Three type 1 diabetes associated regions on distal mouse chromosome 6 have recently been defined by the construction and analysis of a series of congenic strains, carrying C3H/HeJ genomic material on a NOD/Lt genetic background. Whilst NOD/Lt alleles at the most distal locus Idd6 confer susceptibility, C3H/HeJ alleles confer resistance to diabetes. Idd6 overlaps with a locus controlling low rates of proliferation in immature NOD-thymocytes, suggesting that Idd6 could be controlling diabetes development through an effect on T cell proliferation rates. Candidates for Idd6 therefore include genes, which are implicated in the immune system and/or in the control of cell proliferation rates, such as Lrmp (Jaw1), Bcat1 and Kras2 that map to the Idd6 candidate region. In the present study, we have undertaken an expression and mutational analysis of all three genes. A surprisingly large number of polymorphisms and amino acid changes were identified in both Lrmp and Bcat1 indicating that they are candidates for Idd6. The two genes are located within a genomic interval of about 3 Mb that contains a large number of single nucleotide polymorphisms (SNP) and which has possibly been derived from distinct ancestral haplotypes in the C3H/HeJ and NOD/Lt strains.

OBJECTIVE

To assess the prevalence of dysthyroid optic neuropathy (DON) in patients with diabetes mellitus (DM) and Graves' orbitopathy (GO) and to investigate the complications of surgery for GO in these patients.

METHODS

The records of 482 consecutive patients with GO referred in a 5 year period were studied. Those patients who also had DM were selected for further study. The prevalence of insulin dependent diabetes mellitus (IDDM) and non-insulin dependent diabetes mellitus (NIDDM) was registered, as well as the prevalence and course of DON. In the patients who underwent surgery for GO the postoperative complications were recorded.

RESULTS

Out of 482 patients with GO, 15 (3.1%) also had DM. Eight (1.7%) had IDDM, 7 (1.4%) had NIDDM. Five patients (33.3%) three with IDDM and two with NIDDM developed DON with 50% improvement of visual acuity after treatment, whereas in the whole population of 482 GO patients 19 had DON (3.9%), showing 69.4% improvement of vision after treatment. 10 patients with GO and DM were operated for GO; in one of them an optic atrophy developed as a result of a postoperative haemorrhage directly after a three wall orbital decompression by coronal approach. No other postoperative complications occurred.

CONCLUSIONS

The prevalence of IDDM in patients with GO is higher than in the normal population. DON occurs much more frequently in patients with GO and DM than in the total group of GO patients and seems to have a worse visual prognosis.

OBJECTIVE

The purpose of this study was to investigate factors associated with depression in type 1 and type 2 diabetes and test whether these differ from factors associated with depression in the nondiabetic population.

METHODS

In an unselected population study comprising 60,869 individuals, potential sociodemographic, lifestyle, and clinical factors were investigated in participants with and without diabetes. The associations between hyperglycemia and depression in types 1 and 2 diabetes were also studied. The levels of depression were self-rated by using the Hospital Anxiety and Depression Scale.

RESULTS

Several factors were correlated with depression in types 1 and 2 diabetes. However, these factors were not different from those of the nondiabetic population. Comorbid chronic somatic diseases were associated with depression in type 2 but not type 1 diabetes. In type 2 diabetes, those without comorbidity had the same odds of depression as the nondiabetic population with no chronic somatic diseases. No significant associations were found for hyperglycemia in relation to depression in type 1 and type 2 diabetes.

CONCLUSIONS

Type 2 diabetes without other chronic somatic diseases did not increase the risk of depression. Factors associated with depression in type 1 and type 2 diabetes were shared with the nondiabetic population.

