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1.
Diabetes Res Clin Pract ; 133: 21-29, 2017 Nov.
Article in English | MEDLINE | ID: mdl-28888147

ABSTRACT

BACKGROUND: The aims of this study were to estimate the risk for diabetic retinopathy (DR) and to identify risk factors. We investigated a nationwide population-based cohort with diabetes diagnosed at age 15-34years. PATIENTS AND METHODS: Of 794 patients registered 1987-1988 in the Diabetes Incidence Study in Sweden (DISS) 444 (56%) patients with retinal photos available for classification of retinopathy participated in a follow-up study 15-19 (median 17) years after diagnosis. Mean age was 42.3±5.7years, BMI 26.1±4.1kg/m2, 62% were male and 91% had type 1 diabetes. A sub-study was performed in 367 patients with retinal photos from both the 9 and 17year follow up and the risk for development of retinopathy between 9 and 17years of follow up was calculated. RESULTS: After median 17years 324/444 (73%, 67% of T1D and 71% of T2D), had developed any DR but only 5.4% proliferative DR. Male sex increased the risk of developing retinopathy (OR 1.9, 95% CI 1.2-2.9). In the sub-study obesity (OR 1.2, 95% CI 1.04-1.4), hyperglycemia (OR 2.5, 95% CI 1.6-3.8) and tobacco use (OR 2.9, 95% CI 1.1-7.3) predicted onset of retinopathy between 9 and 17years after diagnosis of diabetes. CONCLUSION: The number of patients with severe retinopathy after 17years of diabetes disease was small. The risk of developing retinopathy with onset between 9 and 17years after diagnosis of diabetes was strongly associated to modifiable risk factors such as glycemic control, obesity and tobacco use.


Subject(s)
Blood Glucose/metabolism , Diabetes Complications/etiology , Diabetic Retinopathy/etiology , Hyperglycemia/complications , Overweight/complications , Tobacco Use/adverse effects , Adolescent , Adult , Cohort Studies , Diabetes Complications/epidemiology , Diabetic Retinopathy/epidemiology , Female , Follow-Up Studies , Humans , Hyperglycemia/physiopathology , Male , Retrospective Studies , Risk Factors , Time Factors , Young Adult
2.
Diabetes Metab Res Rev ; 31(2): 138-46, 2015 Feb.
Article in English | MEDLINE | ID: mdl-25044633

ABSTRACT

AIMS: The main objective of this study was to estimate the occurrence of diabetic nephropathy in a population-based cohort of patients diagnosed with diabetes as young adults (15-34 years). METHODS: All 794 patients registered 1987-1988 in the Diabetes Incidence Study in Sweden (DISS) were invited to a follow-up study 15-19 years after diagnosis, and 468 (58%) participated. Analysis of islet antibodies was used to classify type of diabetes. RESULTS: After median 17 years of diabetes, 15% of all patients, 14% T1DM and 25% T2DM, were diagnosed with diabetic nephropathy. Ninety-one percent had microalbuminuria and 8.6% macroalbuminuria. Older age at diagnosis (HR 1.05; 95% CI 1.01-1.10 per year) was an independent and a higher BMI at diabetes diagnosis (HR 1.04; 95% CI 1.00-1.09 per 1 kg/m²), a near-significant predictor of development of diabetic nephropathy. Age at onset of diabetes (p = 0.041), BMI (p = 0.012) and HbA1c (p < 0.001) were significant predictors of developing diabetic nephropathy between 9 and 17 years of diabetes. At 17 years of diabetes duration, a high HbA1c level (OR 1.06; 95% CI 1.03-1.08 per 1 mmol/mol increase) and systolic blood pressure (OR 1.08; 95% CI 1.05 1.12 per 1 mmHg increase) were associated with DN. CONCLUSIONS: Patients with T2DM diagnosed as young adults seem to have an increased risk to develop diabetic nephropathy compared with those with T1DM. Older age and higher BMI at diagnosis of diabetes were risk markers for development of diabetic nephropathy. In addition, poor glycaemic control but not systolic blood pressure at 9 years of follow-up was a risk marker for later development of diabetic nephropathy.


Subject(s)
Diabetes Mellitus, Type 1/complications , Diabetes Mellitus, Type 2/complications , Diabetic Nephropathies/epidemiology , Overweight/complications , Renal Insufficiency/epidemiology , Adolescent , Adult , Age of Onset , Albuminuria/etiology , Body Mass Index , Cross-Sectional Studies , Diabetes Mellitus, Type 1/blood , Diabetes Mellitus, Type 1/epidemiology , Diabetes Mellitus, Type 1/therapy , Diabetes Mellitus, Type 2/blood , Diabetes Mellitus, Type 2/epidemiology , Diabetes Mellitus, Type 2/therapy , Diabetic Nephropathies/complications , Diabetic Nephropathies/physiopathology , Diabetic Nephropathies/prevention & control , Female , Follow-Up Studies , Glycated Hemoglobin/analysis , Humans , Hyperglycemia/prevention & control , Incidence , Male , Renal Insufficiency/complications , Renal Insufficiency/physiopathology , Renal Insufficiency/prevention & control , Risk Factors , Severity of Illness Index , Sweden/epidemiology , Young Adult
3.
J Intern Med ; 275(1): 39-48, 2014 Jan.
Article in English | MEDLINE | ID: mdl-24482829

