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Pregnancy could damage kidney function in diabetic nephropathy. We investigated the long-term impact of pregnancy on the progression of diabetic nephropathy. Our observational follow-up study included all women patients with Type I (insulin-dependent) diabetes mellitus who developed diabetic nephropathy between 1970 and 1989 at Steno Diabetes Center (n = 93). Follow-up lasted 16 years (range 3–28) from the onset of diabetic nephropathy until death or the year 2000. A total of 26 women became pregnant after the onset of diabetic nephropathy (group A). The remaining 67 served as control subjects (group B). All patients received aggressive antihypertensive treatment (blood pressure goal < 140/90 mmHg). The two groups were comparable at onset of diabetic nephropathy regarding blood pressure, albuminuria, s-cholesterol, smoking, retinopathy and s-creatinine (mean 79(SD 23) μmol/l). The slopes of 1/s-creatinine (1000 · l ·μmol–1· year–1) during the whole observation period were –0.39(0.40) compared with –0.41(0.70) (group A vs B – NS). The slopes of 1/s-creatinine before and after pregnancy were similar. Decline in creatinine clearance (ml/min/yr) was 3.2 (3.4) compared with 3.2 (5.1) (group A vs B -NS). At the end of follow-up, 35 % (95 %-CI:17–53) of the pregnant women had died and 19 % (7–39) had reached end stage renal disease compared to 34 % (23–45) and 24 %(14–34) of the control subjects, respectively(NS). Group A and B had similar blood pressure levels during the whole observation period: 136(13)/83(7) vs 139 (14)/85(7) mmHg (NS). Pregnancy has no adverse long-term impact on kidney function and survival in Type I diabetic patients with well-preserved kidney function (normal serum creatinine) suffering from diabetic nephropathy. [Diabetologia (2002) 45: 36–41]

Aims/hypothesis. An A to G transition at nucleotide position 3243 in the mitochondrial tRNA Leu(UUR) gene has been identified in patients with maternally inherited diabetes and deafness, as well as in patients with mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes, chronic progressive external ophpthalmoplegia, cardiomyopathy and progressive kidney disease. Variations in the mitochondrial DNA haplotype as well as differences in the degree and distribution of heteroplasmy in a certain tissue are factors that may contribute to the variety in phenotypical expression of the 3243 tRNA Leu(UUR) mutation. We have done morphological and functional experiments on mitochondria carrying the 3243 mutation derived from patients with either maternally inherited diabetes and deafness or progressive kidney disease to prove the pathogenicity of the 3243 mutation and to examine whether the mtDNA haplotype modulates the pathobiochemistry of this mutation. Methods. We constructed clonal cell lines that contain predominantly mutated or exclusively wild-type mtDNA with a distinct mtDNA haplotype by the methodology of mitochondria-mediated transformation. Cells lacking mitochondrial DNA (ϱ°) were used as recipients and donor mitochondria were derived from fibroblasts of a patient with either maternally inherited diabetes and deafness or progressive kidney disease. The fibroblasts from these clinically distinct patients carry different mitochondrial DNA haplotypes with the 3243 mutation in heteroplasmic form. Results. Heteroplasmy in the clonal cybrid cells ranged from 0 to 100 %, reflecting the heterogeneity of the mitochondrial donor cell. Cybrid cells containing predominantly mutant mitochondrial DNA showed lactic acidosis, poor respiration and marked defects in mitochondrial morphology and respiratory chain complex I and IV activities. No differences were observed in the extent of the mitochondrial dysfunction between the mutant cells derived from the two donors. Conclusion/interpretation. These results provide evidence for a pathogenic effect of the tRNA Leu(UUR) mutation in maternally inherited diabetes and deafness and progressive kidney disease, and show no evidence of a contribution of the mitochondrial DNA haplotype as a modulating the biochemical expression of the mutation. [Diabetologia (1999) 42: 485–492]

Treatment guidelines recommend the UK Prospective Diabetes Study (UKPDS) risk engine for predicting cardiovascular risk in patients with type 2 diabetes, although validation studies showed moderate performance. The methods used in these validation studies were diverse, however, and sometimes insufficient. Hence, we assessed the discrimination and calibration of the UKPDS risk engine to predict 4, 5, 6 and 8 year cardiovascular risk in patients with type 2 diabetes. The cohort included 1,622 patients with type 2 diabetes. During a mean follow-up of 8 years, patients were followed for incidence of CHD and cardiovascular disease (CVD). Discrimination and calibration were assessed for 4, 5, 6 and 8 year risk. Discrimination was examined using the c-statistic and calibration by visually inspecting calibration plots and calculating the Hosmer–Lemeshow χ2 statistic. The UKPDS risk engine showed moderate to poor discrimination for both CHD and CVD (c-statistic of 0.66 for both 5 year CHD and CVD risks), and an overestimation of the risk (224% and 112%). The calibration of the UKPDS risk engine was slightly better for patients with type 2 diabetes who had been diagnosed with diabetes more than 10 years ago compared with patients diagnosed more recently, particularly for 4 and 5 year predicted CVD and CHD risks. Discrimination for these periods was still moderate to poor. We observed that the UKPDS risk engine overestimates CHD and CVD risk. The discriminative ability of this model is moderate, irrespective of various subgroup analyses. To enhance the prediction of CVD in patients with type 2 diabetes, this model should be updated.