The relation between urinary albumin excretion rate (UAE), transcapillary escape rate of albumin (TERalb), haemostatic factors, ambulatory blood pressure, and metabolic variables was investigated in 45 Type II (non-insulin-dependent) diabetic patients without overt nephropathy or uncontrolled blood pressure. We enrolled 44 patients in a placebo controlled study to test the effects of 3 week long treatment with low-molecular weight heparin (tinzaparin) on the same variables. BMI, 24 h systolic and diastolic blood pressure, plasma concentrations of triglycerides, fasting glucose, factor VIII, von Willebrand factor (vWf), fibrinogen, alpha-2 macroglobulin, and fibronectin were notably higher in patients with increased albuminuria compared with normoalbuminuric patients, whereas the TERalb was similar in the two groups. TERalb correlated with fasting plasma glucose. UAE correlated more closely than TERalb with 24 h ambulatory blood pressure, vWf, and factor VIII. Urinary albumin excretion rate was unchanged during tinzaparin [28.9+/-5.6 vs 28.1+/-6.0 microg/min (geometric mean (antilog SD)] vs placebo (18.0+/-5.4 vs 17.6+/-5.3 microg/min), and no change was found in TERalb [6.3+/-1.6 vs 6.0+/-1.5%/h (means +/- SD), and 6.3+/-1.5 vs 5.6+/-1.8%/h; tinzaparin versus placebo, respectively]. Only minor changes were observed in blood pressure, lipids, glycaemic control and haemostatic factors. This study shows no correlation between albuminuria and transcapillary escape rate in Type II diabetic patients without overt nephropathy or uncontrolled-blood pressure. UAE is related to markers of atherosclerosis, endothelial injury and dysfunction, and haemostatic factors. Moreover, UAE correlates much more than TERalb with 24 h ambulatory blood pressure, von Willebrand factor, and factor VIII. Finally, short-term treatment with tinzaparin does not change the transvascular or glomerular leakage of albumin. These results indicate that TERalb is not a sensitive marker of microvascular dysfunction in such patients and that factors other than abnormal glycosaminoglycan metabolism may contribute to the vascular damage of these patients.

Diabetic nephropathy is a progressive renal disease with thickening of the glomerular basement membrane and mesangial expansion and proliferation as histological hallmarks. The presence of the glycosaminoglycan side chains of heparan sulfate proteoglycan, an important constituent of the glomerular basement membrane, is decreased in diabetic nephropathy proportionally to the degree of proteinuria. Danaparoid sodium is a mixture of sulfated glycosaminoglycans consisting mainly of heparan sulfate. The study presented here involved performing a randomized placebo-controlled crossover study with danaparoid sodium in diabetic patients with overt proteinuria. The aim of the study was to evaluate the effect on proteinuria and safety/tolerability. Nine patients completed the study, without major side effects; the crossover study consisted of two 6-wk periods of treatment with 750 anti-Xa units danaparoid sodium subcutaneously once-daily or placebo. Following danaparoid sodium, significant declines of both albuminuria and proteinuria were found. After danaparoid sodium, the albumin excretion ratio standardized for urinary creatinine reduced with 17% in comparison with an increase of 23% after placebo (95% confidence interval of the difference,-75.9-3.9%; P = 0.03). The percentage change of the urinary protein excretion corrected for urinary creatinine differed at 8 wk significantly between both treatment arms (P = 0.001). Additional parameters for safety as hematological, hemostasis, biochemical parameters, and fundusphotography did not show any clinically significant difference for both groups. Only two patients had minor skin hematomas at the injection site while using danaparoid sodium. In conclusion, the supplementation was found to be feasible and was not associated with side effects. A significant decline of proteinuria was found. More prospective dose-finding and long-term studies must be performed to see whether danaparoid sodium could not only induce a reduction of proteinuria but also halt the progression of renal disease.

Development of new insulins aims to mimic in a better way the natural physiology of this hormone secreted by the pancreas. Rapid insulin analogues have proven a better capacity to reduce postprandial glycaemic peaks after eating. Nevertheless, these molecules are still quite inaccurate to limit glycaemic excursions after the meals. This reality is often described by patients using continuous glucose monitoring systems. So, there is undeniably a place for even more rapid insulins. The ones named «ultra-rapid insulin» tend to better control hyperglycaemia after meals thanks to more favourable profiles regarding pharmacodynamics and pharmacokinetics. Ultra-rapid lispro (URLi) Lyumjev®, is the new ultra-rapid insulin available in Belgium. This review aims to describe its advantages compared to some other rapid insulins thanks to data obtained from trials in type 1 and type 2 diabetes.