ABSTRACT

OBJECTIVE: Simple methods for the evaluation of dynamic b-cell function in epidemiological and clinical studies of patients with type 2 diabetes (T2D) are needed. The aim of this study was to evaluate the dynamic beta-cell function in young patients with T2D with different disease durations and treatments. METHODS: Overall, 54 subjects with T2D from the Diabetes Incidence Study in Sweden (DISS) and 23 healthy control participants were included in this cross-sectional study. Beta-cell function was assessed by intravenous (i.v.) administration of arginine followed by i.v. glucose. The acute insulin and C-peptide responses to arginine (AIRarg and Ac-pepRarg, respectively) and to glucose (AIRglu and Ac-pepRglu, respectively)were estimated.Homeostasis model assessment of b-cell function(HOMA-b) andCpeptide assessments were also used for comparisons between patients with T2D and control participants. RESULTS: AIRarg and Ac-pepRarg, but not AIRglu and Ac-pepRglu, could differentiate between patients with different disease durations. AIRglu values were 89% (P < 0.001) lower and AIRarg values were 29% (P < 0.01) lower in patients with T2D compared with control participants. HOMA-b and fasting plasma C-peptide levels did not differ between the T2D and control groups. CONCLUSION: In young patients with T2D, the insulin secretory response to i.v. glucose is markedly attenuated, whereas i.v. arginine-stimulated insulin release is better preserved and can distinguish between patients with different disease duration and antidiabetic therapies. This suggests that the i.v. arginine stimulation test may provide an estimate of functional beta-cell reserve.


Subject(s)
Arginine , C-Peptide , Diabetes Mellitus, Type 2 , Insulin-Secreting Cells/metabolism , Insulin , Administration, Intravenous , Adult , Arginine/administration & dosage , Arginine/analysis , Arginine/metabolism , C-Peptide/blood , C-Peptide/metabolism , Cell Physiological Phenomena/drug effects , Cross-Sectional Studies , Diabetes Mellitus, Type 2/diagnosis , Diabetes Mellitus, Type 2/drug therapy , Diabetes Mellitus, Type 2/metabolism , Diabetes Mellitus, Type 2/physiopathology , Female , Glucose/administration & dosage , Glucose/metabolism , Humans , Hypoglycemic Agents/pharmacology , Insulin/blood , Insulin/metabolism , Insulin/pharmacology , Insulin Secretion , Male , Middle Aged , Reproducibility of Results
4.
Endocr Connect ; 3(1): 17-23, 2014.
Article in English | MEDLINE | ID: mdl-24327601

ABSTRACT

In type 1 diabetes mellitus (T1DM), low concentrations of IGF1 and high concentrations of IGF-binding protein 1 (IGFBP1) have been reported. It has been suggested that these abnormalities in the GH-IGF1 axis are due to low insulin concentrations in the portal vein. We hypothesized that the i.p. route of insulin administration increases IGF1 concentrations when compared with the s.c. route of insulin administration. IGF1 and IGFBP1 concentrations in samples derived from an open-label, randomized cross-over trial comparing the effects of s.c. and i.p. insulin delivery on glycaemia were determined. T1DM patients were randomized to receive either 6 months of continuous i.p. insulin infusion (CIPII) through an implantable pump (MIP 2007C, Medtronic) followed by 6 months of s.c. insulin infusion or vice versa with a washout phase in between. Data from 16 patients who had complete measurements during both treatment phases were analysed. The change in IGF1 concentrations during CIPII treatment was 10.4 µg/l (95% CI -0.94, 21.7 µg/l; P=0.06) and during s.c. insulin treatment was -2.2 µg/l (95% CI -13.5, 9.2 µg/l; P=0.69). When taking the effect of treatment order into account, the estimated change in IGF1 concentrations was found to be 12.6 µg/l (95% CI -3.1, 28.5 µg/l; P=0.11) with CIPII treatment compared with that with s.c. insulin treatment. IGFBP1 concentrations decreased to -100.7 µg/l (95% CI -143.0, -58.3 µg/l; P<0.01) with CIPII treatment. During CIPII treatment, parts of the GH-IGF1 axis changed compared with that observed during s.c. insulin treatment. This supports the hypothesis that the i.p. route of insulin administration is of importance in the IGF1 system.

5.
Horm Metab Res ; 42(13): 961-6, 2010 Dec.
Article in English | MEDLINE | ID: mdl-20925018

ABSTRACT

Our aim was to investigate the usefulness of circulating levels of adrenocorticotropic hormone (ACTH) and also salivary cortisol to monitor cortisone substitution in patients with Addison's disease. 13 patients with primary adrenal insufficiency (8 women and 5 men, age 44 ± 11 years) received 12.5 mg cortisone acetate orally at 16:00 h and 25 mg at 07:00 h. Blood samples for cortisol and ACTH analysis were drawn every hour for 24 h, and also every half hour between 07:00 and 12:00 h. Samples for salivary cortisol were collected in parallel. Total ACTH levels showed large inter-individual variations and a diurnal rhythm with a nadir in the early evening at 19:00 (median 19 ng/l, range 2-434 ng/l) and high levels in the early morning, with a peak around 07:30 (median 844 ng/l, range 45-2,249 ng/l). Plasma cortisol concentrations showed 2 peaks distinct in time, but variable in height, 1-2 h after intake of cortisone. Plasma cortisol correlated significantly with ln(ACTH) at 17:00 h (r=-0.56), at 10:00 h (r=-0.51), and at 10.30 h (r=-0.57). When tested at different time points, ln(ACTH) at 10:00 to 12:00 h was negatively correlated with plasma cortisol between 08:30 and 12:00 h. Plasma cortisol was highly correlated to ln(salivary cortisol) most of the time points measured, but 30-60 min after intake of cortisone acetate the correlation disappeared. In conclusion, the large interindividual variation in ACTH levels most likely indicates varying sensitivity to cortisol with a need for individualized dosing schemes. Furthermore ACTH-determinations may be useful for dose titration of cortisol.


