Type 1 diabetes mellitus Katsarou, Anastasia; Gudbjörnsdottir, Soffia; Rawshani, Araz ...
Nature reviews. Disease primers,
03/2017, Letnik:
3
Journal Article
Recenzirano
Type 1 diabetes mellitus (T1DM), also known as autoimmune diabetes, is a chronic disease characterized by insulin deficiency due to pancreatic β-cell loss and leads to hyperglycaemia. Although the ...age of symptomatic onset is usually during childhood or adolescence, symptoms can sometimes develop much later. Although the aetiology of T1DM is not completely understood, the pathogenesis of the disease is thought to involve T cell-mediated destruction of β-cells. Islet-targeting autoantibodies that target insulin, 65 kDa glutamic acid decarboxylase, insulinoma-associated protein 2 and zinc transporter 8 - all of which are proteins associated with secretory granules in β-cells - are biomarkers of T1DM-associated autoimmunity that are found months to years before symptom onset, and can be used to identify and study individuals who are at risk of developing T1DM. The type of autoantibody that appears first depends on the environmental trigger and on genetic factors. The pathogenesis of T1DM can be divided into three stages depending on the absence or presence of hyperglycaemia and hyperglycaemia-associated symptoms (such as polyuria and thirst). A cure is not available, and patients depend on lifelong insulin injections; novel approaches to insulin treatment, such as insulin pumps, continuous glucose monitoring and hybrid closed-loop systems, are in development. Although intensive glycaemic control has reduced the incidence of microvascular and macrovascular complications, the majority of patients with T1DM are still developing these complications. Major research efforts are needed to achieve early diagnosis, prevent β-cell loss and develop better treatment options to improve the quality of life and prognosis of those affected.
Skeletal muscle sodium channel disorders give rise to episodic symptoms such as myotonia and/or periodic paralysis. Chronic symptoms with permanent weakness are not considered characteristic of the ...phenotypes. Muscle fat replacement represents irreversible damage that inevitably will impact on muscle strength. This study investigates muscle fat replacement and contractility in patients with pathogenic SCN4A variants compared to healthy controls. T1-weighted and 2-point Dixon MRI of the legs were conducted to assess fat replacement. Stationary dynamometry was used to assess muscle strength. Contractility was determined by maximal muscle contraction divided by cross-sectional muscle area. The average cross-sectional intramuscular fat fraction was greater in patients compared with controls by 2.5% in the calves (95% CI 0.74-4.29%, p = 0.007) and by 2.0% in the thighs (95% CI 0.75-3.2%, p = 0.003). Muscle contractility was less in patients vs. controls by 14-27% (p < 0.05). Despite greater fat fraction and less contractility, absolute strength was not significantly less. This study quantitatively documents greater fat fraction and additionally describes difference in muscle contractility in a large cohort of patients with skeletal muscle sodium channel disorders. The clinical impact of these abnormal findings is likely limited as muscle hypertrophy in the patients served to preserve absolute muscle strength. Subgroup analysis indicated significant difference in phenotype by genotype, however these findings lack statistical significance and serve as inspiration for future researchers to probe into the geno- phenotype relationship in these disorders.Trial registration: The study was registered at http://clinicaltrials.gov (identifier: NCT04808388).
Aims/hypothesis
Young children who develop multiple autoantibodies (mAbs) are at very high risk for type 1 diabetes. We assessed whether a population with mAbs detected by screening is also at very ...high risk, and how risk varies according to age, type of autoantibodies and metabolic status.
Methods
Type 1 Diabetes TrialNet Pathway to Prevention participants with mAbs (
n
= 1815; age, 12.35 ± 9.39 years; range, 1–49 years) were analysed. Type 1 diabetes risk was assessed according to age, autoantibody type/number (insulin autoantibodies IAA, glutamic acid decarboxylase autoantibodies GADA, insulinoma-associated antigen-2 autoantibodies IA-2A or zinc transporter 8 autoantibodies ZnT8A) and Index60 (composite measure of fasting C-peptide, 60 min glucose and 60 min C-peptide). Cox regression and cumulative incidence curves were utilised in this cohort study.