: L’arrivée des nouvelles insulines est motivée par la volonté de proposer aux personnes diabétiques un traitement avec des molécules qui s’approchent le plus de la physiologie normale de cette hormone. Le développement des analogues rapides de l’insuline avait comme objectif de mieux mimer la sécrétion endogène d’insuline après chaque prise alimentaire. Ces molécules ont démontré des avantages par rapport aux insulines humaines précédentes grâce à une plus grande rapidité d’action après l’injection sous-cutanée. Néanmoins, ces analogues rapides restent imparfaits en termes de rapidité d’action et de pharmacocinétique au sens large. Les personnes diabétiques de type 1 observent régulièrement des phénomènes d’hyperglycémies postprandiales lorsqu’elles utilisent les mesures continues ou intermittentes du glucose interstitiel. Dès lors, de nouvelles insulines, dites «insulines ultra-rapides», ont comme objectif d’améliorer encore cette cinétique de l’insuline injectée avant un repas, en agissant «vite et fort» pour maîtriser, au mieux, le pic glycémique postprandial. L’insuline ultra-rapide lispro (URLi), Lyumjev®, est la nouvelle insuline de ce type commercialisée en Belgique. Le but de cette revue est de décrire ses avantages par rapport à d’autres insulines rapides grâce aux données actuellement disponibles, à la fois dans le diabète de type 1 et de type 2.

Keywords: Hypoglycaemia; Insulin therapy; Postprandial hyperglycaemia; Ultra; Diabetes; rapid insulin.

OBJECTIVE

Evaluating efficiency of the education and rehabilitation programme for patients suffering from diabetes on the level of metabolic equalization. Two modules for patients have been introduced. The first is group education conducted in groups of 20 patients. This covers basic information concerning diabetes, self-monitoring interventional actions and using the insulin-injector. The second model is repeated every three months: one-day observation in a room for daily-basis patients, which is combined with an individual educational programme and evaluation of metabolic equalization. After 6 and 24 months the level of patients knowledge was checked with the test containing 12 questions and with application of 1-5 point scale. The state of metabolic equalization was also tested, by means of evaluating the average glycaemia, serum concentration of HbA1c and the dosage of insulin. The level of patients knowledge increased after 6 months from 39 +/- 18% to 44 +/- 19%, and after 24 months by 68 +/- 21. The average glycaemia was lowered from 14.04 +/- 9.32 to 8.10 +/- 5.05 mmol/l after 24 months. The average serum cholesterol level was lowered from 6.7 +/- 1.21 to 6.51 +/- 1.39 mmol/l. At the same time there was an increase in the fractions HDL from 1.26 +/- 0.32 to 1.34 +/- 0.46 mmol/l HbA1c from 10.1 +/- 1.4% to 8.5 +/- 1.2%. The daily dose of insulin was reduced from 58.6 +/- 29.3 units a day 44.2 +/- 22.1 +/- units a day. A positive body weight reduction was observed. BMI was lowered from 30.1 +/- 3.96 to 28 +/- 5 kg/m2.

OBJECTIVE

To investigate the relationship between dietary intakes and in vivo oxidative stress (OS) status in diabetic patients.

METHODS

Case-control study.

METHODS

Outpatient-Clinic and Laboratory Endocrinology, University Antwerp.

METHODS

A total of 30 patients (24 type 1 diabetes mellitus (T1DM)/6 type 2 diabetes mellitus (T2DM) were asked to complete a 2 weekdays+1 weekend day food consumption questionnaire during the week preceding their yearly diabetes control consultation, when samples were collected for the assay of oxidative stress (OS) (blood levels of antioxidants, peroxides, malondialdehyde (MDA) and minerals). Blood samples were also collected from 25 age- and sex-matched healthy controls.