Subject(s)
Addison Disease/blood , Adrenocorticotropic Hormone/blood , Glucocorticoids/blood , Hydrocortisone/blood , Addison Disease/drug therapy , Adult , Cortisone/administration & dosage , Cortisone/analogs & derivatives , Cortisone/therapeutic use , Female , Humans , Hydrocortisone/urine , Male , Saliva/metabolism , Time Factors
6.
Diabetologia ; 53(6): 1084-92, 2010 Jun.
Article in English | MEDLINE | ID: mdl-20020097

ABSTRACT

AIMS/HYPOTHESIS: Young adults in the early stages of their participation in the labour market may be particularly vulnerable to the effects of onset of a chronic disease. Our aim was to quantify the consequences of the onset of type 1 diabetes in young adults on annual earnings, using individual-level longitudinal data before and after the onset of diabetes. METHODS: The Econ-DISS database contains annual socioeconomic information for 1990-2005 from Statistics Sweden. Econ-DISS includes data for persons with diabetes onset at the age of 15-34 years between 1983 and 2005, registered in the national Diabetes Incidence Study in Sweden (DISS) database, and for controls. Considering the onset of type 1 diabetes as an unanticipated and significant life event, we compared the progression of annual earnings for 3,650 cases born between 1949 and 1970 before and after onset of diabetes with that of 14,629 controls. Possible confounders--education, participation in the labour market, sick leave and parental education--were analysed. RESULTS: We found no differences between the groups in annual earnings or participation in the labour market before onset of diabetes. After onset, persons with type 1 diabetes gradually lagged behind the controls. Their median annual earnings were lower in each year from 1995 to 2005 (p < 0.01). The difference in 2005 was euro (EUR) 1,411 (5.3%). Controlling for confounders, duration of type 1 diabetes > or = 10 years was associated with 4.2% (men) and 8.1% (women) lower average annual earnings for persons with upper secondary education only who were active in the labour market. CONCLUSION/INTERPRETATION: The onset of type 1 diabetes in young adults has long-term detrimental consequences on earnings that cannot be attributed to confounders.


Subject(s)
Diabetes Mellitus, Type 1/economics , Income , Adolescent , Adult , Age of Onset , Chi-Square Distribution , Cost of Illness , Disease Progression , Female , Humans , Male , Middle Aged , Models, Economic , Registries , Regression Analysis
7.
J Mol Endocrinol ; 43(6): 231-9, 2009 Dec.
Article in English | MEDLINE | ID: mdl-19589910

ABSTRACT

Whether insulin, at physiological concentrations, has direct effects on vascular smooth muscle cells (VSMCs) remains controversial. Our aim was to characterize the mechanism for insulin resistance in VSMCs. For comparison, the effects of IGF1 and IGF2 were also studied. Cultured human aortic smooth muscle cells (HASMC) were used. Receptor mRNA was analyzed by quantitative reverse transcription PCR and receptor protein by ELISA and western blot. Biological effects were studied by thymidine incorporation and glucose accumulation. In HASMC, both mRNA and protein expression of IGF1 receptors (IGF1R) were fivefold higher compared to insulin receptor (IR). IR isoform A mRNA was 13-fold more expressed than IR isoform B. IR and IGF1R co-precipitated, indicating the presence of hybrid IR/IGF1R. Phosphorylation of the IGF1R beta-subunit was obtained by IGF1 10(-9)-10(-8) mol/l and IGF2 10(-8) mol/l. IR beta-subunit was phosphorylated by IGF1 10(-8) mol/l but not by insulin. IGF1 stimulated IR substrate-1 and AKT at 10(-8) mol/l and extracellular signal-regulated kinases 1 and 2 at 10(-9)-10(-8) mol/l respectively. IGF1 and 2 at a concentration of 10(-8)-10(-7) mol/l significantly stimulated (3)H-thymidine incorporation, whereas insulin did not. (14)C-Glucose accumulation was stimulated by IGF1 or IGF2 10(-8)-10(-7) mol/l, and also by insulin 10(-7) mol/l. Our results suggest that IGF1R and hybrid IR/IGF1R are activated by physiological concentrations of IGF1 and 2 in HASMC and this propagates downstream signaling and biological effects, while insulin has no effect on its receptor or downstream signaling probably due to a preponderance of IGF1R and incorporation of IR into hybrid IR/IGF1R.


Subject(s)
Aorta/cytology , Insulin-Like Growth Factor II/pharmacology , Insulin-Like Growth Factor I/pharmacology , Insulin/pharmacology , Muscle, Smooth, Vascular/cytology , Myocytes, Smooth Muscle/drug effects , Myocytes, Smooth Muscle/metabolism , Blotting, Western , Cells, Cultured , Electrophoresis, Polyacrylamide Gel , Enzyme-Linked Immunosorbent Assay , Humans , Models, Genetic , Phosphorylation/drug effects , Protein Isoforms/genetics , Protein Isoforms/metabolism , Receptor, IGF Type 1/genetics , Receptor, IGF Type 1/metabolism , Receptor, Insulin/genetics , Receptor, Insulin/metabolism , Reverse Transcriptase Polymerase Chain Reaction
8.
Br J Anaesth ; 103(2): 166-72, 2009 Aug.
Article in English | MEDLINE | ID: mdl-19454546

ABSTRACT

BACKGROUND: Surgical trauma causes stress and inflammatory reactions with elevated serum free fatty acids (FFA) and glucose levels characteristic of intraoperative insulin resistance. Our aim was to compare microdialysis findings with those using the classical organ balance technique and to test the clinical feasibility of microdialysis during cardiac surgery. METHODS: Nine diabetic and nine non-diabetic patients, undergoing routine coronary artery bypass grafting surgery, were studied using both microdialysis and the organ balance technique in the brachio-radial muscle of the forearm, and microdialysis in the pre-pectoral fat tissue. Glucose, lactate, and glycerol were measured in arterial and venous plasma and in the microdialysate before administration of heparin, at the release of the aortic cross-clamp, and before transfer to the intensive care unit. RESULTS: Glucose release from the diabetic muscle at the last sampling time was detected. This was confirmed by a negative glucose A-I (arterial-interstitial difference) in the muscle. No differences were observed regarding lipolysis in the fat tissue in terms of A-I of glycerol. Intergroup differences were detected at the first sampling time, where arterial plasma glucose and plasma insulin levels were higher and muscle interstitial glucose lower in the diabetic patients. Plasma insulin was higher in the diabetic patients even at the final measurement time. CONCLUSIONS: In terms of lipolysis in the fat tissue and glucose transport in the muscle, the non-diabetic patients were metabolically 'diabetics' during surgery. Despite strict blood glucose control, disturbances in glucose homeostasis in the diabetic muscle persist. Microdialysis was easy to use during cardiac surgery.