The cause of the pronounced insulin resistance of the hereditary obese-hyperglycemic syndrome in mice (obob) is so far unknown. To evaluate whether growth hormone (GH) is of pathogenetic significance in this context thein vivo incorporation of sulfate into costal cartilage was measured in obese-hyperglycemic mice and their lean littermates at various ages. It was found that a) GH administration raised the sulfation activity of the costal cartilage in both types of mice; b) the hormone further increased the insulin resistance of the obesehyperglycemic animals; c) the sulfate incorporation of the obese mice was considerably elevated after 1 month of age and remained high until the age of about 10 months. In 17 months old animals it had returned to a level similar to that of the lean littermates. In addition, the epiphyseal width of the tibia was increased in the obese mice. Since it was not clear whether the increased rate of sulfate in corporation was due to an elevated endogenous GH activity and/or the high serum insulin levels prevailing in the obese mice at this period of life a study of the pituitary morphology was carried out. The lack of obvious structural or quantitative differences between the pituitary alpha cells of the lean and obese mice did not exclude the possibility that the elevated sulfation activity was caused by the high serum insulin levels rather than an increased circulating GH activity. — Glucokinase activity, characterized by a highK m value, was found in the livers of both lean and obese mice. A significant elevation of this enzyme activity, but not of the hexokinase activity, in the obese mice strongly suggests that the insulin resistance does not extend to the liver cells in the obese-hyperglycemic syndrome.

The aim of this work was to investigate diabetes incidence after infection with coronavirus disease-2019 (Covid-19). Individuals with acute upper respiratory tract infections (AURI), which are frequently caused by viruses, were selected as a non-exposed control group. We performed a retrospective cohort analysis of the Disease Analyzer, which comprises a representative panel of 1171 physicians’ practices throughout Germany (March 2020 to January 2021: 8.8 million patients). Newly diagnosed diabetes was defined based on ICD-10 codes (type 2 diabetes: E11; other forms of diabetes: E12–E14) during follow-up until July 2021 (median for Covid-19, 119 days; median for AURI 161 days). Propensity score matching (1:1) for sex, age, health insurance, index month for Covid-19/AURI and comorbidity (obesity, hypertension, hyperlipidaemia, myocardial infarction, stroke) was performed. Individuals using corticosteroids within 30 days after the index dates were excluded. Poisson regression models were fitted to obtain incidence rate ratios (IRRs) for diabetes. There were 35,865 individuals with documented Covid-19 in the study period. After propensity score matching, demographic and clinical characteristics were similar in 35,865 AURI controls (mean age 43 years; 46% female). Individuals with Covid-19 showed an increased type 2 diabetes incidence compared with AURI (15.8 vs 12.3 per 1000 person-years). Using marginal models to account for correlation of observations within matched pairs, an IRR for type 2 diabetes of 1.28 (95% CI 1.05, 1.57) was estimated. The IRR was not increased for other forms of diabetes. Covid-19 confers an increased risk for type 2 diabetes. If confirmed, these results support the active monitoring of glucose dysregulation after recovery from mild forms of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection.

Aims/hypothesis. Diabetes mellitus leads to functional and structural changes in the brain which appear to be most pronounced in the elderly. Because the pathogenesis of brain ageing and that of diabetic complications show close analogies, it is hypothesized that the effects of diabetes and ageing on the brain interact. Our study examined the effects of diabetes and ageing on learning and hippocampal synaptic plasticity in rats.¶Methods. Young adult (5 months) and aged (2 years) rats were examined after 8 weeks of streptozotocin-diabetes. Learning was tested in a Morris water maze. Synaptic plasticity was tested ex vivo, in hippocampal slices, in response to trains of stimuli of different frequency (0.05 to 100 Hz).¶Results. Statiscally significant learning impairments were observed in young adult diabetic rats compared with controls. These impairments were even greater in aged diabetic animals. In hippocampal slices from young adult diabetic animals long-term potentiation induced by 100 Hz stimulation was impaired compared with controls (138 vs 218 % of baseline). In contrast, long-term depression induced by 1 Hz stimulation was enhanced in slices from diabetic rats compared with controls (79 vs 92 %). In non-diabetic aged rats synaptic responses were 149 and 93 % of baseline in response to 100 and 1 Hz stimulation, compared with 106 and 75 % in aged diabetic rats.¶Conclusion/interpretation. Both diabetes and ageing affect learning and hippocampal synaptic plasticity. The cumulative deficits in learning and synaptic plasticity in aged diabetic rats indicate that the effects of diabetes and ageing on the brain could interact. [Diabetologia (2000) 43: 500–506]

Diabetes and its complications cause a heavy disease burden globally. Identifying exposures, risk factors and molecular processes causally associated with the development of diabetes can provide important evidence bases for disease prevention and spur novel therapeutic strategies. Mendelian randomisation (MR), an epidemiological approach that uses genetic instruments to infer causal associations between an exposure and an outcome, can be leveraged to complement evidence from observational and clinical studies. This narrative review aims to summarise the evidence on potential causal risk factors for diabetes by integrating published MR studies on type 1 and 2 diabetes, and to reflect on future perspectives of MR studies on diabetes. Despite the genetic influence on type 1 diabetes, few MR studies have been conducted to identify causal exposures or molecular processes leading to increased disease risk. In type 2 diabetes, MR analyses support causal associations of somatic, mental and lifestyle factors with development of the disease. These studies have also identified biomarkers, some of them derived from the gut microbiota, and molecular processes leading to increased disease risk. These studies provide valuable data to better understand disease pathophysiology and explore potential therapeutic targets. Because genetic association studies have mostly been restricted to participants of European descent, multi-ancestry cohorts are needed to examine the role of different types of physical activity, dietary components, metabolites, protein biomarkers and gut microbiome in diabetes development.

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