RESULTS

Diabetic patients had lower glutathione (5.80+/-1.15 vs 6.75+/-1.03 micromol/g Hb in the controls, P=0.002) and higher MDA (0.687+/-0.212 vs 0.545+/-0.101 micromol/l, P=0.002). Although the group average intakes were within the Belgian RDA, intakes of fat >35% energy, fibre <15 g/1000 kcal, fruit <2 portions and vitamin E <10 mg/day were seen in more than 20 patients. Blood antioxidants did not correlate with intakes of energy, fat, protein or fibres or of their respective antioxidant. Vitamins A and E correlated with serum lipids (r=0.58, P <0.0005 between serum alpha-tocopherol and cholesterol). Blood peroxide levels were only related to intakes of saturated fat and cholesterol (P<0.05). In diabetic subjects but not in controls (P<0.05) MDA was related to glutathione and uric acid.

CONCLUSIONS

In diabetic patients, blood levels of antioxidants are not related to their dietary intakes but to serum lipids. Levels of oxidative damage products are only related to intakes of saturated fats and cholesterol and to levels of endogenous antioxidants.

OBJECTIVE

To perform a longitudinal evaluation of high-sensitivity C-reactive protein (hs-CRP) in young people with type 1 diabetes in relation to the development of microalbuminuria (MA).

METHODS

hs-CRP was measured in 329 blood samples collected from 49 subjects with type 1 diabetes with MA and 49 normoalbuminuric subjects matched for age, sex, and duration of diabetes.

RESULTS

In subjects developing MA, a progressive rise in hs-CRP was detected with levels significantly higher in the years after the onset of MA when compared with levels before MA onset (P = 0.003; age-adjusted P = 0.06). After the onset of MA, hs-CRP levels were significantly higher in subjects with MA when compared with normoalbuminuric subjects (median 1.9 mg/l [range 0.2-9.8] vs. 1.1 mg/l [0.2-6.4]; P = 0.02; adjusted P = 0.036).

CONCLUSIONS

In this population of young subjects with type 1 diabetes, there was a significant increase in hs-CRP levels after the onset of MA, likely reflecting a general state of inflammation.

To understand the ability of regulatory T-cells to control diabetes development in clinically relevant situations, we established a new model of accelerated diabetes in young DP-BB rats by transferring purified T-cells from DR-BB rats made acutely diabetic. Transfer of 3, 5, 10, or 23 million pure in vitro-activated T-cells accelerated diabetes onset in >90% of the recipients, with the degree of acceleration being dosage dependent. Cotransfer of unfractionated leukocytes from healthy donors prevented diabetes. Full protection was achieved when protective cells were transferred 3-4 days before diabetogenic cells, whereas transfer 2 days before conferred only partial protection. Protection resided in the CD4(+) fraction, as purified CD4(+) T-cells prevented the accelerated diabetes. When CD25(+) cells were depleted from these cells before they were transferred, their ability to prevent diabetes was impaired. In contrast, two million CD4(+)CD25(+) cells (expressing Foxp3) prevented the accelerated diabetes when transferred both before and simultaneously with the diabetogenic T-cells. In addition, 2 million CD4(+)CD25(+) T-cells prevented spontaneous diabetes, even when given to rats age 42 days, whereas 20 million CD4(+)CD25(-) cells (with low Foxp3 expression) were far less effective. We thus demonstrated that CD4(+)CD25(+) cells exhibit powerful regulatory potential in rat diabetes.

While previous reports have demonstrated the efficacy of regulatory T cell therapy in the prevention of diabetes, systemic immunocompromise and Treg instability remain key safety concerns. Here we examined the influence of induced Treg (iTreg) cell therapy on anti-viral host defense and autoimmune T cell responses during acute viral infection in a murine model of autoimmune diabetes. Protective transfers of iTregs maintained IL-10 expression, expanded in vivo and controlled diabetes, despite losing FoxP3 expression. Adoptive transfer of iTregs affected neither the primary anti-viral CD8 T cell response nor viral clearance, although a significant and sustained suppression of CD4 T cell responses was observed. Following acute viral clearance, iTregs transferred early suppressed both CD4 and CD8 T cell responses, which resulted in the reversion of diabetes. These observations indicate that iTregs suppress local autoimmune processes while preserving the immunocompetent host's ability to combat acute viral infection.