Subject(s)
Coronary Artery Bypass , Diabetes Mellitus, Type 2/metabolism , Lipid Metabolism , Microdialysis/methods , Monitoring, Intraoperative/methods , Muscle, Skeletal/metabolism , Aged , Anesthesia, General/methods , Blood Glucose/metabolism , Feasibility Studies , Female , Forearm/blood supply , Glycerol/blood , Humans , Lactic Acid/blood , Male , Middle Aged , Muscle, Skeletal/blood supply , Regional Blood Flow
9.
Diabetologia ; 51(12): 2224-32, 2008 Dec.
Article in English | MEDLINE | ID: mdl-18839133

ABSTRACT

AIMS/HYPOTHESIS: Type 1 diabetes in children is characterised by autoimmune destruction of pancreatic beta cells and the presence of certain risk genotypes. In adults the same situation is often referred to as latent autoimmune diabetes in adults (LADA). We tested whether genetic markers associated with type 1 or type 2 diabetes could help to discriminate between autoimmune and non-autoimmune diabetes in young (15-34 years) and middle-aged (40-59 years) diabetic patients. METHODS: In 1,642 young and 1,619 middle-aged patients we determined: (1) HLA-DQB1 genotypes; (2) PTPN22 and INS variable-number tandem repeat (VNTR) polymorphisms; (3) two single nucleotide polymorphisms (rs7903146 and rs10885406) in the TCF7L2 gene; (4) glutamic acid decarboxylase (GAD) and IA-2-protein tyrosine phosphatase-like protein (IA-2) antibodies; and (5) fasting plasma C-peptide. RESULTS: Frequency of risk genotypes HLA-DQB1 (60% vs 25%, p = 9.4 x 10(-34); 45% vs 18%, p = 1.4 x 10(-16)), PTPN22 CT/TT (34% vs 26%, p = 0.0023; 31% vs 23%, p = 0.034), INS VNTR class I/I (69% vs 53%, p = 1.3 x 10(-8); 69% vs 51%, p = 8.5 x 10(-5)) and INS VNTR class IIIA/IIIA (75% vs 63%, p = 4.3 x 10(-6); 73% vs 60%, p = 0.008) was increased in young and middle-aged GAD antibodies (GADA)-positive compared with GADA-negative patients. The type 2 diabetes-associated genotypes of TCF7L2 CT/TT of rs7903146 were significantly more common in young GADA-negative than in GADA-positive patients (53% vs 43%; p = 0.0004). No such difference was seen in middle-aged patients, in whom the frequency of the CT/TT genotypes of TCF7L2 was similarly increased in GADA-negative and GADA-positive groups (55% vs 56%). CONCLUSIONS/INTERPRETATION: Common variants in the TCF7L2 gene help to differentiate young but not middle-aged GADA-positive and GADA-negative diabetic patients, suggesting that young GADA-negative patients have type 2 diabetes and that middle-aged GADA-positive patients are different from their young GADA-positive counterparts and share genetic features with type 2 diabetes.


Subject(s)
Autoimmune Diseases/genetics , Diabetes Mellitus/genetics , TCF Transcription Factors/genetics , Adolescent , Adult , Antibodies/immunology , Autoimmune Diseases/blood , Autoimmune Diseases/epidemiology , Autoimmune Diseases/immunology , Diabetes Mellitus/blood , Diabetes Mellitus/epidemiology , Diabetes Mellitus/immunology , Female , Genotype , Humans , Male , Middle Aged , TCF Transcription Factors/blood , TCF Transcription Factors/immunology , Transcription Factor 7-Like 2 Protein
10.
Horm Metab Res ; 40(9): 588-92, 2008 Sep.
Article in English | MEDLINE | ID: mdl-18792869

ABSTRACT

Insulin and IGF-I are closely related peptides, which interact by several mechanisms. In high supraphysiological concentrations (> or = 10 (-8) M), they cross-react with each other's receptors with 100- to 1000-fold lower affinity than with their cognate receptors. This can cause confusion, since in many in vitro studies, insulin has been used in high unphysiological concentrations, which activate IGF-I receptors. Due to the differences in affinity, insulin and IGF-I probably do not activate each other's receptors in vivo. IGF-I receptors are several-fold more abundant than insulin receptors in human micro- and macrovascular endothelial cells and in human vascular smooth muscle cells. Both insulin and IGF-I receptor protein can be demonstrated and they are activated by their cognate ligand at physiological concentrations of 10 (-9)-10 (-10) M. In vascular smooth muscle cells, IGF-I but not insulin stimulates metabolism and growth. IGF-I stimulates DNA-synthesis and growth in microvascular endothelial cells, but neither insulin nor IGF-I have any effect on macrovascular endothelial cells. Both insulin and IGF-I have been shown to stimulate nitric oxide production in endothelial cells, but only the effect of IGF-I was obtained at a physiological concentration. In both endothelial and vascular smooth muscle cells, insulin and IGF-I receptors occur as insulin/IGF-I hybrid receptors with high affinity to IGF-I and low for insulin. Due to the low number of insulin receptors and the presence of hybrid receptors the insulin receptor signal is probably too attenuated to elicit biological effects, explaining the insulin resistance of vascular cells in vitro. In vivo both insulin and IGF-I have been reported to increase muscle blood flow in physiological concentrations. Whether this is due to direct effects on endothelial cells or indirectly induced is not clear. The effect of insulin is attenuated by insulin resistance. In conclusion, the in vitro data suggest that endothelial cells and vascular smooth muscle cells are sensitive to IGF-I, but insensitive to insulin, and this is due to a preponderance of IGF-I receptors and the presence of insulin/IGF-I hybrid receptors.