Results
Age was inversely related to type 1 diabetes risk in those with mAbs (HR 0.97 95% CI 0.96, 0.99). Among participants with 2 autoantibodies, those with GADA had less risk (HR 0.35 95% CI 0.22, 0.57) and those with IA-2A had higher risk (HR 2.82 95% CI 1.76, 4.51) of type 1 diabetes. Those with IAA and GADA had only a 17% 5 year risk of type 1 diabetes. The risk was significantly lower for those with Index60 <1.0 (HR 0.23 95% CI 0.19, 0.30) vs those with Index60 values ≥1.0. Among the 12% (225/1815) ≥12.0 years of age with GADA positivity, IA-2A negativity and Index60 <1.0, the 5 year risk of type 1 diabetes was 8%.
Conclusions/interpretation
Type 1 diabetes risk varies substantially according to age, autoantibody type and metabolic status in individuals screened for mAbs. An appreciable proportion of older children and adults with mAbs appear to have a low risk of progressing to type 1 diabetes at 5 years. With this knowledge, clinical trials of type 1 diabetes prevention can better target those most likely to progress.
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Metabolic zones were developed to characterize heterogeneity of individuals with islet autoantibodies.
Baseline 2-h oral glucose tolerance test data from 6,620 TrialNet Pathway to Prevention Study ...(TNPTP) autoantibody-positive participants (relatives of individuals with type 1 diabetes) were used to form 25 zones from five area under the curve glucose (AUCGLU) rows and five area under the curve C-peptide (AUCPEP) columns. Zone phenotypes were developed from demographic, metabolic, autoantibody, HLA, and risk data.
As AUCGLU increased, changes of glucose and C-peptide response curves (from mean glucose and mean C-peptide values at 30, 60, 90, and 120 min) were similar within the five AUCPEP columns. Among the zones, 5-year risk for type 1 diabetes was highly correlated with islet antigen 2 antibody prevalence (r = 0.96, P < 0.001). Disease risk decreased markedly in the highest AUCGLU row as AUCPEP increased (0.88-0.41; P < 0.001 from lowest AUCPEP column to highest AUCPEP column). AUCGLU correlated appreciably less with Index60 (an indicator of insulin secretion) in the highest AUCPEP column (r = 0.33) than in other columns (r ≥ 0.78). AUCGLU was positively related to "fasting glucose × fasting insulin" and to "fasting glucose × fasting C-peptide" (indicators of insulin resistance) before and after adjustments for Index60 (P < 0.001).
Phenotypes of 25 zones formed from AUCGLU and AUCPEP were used to gain insights into type 1 diabetes heterogeneity. Zones were used to examine GCRC changes with increasing AUCGLU, associations between risk and autoantibody prevalence, the dependence of glucose as a predictor of risk according to C-peptide, and glucose heterogeneity from contributions of insulin secretion and insulin resistance.
Background and purpose
Myotonia congenita (MC) is a muscle channelopathy in which pathogenic variants in a key sarcolemmal chloride channel Gene (CLCN1) cause myotonia. This study used muscle ...magnetic resonance imaging (MRI) to quantify contractile properties and fat replacement of muscles in a Danish cohort of MC patients.
Methods
Individuals with the Thomsen (dominant) and Becker (recessive) variants of MC were studied. Isometric muscle strength, whole‐body MRI, and clinical data were collected. The degree of muscle fat replacement of thigh, calf, and forearm muscles was quantitively calculated on Dixon MRI as fat fractions (FFs). Contractility was evaluated as the muscle strength per contractile muscle cross‐sectional area (PT/CCSA). Muscle contractility was compared with clinical data.
Results
Intramuscular FF was increased and contractility reduced in calf and in forearm muscles compared with controls (FF = 7.0–14.3% vs. 5.3–9.6%, PT/CCSA = 1.1–4.9 Nm/cm2 vs. 1.9–5.8 Nm/cm2 p < 0.05). Becker individuals also showed increased intramuscular FF and reduced contractility of thigh muscles (FF = 11.9% vs. 9.2%, PT/CCSA = 1.9 Nm/cm2 vs. 3.2 Nm/cm2 p < 0.05). Individual muscle analysis showed that increased FF was limited to seven of 18 examined muscles (p < 0.05). There was a weak correlation between reduced contractility and severity of symptoms.
Conclusions
Individuals with MC have increased fat replacement and reduced contractile properties of muscles. Nonetheless, changes were small and likely did not impact clinically on their myotonic symptoms.
