BACKGROUND. The β cell killing that characterizes type 1 diabetes (T1D) is thought to begin years before patients present clinically with metabolic decompensation; however, this primary pathologic process of the disease has not been measured. METHODS.Here, we measured β cell death with an assay that detects β cell-derived unmethylated insulin (INS) DNA. Using this assay, we performed an observational study of 50 participants from 2 cohorts at risk for developing T1D from the TrialNet Pathway to Prevention study and of 4 subjects who received islet autotransplants. RESULTS.In at-risk subjects, those who progressed to T1D had average levels of unmethylated INS DNA that were elevated modestly compared with those of healthy control subjects. In at-risk individuals that progressed to T1D, the observed increases in unmethylated INS DNA were associated with decreases in insulin secretion, indicating that the changes in unmethylated INS DNA are indicative of β cell killing. Subjects at high risk for T1D had levels of unmethylated INS DNA that were higher than those of healthy controls and higher than the levels of unmethylated INS DNA in the at-risk progressor and at-risk nonprogressor groups followed for 4 years. Evaluation of insulin secretory kinetics also distinguished high-risk subjects who progressed to overt disease from those who did not. CONCLUSION.We conclude that a blood test that measures unmethylated INS DNA serves as a marker of active β cell killing as the result of T1D-associated autoimmunity. Together, the data support the concept that β cell killing occurs sporadically during the years prior to diagnosis of T1D and is more intense in the peridiagnosis period.TRIAL REGISTRATION. Clinicaltrials.gov NCT00097292. FUNDING.Funding was from the NIH, the Juvenile Diabetes Research Foundation, and the American Diabetes Association. University of Washington, Seattle, Washington, USA. cose tolerance and insulin secretion are normal. In the time period near presentation of clinical disease, β cell killing was consistently increased. In addition to β cell death, the progression to disease was indicated by a reversible delay in the kinetics of insulin secretion. Our findings suggest a new model of disease progression in which β cell destruction and metabolic dysfunction are events closely associated with disease onset. Conflict of interest: Results Demographic and metabolic features of high-risk participants in theTrialNet Natural History study. We studied 50 relatives of patients with T1D who were at risk for the disease, from 2 cohorts in the TrialNet Pathway to Prevention (PTP) study ( Figure 1). All of the individuals had normal HbA1c levels. We identified 10 at-risk participants who developed T1D over a 3-to 4-year follow-up period (progressors, n = 10) and a group of at-risk participants of similar age who were followed over a similar time period but did not develop T1D (nonprogressors, n = 10). The demographic and metabolic features of these two groups were comparable (Table 1), but the progressors had a hig...
OBJECTIVEGlucagon-like peptide 1 (GLP-1) is an incretin hormone that is released from the gastrointestinal tract. Treatment with GLP-1 analogs has proven to be of clinical use for patients with type 2 diabetes. Patients with type 1 diabetes, particularly those with residual β-cell function, may also respond to treatment, but the acute metabolic effects of GLP-1 analogs on these patients in reaction to both oral and intravenous glucose challenges are not well understood.RESEARCH DESIGN AND METHODSSeventeen patients with type 1 diabetes, half of whom had residual insulin production, underwent two mixed-meal tolerance tests (MMTTs) and two intravenous glucose tolerance tests (IVGTTs), with and without pretreatment with exenatide. No exogenous bolus insulin was administered for the studies. Glucose excursions, insulin secretion rates (ISRs), and levels of glucagon, endogenous GLP-1, and gastric inhibitory polypeptide were measured after the meal or glucose loads.RESULTSDuring the MMTT, glucose levels were suppressed with exenatide in patients with or without residual insulin production (P = 0.0003). Exenatide treatment did not change the absolute ISR, but the ISR to glucose levels were increased (P = 0.0078). Gastric emptying was delayed (P = 0.0017), and glucagon was suppressed (P = 0.0015). None of these hormonal or glucose changes were detected during the IVGTT with exenatide administration.CONCLUSIONSExenatide showed a significant antidiabetogenic effect prior to an oral meal in patients with type 1 diabetes involving glucagon suppression and gastric emptying, while preserving increased insulin secretion. GLP-1 analogs may be useful as an adjunctive treatment in type 1 diabetes.
Meal-stimulated insulin secretory responses are seen in those with long-standing T1D and detectable C-peptide. Delayed insulin secretory responses are more common in individuals with longer disease duration. Residual insulin secretory responses are associated with improved clinical parameters.
Introduction In the Muslim world, the use and acceptance of long-term and permanent contraceptives were limited. Our aim was to investigate those limiting factors so we can help making these methods widely available and acceptable to the society. Methods and data analysis There were 1365 women from Facebook groups in the period 08/10/2020–8/11/2020. Participants were married women, living in Jordan. This was a cross-sectional study. Statistical Package for Social Sciences (SPSS), version 16, software was used for statistical analysis (Chicago, Illinois, USA). Results Among participants, 22.3% had never used any contraceptives. Non-hormonal IUCD was the most commonly used method. There was a statistically significant association between the use of hormonal IUCD and women's age, marriage duration, education and number of children (p < 0.0001). Tubal ligation was adopted by only 44 (3.22%) participants. 19.68% of participants declined tubal ligation merely due to religious issues. Women who completed only high school level of education underwent tubal ligation significantly more than those with university (Bachelor) and post-university (Master or PhD) degrees (p < 0.0001 and 0.026, respectively). Only 1.83% of women's partners underwent vasectomy, the majority of these vasectomies (72.0%) were done because of the need for lifelong contraception. Around 17% of women's partners had poor knowledge about vasectomy. Further, women's employment status (housewives or full-time employees) was found to be the only variable that affected acceptance of vasectomy (p = 0.0047). Conclusions Women endured a heavy burden of contraception. Cultural and religious taboos influenced tubal ligation. Vasectomy was still very rarely adopted by men due to the lack of knowledge about the procedure. Our results raised the need for further dissemination of contraception knowledge and counselling through the primary care and maternity centers, mosques and media in official, comprehensive and integrated programs. Future research is needed in the field of permanent contraceptive methods.
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