Subject(s)
Endothelial Cells/metabolism , Insulin Resistance , Muscle, Smooth, Vascular/metabolism , Somatomedins/metabolism , Humans , Insulin/metabolism , Muscle, Smooth, Vascular/cytology , Receptor, IGF Type 1/metabolism
11.
Mol Cell Endocrinol ; 296(1-2): 58-63, 2008 Dec 16.
Article in English | MEDLINE | ID: mdl-18708119

ABSTRACT

Human microvascular endothelial cells (HMVEC) are sensitive to IGF-I but insulin resistant and express several times more IGF-I receptors (IGF-IR) than insulin receptors (IR). Our aim was to investigate the mechanism of this insulin resistance in cultured HMVEC by studying receptor activation and signal propagation downstream. The IGF-IR beta-subunit and the IR beta-subunit were detected and found to co-precipitate. IRA was the major IR isoform expressed in HMVEC. IGF-I 10(-9) to 10(-8)M phosphorylated its cognate receptor beta-subunit. IGF-I also phosphorylated the IR beta-subunit at 10(-9)M. Phosphorylation of insulin receptor substrate 1 was obtained by IGF-I 10(-9) to 10(-8)M. Akt was phosphorylated by IGF-I at 10(-8) to 10(-7)M and by insulin 10(-7)M. IGF-I at 10(-8) to 10(-6)M significantly increased DNA-synthesis. We conclude that microvascular endothelial cells are sensitive to IGF-I but resistant to insulin due to a preponderance of IGF-I receptors and sequestration of insulin receptors into insulin/IGF-I hybrid receptors.


Subject(s)
Drug Resistance/genetics , Endothelial Cells/drug effects , Insulin-Like Growth Factor I/pharmacology , Insulin/pharmacology , Receptor, Insulin/genetics , Adult , Cell Proliferation/drug effects , Cells, Cultured , Drug Resistance/physiology , Endothelial Cells/metabolism , Humans , Insulin/metabolism , Insulin-Like Growth Factor I/metabolism , Microcirculation/drug effects , Phosphorylation , Protein Binding , Protein Isoforms/metabolism , Protein Kinases/metabolism , RNA, Messenger/metabolism , Receptor, IGF Type 1/genetics , Receptor, IGF Type 1/metabolism , Receptor, Insulin/metabolism
12.
Horm Metab Res ; 40(6): 369-74, 2008 Jun.
Article in English | MEDLINE | ID: mdl-18393172

ABSTRACT

The aim of the study was to investigate if the insulin analogue glargine, with an increased affinity for the IGF-I receptor (IGF-IR), affects the cell growth to a larger extent than human insulin in malignant cells expressing IGF-IRs. The breast cancer cell lines MCF-7 and SKBR-3, and the osteosarcoma cell line SaOS-2 were used. Gene expression was determined by real-time RT-PCR and receptor protein quantified by ELISAs. Receptor phosphorylation was assessed by immunoprecipitation and Western blot. Mitogenic effect was determined as (3)H-thymidine incorporation into DNA. The gene expression of insulin receptor (IR) varied between 4.3-7.5 x 10(-3) and the expression of IGF-IR between 7.7-147.7 x 10(-3) in relation to GAPDH (glyceraldehyde-3-phosphate dehydrogenase). Insulin receptor and IGF-IR protein varied between 2.0-4.1 ng/mg protein and 2.0-40.4 ng/mg protein, respectively. The IGF-IR was phosphorylated by IGF-I at a concentration of 10(-10)-10(-9) M. All three polypeptides stimulated DNA synthesis in MCF-7, SKBR-3, and SaOS-2 cells. SaOS-2 cells were more sensitive to IGF-I than to insulin and glargine. MCF-7 cells were more sensitive to des(1-3)IGF-I than to IGF-I. In SKBR-3 and SaOS-2 cells, glargine tended to be more potent than human insulin to stimulate DNA synthesis. Our results suggest that glargine, compared to human insulin, has little or no increased mitogenic effect in malignant cells expressing IGF-IRs.


Subject(s)
Breast Neoplasms/metabolism , Hypoglycemic Agents/pharmacology , Insulin-Like Growth Factor I/metabolism , Insulin/analogs & derivatives , Osteosarcoma/metabolism , Receptor, IGF Type 1/drug effects , Analysis of Variance , Breast Neoplasms/pathology , Cell Division/drug effects , Humans , Insulin/metabolism , Insulin/pharmacology , Insulin Glargine , Insulin, Long-Acting , Mitogens/pharmacology , Osteosarcoma/pathology , Statistics, Nonparametric , Tumor Cells, Cultured
13.
J Intern Med ; 263(4): 386-94, 2008 Apr.
Article in English | MEDLINE | ID: mdl-18205768

ABSTRACT

OBJECTIVES: To establish the gender difference amongst newly diagnosed type 1 diabetic patients aged 15-34 years, considering age at diagnosis, temporal trend and seasonal variation at time of diagnosis. STUDY DESIGN: A population-based prospective study with a mean annual population at risk of 2.3 million. SETTING: All departments of medicine, endocrinology and paediatrics and primary health care units in Sweden. SUBJECTS: Incident cases of diabetes aged 15-34 years at diagnosis 1983-2002. MEASURE INSTRUMENT: Basic characteristics of patients at diagnosis were reported by the diagnosing doctor on a standardized form. Level of ascertainment was estimated at 80-90%. RESULTS: Amongst all incident cases (n = 8012), 74% was diagnosed with type 1 diabetes. The mean annual incidence rate of type 1 diabetes was 12.7/100,000, in men 16.4/100,000 and in women 8.9/100,000. The incidence of type 1 diabetes decreased slowly by increasing age but was in all age groups higher in men, yielding an overall male/female ratio of 1.8. In both genders the incidence of type 1 diabetes decreased in average of 1.0% per year. A seasonal pattern with significantly higher incidence during January-March and lower during May-July was seen in both genders. CONCLUSIONS: A clear male predominance of type 1 diabetes was seen in all ages. The temporal trend and the seasonal pattern was similar in men and women. Hence, internal factors related to the gender rather than differences in the exposure to environmental factors seem to explain the consistent male-female bias in the postpubertal risk of developing type 1 diabetes.