The COVID-19 pandemic and rapid expansion of telemedicine has increased the need for accurate and reliable capillary A1c testing. Nevertheless, validation studies of commercially available kits have ...been in short supply. As such, capillary and venous A1c samples were assessed using 3 commercial home kits (Home Access, CoreMedica, A1cNow) and 2 non-commercial kits from academic centers (U of MN Advanced Research and Diagnostic Lab ARDL and Children's Mercy Hospital CMH). Samples were collected either with study staff guidance (non-commercial) or hands-on assistance (commercial) and sent by USPS for processing except for the immediate response A1cNow+ kit. Differences in A1c between commercial kits and reference values were appreciable (Table). Notably, none of the commercially tested kits reached the National Glycohemoglobin Standardization Program target of more than 90% of values within 5% of DCCT venous reference values although the Home Access kit performed much better than the other two. In contrast, evaluation of kits from ARDL and CMH showed 97.4% of values within the 5% standard. Ease of use and discomfort with sample collection varied between kits. While the accuracy of the commercial kits analyzed was limited, participants' response was positive overall. Telemedicine is likely to persist as a mainstay of diabetes care well after the COVID-19 era. As such, accurate home A1c testing represents an urgent need for the diabetes community.
Insulin immunotherapy for pretype 1 diabetes Jacobsen, Laura M.; Schatz, Desmond A.
Current opinion in endocrinology, diabetes and obesity./Current opinion in endocrinology, diabetes and obesity,
08/2021, Letnik:
28, Številka:
4
Journal Article
Recenzirano
Odprti dostop
Purpose of review
Loss of tolerance to insulin likely contributes to the immunopathogenesis of type 1 diabetes (T1D). Several large clinical trials and smaller mechanistic studies have failed to ...demonstrate the efficacy of insulin antigen therapy. The growing awareness of the heterogeneity of T1D likely affects the response to various immune therapies including insulin. Identification of biomarkers of clinical response will provide further insight into mechanisms leading to the disease and classify responders in the quest for personalized therapy.
Recent findings
Several biomarkers have identified subpopulations in posthoc analyses that showed benefit from oral insulin even though the placebo-controlled study was as a whole unsuccessful. High insulin autoantibody titer, low first phase insulin response, and high Diabetes Prevention Trial-Type 1 Risk Score identify at-risk relatives more likely to benefit from oral insulin. Future incorporation of human leukocyte antigen and the variable number of tandem repeats polymorphism located in the insulin gene promoter (
INS
VNTR) is of interest for both primary and secondary prevention studies.
Summary
Although primary and secondary prevention trials using oral insulin are ongoing, those completed have been largely unsuccessful. However, we believe that oral insulin should be considered in future trials as part of combination therapies as prerandomization biomarker testing is refined.
Among Ab+ individuals, reports suggest glucose is atypically associated with other T1D risk factors, such as a positive association with C-peptide. Using baseline OGTT data from 6,589 Ab+ TrialNet ...Pathway to Prevention participants, we hypothesized this finding is explained by a glucose fraction unrelated to insulin secretion. Index60 (fasting C-peptide, 60-min AUC glucose and C-peptide) was used as an insulin secretion proxy in regression AUC Glucose=131.0+(8.9*Index60) to quantify two AUC glucose fractions, each present to a degree in all individuals: one dependent on insulin secretion (DEP); the other independent (INDEP). DEP equaled predicted AUC glucose; INDEP equaled actual AUC glucose - predicted AUC glucose. The phenotype of the top DEP quartile was more typical for T1D than the top INDEP quartile (Table). INDEP correlated positively with AUC C-peptide r=0.54 (p<0.001), 29% of AUC C-peptide variance. With C-peptide index (30-0 min C-peptide) / (30-0 min glucose) as the insulin secretion proxy, findings were similar. In conclusion, Ab+ individuals with high proportions of INDEP have less typical features of T1D. The INDEP AUC glucose fraction’s positive correlation with AUC C-peptide, accounting for appreciable AUC C-peptide variance, suggests that INDEP is related to insulin resistance. Those with a higher proportion of INDEP may represent an atypical subset of the at-risk population.
Disclosure
J.Sosenko: None. D.D.Cuthbertson: None. M.J.Redondo: None. H.M.Ismail: Consultant; Rise Therapeutics. E.K.Sims: Speaker's Bureau; Medscape, American Diabetes Association. L.M.Jacobsen: None. B.M.Nathan: None.
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