CD4(+)CD25(+)Foxp3(+) regulatory T cells (T regs) are important for preventing autoimmune diabetes and are either thymic-derived (natural) or differentiated in the periphery outside the thymus (induced). Here we show that beta-cell peptide-pulsed dendritic cells (DCs) from nonobese diabetic (NOD) mice can effectively induce CD4(+)CD25(+)Foxp3(+) T cells from naïve islet-specific CD4(+)CD25(-) T cells in the presence of TGF-beta1. These induced, antigen-specific T regs maintain high levels of clonotype-specific T cell receptor expression and exert islet-specific suppression in vitro. When cotransferred with diabetogenic cells into NOD scid recipients, T regs induced with DCs and TGF-beta1 prevent the development of diabetes. Furthermore, in overtly NOD mice, these cells are able to significantly protect syngeneic islet grafts from established destructive autoimmunity. These results indicate a role for DCs in the induction of antigen-specific CD4(+)CD25(+)Foxp3(+) T cells that can inhibit fully developed autoimmunity in a nonlymphopoenic host, providing an important potential strategy for immunotherapy in patients with autoimmune diabetes.

CD8(+) T cells are important effectors, as well as regulators, of organ-specific autoimmunity. Compared with Tc1-type CD8(+) cells, Tc2 cells have impaired anti-viral and anti-tumor effector functions, although no data are yet available on their pathogenic role in autoimmunity. Our aim was to explore the role of autoreactive Tc1 and Tc2 cells in autoimmune diabetes. We set up an adoptive transfer model in which the recipients were transgenic mice expressing influenza virus hemagglutinin (HA) specifically in their pancreatic ss islet cells (rat insulin promoter-HA mice) and islet-specific Tc1 and Tc2 cells were generated in vitro from HA-specific CD8(+) cells of TCR transgenic mice (CL4-TCR mice). One million Tc1 cells, differentiated in vitro in the presence of IL-12, transferred diabetes in 100% of nonirradiated adult rat insulin promoter-HA recipients; the 50% diabetogenic dose was 5 x 10(5). Highly polarized Tc2 cells generated in the presence of IL-4, IL-10, and anti-IFN-gamma mAb had a relatively low, but definite, diabetogenic potential. Thus, 5 x 10(6) Tc2 cells caused diabetes in 6 of 18 recipients, while the same dose of naive CD8(+) cells did not cause diabetes. Looking for the cause of the different diabetogenic potential of Tc1 and Tc2 cells, we found that Tc2 cells are at least as cytotoxic as Tc1 cells but their accumulation in the pancreas is slower, a possible consequence of differential chemokine receptor expression. The diabetogenicity of autoreactive Tc2 cells, most likely caused by their cytotoxic activity, precludes their therapeutic use as regulators of autoimmunity.

MAIT cells are a separate cell population differentiating in the thymus. They are mostly present in the peripheral blood, liver, intestine, and lungs, less often in other tissues, and infrequently in the lymph nodes. The presentation molecules for MAIT cells are MR1 proteins. They are evolutionarily conserved and non-polymorphic, resemble class I HLA molecules, and are expressed by all cell types. They present bacterial and yeast vitamin metabolites which arise during the synthesis of vitamin B2. The effector functions of MAIT cells are promoted through cytokine synthesis. They also act cytotoxically, directly killing infected or tumour cells. MAIT cells may also play a role in pathological processes. Their involvement in the development of rheumatoid arthritis, systemic lupus erythematosus, autoimmune diabetes mellitus, Crohn&#39;s disease, and bronchial asthma has been demonstrated. In practical terms, MAIT cells are very sensitive to therapeutic doses of glucocorticoids. Treatment of patients with BA or chronic obstructive pulmonary disease with glucocorticoids increases their susceptibility to pneumonia, especially when caused by Streptococcus pneumoniae.

Keywords: MAIT cells; presentation molecule MR1; role in disease pathogenesis; susceptibility to glucocorticoids.