Subject(s)
Diabetes Mellitus, Type 1/epidemiology , Adolescent , Adult , Age Distribution , Diabetes Mellitus, Type 1/diagnosis , Diabetes Mellitus, Type 1/economics , Female , Humans , Incidence , Male , Medical Records/statistics & numerical data , Prospective Studies , Seasons , Sex Factors , Sweden/epidemiology
14.
Diabetologia ; 49(12): 2847-52, 2006 Dec.
Article in English | MEDLINE | ID: mdl-17072585

ABSTRACT

AIMS/HYPOTHESIS: Low plasma vitamin D concentrations may promote the development of type 1 diabetes. To test this hypothesis, we measured plasma 25-hydroxyvitamin D (25OHD) in young adults with type 1 diabetes. METHODS: The nationwide Diabetes Incidence Study in Sweden (DISS) covers 15- to 34-year-old people with newly diagnosed diabetes. Blood samples at diagnosis were collected during the 2-year period 1987/1988. Patients with islet antibodies (islet cell antibodies, GAD antibodies or tyrosine phosphatase-like protein antibodies) were defined as having autoimmune type 1 diabetes. Plasma 25OHD was measured in samples taken from 459 patients at the time of diagnosis, and in 138 of these subjects 8 years later. The results were compared with age- and sex-matched control subjects (n=208). RESULTS: At diagnosis, plasma 25OHD levels were significantly lower in patients with type 1 diabetes than in control subjects (82.5+/-1.3 vs 96.7+/-2.0 nmol/l; p<0.0001). Eight years later, plasma 25OHD had decreased in patients (81.5+/-2.6 nmol/l; p=0.04). Plasma 25OHD levels were significantly lower in diabetic men than in diabetic women at diagnosis (77.9+/-1.4 vs 90.1+/-2.4 nmol/l; p<0.0001) and at follow-up (77.1+/-2.8 nmol/l vs 87.2+/-4.5 nmol/l; p=0.048). CONCLUSIONS/INTERPRETATION: The plasma 25OHD level was lower at diagnosis of autoimmune type 1 diabetes than in control subjects, and may have a role in the development of type 1 diabetes. Plasma 25OHD levels were lower in men than in women with type 1 diabetes. This difference may be relevant to the high incidence of type 1 diabetes among young adult men.


Subject(s)
Diabetes Mellitus, Type 1/epidemiology , Vitamin D Deficiency/epidemiology , Vitamin D/analogs & derivatives , Adolescent , Adult , Cohort Studies , Follow-Up Studies , Humans , Incidence , Reference Values , Sweden/epidemiology , Vitamin D/blood
15.
Diabetologia ; 49(8): 1785-94, 2006 Aug.
Article in English | MEDLINE | ID: mdl-16783473

ABSTRACT

AIMS/HYPOTHESIS: The World Health Organization considers an aetiological classification of diabetes to be essential. The aim of this study was to evaluate whether HLA-DQB1 genotypes facilitate the classification of diabetes as compared with assessment of islet antibodies by investigating young adult diabetic patients. SUBJECTS AND METHODS: Blood samples were available at diagnosis for 1,872 (90%) of the 2,077 young adult patients (aged 15-34 years old) over a 5-year period in the nationwide Diabetes Incidence Study in Sweden. Islet antibodies were measured at diagnosis in 1,869 patients, fasting plasma C-peptide (fpC-peptide) after diagnosis in 1,522, while HLA-DQB1 genotypes were determined in 1,743. RESULTS: Islet antibodies were found in 83% of patients clinically considered to have type 1 diabetes, 23% with type 2 diabetes and 45% with unclassifiable diabetes. After diagnosis, median fpC-peptide concentrations were markedly lower in patients with islet antibodies than in those without (0.24 vs 0.69 nmol/l, p<0.0001). Irrespective of clinical classification, patients with islet antibodies showed increased frequencies of at least one of the risk-associated HLA-DQB1 genotypes compared with patients without. Antibody-negative patients with risk-associated HLA-DQB1 genotypes had significantly lower median fpC-peptide concentrations than those without risk-associated genotypes (0.51 vs 0.74 nmol/l, p=0.0003). CONCLUSIONS/INTERPRETATION: Assessment of islet antibodies is necessary for the aetiological classification of diabetic patients. HLA-DQB1 genotyping does not improve the classification in patients with islet antibodies. However, in patients without islet antibodies, HLA-DQB1 genotyping together with C-peptide measurement may be of value in differentiating between idiopathic type 1 diabetes and type 2 diabetes.


