5 and 15 microg/min, low and high dose, respectively), an endothelium-dependent vasodilator, and to sodium nitroprusside (SNP, 3 and 10 micro g/min), an endothelium-independent vasodilator. Before treatment, blood flow responses (fold increase in flow) to low-dose SNP were 30% lower in the RA versus the control group (4.1+/-0.4-fold versus 5.9+/-0.5-fold, respectively), and responses to high-dose SNP were 34% lower in the RA group versus the control group (5.1+/-0.6-fold versus 7.7+/-0.7-fold, respectively; P<0.001). The responses to low-dose ACh were 50% lower in the RA group versus the control group (3.0+/-0.5-fold versus 6.6+/-0.7-fold, respectively), and responses to high-dose ACh were 37% lower in the RA group versus the control group (5.0+/-0.4-fold versus 7.9+/-0.8-fold, respectively; P<0.001). After therapy, clinical and laboratory markers of inflammation had significantly decreased. Blood flow responses to ACh increased significantly (P=0.02). CONCLUSIONS: We conclude that newly diagnosed patients with RA have vascular dysfunction, which is reversible with successful therapy. Therefore, early suppression of inflammatory activity may reduce long-term vascular damage.