YKL-40 is a marker of inflammation and endothelial dysfunction, both of which play important roles in the progression of diabetic complications. However, little information has been obtained about serum YKL-40 levels in type 1 diabetic patients. We evaluated YKL-40 levels and its association with diabetic micro- and macroandgiopathy in 131 young Japanese type 1 diabetic patients without advanced diabetic complications (aged 24.7±5.9 years) and 97 age- and gender-matched healthy controls. YKL-40 levels were significantly elevated in type 1 diabetic patients than in healthy controls (median (range) 46.4 (20.3-136.7) and 52.3 (21.4-274.1) ng/mL, respectively, p = 0.003). There was a significant positive association between YKL-40 levels and urinary albumin creatinine ratio (UACR) (r = 0.226, p = 0.013). Furthermore, a multivariate regression analysis demonstrated that YKL-40 levels were a determinant of UACR independently of conventional risk factors. In addition, YKL-40 levels were significantly higher in participants with diabetic retinopathy compared to those without it (median (range) 55.5 (23.3-274.1) and 50.3 (21.4-237.4) ng/mL, respectively, p = 0.039). Serum YKL-40 levels were elevated in type 1 diabetic patients and associated with increasing level of albuminuria. YKL-40 could be a predictor to assess the risk of diabetic microangiopathy in the early stage in type 1 diabetic patients.

Diabetic nephropathy is the main cause of the increased morbidity and mortality in patients with insulin dependent diabetes. The prevalence of microalbuminuria was determined in adults with insulin dependent diabetes of five or more years' duration that had started before the age of 41. All eligible patients (n = 982) attending a diabetes clinic were asked to collect a 24 hour urine sample for analysis of albumin excretion by radioimmunoassay; 957 patients complied. Normoalbuminuria was defined as urinary albumin excretion of less than or equal to 30 mg/24 h (n = 562), microalbuminuria as 31-299 mg/24 h (n = 215), and macroalbuminuria as greater than or equal to 300 mg/24 h (n = 180). The prevalence of microalbuminuria and macroalbuminuria was significantly higher in patients whose diabetes had developed before rather than after the age of 20. The prevalence of arterial hypertension increased with increased albuminuria, being 19%, 30%, and 65% in patients with normoalbuminuria, microalbuminuria, and macroalbuminuria respectively. The prevalence of proliferative retinopathy and blindness rose with increasing albuminuria, being 12% and 1.4%, respectively, in patients with normoalbuminuria, 28% and 5.6% in those with microalbuminuria and 58% and 10.6% in those with macroalbuminuria. An abnormal vibratory perception threshold was more common in patients with microalbuminuria (31%) and macroalbuminuria (50%) than in those with normoalbuminuria (21%). This study found a high prevalence (22%) of microalbuminuria, which is predictive of the later development of diabetic nephropathy. Microalbuminuria is also characterised by an increased prevalence of arterial hypertension, proliferative retinopathy, blindness, and peripheral neuropathy. Thus, urinary excretion of albumin should be monitored routinely in patients with insulin dependent diabetes.

Background: Diabetes mellitus (DM) could be classified as type 1 diabetes mellitus (T1DM), type 2 diabetes mellitus (T2DM), gestational diabetes mellitus (GDM) and others according to etiology and pathology. Diabetic nephropathy (DN) is one of the most serious complications of DM. YKL-40 is a marker of inflammation and some studies have indicated that DM was related with inflammation. The objective of our study is to perform a systematic review and meta-analysis to confirm the relationship between YKL-40 and DM as well as DN.

Methods: Pubmed, Embase, CNKI and Chinese wanfang databases were searched for eligible studies by two independent authors. Studies were included in this meta-analysis if they fulfilled the following inclusion criteria: (1) a study involving the role of YKL-40 in DM (or DN) designed as a case-control study or cohort study; (2) the data of serum YKL-40 levels were available; (3) studies were published in English or Chinese. Finally, twenty-five studies were included in this meta-analysis.