Subject(s)
Autoantibodies/analysis , Diabetes Mellitus/epidemiology , Diabetes Mellitus/genetics , HLA-DQ Antigens/genetics , Insulin-Secreting Cells/physiology , Adolescent , Adult , C-Peptide/blood , DNA Primers , Diabetes Mellitus/pathology , Female , Genotype , Glutamate Decarboxylase/analysis , HLA-DQ beta-Chains , Humans , Isoenzymes/analysis , Male , Sweden/epidemiology
16.
Diabetologia ; 49(4): 653-9, 2006 Apr.
Article in English | MEDLINE | ID: mdl-16447054

ABSTRACT

AIMS/HYPOTHESIS: The objective of the study was to analyse the mortality, survival and cause of death patterns in incident cases of diabetes in the 15-34-year age group that were reported to the nationwide prospective Diabetes Incidence Study in Sweden (DISS). MATERIALS AND METHODS: During the study period 1983-1999, 6,771 incident cases were reported. Identification of deaths was made by linking the records to the nationwide Cause of Death Register. RESULTS: With an average follow-up of 8.5 years, resulting in 59,231 person-years, 159 deaths were identified. Diabetes was reported as the underlying cause of death in 51 patients (32%), and as a contributing cause of death in another 42 patients (26%). The standardised mortality ratio (SMR) was significantly elevated (RR=2.4; 95% CI: 2.0-2.8). The SMR was higher for patients classified by the reporting physician as having type 2 diabetes at diagnosis than for those classified as type 1 diabetic (2.9 and 1.8, respectively). Survival analysis showed significant differences in survival curves between males and females (p=0.0003) as well as between cases with different types of diabetes (p=0.005). This pattern was also reflected in the Cox regression model showing significantly increased hazard for males vs females (p=0.0002), and for type 2 vs type 1 (p=0.015) when controlling for age. CONCLUSIONS/INTERPRETATION: This study shows a two-fold excess mortality in patients with type 1 diabetes and a three-fold excess mortality in patients with type 2 diabetes. Thus, despite advances in treatment, diabetes still carries an increased mortality in young adults, even in a country with a good economic and educational patient status and easy access to health care.


Subject(s)
Demography , Diabetes Mellitus/diagnosis , Diabetes Mellitus/mortality , Adolescent , Adult , Age Distribution , Cause of Death , Death Certificates , Diabetes Mellitus/etiology , Female , Humans , Male , Middle Aged , Risk Factors , Sex Characteristics , Survival Rate , Sweden/epidemiology , Time Factors
17.
Scand J Clin Lab Invest ; 65(7): 585-94, 2005.
Article in English | MEDLINE | ID: mdl-16271990

ABSTRACT

OBJECTIVE: To investigate whether measurements of proinsulin and/or intermediate proinsulin degradation products could be used to differentiate between autoimmune (type 1) and non-autoimmune (type 2) diabetes in young adults. MATERIAL AND METHODS: Total proinsulin, intact proinsulin and 32,33 split proinsulin concentrations were measured in 25 patients aged 15-34 years with type 1 diabetes, as defined by the presence of at least two positive islet autoantibodies, and in 23 antibody-negative patients of similar age with type 2 diabetes, at the time of clinical onset of diabetes and at 3-4 months thereafter. Comparisons were made with data from 25 healthy subjects matched for gender and age. RESULTS: Plasma levels of total proinsulin, intact proinsulin and 32,33 split proinsulin were significantly increased 2-3-fold in the patients with newly diagnosed type 2 diabetes as compared with the controls, both in absolute terms (p<0.0001) and when related to circulating insulin (p<0.01-0.0002). In contrast, absolute proinsulin and 32,33 split proinsulin concentrations were significantly lower in patients with onset of type 1 diabetes than in controls. When proinsulin and split proinsulin release were related to plasma insulin, however, similar ratios were found in the type 1 diabetes patients and in controls. Using the 90th percentile for total proinsulin in the control group as the cut-off, the sensitivity and specificity for differentiation between autoimmune and non-autoimmune diabetes were 87% and 92%, respectively. At 3-4 months after clinical onset of diabetes, proinsulin secretion was still 2-3 times higher in type 2 than in type 1 diabetes patients (p<0.001). CONCLUSIONS: Young adult patients with newly diagnosed type 2 diabetes display disproportionate hyperproinsulinemia, whereas proinsulin secretion appears to be normal in patients with clinical onset of type 1 diabetes. Evaluation of proinsulin and 32,33 split proinsulin concentrations may be useful as a diagnostic tool in differentiating between autoimmune and non-autoimmune diabetes in young adults, particularly in those lacking islet autoantibodies at diagnosis.


Subject(s)
Diabetes Mellitus, Type 1/complications , Diabetes Mellitus, Type 1/diagnosis , Diabetes Mellitus, Type 2/complications , Diabetes Mellitus, Type 2/diagnosis , Hyperinsulinism/complications , Hyperinsulinism/diagnosis , Adolescent , Adult , Diabetes Mellitus, Type 1/blood , Diabetes Mellitus, Type 2/blood , Female , Humans , Hyperinsulinism/blood , Insulin/blood , Male
18.
Diabetologia ; 48(10): 2155-61, 2005 Oct.
Article in English | MEDLINE | ID: mdl-16094530

ABSTRACT

AIMS/HYPOTHESIS: Hyperinsulinaemia and insulin resistance, as well as low IGF-I, have been implicated in the pathogenesis of cardiovascular disease. Little is known about direct effects of IGF-I and insulin on human coronary artery smooth muscle cells (HCASMCs). Our aim was to characterise the expression and function of IGF-I receptor (IGF-IR) and insulin receptor (IR) in HCASMCs. MATERIALS AND METHODS: Cultured HCASMCs were used. mRNA expression was measured by quantitative real-time RT-PCR analysis. Receptor proteins, phosphorylation of beta-subunits and the presence of hybrid IR/IGF-IR were analysed by immunoprecipitation and western blotting. DNA synthesis and glucose metabolism were assessed using [3H]thymidine incorporation and D-[U-14C]glucose accumulation respectively. RESULTS: The mRNA expression of IGF-IR was approximately eight-fold higher than that of IR in HCASMCs. The presence of IGF-IR and IR could be demonstrated by immunoprecipitation and western blot analysis. Phosphorylation of the IGF-IR beta-subunit was obtained by IGF-I at 10(-10)-10(-8) mol/l and insulin at 10(-8) mol/l. Insulin and IGF-I at 10(-10)-10(-9) mol/l phosphorylated the IR beta-subunit. When immunoprecipitated with monoclonal anti-IR alpha-subunit or IGF-IR alpha-subunit antibodies, we found bands in slightly different positions, suggesting the presence of hybrid IR/IGF-IR. IGF-I at 10(-9)-10(-8) mol/l significantly stimulated [3H]thymidine incorporation and at a concentration of 10(-9)-10(-7) mol/l also D-[U-14C]glucose accumulation in HCASMCs. Insulin at 10(-9)-10(-7) mol/l had no effect on DNA synthesis, but increased glucose accumulation at 10(-7) mol/l. CONCLUSIONS/INTERPRETATION: Our study provides experimental evidence that IGF-IR and possibly hybrid IR/IGF-IR play a role in HCASMCs.


Subject(s)
Coronary Vessels/metabolism , Myocytes, Smooth Muscle/metabolism , Receptor, IGF Type 1/biosynthesis , Receptor, Insulin/biosynthesis , Blotting, Western , Cells, Cultured , Coronary Vessels/cytology , DNA, Complementary/biosynthesis , Glucose/metabolism , Humans , Immunoprecipitation , Phosphorylation , RNA/biosynthesis , Receptor, IGF Type 1/genetics , Receptor, Insulin/genetics , Reverse Transcriptase Polymerase Chain Reaction , Thymidine/metabolism , Tyrosine/metabolism
19.
Diabetologia ; 47(7): 1266-1272, 2004 Jul.
Article in English | MEDLINE | ID: mdl-15235773

ABSTRACT

AIMS/HYPOTHESIS: In a previous study conducted over the last decades we found a decreased incidence of nephropathy but unchanged incidence of severe retinopathy among patients with Type 1 diabetes diagnosed in childhood and with 20 years duration of diabetes. The aim of our current study was to investigate the incidence 5 to 10 years later in the same population. METHODS: We studied all 269 patients in whom Type 1 diabetes was diagnosed in childhood between 1961 and 1985 in a district in southeastern Sweden. Ninety-one percent were monitored for retinopathy until at least 1997 and 95% were monitored for nephropathy. Severe retinopathy was defined as laser-treated retinopathy and nephropathy as persistent proteinuria. Survival analysis was used and the patients divided into five cohorts according to the time of onset of diabetes. RESULTS: The cumulative proportion of severe retinopathy had declined ( p=0.006). After 25 years it was 47% (95% CI 34-61), 28% (15-40) and 24% (12-36) in the cohorts 1961 to 1965, 1966 to 1970 and 1971 to 1975 respectively. After 30 years it was 53% (40-66) and 44% (28-59) in the oldest cohorts. The cumulative proportion of nephropathy after 25 years duration was 30% (18-42), 8% (1-16) and 13% (4-23) in the cohorts 1961 to 1965, 1966 to 1970 and 1971 to 1975 respectively. After 30 years, it was 32% (20-44) and 11% (2-20) for the oldest cohorts ( p<0.0001). CONCLUSIONS/INTERPRETATION: In an unselected population with Type 1 diabetes diagnosed in childhood, modern diabetes care markedly reduced the incidence of severe retinopathy and nephropathy.


Subject(s)
Diabetes Mellitus, Type 1/physiopathology , Diabetic Nephropathies/epidemiology , Diabetic Retinopathy/epidemiology , Adolescent , Age of Onset , Child , Cohort Studies , Diabetes Mellitus, Type 1/epidemiology , Diabetic Nephropathies/mortality , Diabetic Nephropathies/prevention & control , Diabetic Retinopathy/mortality , Diabetic Retinopathy/prevention & control , Female , Humans , Incidence , Male , Puberty , Survival Analysis , Sweden/epidemiology
20.
Scand J Clin Lab Invest ; 64(2): 132-9, 2004 Apr.
Article in English | MEDLINE | ID: mdl-15115251

ABSTRACT

OBJECTIVE: To assess the usefulness of measuring plasma cortisol profiles in growth hormone-treated hypopituitary adults and to compare these with cortisol levels in healthy controls. METHODS: Eleven ACTH-deficient adult patients received 12.5 mg cortisone-acetate orally at 16.00 h and 25 mg at 07.00 h. The patients arrived in the ward at 12.00 h. After tablet intake at 16.00 h, samples for serum cortisol were taken at hourly intervals for the next 24 h, except between 07.00 and 12.00 h when samples were drawn every half hour; 24-h urinary free cortisol (24-h-UFC) excretion was collected simultaneously. For comparison, 8 healthy controls were investigated. RESULTS: The patients had circulating cortisol levels with very low plasma cortisol at 07.00 h before their morning dose of cortisone acetate. At the same time period, controls had their highest plasma cortisol levels. After tablet intake the patients had a rapid initial absorption of cortisol, but a marked variability in the morning peak levels (Cmax), and the Cmax was in general higher and occurred 90 min later than the Cmax in the controls. The 24-h-UFC excretion and 24-h area under the curve (24-h-AUC) did not differ between patients and controls. The female patients had higher 24-h-AUC for plasma cortisol (p=0.032) and tended to have higher plasma cortisol peaks in the morning, but had levels of 24-h-UFC similar to those of the male patients. CONCLUSIONS: Conventional cortisone substitution with a twice-daily replacement regimen in hypopituitary adults results in abnormal circulating cortisol profiles with low or non-measurable morning values and variable individual peaks. This suggests that the present dosing schemes have to be improved and that cortisone substitution should be individualized.


Subject(s)
Cortisone/analogs & derivatives , Cortisone/blood , Cortisone/therapeutic use , Growth Hormone/therapeutic use , Hydrocortisone/blood , Hydrocortisone/urine , Hypopituitarism/blood , Hypopituitarism/drug therapy , Adult , Aged , Body Weight , Cortisone/administration & dosage , Cortisone/urine , Female , Humans , Male , Middle Aged , Sex Characteristics , Time Factors
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