Results: Compared with healthy controls, DM patients had significantly higher levels of YKL-40 (DM: SMD = 1.62, 95% CI 1.08 to 2.25, P = 0.000; GDM: SMD = 2.85, 95% CI 1.01 to 4.70, P = 0.002). Additionally, DM patients with different degree of albuminuria had significantly higher levels of YKL-40 compared with healthy controls (normoalbuminuria: SMD = 1.58, 95% CI 0.59 to 2.56, P = 0.002; microalbuminuria: SMD = 2.57, 95% CI 0.92 to 4.22, P = 0.002; macroalbuminuria: SMD = 2.69, 95% CI 1.40 to 3.98, P = 0.000) and serum YKL-40 levels increased with increasing severity of albuminuria among DM patients (microalbuminuria vs normoalbuminuria: SMD = 1.49, 95% CI 0.28 to 2.71, P = 0.016; macroalbuminuria vs microalbuminuria: SMD = 0.93, 95% CI 0.34 to 1.52, P = 0.002).

Conclusions: Our current meta-analysis demonstrates that serum level of YKL-40 is increased in DM and positively associated with the severe degree of albuminuria. Therefore, we suggest that YKL-40 could be considered to be detected, along with other inflammatory markers, if DM, especially DN, is suspected.

Keywords: Diabetes mellitus; Diabetic nephropathy; Meta-analysis; YKL-40.

Classification and family history of diabetes were examined in 551 Japanese patients whose diabetes were found before the age of thirty. These patients were treated at the Diabetes Center of Tokyo Women's Medical College from 1976 to 1981. Among those 551 diabetics, 198 patients were classified into insulin-dependent diabetes mellitus (IDDM) and 337 into non-insulin-dependent diabetes mellitus (NIDDM). IDDM was found mainly in the group of diabetics whose onset of diabetes was before the age of fifteen. The number of NIDDM was significantly increased after the age of twenty. Family history of diabetes was much less in the IDDM group than in the NIDDM group in the first degree relatives. To compare the family history of IDDM with that of NIDDM, 148 diabetics were selected from those 551 patients. The selected diabetics had the onset of the disease before 20 years of age, their present age was between 20 and 40, and the duration of diabetes of these patients was three years or longer. Six of the selected 75 diabetics with IDDM had parents with NIDDM and two of these 75 patients had siblings with IDDM. Thirty-nine of the selected 73 diabetics with NIDDM had positive family history of NIDDM alone. And the selected diabetics with earlier onset of IDDM showed higher risk for IDDM case in their siblings.

OBJECTIVE

While cytokines play a role in the etiology of type 1 diabetes, cytokines later in the disease are less understood. We therefore investigated associations of pro-inflammatory tumor necrosis factor-α levels measured at prolonged disease duration with C-peptide at diagnosis, long-term glycemic control, diabetes duration, clinical factors, and health behaviors.

METHODS

Data and blood were collected during an ancillary study to the longitudinal Wisconsin Diabetes Registry, a population-based cohort followed since diagnosis of type 1 diabetes. The ancillary study was conducted at 13-18 years diabetes duration, and enrolled premenopausal women age 18-45 years (n=87).

RESULTS

Higher tumor necrosis factor-α levels at 13-18 years diabetes duration were independently associated with longer duration (p=0.0004) and worse current renal function (p=0.02). Additionally, diabetes duration modified both of the positive associations of tumor necrosis factor-α levels (both interactions p≤0.01) with mean glycemic control during the previous 10 years (significant only in women with longer durations) and current daily caffeine intake (significant only in women with shorter durations). In women with C-peptide measured at diagnosis (n=50), higher tumor necrosis factor-α levels at 13-18 years duration were associated with lower C-peptide (p=0.01), independent of glycemic control during the previous 10 years.

CONCLUSIONS

Lower residual C-peptide at diagnosis and poor long-term glycemic control independently predicted higher pro-inflammatory tumor necrosis factor-α levels years later. The novel relationship with C-peptide needs confirmation in a larger cohort. Given the association between tumor necrosis factor-α and diabetes complications, further longitudinal studies may help clarify the potentially complex associations between glycemic control, inflammatory cytokines, and complications.